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ArticleJune 25, 2021

Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-Enynes
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Ramón E. Millán
Ramón E. Millán
Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
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Jaime Rodríguez
Jaime Rodríguez
Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
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https://orcid.org/0000-0001-5348-6970
Luis A. Sarandeses
Luis A. Sarandeses
Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
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https://orcid.org/0000-0003-1114-7107
Enrique Gómez-Bengoa*
Enrique Gómez-Bengoa
Departamento de Química Orgánica I, Universidad del País Vasco UPV/EHU, 20009 Donostia-San, Sebastián
*Email: [email protected]
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https://orcid.org/0000-0002-8753-3760
José Pérez Sestelo*
José Pérez Sestelo
Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
*Email: [email protected]
More by José Pérez Sestelo
https://orcid.org/0000-0001-7036-6217

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The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2021, 86, 14, 9515–9529

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https://doi.org/10.1021/acs.joc.1c00825

Published June 25, 2021

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Abstract

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The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI₃ (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through 1,5-enyne cyclization (6-endo-dig) and subsequent C–C hydroarylation or C–O phenoxycyclization. Density functional theory (DFT) computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produces a nonclassical carbocation intermediate that evolves to the tricyclic reaction product through a S_EAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.

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Subjects

Introduction

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The design of synthetic methodologies based on catalytic cascade reactions constitutes an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. (1) In particular, catalytic cascade cycloisomerization reactions allow the synthesis of a large structural diversity of molecules under complete atom economy and mild reaction conditions. As an example, cascade polyene cyclizations are one of the most impressive biosynthetic transformations known, and their chemical emulation represents a major challenge in modern synthetic chemistry. (2) Usually, these transformations involve the epoxide activation in a polyenic compound using oxophilic Lewis acids under stoichiometric or catalytic conditions. (3) Alternatively, electrophilic alkyne activation under metal catalysis has been recently envisaged as a different synthetic approach to promote catalytic cascade polyenynic π-cyclizations. (4) The catalytic electrophilic activation of alkynes promotes the addition of nucleophiles and allows the formation of new carbon–carbon and carbon–heteroatom bonds in an intermolecular and intramolecular manner. Although this methodology has been associated with the use of carbophilic late precious transition metals such as platinum (5) or gold (6) as catalysts, main group metals such as gallium (7) or indium (8) have been shown as valuable alternatives (Scheme 1a).

Scheme 1. Indium(III)-Catalyzed Electrophilic Activation of Alkynes

Indium(III) is a soft Lewis acid that exhibits a dual-mode catalytic activity as σ-acid and π-acid, enabling both the electrophilic activation of carbon–heteroatom and to carbon–carbon unsaturated bonds. (9) In addition, reactions involving indium are used to provide high chemoselectivity and substantial economical, environmental, and safety advantages. (10) Along the years, these attractive chemical properties have been exploited in classical synthetic transformations as oxophilic Lewis acid either by using stoichiometric or catalytic conditions. (11) Recent contributions have demonstrated the synthetic utility of indium(III) salts as carbophilic π-acid catalysts in the electrophilic activation of alkynes. (12)

Metal-catalyzed 1,n-enyne cycloisomerization reactions constitute a straightforward methodology for the synthesis of polycyclic structures. (13) In particular, gold(I)-catalyzed cycloisomerization reactions of functionalized 1,5- and 1,6-enynes have been widely explored for the synthesis of polycyclic organic compounds. (14) On the other hand, indium(III)-catalyzed enyne cycloisomerization reactions were first reported by Chatani, (15) and more recently, Corey described the stereoselective synthesis of complex chiral polycyclic molecules by cascade cycloisomerization of chiral aryl polyenynes under indium(III) catalysis. (16a) In this contribution, the catalytic activity of In(III) as π-acid for the electrophilic activation of alkynes is remarked and attributed to the vacant 5s and 5p orbitals, which might lead to coordinate the C–C triple bond by bidentate complexation. Later on, Corey also reported the superior catalytic activity of diiodoindium(III) cation (InI₂⁺), generated by the addition of Ag(I) salts to InI₃. (16b)

As part of a long-term research on indium chemistry, (17) our group has recently reported intramolecular hydroarylation and hydroalkoxylation reactions and sequential indium-catalyzed polyyne reactions under indium(III) catalysis (Scheme 1b). (18) Herein, we report the In(III)-catalyzed cascade cycloisomerization reactions of 1,5-enynes (E and Z isomers) furnished with aryl nucleophiles and density functional theory (DFT) studies about the mechanism of the reaction and the nature of the organoindium intermediates involved (Scheme 1c).

Results and Discussion

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Our investigation started with the cycloisomerization reaction of (E)-1,5-enynyl aryl ether 1a under In(III) catalysis. This substrate was chosen to measure the indium alkynophilicity, the regioselectivity of the reaction (6-endo vs 5-exo), and to establish comparisons with other metal catalysts. (14a) In our first experiments, we found that the treatment of (E)-1a with 5 mol % InI₃ in 1,2-dichloroethane (DCE) at 60 °C resulted in the stereoselective formation of the tricyclic compound 2a in 58% yield after 5 h as the only isolated product as a separable mixture of diastereoisomers (cis/trans = 25:75, Table 1, entry 1). Alternatively, the use of InBr₃ (5 mol %) also provided 2a in similar yield and diastereoselectivity, whilst InCl₃ (5 mol %) resulted to be ineffective (entries 2 and 3, respectively). In all cases, trans-fused 2a was identified as the major diastereoisomer and its formation can be explained by a double regioselective 6-endo-dig/endo-trig cyclization in cascade.

Table 1. Indium-Catalyzed Reactions with (E)-1,3-Dimethoxy-5-[(3-methylhept-2-en-6-yn-1-yl)oxy]benzene (1a)

entry	InX₃	solvent	T (°C)	t (h)^a	yield (%)^b	2a (cis/trans)^c
1	InI₃	DCE	60	5	58	25:75
2	InBr₃	DCE	60	20	53	33:67
3	InCl₃	DCE	60	48	^d
4	InI₃^e	DCE	60	24	55	31:69
5	InI₃	toluene	60	2	65	11:89
6	InI₃^f	toluene	rt	6	62	20:80
7	InI₃^f	DCM	rt	7	63	19:81
8	InI₃^f	DCM	–20	24	^d
9	InI₃^g	DCE	60	5	72^h
10	In(NTf₂)₃	DCE	60	5	63ⁱ
11	In(OTf)₃	DCE	60	24	^j
12	In(acac)₃	DCE	60	48	^d

^{^a}

Monitored by thin-layer chromatography (TLC).

^{^b}

Isolated yield.

^{^c}

Determined by gas chromatography–mass spectrometry (GCMS).

^{^d}

No reaction observed.

^{^e}

2 mol %.

^{^f}

20 mol %.

^{^g}

AgSbF₆ (5 mol %) as a cocatalyst.

^{^h}

Mixture of products I:2a (4:1 ratio).

^ⁱ

Compound II was isolated.

^{^j}

Decomposition.

The stereoselectivity of this In(III)-catalyzed 1,5-enyne cycloisomerization was then studied under different reaction conditions. In this endeavor, we found that the reaction also takes place with 2 mol % of InI₃ in similar stereoselectivity but longer reaction times (55%, cis/trans = 31:69, entry 4). Interestingly, the yield, stereoselectivity, and reaction time were slightly improved using toluene as a solvent (65%, cis/trans = 11:89, entry 5). The reaction also proceeds at room temperature using 20 mol % of InI₃ in toluene or dichloromethane (DCM) with similar results (entries 6 and 7), but no reaction was observed at −20 °C (entry 8). Surprisingly, the combination of InI₃ (5 mol %) with the halide abstractor AgSbF₆ (5 mol %) to generate the diiodonium cation (InI₂⁺) gave a new major tricyclic product (I) concomitant with 2a (I:2a = 4:1 ratio) as a separable mixture in a combined 72% isolated yield (entry 9). The formation of compound I, as a mixture of cis/trans (11:89) diastereoisomers, can be explained by ether cleavage, Friedel–Crafts C-alkylation, and 1,5-enyne phenoxycyclization reaction. In a similar pathway, treatment with In(NTf₂)₃ (5 mol %) resulted in the formation of the bicyclic compound II (63% yield, entry 10) with an alkene phenoxycyclization as the last step. The use of In(OTf)₃ as a catalyst resulted in decomposition (entry 11). No reaction was observed employing In(acac)₃ as the catalyst, recovering the starting 1,5-enyne 1a (entry 12). In this optimization process, the important role of the catalyst counteranion is noteworthy, confirming InI₃ as the most efficient π-catalyst. Although different solvents can be used, toluene was the solvent of choice for this 1,5-enyne cyclization. The high chemoselectivity of InI₃ in the electrophilic activation of the alkyne over the ether cleavage is remarkable.

To further study the chemo-, regio-, and stereoselectivity and access to novel functionalized benzo[b]chromenes, our investigation was extended to 1,5-enynes functionalized at the arene and alkyne units and with different alkene geometries. Under the previously optimized reaction conditions, we were pleased to find that the reaction of 1,5-enyne (E)-1b furnished with a methyl group at the terminal alkyne proceeded successfully to give trans-2b in 68% yield as a separable diastereoisomeric mixture (cis/trans= 22:78, Table 2, entry 2). This synthetic transformation was more efficient and selective than using Hg(II), probably due to the softer Lewis acid character of In(III). (14a) Interestingly, the reaction using 1-bromo-1,5-enyne (E)-1c also provided 7-bromobenzo[b]chromene trans-2c diastereoselectively in good yield (62%, cis/trans= 27:73, entry 3). The synthesis of trans-2c should allow access to a variety of substituted benzo[b]chromenes by metal-catalyzed cross-coupling reactions. (17)

Table 2. Indium-Catalyzed Reactions with 1,5-Enynyl Aryl Ethers 1a–d^c

^{^a}

Major isolated diastereomer.

^{^b}

Isolated yield.

^{^c}

Measured by ¹H NMR.

The role of electronic effects was examined using phenyl 1,5-enynyl ether (E)-1d. Interestingly, under the previously developed reaction conditions, the double cycloisomerization proceeded with complete stereochemical inversion giving rise to the cis-benzo[b]chromene cis-2d as a single diastereoisomer by ¹H NMR (61% yield, Table 2, entry 4). The isomerization suggests a two-step mechanism, where the lower nucleophilicity of the phenyl group facilitates the stereochemical inversion after the first 6-endo-dig cycloisomerization reaction to produce the most thermodynamically stable diastereoisomer.

Prompted by these interesting results, we studied the influence of alkene stereochemistry on the reactivity, regio-, and stereoselectivity. Previous metal-catalyzed 1,5-enyne cycloisomerization reactions have shown a divergent outcome based on the alkene geometry. (14c) In our case, the In(III)-catalyzed cycloisomerization with (Z)-1a also proceeded with 6-endo regioselectivity without isomerization providing the cis-2a as a single diastereoisomer as determined by ¹H NMR in 64% yield (Table 2, entry 5). The same regiochemistry and stereochemical outcomes were observed using 1-bromo-1,5-enyne (Z)-1c (entry 6). Interestingly, the reaction with 1,5-enyne (Z)-1d also proceeded with full retention of the stereochemistry to obtain cis-2d as the only diastereoisomer as established by ¹H NMR (entry 7). These results point out at least three reactivity patterns: the reaction is stereospecific through a two-step mechanism; electronic effects affect the stereochemical outcome; and the cis stereoisomer is thermodynamically more favorable.

After these interesting results, we explored the reaction with 1,5-enynyl phenyl N-tosylamines, substrates of interest for the synthesis of nitrogen heterocycles such as phenanthridines or indoles. In this venture, we found that the reaction of 3,5-dimethoxyphenyl 1,5-enynyl N-tosylamine (E)-3a with InI₃ (5 mol %) in toluene at 60 °C gave the phenanthridine trans-4a in 90% yield in just 2 h as the only diastereoisomer detected by ¹H NMR (Table 3, entry 1). Analogously, the reaction with 1,5-enynes (E)-3b and (E)-3c furnished with a methyl and a phenyl group at the alkyne afforded phenanthridines trans-4b and trans-4c stereoselectively as the only isolated products in 85 and 82% yield (Table 3, entries 2 and 3, respectively). Furthermore, the reaction with 1-bromo-1,5-enyne (E)-3d led to the 7-bromo-hexahydrophenanthridine trans-4d in 73% yield (entry 4). Although no isomerization was detected with these 1,5-enynes, the reaction of (E)-1,5-enyne 3e, furnished with an unsubstituted phenyl group, proceeded with complete inversion and the cis-4e was obtained as a single diastereoisomer (49% yield, entry 5). As previously reported, the isomerization can be explained by a stepwise mechanism where after the first 6-endo-dig cyclization, the synthetic intermediate could isomerize toward the most thermodynamically stable polycyclic compound. Therefore, we can conclude that aryl 1,5-enynes 3a–d furnished with the N-tosylamine moiety are more reactive than the ethers 1a–d and the cycloisomerization reaction takes place with complete retention of the alkene configuration.

Table 3. Indium-Catalyzed Reactions of 1,5-Enynyl Aryl N-Tosylamines 3a–f

^{^a}

Isolated yield.

The stereospecificity of the cycloisomerization reaction was also explored with the Z-alkene analogues. In this case, we observed that the reaction with 1,5-enyne (Z)-3a afforded phenanthridine cis-4a as a single diastereoisomer in 88% yield (entry 6). Analogously, the reaction with bromoalkyne (Z)-3d provided phenanthridine cis-4d in 72% yield (entry 7) and the reaction with 1,5-enyne (Z)-3e without methoxy groups at the phenyl unit gave cis-4e in 63% yield (entry 8). As previously observed with the 1,5-enynyl ether (Z)-1d, in this case, the reaction proceeded with full retention of the alkene stereochemistry. Finally, we also explored the reaction with (E)-1,5-enyne 3f, where the alkene moiety is disubstituted. Gratifyingly, the cascade cycloisomerization proceeded with complete regio- and stereospecificity to afford trans-4f in 79% yield as the only detected and isolated product. (19) This result demonstrates that the cascade cycloisomerization reaction is not limited to trisubstituted alkenes and resembles a biomimetic cascade olefin process.

The synthetic utility of the In(III)-catalyzed double cycloisomerization was then explored using 1,5-enynes equipped with a phenol moiety. Although InI₃ showed as an efficient catalyst for the synthesis of benzo[b]furans from ortho-alkynylphenols, (18d) this cascade cycloisomerization process found some synthetic limitations using other transition metal catalysts. (20) In addition, the regioselective phenoxycyclization should provide access to xanthenes, a tricyclic skeleton of a relevant class of natural products. (21)

Using 1,5-enyne (E)-5a as a model substrate, (20) we found that InI₃ (5 mol %) catalyzes the double cycloisomerization reaction in toluene at room temperature to afford the tricyclic 6-endo-dig/endo-trig product trans-6a in 86% isolated yield as a single diastereoisomer in 5 h (Table 4, entry 1). It is interesting to note the higher reactivity exhibited compared to the previous aryl 1,5-enynyl ethers 1a–d and N-tosylamines 3a–f as well as the chemical compatibility of the In(III) catalysis with the free hydroxyl group of the phenol. Furthermore, the reaction with (Z)-5a provided the cis-fused xanthene cis-6a in an excellent yield of 87% as the only isolated product (entry 2). These experimental results could be explained either by a stereospecific concerted or by a stepwise mechanism.

Table 4. Indium-Catalyzed Phenoxycyclization of 1,5-Enynes 5a–b

^{^a}

Isolated yield.

As the next step, we also tested the reaction of aryl 1,5-enynes 5 substituted at the alkyne. However, the complex synthesis of these substrates led us to consider a sequential procedure based on indium-catalyzed cascade cycloisomerization of the 1-bromo-1,5-enyne (E)-5b (14c) and subsequent functionalization by the cross-coupling reaction. With this approach in mind, we found that the reaction of 1-bromo-1,5-enyne (E)-5b and (Z)-5b with InI₃ (5 mol %) results in a stereospecific manner, affording the expected 1-bromo-tetrahydroxanthenes trans-6b and cis-6b in 89 and 92% yield, respectively, as the only isolated products (Table 4, entries 3 and 4).

Having demonstrated the feasibility of both alkene isomers of 1-bromo-1,5-enyne 5b in the double cycloisomerization reaction, we assayed the one-pot sequential indium(III)-catalyzed 1,5-enyne cyclization and palladium-catalyzed cross-coupling reaction using triorganoindium reagents. (17,22) Gratifyingly, the treatment of (E)-5b with InI₃ (5 mol %) in toluene at room temperature followed by addition of a solution of Ph₃In (70 mol %) and Pd(PPh₃)₄ (5 mol %) in tetrahydrofuran (THF) at 80 °C afforded the 4-phenyltetrahydroxhantene trans-6c in 76% yield (Scheme 2). The sequential protocol using Me₃In and n-Bu₃In also gave the xanthene derivatives trans-6d and trans-6e in 83 and 81% yield, respectively. These results show the versatility of the In-catalyzed cascade cycloisomerization reaction using aryl 1,5-enynes and its chemical compatibility with Pd-catalyzed cross-coupling reactions.

Scheme 2. Sequential One-Pot In-Catalyzed 1,5-Enyne Cycloisomerization and Pd-Catalyzed Cross-Coupling Reaction with (E)-5b

Finally, the indium-catalyzed cycloisomerization reaction of 1,5-enynes with aryl nucleophiles at the C-5 alkene unit (7a–c) was also briefly studied (Table 5). These substrates should allow the synthesis of spiroheterocycles if the cycloisomerization proceeds with 6-endo regioselectivity according to the previously described cation-olefin mechanism. (14a) Interestingly, the treatment of 1,5-enyne 7a with InI₃ (5 mol %) in toluene at 60 °C afforded oxaspirane 8a as the only isolated product in an excellent yield of 84% (Table 5, entry 1). As expected, the cascade cycloisomerization reaction proceeded with 6-endo-dig/endo-trig regioselectivity to afford the Markovnikov product exclusively. Analogously, the reaction using 1,5-enynyl benzyl N-tosylamine 7b provided the azaspirane 8b in 92% yield (entry 2). The reaction with 1-bromo-1,5-enyne 7c afforded the corresponding spirane 8c in 76% yield (entry 3). In addition, the one-pot sequential indium-catalyzed cycloisomerization of 7c followed by the cross-coupling reaction with Ph₃In using Pd(PPh₃)₄ as the catalyst provided the phenyl-substituted azaspirane 8d in 61% overall yield (two steps, entry 4).

Table 5. Synthesis of Spiroheterocycles by Indium-Catalyzed Reaction with 1,5-Enynes 7a–c^c

^{^a}

Isolated yield.

^{^b}

Obtained from 7c by sequential In-catalyzed cycloisomerization and Pd-catalyzed cross-coupling.

^{^c}

Overall yield (two steps).

Mechanistic Studies

According to the experimental results, we postulate that the course of the indium(III)-catalyzed double cascade cycloisomerization could be viewed as either a concerted process or a stepwise route depending on the arene nucleophilicity (Scheme 3). In a two-step mechanism, we postulate that the initial η² coordination of the indium(III) halide with the alkyne moiety (C) would trigger 1,5-enyne cyclization to form the intermediate D. (2) This intermediate should not be a pure carbocation and could be seen as a resonance hybrid of two resonance structures, an indium-stabilized homoallylic carbocation (D) and a cyclopropylindium ylide. Once there, the second cyclization should proceed through a Friedel–Crafts type alkylation reaction, subsequent aromatization and protodemetallation should provide the corresponding tricyclic compound, regenerating the catalytic species (Scheme 3). The mechanistic pathway and the nature of the transition states and synthetic intermediates should also depend on the substituents at the alkene, alkyne, or arene units.

Scheme 3. General Plausible Mechanism for the In(III)-Catalyzed Cascade Cycloisomerization Reaction of 1,5-Enynes **1a–d** and **3a–f**

Our experimental data show that the In(III)-catalyzed double cycloisomerization reaction of aryl-substituted (Z)-1,5-enynes is stereoselective, yielding in all cases the cis adducts with complete selectivity. For example, independently of the electronic nature of the aromatic ring, the final cis-products are obtained, cis-2a, cis-2c, and cis-2d from (Z)-1a, (Z)-1c, and (Z)-1d, respectively (Table 2, entries 5–7), as for the 1,5-enyne cycloisomerizations of Table 3 (entries 6–8) and Table 4. Accordingly, one would expect that using (E)-1,5-enynes, the tricyclic products would belong to the trans series. In fact, this is true for all of the dimethoxyphenyl, electron-rich arenes, 1,5-enynes like (E)-1a (Table 2, entry 1, cis/trans = 11:89), and others (Table 2, entries 1–3; Table 3, entries 1–4; Table 4). However, surprisingly, the unsubstituted phenyl 1,5-enynes (E)-1d and (E)-3e break this rule, affording the opposite cis diastereoisomers of the final adduct cis-2d (Table 2, entry 4) and cis-4e (Table 3, entry 5). In other words, phenyl ether 1,5-enynes 1d and 3e lead diastereoselectively to the cis final adducts, regardless of the E or Z configuration of the initial double bonds. To gain insights into the intriguing behavior of aryl 1,5-enynyl ethers (E)-1d and (E)-3e, we set out to study the reaction theoretically. (23)

Computational studies (24) for (Z)- and (E)-1,5-enynyl aryl ether 1a (Scheme 4) showed that the formation of the first cycle occurs viaTS1-Z or TS1-E, two transition states originated by the nucleophilic 6-endo-dig alkene attack to the indium-activated electrophilic triple bond. The activation energy is very similar for the two compounds, 17.3 and 18.9 kcal/mol, respectively. As expected, the aromatic ring does not participate in the formation of the first ring, which affords intermediates INT1 stereospecifically, INT1-cis from Z, and INT1-trans from E starting materials. These intermediates are low in energy, 0.3–1.8 kcal/mol, presenting a bicyclic structure [4.1.0] and a partial indium carbene character. The computational data shows that the first step (TS1) is rate limiting since the formation of the second cycle by an electrophilic aromatic substitution in TS2-type transition states proceeds with lower activation energies, 8.9 for TS2-cis and 12.6 kcal/mol for TS2-trans. As expected for this type of reaction (S_EAr), electron-rich arenes are positively affected by the stabilization of the incipient positive charge in the aryl ring by the electron-releasing methoxy groups. For the same reason, the arenium intermediates INT2a (cis and trans) are very stable in the presence of methoxy substituents (−12.3 and −7.6 kcal/mol). Although we did not compute them, the easy final deprotonation and hydrolysis (protodemetallation) of the C–In bond after INT2a intermediates would render exclusive adducts cis-2a (from Z-1a, black pathway in Scheme 4) and trans-2a (from E-1a, red line), in complete agreement with the experimental results.

Scheme 4. DFT-Calculated Mechanism of the Reaction of (Z)-1a and (E)-1a for the Selective Formation of **INT2**-*cis* and *-trans*

Intermediate INT1 presents very interesting structures, as they can be described by two resonance forms, I and II (Scheme 5, top). The former is a fused bicyclic skeleton with a polarized C–In bond, whilst II shows the zwitterionic character, with the positive charge on the methylated tertiary carbon and an anionic alkenyl-indium motif. The NBO analysis of INT1(OMe) and INT1(H) affords Wiberg bond orders showing the mixed character of both structures, slightly more akin to structure I, since the internal C–C bond b is advanced but not completely formed (BO = 0.67–0.81), and the C–C bond a presents slight but not complete double bond character (BO = 1.33–1.43). The bonding distances also show mixed characteristics of both resonance forms, with computed values of δ_a = 1.40 Å and δ_b = 1.68 Å. Thus, resonance form II also has a significant participation in the actual structure of these intermediates. We rationalized that, given the weakness of bond b and the partial carbocationic character at the C-3 position (Scheme 5, bottom), the bicyclic species INT1-cis and INT1-trans could potentially interconvert by an isomerization equilibrium. Indeed, a transition state was located (TS-isom) bearing an almost planar tertiary carbocation, where the adjacent carbon (labeled as C-3) is flipping between the upper and lower faces of the cyclohexene plane (Scheme 5). The activation energy of this process is quite low, ca. 13.5–15.1 kcal/mol, making the isomerization plausible, at least in some circumstances. However, as mentioned before for, the 1a starting materials, the second step (TS2) is low enough in energy (8.9 and 12.6 kcal/mol, Scheme 4) to outcompete the isomerization, providing a complete selectivity (experimental > 95:5) for the cis and trans final products.

Scheme 5. DFT-Calculated Isomerization Process between the Intermediates **INT1**-*cis* and **INT1**-*trans*

The scenario is quite different for 1,5-enynes (E)- and (Z)-1d without methoxy groups (Scheme 6). The initial cyclization through TS1 is also rate limiting, with values of 17.4 and 19.6 kcal/mol. After the first transition state, the structure and energies of INT1 intermediates are very similar to the previous ones. However, due to the absence of stabilizing methoxy groups in the aromatic ring, the second cyclization (TS2) increases its energy significantly in ca. 5–7 kcal/mol (12.8 and 19.1 kcal/mol, Scheme 6) above the values noted for 1a. This fact is especially important in the case of the trans cyclization, which also shows larger ring strain, producing a sluggish cyclization (19.1 kcal/mol), which becomes slower than the isomerization (15.1 kcal/mol) between the two INT1 isomers. Therefore, intermediate INT1-trans prefers to isomerize to INT1-cis rather than cyclize, and the reaction follows the red line in Scheme 6 to cis isomer. Meanwhile, the double cyclization of the Z isomer proceeds via the black line to lead stereospecifically to the cis isomer. These observations can explain how both starting materials converge in INT1-cis to give the same cis final isomer under Curtin–Hammett conditions.

Scheme 6. DFT-Calculated Mechanism of the Reaction of (Z)-1d and (E)-1d under Curtin–Hammett Conditions

Conclusions

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Indium(III) iodide is an efficient catalyst to promote a double cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles. The reaction can be performed under mild reaction conditions using 5 mol % of catalyst and proceeds in cascade through alkyne electrophilic activation with complete 6-endo regioselectivity via a biomimetic cascade cation-olefin process. In some cases, the double cycloisomerization is stereospecific with the retention of the alkene configuration. In addition, the synthetic transformation is highly versatile, allowing 1,5-enynes substituted at the alkyne and alkene units and phenyl groups and phenol derivatives as nucleophiles. Accordingly, a diverse group of polycyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds was synthesized. Computational studies on aryl 1,5-enynyl ethers support a mechanism consisting of two consecutive cyclizations: the first one is a 6-endo-dig process catalyzed by a regioselective alkyne electrophilic activation and a second cyclization through a nonstereospecific S_EAr process.

Experimental Section

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General Methods

All reactions were carried out in flame-dried glassware under argon using standard gastight syringes, cannulae, and septa. Toluene and THF were distilled from sodium/benzophenone. Dry MeOH, DCE, Et₃N, and other commercially available reagents were used as received. Reaction temperatures refer to external bath temperatures. Butyllithium was titrated prior to use. Indium(III) iodide (99.998%) and indium(III) bromide (99.999%) were purchased from Aldrich and used as received under argon. The reactions were monitored by TLC using precoated silica gel plates (Alugram Xtra SIL G/UV254, 0.20 mm thick), UV light as the visualizing agent, and ethanolic phosphomolybdic acid as the developing agent. Flash column chromatography was performed with 230–400 mesh silica gel. ¹H and ¹³C NMR spectra were recorded in CDCl₃ at 300 K using a Bruker Advance 300 MHz, 400 MHz or a Bruker Advance 500 MHz spectrometer and calibrated to the solvent peak. Mass spectra were obtained with a MAT 95XP Magnetic Sector EI spectrometer or with a QSTAR Elite hybrid quadrupole time-of-flight (TOF) ESI mass spectrometer, both operating in the positive ionization mode. Gas chromatography (GC) was performed on a Trace 1300 autosampling GC with a TG-5SILMS capillary column and equipped with an ISQ QD mass spectrometer.

(E)-1,3-Dimethoxy-5-[(3-methyloct-2-en-6-yn-1-yl)oxy]benzene [(E)-1b] (14a)

To a cooled solution of enyne (E)-1a (14c) (202.8 mg, 0.78 mmol) in dry THF (10 mL) at 0 °C, n-BuLi (0.38 mL, 0.82 mmol, 2.19 M in hexanes) was added dropwise. After 30 min, MeI (0,06 mL, 0.94 mmol) was added, and the reaction mixture was stirred for 2 h. The reaction was quenched with EtOH (1 mL), the solvent was evaporated, and the corresponding residue was purified by flash chromatography (2% EtOAc/hexanes) to afford (E)-1b (162.6 mg, 76%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.11–6.09 (m, 3H), 5.54–5.50 (m, 1H), 4.51 (d, J = 6.5 Hz, 2H), 3.77 (s, 6H), 2.26 (m, 4H), 1.77 (s, 3H), 1.74 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.6, 160.9, 139.9, 120.5, 93.7, 93.1, 78.6, 76.2, 65.0, 55.5, 39.0, 17.7, 16.7, 3.6; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₇H₂₂O₃Na 297.1461; found 297.1458.

(E)-1-[(7-Bromo-3-methylhept-2-en-6-yn-1-yl)oxy]-3,5-dimethoxybenzene [(E)-1c]

To a room temperature solution of (E)-3-methylhept-2-en-6-yn-1-ol (25) (105.7 mg, 0.85 mmol) in acetone (5 mL), N-bromosuccinimide (NBS) (166.7 mg, 0.93 mmol) and AgNO₃ (15.8 mg, 0.09 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with Et₂O (10 mL), washed with H₂O (10 mL) and brine (10 mL), dried with anhydrous MgSO₄, filtered, and concentrated in vacuo to afford (E)-7-bromo-3-methylhept-2-en-6-yn-1-ol as an orange oil, which was used in the next step without further purification. The crude product was added to a solution of triphenylphosphine (329.4 mg, 1.25 mmol) and 3,5-dimethoxyphenol (193.2 mg, 1.25 mmol) in THF (10 mL). To this solution at 0 °C, diisopropyl azodicarboxylate (DIAD) (0.25 mL, 1.25 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 60 °C. Then, the solvent was evaporated in vacuo and the corresponding residue was purified by flash chromatography (5% EtOAc/hexanes) to afford (E)-1c (161.0 mg, 56% in two steps) as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 6.10 (m, 3H), 5.54–5.50 (m, 1H), 4.50 (d, J = 6.6 Hz, 2H), 3.76 (s, 6H), 2.36–2.29 (m, 4H), 1.74 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.6, 160.8, 139.1, 120.9, 93.7, 93.1, 79.6, 64.8, 55.4, 38.6, 38.0, 18.6, 16.6; IR (neat) ν_max 2929, 2841, 1594, 1460, 1204, 1150, 1062, 819 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₁₉BrO₃Na 361.0409; found 361.0416.

(E)-[(3-Methylhept-2-en-6-yn-1-yl)oxy]benzene [(E)-1d]

To a 0°C solution of (E)-3-methylhept-2-en-6-yn-1-ol (25) (201.9 mg, 1.63 mmol), triphenylphosphine (640.0 mg, 2.44 mmol) and phenol (229.6 mg, 2.44 mmol) in THF (10 mL), DIAD (0.48 mL, 2.44 mmol) was added dropwise. The reaction mixture was stirred for 5 h at 60 °C in an oil bath and the solvent was evaporated in vacuo. Then, the corresponding residue was purified by flash chromatography (5% EtOAc/hexanes) to afford (E)-1d (251.4 mg, 77%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.31–7.28 (m, 2H), 6.94–6.93 (m, 3H), 5.58–5.53 (m, 1H), 4.56 (d, J = 6.5 Hz, 2H), 2.35–2.31 (m, 4H), 1.95 (t, J = 2.3 Hz, 1H), 1.75 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 158.9, 139.1, 129.5, 121.1, 120.8, 114.8, 83.9, 68.9, 64.7, 38.3, 17.3, 16.6; HRMS (EI) m/z: [M]⁺ calcd for C₁₄H₁₆O 200.1201; found 200.1196.

(Z)-1,3-Dimethoxy-5-[(3-methylhept-2-en-6-yn-1-yl)oxy]benzene [(Z)-1a]

DIAD (0.51 mL, 2.57 mmol) was added dropwise at 0 °C to a solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (212.6 mg, 1.71 mmol), triphenylphosphine (674.1 mg, 2.57 mmol), and 3,5-dimethoxyphenol (396.2 mg, 2.57 mmol) in THF (10 mL). The reaction mixture was stirred for 3 h at 60 °C in an oil bath and the solvent was evaporated in vacuo. Then, the corresponding residue was purified by flash chromatography (5% EtOAc/hexanes) to afford (Z)-1a (227.3 mg, 51%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.11–6.09 (m, 3H), 5.60 (td, J = 6.8, 1.6 Hz, 1H), 4.51 (d, J = 6.8 Hz, 2H), 3.76 (s, 6H), 2.36–2.34 (m, 4H), 1.97 (t, J = 2.4 Hz, 1H), 1.81 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.6, 160.7, 139.7, 122.0, 93.6, 93.0, 83.7, 69.0, 64.5, 55.4, 31.2, 23.3, 17.5; IR (neat) ν_max 3289, 2935, 2840, 1593, 1474, 1204, 1147, 1060, 818 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₂₀O₃Na 283.1304; found 283.1313.

(Z)-1-[(7-Bromo-3-methylhept-2-en-6-yn-1-yl)oxy]-3,5-dimethoxybenzene [(Z)-1c]

To a room temperature solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (115.7 mg, 0.93 mmol) in acetone (5 mL), NBS (182.4 mg, 1.02 mmol) and AgNO₃ (17.3 mg, 0.10 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with Et₂O (10 mL) and washed with H₂O (10 mL) and brine (10 mL), dried with MgSO₄ (anhydrous), filtered, and concentrated in vacuo to afford (Z)-7-bromo-3-methylhept-2-en-6-yn-1-ol as an orange oil, which was used in the next step without further purification. The crude product was added to a solution of triphenylphosphine (354.0 mg, 1.35 mmol) and 3,5-dimethoxyphenol (208.9 mg, 1.35 mmol) in THF (10 mL), DIAD (0.26 mL, 1.35 mmol) at 0 °C was added dropwise, and the reaction mixture was heated at 60 °C for 5 h. Then, the solvent was evaporated in vacuo and the corresponding residue was purified by flash chromatography (5% EtOAc/hexanes) to afford (Z)-1c (149.9 mg, 47% in two steps) as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 6.11–6.09 (m, 3H), 5.61 (m, 1H), 4.49 (d, J = 6.7 Hz, 2H), 3.77 (s, 6H), 2.34 (m, 4H), 1.80 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 161.5, 160.7, 139.5, 122.0, 93.6, 93.1, 79.5, 64.4, 55.4, 38.8, 31.0, 23.3, 18.8; IR (neat) ν_max 2927, 2840, 1593, 1474, 1204, 1148, 1061, 818 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₁₉BrO₃Na 361.0409; found 361.0403.

(Z)-[(3-Methylhept-2-en-6-yn-1-yl)oxy]benzene [(Z)-1d]

To a cooled solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (215.8 mg, 1.74 mmol), triphenylphosphine (684.6 mg, 2.61 mmol) and phenol (245.6 mg, 2.61 mmol) in THF (10 mL) at 0 °C, DIAD (0.52 mL, 2.61 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 60 °C in an oil bath. The solvent was evaporated in vacuo and the corresponding residue was purified by flash chromatography (5% EtOAc/hexanes) to afford (Z)-1d (236.7 mg, 68%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.31–7.25 (m, 2H), 6.95–6.91 (m, 3H), 5.62–5.60 (m, 1H), 4.55 (d, J = 6.8, 2H), 2.38–2.33 (m, 4H), 1.98–1.96 (m, 1H), 1.82 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 158.8, 139.5, 129.5, 122.2, 120.8, 114.8, 83.8, 69.0, 64.3, 31.3, 23.3, 17.5; IR (neat) ν_max 3292, 2917, 2868, 1598, 1494, 1235, 1172, 1006, 752 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₄H₁₆O 200.1201; found 200.1197.

(E)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methyloct-2-en-6-yn-1-yl)benzenesulfonamide [(E)-3b]

To a 0 °C solution of 1,5-enyne (E)-3a (14c) (205.6 mg, 0.50 mmol) in dry THF (10 mL), n-BuLi (0.21 mL, 0.52 mmol, 2.5 M in hexanes) was added dropwise. After 30 min, MeI (0,04 mL, 0.60 mmol) was added and the reaction mixture was left stirring for 2 h. The reaction was quenched with EtOH (3 mL), the solvent was evaporated, and the corresponding residue was purified by flash chromatography (10% EtOAc/hexanes) to afford (E)-3b (108.4 mg, 51%) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J = 8.4 Hz, 2H), 7.28–7.25 (m, 2H), 6.36 (d, J = 2.1 Hz, 1H), 6.20 (d, J = 2.1 Hz, 2H), 5.15 (t, J = 7.0 Hz, 1H), 4.13 (d, J = 6.9 Hz, 2H), 3.71 (s, 6H), 2.42 (s, 3H), 2.07 (m, 4H), 1.72 (s, 3H), 1.52 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.5, 143.4, 141.3, 139.1, 135.8, 129.4, 127.9, 119.7, 107.0, 100.1, 78.5, 76.0, 55.5, 48.7, 38.8, 21.6, 17.7, 16.2, 3.5; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₃₀NO₄S 428.1890; found 428.1893.

(E)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methyl-7-phenylhept-2-en-6-yn-1-yl)benzenesulfonamide [(E)-3c]

To a solution of 1,5-enyne (E)-3a (14c) (163.0 mg, 0.39 mmol) in Et₃N (4 mL), CuI (3.75 mg, 0.02 mmol), Pd(PPh₃)₂Cl₂ (13.83 mg, 0.02 mmol), and iodobenzene (103.4 mg, 0.51 mmol) were added and the reaction mixture was stirred overnight at room temperature. Then, the reaction was quenched with H₂O (15 mL) and the aqueous phase was extracted with Et₂O (3 × 15 mL). The combined organic phase was washed with brine (50 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford (E)-3c (107.9 g, 57%) as an amorphous white solid after purification by column chromatography (10% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 6.7, 3.1 Hz, 2H), 7.27–7.24 (m, 5H), 6.35 (t, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 2H), 5.22 (t, J = 6.7 Hz, 1H), 4.15 (d, J = 6.8 Hz, 2H), 3.68 (s, 6H), 2.42 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.58 (s, J = 1.3 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.6, 143.5, 141.3, 138.9, 135.8, 131.6, 129.5, 128.3, 127.9, 127.7, 123.9, 120.1, 107.1, 100.2, 89.6, 82.2, 81.1, 55.5, 48.7, 38.5, 21.7, 18.6, 16.4; IR (neat) ν_max 2925, 2841, 1596, 1458, 1346, 1205, 1154, 1066, 663 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₉H₃₁NO₄SNa: 512.1866; found 512.1853.

(E)-N-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide [(E)-3d] (14c)

NBS (125.0 mg, 0.70 mmol) and AgNO₃ (12.0 mg, 0.07 mmol) were added to a solution of the enyne (E)-3a (266.3 mg, 0.64 mmol) in acetone (6 mL), and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with Et₂O (10 mL), the organic phase was washed with H₂O (10 mL) and brine (10 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford, after purification by column chromatography (15% EtOAc/hexanes), (E)-3d (198.0 mg, 74%) as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J = 8.0 Hz, 2H), 7.28 (m, 2H), 6.37 (m, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 2H), 5.16 (t, J = 6.7 Hz, 1H), 4.13 (d, J = 6.9 Hz, 2H), 3.71 (s, 6H), 2.42 (s, 3H), 2.16–2.10 (m, 4H), 1.55 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.6, 143.5, 141.3, 138.5, 135.9, 129.5, 127.9, 120.2, 107.1, 100.2, 79.6, 55.5, 48.6, 38.4, 38.0, 21.7, 18.7, 16.3; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₆BrNO₄SNa 514.0658; found: 514.0645.

(E)-4-Methyl-N-(3-methylhept-2-en-6-yn-1-yl)-N-phenylbenzenesulfonamide [(E)-3e]

DIAD (0.36 mL, 1.81 mmol) was added dropwise at 0 °C to a solution of (E)-3-methylhept-2-en-6-yn-1-ol (25) (150.0 mg, 1.21 mmol), triphenylphosphine (474.7 mg, 1.81 mmol), and p-toluenesulfonanilide (447.6 mg, 1.81 mmol) in THF (10 mL). The reaction mixture was stirred for 5 h at 60 °C in an oil bath and the solvent was evaporated in vacuo. The corresponding residue was purified by flash chromatography (20% EtOAc/hexanes) to afford (E)-3e (303.7 mg, 71%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J = 8.3 Hz, 2H), 7.27–7.24 (m, 5H), 7.06–7.04 (m, 2H), 5.18 (ddt, J = 8.2, 6.9, 1.3 Hz, 1H), 4.19 (d, J = 7.0 Hz, 2H), 2.42 (s, 3H), 2.10 (m, 4H), 1.84 (m, 1H), 1.49 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 143.4, 139.4, 138.7, 135.8, 129.5, 129.0, 128.9, 127.9, 127.8, 120.1, 83.7, 68.8, 48.5, 38.1, 21.7, 17.3, 16.1; IR (neat) ν_max 3295, 2972, 2922, 1598, 1494, 1345, 1156, 1091, 654 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₁H₂₃NO₂SNa: 376.1341; found: 376.1338.

(Z)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methylhept-2-en-6-yn-1-yl)benzenesulfonamide [(Z)-3a]

DIAD (0.34 mL, 1.74 mmol) was added dropwise at 0 °C to a solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (144.2 mg, 1.16 mmol), triphenylphosphine (456.4 mg, 1.74 mmol), and N-(3,5-dimethoxybenzyl)-4-methylbenzenesulfonamide (27) (534.4 mg, 1.74 mmol) in THF (10 mL). The reaction mixture was stirred for 5 h at 60 °C in an oil bath and the solvent was evaporated in vacuo. The corresponding crude reaction product was purified by flash chromatography (15% EtOAc/hexanes) to afford (Z)-3a (359.8 mg, 75%) as a white solid; mp 100–102 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J = 8.3 Hz, 2H), 7.28–7.25 (m, 2H), 6.37 (t, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 2H), 5.24–5.20 (m, 1H), 4.15 (dd, J = 7.0, 1.2 Hz, 2H), 3.71 (s, 6H), 2.43 (s, 3H), 2.14–2.09 (m, 4H), 1.90 (m, 1H), 1.63 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.6, 143.4, 141.2, 138.2, 135.7, 129.4, 127.8, 121.4, 107.1, 100.1, 83.8, 68.8, 55.4, 48.5, 30.7, 23.0, 21.6, 17.1; IR (neat) ν_max 3294, 2927, 2840, 1594, 1459, 1348, 1154, 1065, 663 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₇NO₄SNa 436.1553; found 436.1555.

(Z)-N-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide [(Z)-3d]

NBS (75.0 mg, 0.42 mmol) and AgNO₃ (7.1 mg, 0.04 mmol) were added to a solution of 1,5-enyne (Z)-3a (158.3 mg, 0.38 mmol) in acetone (5 mL), and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with Et₂O (10 mL), the organic phase was washed with H₂O (10 mL) and brine (10 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo. After purification by column chromatography (15% EtOAc/hexanes), (Z)-3d was obtained (128.9 mg, 69%) as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J = 8.0 Hz, 2H), 7.28–7.25 (m, 2H), 6.37 (t, J = 2.3 Hz, 1H), 6.19 (dt, J = 2.3, 1.3 Hz, 2H), 5.24–5.20 (m, 1H), 4.13 (d, J = 7.0 Hz, 2H), 3.71 (s, 6H), 2.42 (s, 3H), 2.10 (m, 4H), 1.62 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.7, 143.5, 141.2, 138.2, 135.8, 129.5, 127.9, 121.5, 107.1, 100.2, 79.7, 55.5, 48.6, 38.5, 30.6, 23.2, 21.7, 18.5; IR (neat) ν_max 2925, 2839, 1592, 1457, 1347, 1204, 1152, 1065, 662 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₆BrNO₄SNa 514.0658; found 514.0651.

(Z)-4-Methyl-N-(3-methylhept-2-en-6-yn-1-yl)-N-phenylbenzenesulfonamide [(Z)-3e]

To a 0 °C solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (151.4 mg, 1.21 mmol), triphenylphosphine (479.2 mg, 1.81 mmol) and p-toluene-sulfonanilide (451.8 mg, 1.81 mmol) in THF (15 mL), DIAD (0.36 mL, 1.81 mmol) was added dropwise. The reaction mixture was stirred for 5 h at 60 °C in an oil bath and the solvent was evaporated in vacuo. The corresponding residue was purified by flash chromatography (10% EtOAc/hexanes) to afford (Z)-3e as a colorless oil (329.3 mg, 77%); ¹H NMR (300 MHz, CDCl₃) δ 7.49 (d, J = 8.3 Hz, 2H), 7.29–7.25 (m, 5H), 7.05–7.02 (m, 2H), 5.24–5.19 (m, 1H), 4.19 (d, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.10–2.05 (m, 4H), 1.89 (t, J = 2.4 Hz, 1H), 1.61 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 143.4, 139.4, 138.3, 135.8, 129.5, 129.0, 129.0, 127.9, 127.8, 121.4, 83.8, 68.8, 48.5, 30.7, 23.0, 21.6, 17.1; IR (neat) ν_max 3290, 2920, 2869, 1596, 1493, 1345, 1162, 1092, 656 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₁H₂₃NO₂SNa 376.1341; found 376.1334.

(E)-N-(3,5-Dimethoxyphenyl)-N-(hept-2-en-6-yn-1-yl)-4-methylbenzenesulfonamide [(E)-3f]

To a 0 °C solution of (E)-hept-2-en-6-yn-1-ol (28) (150.0 mg, 1.36 mmol), triphenylphosphine (535.1 mg, 2.04 mmol), and N-(3,5-dimethoxybenzyl)-4-methylbenzenesulfonamide (27) (627.0 mg, 2.04 mmol) in THF (10 mL), DIAD (0.40 mL, 2.04 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 60 °C in an oil bath. The solvent was evaporated in vacuo and the corresponding residue was purified by flash chromatography (20% EtOAc/hexanes) to afford (E)-3f (396.6 g, 73%) as a white solid; mp 90–92 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.35 (t, J = 2.3 Hz, 1H), 6.18 (d, J = 2.3 Hz, 2H), 5.56–5.40 (m, 2H), 4.07 (d, J = 5.9 Hz, 2H), 3.68 (s, 6H), 2.40 (s, 3H), 2.10 (m, J = 3.1, 2.6 Hz, 4H), 1.87 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.5, 143.5, 140.9, 135.6, 133.2, 129.4, 127.8, 125.8, 107.2, 100.1, 83.5, 68.8, 55.4, 52.9, 31.0, 21.6, 18.3; IR (neat) ν_max 3289, 2934, 2840, 1593, 1458, 1345, 1153, 1090, 662 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₂H₂₅NO₄SNa 422.1396; found 422.1385.

(Z)-4-Methoxy-2-(3-methylhept-2-en-6-yn-1-yl)phenol [(Z)-5a]

PBr₃ (162.4 mg, 0.60 mmol) was added dropwise to a solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (150.2 mg, 1.21 mmol) in Et₂O (10 mL) at 0 °C and was stirred for 30 min. The reaction was quenched with H₂O (10 mL) and the aqueous phase was extracted with Et₂O (3 × 10 mL). The combined organic phase was washed with H₂O (30 mL), NaHCO₃ (30 mL, satd. sol.), and brine (10 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford (Z)-7-bromo-5-methylhept-5-en-1-yne as an orange oil, which was used in the next step without further purification. The crude product was dissolved in toluene (10 mL) and NaH 95% (35.5 mg, 1.33 mmol) and 4-methoxyphenol (165.2 mg, 1.33 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with a NH₄Cl saturated solution, and the aqueous phase was extracted with Et₂O (3 × 10 mL). The resulting organic phase was washed with H₂O (30 mL) and brine (30 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to yield, after purification by column chromatography (10% EtOAc/hexanes), (Z)-5a (158.8 mg, 57%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.73 (d, J = 8.5 Hz, 1H), 6.68–6.64 (m, 2H), 5.41–5.36 (m, 1H), 4.68 (s, 1H), 3.75 (s, 3H), 3.37 (d, J = 7.1 Hz, 2H), 2.42–2.40 (m, 2H), 2.38–2.35 (m, 2H), 1.99 (t, J = 2.5 Hz, 1H), 1.78 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.7, 148.1, 136.2, 128.2, 124.2, 116.3, 115.9, 112.1, 84.1, 68.9, 55.9, 30.8, 29.6, 23.1, 17.2; IR (neat) ν_max 3405, 3290, 2913, 2834, 1497, 1430, 1199, 1039, 803 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₅H₁₈O₂ 230.1301; found 230.1296.

(Z)-2-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-4-methoxyphenol [(Z)-5b]

To a room temperature solution of (Z)-3-methylhept-2-en-6-yn-1-ol (26) (84.8 mg, 0.68 mmol) in acetone (5 mL), NBS (133.8 mg, 0.75 mmol) and AgNO₃ (12.7 mg, 0.07 mmol) were added, and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with Et₂O (10 mL), washed with H₂O (10 mL) and brine (10 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford (Z)-7-bromo-3-methylhept-2-en-6-yn-1-ol as an orange oil, which was used in the next step without further purification. The crude product was dissolved in Et₂O (10 mL) and cooled at 0 °C, PBr₃ (92.4 mg, 0.34 mmol) was then added dropwise, and the reaction mixture was stirred for 30 min. The reaction was quenched with H₂O (10 mL), and the aqueous phase was extracted with Et₂O (3 × 10 mL). The resulting organic phase was washed with H₂O (30 mL), a NaHCO₃ saturated solution (30 mL), and brine (10 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford (Z)-1,7-dibromo-5-methylhept-5-en-1-yne as an orange oil, which was used in the next step without further purification.

The crude product in toluene (10 mL) was added to a solution of NaH 95% (20.0 mg, 0.75 mmol) and 4-methoxyphenol (92.9 mg, 0.75 mmol) at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was quenched with a NH₄Cl saturated solution (2 mL) and was extracted with Et₂O (3 × 10 mL). The combined organic phase was washed with H₂O (30 mL) and brine (30 mL), dried with MgSO₄ (anhyd.), filtered, and concentrated in vacuo to afford, after purification by column chromatography (10% EtOAc/hexanes), (Z)-5b (90.4 mg, 43%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.74–6.63 (m, 3H), 5.42–5.38 (m, 1H), 4.89 (s, 1H), 3.76 (s, 3H), 3.36 (d, J = 7.2 Hz, 2H), 2.40–2.35 (m, 4H), 1.77 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.7, 148.0, 135.9, 128.3, 124.2, 116.2, 115.8, 112.1, 79.9, 55.9, 38.5, 30.7, 29.3, 23.3, 18.6; IR (neat) ν_max 3408, 2915, 2835, 1504, 1432, 1201, 1041, 805 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₅H₁₇BrO₂Na: 331.0304; found 331.0315.

General Procedure for In(III)-Catalyzed Cascade Cycloisomerization Reactions of 1,5-Enynes

In a Schlenk tube filled with argon, InI₃ (5 mol %) was placed and a solution of the corresponding 1,5-enyne (∼0.07 M) in toluene was added. The reaction mixture was stirred at 60 °C in an oil bath (for 1a–d, 3a–f, and 7a–c) or at room temperature (for 5a–b) until the starting material is consumed (TLC). The reaction was quenched with NH₄Cl (10 mL, satd. sol.), poured into a separatory funnel, and the aqueous phase was extracted with Et₂O (3 × 10 mL). The resulting combined organic phase was washed with brine (15 mL), dried with anhydrous MgSO₄, filtered, and concentrated under reduced pressure to afford, after purification by column chromatography, the corresponding tricyclic product.

(6aS,10aS)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2a] (14c)

According to the general procedure, the reaction of 1,5-enyne (E)-1a (87.4 mg, 0.34 mmol) with InI₃ (8.5 mg, 0.017 mmol) gave 2a (56.8 mg, 65%; cis/trans = 11:89) as a colorless oil. Purification by column chromatography (2% EtOAc/hexanes) provided pure trans-2a: ¹H NMR (300 MHz, CDCl₃) δ 6.05–6.02 (m, 2H), 5.82–5.76 (m, 1H), 5.36 (dq, J = 9.8, 2.1 Hz, 1H), 4.08 (dd, J = 10.3, 4.1 Hz, 1H), 3.99 (dd, J = 12.4, 10.3 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.07–3.00 (m, 1H), 2.71–2.67 (m, 1H), 2.22 (m, 2H), 1.57–1.53 (m, 1H), 1.17 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.3, 159.3, 155.8, 129.3, 123.8, 113.8, 94.1, 92.3, 66.4, 55.3, 55.3, 41.7, 33.3, 32.0, 24.4, 18.1. HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₂₀O₃Na 283.1304; found 283.1317.

Scale-Up Experiment for (trans)-2a

In a Schlenk tube filled with argon, InI₃ (38.1 mg, 0.077 mmol) was placed and a solution of the enyne (E)-1a (400.5 mg, 1.54 mmol) in toluene (22 mL) was added. The reaction mixture was stirred at 60 °C in an oil bath for 2 h, quenched with a NH₄Cl (30 mL, satd. sol.), poured into a separatory funnel, and extracted with Et₂O (3 × 30 mL). The combined organic phase was washed with brine (35 mL), dried with anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (2% EtOAc/hexanes) to afford 2a (252.4 mg, 63%; cis/trans = 16:84) as a colorless oil.

(4aS,9aS)-6,8-Dimethoxy-4a-methyl-4,4a,9,9a-tetrahydro-3H-xanthene (I)

According to the general procedure, the reaction of 1,5-enyne (E)-1a (150.2 mg, 0.58 mmol) with InI₃ (14.3 mg, 0.029 mmol) in the presence of AgSbF₆ (10.0 mg, 0.029 mmol) afforded a mixture of I:2a (4:1) by ¹H NMR. After purification by column chromatography (1% EtOAc/hexanes), compound I was isolated as a colorless oil (81.1 mg, 54%, cis/trans = 19:81); ¹H NMR (500 MHz, CDCl₃) δ 6.05 (d, J = 0.9 Hz, 2H), 5.66–5.64 (m, 1H), 5.52 (ddt, J = 9.7, 2.5, 1.7 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.72 (dd, J = 16.2, 5.5 Hz, 1H), 2.50–2.42 (m, 1H), 2.35–2.28 (m, 1H), 2.27–2.18 (m, 1H), 2.11 (dd, J = 16.2, 13.7 Hz, 1H), 1.98–1.92 (m, 1H), 1.86 (td, J = 12.0, 6.9 Hz, 1H), 1.11 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.5, 158.5, 154.9, 128.8, 126.5, 104.0, 93.8, 91.0, 75.9, 55.4, 55.3, 38.6, 35.2, 25.1, 22.3, 15.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₂₁O₃ 261.1491; found 261.1486.

2-(But-3-yn-1-yl)-5,7-dimethoxy-2-methylchromane (II)

According to the general procedure, the reaction of 1,5-enyne (E)-1a (90.1 mg, 0.35 mmol) with In(NTf₂)₃ (16.7 mg, 0.018 mmol) in DCE (5 mL) at 60 °C in an oil bath for 5 h afforded, after purification by column chromatography (5% EtOAc/hexanes), compound II (56.7 mg, 63%) as a yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 6.03 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.64–2.49 (m, 2H), 2.37–2.32 (m, 2H), 1.97–1.91 (m, 2H), 1.86–1.82 (m, 1H), 1.79–1.73 (m, 2H), 1.28 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 159.6, 158.6, 154.8, 102.5, 93.8, 91.1, 84.8, 75.3, 68.3, 55.5, 55.4, 38.4, 30.8, 23.8, 16.3, 13.1; IR (neat) ν_max 3289, 2926, 2853, 1616, 1590, 1202, 1143, 1105, 811 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₂₀NaO₃ 283.1304; found 283.1317.

(6aS,10aS)-1,3-Dimethoxy-7,10a-dimethyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2b] (14a)

According to the general procedure, the reaction of 1,5-enyne (E)-1b (99.2 mg, 0.36 mmol) with InI₃ (8.9 mg, 0.018 mmol) afforded 2b (67.5 mg, 68%; cis/trans = 22:78) as a colorless oil. Purification by column chromatography (2% EtOAc/hexanes) afforded pure trans-2b: ¹H NMR (300 MHz, CDCl₃) δ 6.04–6.01 (m, 2H), 5.46 (m, 1H), 4.38 (dd, J = 10.4, 3.6 Hz, 1H), 4.01–3.94 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.00 (dd, J = 13.1, 6.1 Hz, 1H), 2.66 (d, J = 12.1 Hz, 1H), 2.14 (m, 2H), 1.67 (s, 3H), 1.49–1.41 (m, 1H) 1.18 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 160.3, 159.3, 155.7, 130.0, 123.5, 113.8, 93.9, 92.4, 64.4, 55.3, 55.3, 44.7, 33.7, 31.9, 23.7, 20.8, 18.4; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₇H₂₂O₃Na 297.1461; found 297.1454.

(6aS,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2c]

According to the general procedure, the reaction of 1,5-enyne (E)-1c (68.6 mg, 0.20 mmol) with InI₃ (5.0 mg, 0.010 mmol) afforded 2c (42.5 mg, 62%; cis/trans = 27:73) as a white solid. Purification by column chromatography (2% EtOAc/hexanes) afforded pure trans-2c: ¹H NMR (300 MHz, CDCl₃) δ 6.18–6.16 (m, 1H), 6.05–6.02 (m, 2H), 4.57 (dd, J = 10.4, 3.5 Hz, 1H), 3.95 (dd, J = 11.8, 10.4 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.14–3.07 (m, 1H), 2.99–2.93 (m, 1H), 2.26–2.22 (m, 2H), 1.49 (m, 1H), 1.25 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.9, 159.5, 155.8, 131.1, 119.7, 112.4, 93.9, 92.5, 66.2, 55.4, 55.3, 46.8, 36.3, 31.3, 26.2, 18.5; IR (neat) ν_max 2933, 2837, 1612, 1583, 1463, 1201, 1151, 1104, 814 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₁₉BrO₃Na 361.0409; found 361.0418.

(6aR,10aS)-10a-Methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2d]

According to the general procedure, the reaction of 1,5-enyne (E)-1d (105.4 mg, 0.53 mmol) with InI₃ (13.0 mg, 0.027 mmol) or 1,5-enyne (Z)-1d (99.2 mg, 0.49) with InI₃ (11.8 mg, 0.025 mmol) afforded cis-2d [64.3 mg, 61% from (E)-1d and 64.5 mg, 65% from (Z)-1d] as a yellow oil after purification by column chromatography (2% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.23 (dd, J = 7.8, 1.7 Hz, 1H), 7.08 (ddd, J = 8.0, 7.2, 1.7 Hz, 1H), 6.90 (td, J = 7.5, 1.3 Hz, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 5.82–5.79 (m, 1H), 5.59 (ddt, J = 10.0, 3.8, 2.0 Hz, 1H), 4.22 (dd, J = 11.0, 3.0 Hz, 1H), 3.90 (dd, J = 11.0, 6.6 Hz, 1H), 2.34 (m, 1H), 2.02–1.98 (m, 2H), 1.88–1.68 (m, 2H), 1.35 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 154.3, 130.4, 129.9, 127.3, 127.1, 126.1, 120.9, 117.0, 66.8, 41.3, 33.9, 32.9, 29.1, 22.6; IR (neat) ν_max 2922, 2855, 1579, 1488, 1447, 1218, 751 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₄H₁₆O 200.1201; found 200.1182.

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2a]

According to the general procedure, the reaction of 1,5-enyne (Z)-1a (91.5 mg, 0.35 mmol) with InI₃ (9.1 mg, 0.018 mmol) afforded cis-2a (58.6 mg, 64%) as a colorless oil after purification by column chromatography (2% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 6.07 (d, J = 2.6 Hz, 1H), 6.01 (d, J = 2.6 Hz, 1H), 5.84–5.81 (m, 1H), 5.51 (ddt, J = 9.9, 3.6, 1.8 Hz, 1H), 4.13 (dd, J = 10.7, 2.8 Hz, 1H), 3.84 (dd, J = 10.7, 6.8 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.26–2.24 (m, 1H), 2.22–2.18 (m, 1H), 1.99–1.78 (m, 3H), 1.39 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.7, 159.0, 156.5, 130.5, 125.9, 111.0, 93.7, 92.9, 66.8, 55.3, 55.3, 43.4, 33.2, 30.8, 25.7, 23.0; IR (neat) ν_max 2922, 2837, 1612, 1583, 1463, 1200, 1153, 814 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₆H₂₀O₃ 260.1407; found 260.1402.

(6aR,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2c]

According to the general procedure, the reaction of 1,5-enyne (Z)-1c (84.0 mg, 0.25 mmol) with InI₃ (6.1 mg, 0.012 mmol) afforded cis-2c (47.9 mg, 57%) as a yellow oil after purification by column chromatography (2% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 6.21(m, 1H), 6.07 (d, J = 2.6 Hz, 1H), 6.05 (d, J = 2.6 Hz, 1H), 4.32 (dd, J = 10.9, 2.9 Hz, 1H), 4.06 (dd, J = 10.9, 8.0 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.52–2.49 (m, 1H), 2.03 (m, 3H), 1.89 (m, 1H), 1.44 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 160.3, 159.4, 156.7, 132.5, 121.6, 110.9, 93.9, 93.3, 65.8, 55.3, 51.3, 36.2, 29.2, 25.1, 24.8; IR (neat) ν_max 2935, 2837, 1612, 1584, 1464, 1201, 1153, 815 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₆H₁₉BrO₃ 338.0512; found 338.0511.

(6aS,10aS)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4a] (14c)

According to the general procedure, the reaction of 1,5-enyne (E)-3a (120.0 mg, 0.29 mmol) with InI₃ (7.2 mg, 0.015 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-4a (108.1 mg, 90%) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J = 8.3, 2H), 7.21–7.17 (m, 3H), 6.22 (d, J = 2.5, 1H), 5.71 (dq, J = 9.9, 3.3 Hz, 1H), 5.33 (dq, J = 9.8, 2.1 Hz, 1H), 4.00 (dd, J = 11.9, 4.2 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.22 (dd, J = 13.6, 11.8 Hz, 1H), 2.99 (dt, J = 13.3, 4.1 Hz, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.10–2.05 (m, 2H), 1.30–1.29 (m, 1H), 0.66 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.3, 158.2, 143.8, 137.9, 135.8, 129.6, 128.8, 127.4, 125.0, 120.4, 100.4, 96.3, 55.5, 55.4, 47.9, 41.0, 35.2, 31.9, 23.9, 21.6, 16.4; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₇NO₄SNa 436.1553; found 436.1559.

(6aS,10aS)-1,3-Dimethoxy-7,10a-dimethyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4b]

According to the general procedure, the reaction of 1,5-enyne (E)-3b (48.8 mg, 0.11 mmol) with InI₃ (2.8 mg, 0.006 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-4b (41.5 mg, 85%) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J = 8.3 Hz, 2H), 7.21–7.17 (m, 3H), 6.24 (d, J = 2.5 Hz, 1H), 5.39 (m, 1H), 4.38 (dd, J = 12.6, 3.6 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.20 (t, J = 12.8 Hz, 1H), 2.93 (dd, J = 13.1, 6.2 Hz, 1H), 2.36 (s, 3H), 2.22–2.18 (m, 1H), 2.05–1.98 (m, 2H), 1.70 (s, 3H), 1.15–1.07 (m, 1H), 0.80 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.5, 158.1, 143.8, 137.7, 136.3, 130.8, 129.6, 127.4, 123.3, 120.4, 100.4, 96.6, 55.5, 55.4, 45.2, 44.1, 35.9, 31.9, 23.5, 21.7, 21.2, 17.1; IR (neat) ν_max 2926, 2839, 1606, 1581, 1455, 1350, 1187, 1164, 671 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₄H₂₉NO₄SNa 450.1709; found 450.1705.

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-7-phenyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4c]

According to the general procedure, the reaction of 1,5-enyne (E)-3c (80.9 mg, 0.17 mmol) with InI₃ (4.2 mg, 0.008 mmol) afforded trans-4c (66.3 mg, 82%) as a white solid after purification by column chromatography (5% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J = 8.3 Hz, 2H), 7.36–7.28 (m, 3H), 7.21–7.11 (m, 4H), 7.13 (d, J = 2.5 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 5.67 (q, J = 3.4 Hz, 1H), 4.09 (dd, J = 12.7, 3.4 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.09–3.04 (m, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.79 (dq, J = 12.9, 3.1 Hz, 1H), 2.37 (s, 3H), 2.23–2.21 (m, 2H), 1.41–1.30 (m, 1H), 0.94 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.4, 158.2, 143.7, 141.6, 137.9, 137.5, 136.6, 129.6, 128.3, 127.9, 127.5, 127.3, 126.9, 120.3, 100.5, 96.5, 55.5, 45.7, 43.4, 36.2, 31.7, 23.9, 21.7, 17.3; IR (neat) ν_max 2935, 2837, 1604, 1579, 1418, 1349, 1201, 1163, 1152, 664 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₉H₃₁NO₄SNa 512.1866; found: 512.1860.

(6aS,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4d] (14c)

According to the general procedure, the reaction of 1,5-enyne (E)-3d (79.8 mg, 0.17 mmol) with InI₃ (4.1 mg, 0.008 mg) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-4d (58.3 mg, 73%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.60–7.57 (m, 2H), 7.24–7.21 (m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 2.5 Hz, 1H), 6.08 (dd, J = 4.8, 2.8 Hz, 1H), 4.65 (dd, J = 13.0, 3.5 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.24 (t, J = 12.8 Hz, 1H), 3.00 (dd, J = 13.3, 6.0 Hz, 1H), 2.41 (m, 1H), 2.38 (s, 3H), 2.14–2.05 (m, 2H), 1.20–1.12 (m, 1H), 0.93 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.2, 158.5, 143.9, 137.9, 136.3, 130.8, 129.8, 127.5, 121.0, 119.1, 100.8, 96.8, 55.5, 55.4, 47.2, 46.3, 38.2, 31.4, 25.9, 21.7, 17.3; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₃H₂₇BrNO₄S 492.0838; found 492.0839.

(6aR,10aS)-10a-Methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4e]

According to the general procedure, reactions of 1,5-enyne (E)-3e (85.5 mg, 0.24 mmol) with InI₃ (5.9 mg, 0.012 mmol) or 1,5-enyne (Z)-3e (89.0 mg, 0.25) with InI₃ (6.3 mg, 0.013 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), cis-4e [41.9 mg, 49% from (E)-3e and 56.1 mg, 63% from (Z)-3e] as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.75–7.72 (m, 1H), 7.51–7.48 (m, 2H), 7.26–7.13 (m, 5H), 5.75 (ddd, J = 9.4, 4.7, 2.4 Hz, 1H), 5.45 (ddt, J = 9.2, 4.9, 2.3 Hz, 1H), 4.16 (dd, J = 14.1, 3.4 Hz, 1H), 3.23 (ddd, J = 15.2, 10.8, 4.4 Hz, 1H), 2.37 (s, 3H), 1.99–1.93 (m, 2H), 1.81 (d, J = 11.3 Hz, 1H), 1.57 (dt, J = 9.4, 2.3 Hz, 2H), 0.91 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 143.7, 139.0, 137.4, 135.7, 129.7, 128.9, 127.6, 127.3, 126.4, 125.7, 125.5, 124.5, 48.4, 39.3, 34.7, 33.3, 25.7, 22.4, 21.6; IR (neat) ν_max 2925, 1486, 1447, 1347, 1163, 1090, 658 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₁H₂₃NO₂SNa: 376.1341; found: 376.1348.

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4a]

According to the general procedure, the reaction of 1,5-enyne (Z)-3a (95.3 mg, 0.23 mmol) with InI₃ (5.7 mg, 0.011 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), cis-4a (83.9 mg, 88%) as a white solid; mp 101–103 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 5.79–5.75 (m, 1H), 5.41–5.38 (m, 1H), 4.14 (dd, J = 14.0, 3.2 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.17 (dd, J = 14.0, 11.2 Hz, 1H), 2.37 (s, 3H), 2.15 (dt, J = 13.2, 4.2 Hz, 1H), 1.93–1.87 (m, 2H), 1.74 (d, J = 11.0 Hz, 1H), 1.42 (ddd, J = 13.1, 10.6, 5.4 Hz, 1H), 0.95 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.9, 158.0, 143.7, 137.9, 137.6, 129.7, 129.5, 127.3, 125.6, 120.2, 101.2, 97.8, 55.5, 55.3, 48.3, 41.5, 34.9, 28.0, 22.6, 22.3, 21.6; IR (neat) ν_max 2928, 2837, 1607, 1579, 1460, 1349, 1161, 672 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₇NO₄SNa 436.1553; found 436.1555.

(6aR,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4d]

According to the general procedure, the reaction of 1,5-enyne (Z)-3d (90.2 mg, 0.18 mmol) with InI₃ (4.6 mg, 0.009 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), cis-4d (64.9 mg, 72%) as a white solid; mp 144–146 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 2.6 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 6.12 (t, J = 4.0 Hz, 1H), 4.65 (dd, J = 14.3, 3.2 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.06 (dd, J = 14.3, 11.9 Hz, 1H), 2.37 (s, 3H), 2.30–2.24 (m, 1H), 1.99–1.95 (m, 2H), 1.79–1.75 (m, 1H), 1.25 (ddd, J = 13.6, 10.6, 6.7 Hz, 1H), 0.92 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.4, 158.3, 143.9, 137.8, 136.8, 131.1, 129.7, 127.7, 121.5, 120.1, 102.1, 98.3, 55.6, 55.3, 49.0, 47.4, 37.3, 26.1, 24.7, 21.7, 21.4; IR (neat) ν_max 2932, 1608, 1579, 1461, 1352, 1203, 1164, 672 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₃H₂₆BrNO₄SNa 514.0658; found: 514.0657.

(6aS,10aS)-1,3-Dimethoxy-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4f]

According to the general procedure, the reaction of 1,5-enyne (E)-3f (85.0 mg, 0.22 mmol) with InI₃ (5.5 mg, 0.011 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-4f (67.2 mg, 79%,) as a white solid; mp 101–103 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.55 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 5.66–5.63 (m, 1H), 5.52 (dq, J = 9.7, 2.0 Hz, 1H), 4.22 (dd, J = 12.8, 3.7 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.05 (dd, J = 12.8, 12.1 Hz, 1H), 2.82 (ddt, J = 13.0, 5.5, 2.5 Hz, 1H), 2.38 (s, 3H), 2.21 (td, J = 11.2, 11.2, 2.2 Hz, 1H), 2.19–1.99 (m, 2H), 2.02 (bt, J = 11.5 Hz, 1H), 1.03–0.96 (m, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.6, 158.5, 143.7, 139.1, 137.0, 129.7, 128.8, 127.7, 127.3, 114.8, 101.3, 96.6, 55.6, 55.4, 51.2, 39.2, 38.6, 27.2, 27.1, 21.7; IR (neat) ν_max 2929, 2836, 1607, 1579, 1455, 1346, 1185, 1162, 665 cm^–1; HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₂H₂₅NO₄SNa 422.1396; found 422.1397.

(4S,9S)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6a] (20)

According to the general procedure, the reaction of 1,5-enyne (E)-5a (20) (97.6 mg, 0.42 mmol) with InI₃ (10.5 mg, 0.021 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-6a (83.9 mg, 86%) as a white solid; ¹H NMR (400 MHz, CDCl₃) δ 6.76 (d, J = 8.8 Hz, 1H), 6.70 (dd, J = 8.9, 2.9 Hz, 1H), 6.63 (d, J = 2.9 Hz, 1H), 5.68–5.65 (m, 1H), 5.49 (ddt, J = 9.7, 2.9, 1.6 Hz, 1H), 3.76 (s, 3H), 2.69 (dd, J = 13.9, 3.4 Hz, 1H), 2.67–2.47 (m, 2H), 2.34–2.29 (m, 1H), 2.26–2.22 (m, 1H), 1.98–1.93 (m, 1H), 1.86 (td, J = 11.9, 6.9 Hz, 1H), 1.10 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.1, 148.0, 128.5, 127.0, 123.1, 118.1, 114.5, 113.7, 75.5, 55.8, 39.1, 35.4, 28.5, 25.2, 16.0; HRMS (EI) m/z: [M]⁺ calcd for C₁₅H₁₈O₂ [M]⁺: 230.1301; found: 230.1294.

(4S,9R)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6b] (14c)

According to the general procedure, the reaction of 1,5-enyne (E)-5b (14c) (105.4 mg, 0.31 mmol) with InI₃ (7.7 mg, 0.016 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-6b (93.8 mg, 89%) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 6.78–6.67 (m, 3H), 6.11–6.08 (m, 1H), 3.76 (s, 3H), 3.05 (dd, J = 16.1, 5.2 Hz, 1H), 2.86–2.82 (m, 1H), 2.57 (ddt, J = 16.1, 13.4, 1.0 Hz, 1H), 2.29–2.24 (m, 2H), 1.99–1.89 (m, 2H), 1.15 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.4, 147.2, 129.2, 123.8, 122.6, 117.9, 114.3, 114.1, 76.1, 55.8, 45.1, 34.9, 29.0, 25.9, 16.5; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₅H₁₈BrO₂ 309.0484; found: 309.0481.

(4S,9R)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6a]

According to the general procedure, the reaction of 1,5-enyne (Z)-5a (82.7 mg, 0.35 mmol) with InI₃ (8.9 mg, 0.017 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), cis-6a (71.9 mg, 87%) as a white solid; mp 75–77 °C; ¹H NMR (300 MHz, CDCl₃) δ 6.69–6.67 (m, 2H), 6.58 (d, J = 2.6 Hz, 1H), 5.72–5.68 (m, 1H), 5.35 (dq, J = 9.9, 2.2 Hz, 1H), 3.74 (s, 3H), 3.08 (dd, J = 16.3, 6.1 Hz, 1H), 2.52 (dd, J = 16.3, 3.7 Hz, 1H), 2.43 (dt, J = 5.6, 2.8 Hz, 1H), 2.31 (ddq, J = 15.7, 9.5, 2.9 Hz, 1H), 2.06–1.95 (m, 2H), 1.70 (ddd, J = 13.4, 9.6, 6.6 Hz, 1H), 1.33 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 152.9, 148.1, 128.8, 128.5, 120.0, 117.2, 114.1, 113.5, 73.7, 55.8, 36.8, 33.8, 29.7, 26.0, 22.9; IR (neat) ν_max 2921, 2832, 1494, 1236, 1213, 1101, 1041 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₅H₁₈O₂ 230.1301; found 230.1293.

(4S,9S)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6b]

According to the general procedure, the reaction of 1,5-enyne (Z)-5b (76.0 mg, 0.25 mmol) with InI₃ (6.1 mg, 0.012 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), cis-6b (69.9 mg, 92%) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 6.70–6.69 (m, 2H), 6.61 (d, J = 2.6 Hz, 1H), 6.05 (td, J = 4.1, 1.6 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J = 16.6, 6.0 Hz, 1H), 2.94 (dd, J = 16.6, 6.0 Hz, 1H), 2.62 (m, 1H), 2.36–2.30 (m, 1H), 2.11–2.02 (m, 1H), 1.94 (dt, J = 12.4, 6.1 Hz, 1H), 1.74–1.65 (m, 1H), 1.42 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 153.3, 147.6, 129.9, 124.4, 120.2, 117.1, 113.8, 113.7, 75.9, 55.9, 45.5, 31.6, 29.1, 26.4, 25.0; HRMS (EI) m/z: [M]⁺ calcd for C₁₅H₁₇BrO₂ 308.0406; found: 308.0395.

5′,7′-Dimethoxyspiro[cyclohexane-1,4′-isochroman]-3-ene (8a) (14c)

According to the general procedure, the reaction of 1,5-enyne 7a (98.3 mg, 0.38 mmol) with InI₃ (9.5 mg, 0.019 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), 8a (82.6 mg, 84%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 6.35 (d, J = 2.5 Hz, 1H), 6.12 (d, J = 2.5 Hz, 1H), 5.70 (d, J = 2.6 Hz, 2H), 4.69 (d, J = 0.8 Hz, 2H), 3.92 (d, J = 11.4 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.59 (dd, J = 11.4, 1.3 Hz, 1H), 2.88–2.68 (m, 2H), 2.08–2.01 (m, 3H), 1.46–1.42 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.8, 158.6, 137.5, 126.4, 125.5, 122.5, 99.9, 98.1, 73.9, 70.0, 55.3, 55.1, 34.5, 31.6, 27.5, 22.1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₆H₂₁O₃ 261.1485; found: 261.1479.

5′,7′-Dimethoxy-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8b) (14c)

According to the general procedure, the reaction of 1,5-enyne 7b (88.5 mg, 0.21 mmol) with InI₃ (5.3 mg, 0.011 mmol) afforded, after purification by column chromatography (10% EtOAc/hexanes), 8b (81.4, 92%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 2.5 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 5.76–5.65 (m, 2H), 4.16 (d, J = 14.5 Hz, 1H), 4.00 (d, J = 14.5 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.16 (d, J = 11.7 Hz, 1H), 3.00–2.93 (m, 2H), 2.69 (td, J = 13.1, 12.4, 6.8 Hz, 1H), 2.44 (s, 3H), 2.12 (m, 2H), 1.90 (d, J = 18.2 Hz, 1H), 1.45 (dd, J = 13.5, 5.5 Hz, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.8, 158.7, 143.7, 134.4, 133.0, 129.8, 128.0, 126.0, 125.5, 122.9, 102.1, 98.5, 55.4, 55.2, 52.5, 50.1, 37.0, 31.9, 27.8, 22.0, 21.7; HRMS (EI) m/z: [M]⁺ calcd for C₂₃H₂₇NO₄S 413.1655; found 413.1643.

3-Bromo-5′,7′-dimethoxy-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8c) (14c)

According to the general procedure, the reaction of 1,5-enyne 7c (95.0 mg, 0.19 mmol) with InI₃ (4.8 mg, 0.010 mmol) afforded, after purification by column chromatography (10% EtOAc/hexanes), 8c (72.2 mg, 76%) as a colorless oil; ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 6.35 (d, J = 2.5 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 6.08 (m, 1H), 4.10 (q, J = 14.6 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.51–3.44 (m, 1H), 3.19 (d, J = 12.0 Hz, 1H), 2.95 (d, J = 11.9 Hz, 1H), 2.55 (td, J = 12.3, 6.5 Hz, 1H), 2.44 (s, 3H), 2.26–2.09 (m, 3H), 1.64–1.53 (m, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 159.4, 159.0, 143.8, 134.4, 132.9, 129.8, 127.8, 127.0, 121.0, 120.8, 102.2, 98.4, 55.3, 55.2, 52.2, 49.8, 41.3, 39.6, 26.3, 24.0, 21.6; HRMS (EI) m/z: [M]⁺ calcd for C₂₃H₂₆BrNO₄S: 491.0760; found 491.0770.

General Procedure for the One-Pot Sequential Indium-Catalyzed Cycloisomerization and Palladium-Catalyzed Cross-Coupling Reactions of (E)-5b and 7c

In a Schlenk tube filled with argon, InI₃ (5 mol %) was placed and a solution of 1,5-enyne (E)-5b or 7c (∼0.07 M) in toluene was stirred at room temperature (for 5b) or 60°C in an oil bath (for 7c) until the starting material was consumed (TLC). Then, Pd(PPh₃)₄ (5 mol %) and a solution of R₃In (70 mol %, 0.45 M in dry THF) were added and the mixture was stirred at 80 °C in an oil bath for 10 h. The reaction was quenched by the addition of a few drops of MeOH and the mixture was concentrated in vacuo. H₂O (10 mL) was added and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (15 mL), dried with anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford, after concentration and high vacuo drying, the corresponding products trans-6c–e and 8d.

(4S,9S)-7-Methoxy-4-methyl-1-phenyl-4,9-tetrahydro-3H-xanthene [trans-6c] (20)

According to the general procedure, the reaction of 1,5-enyne (E)-5b (14c) (96.0 mg, 0.31 mmol) with InI₃ (7.1 mg, 0.016 mmol), triphenylindium (0.217 mmol), and Pd(PPh₃)₄ (17.5 mg, 0.016 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-6c (72.2 mg, 76% in two steps) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 7.36–7.28 (m, 3H), 7.26–7.20 (m, 2H), 6.78 (d, J = 8.9 Hz, 1H), 6.69 (dd, J = 8.9, 2.9 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 5.73 (dt, J = 5.1, 2.7 Hz, 1H), 3.70 (s, 3H), 3.08–3.03 (m, 1H), 2.70 (dd, J = 16.7, 5.2 Hz, 1H), 2.45–2.35 (m, 2H), 2.27–2.16 (m, 1H), 2.03–1.99 (m, 2H), 1.19 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.1, 147.5, 141.4, 140.0, 128.2, 127.5, 126.9, 126.1, 123.3, 118.0, 114.2, 114.0, 76.0, 55.8, 40.6, 35.3, 27.3, 24.7, 16.6; HRMS (EI) m/z: [M]⁺ calcd for C₂₁H₂₂O₂ 306.1614; found: 306.1587.

(4S,9S)-7-Methoxy-1,4-dimethyl-4,9-tetrahydro-3H-xanthene [trans-6d] (20)

According to the general procedure, the reaction of 1,5-enyne (E)-5b (96.3 mg, 0.31 mmol) with InI₃ (7.1 mg, 0.016 mmol), trimethylindium (0.217 mmol), and Pd(PPh₃)₄ (17.5 mg, 0.016 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-6d (62.9 mg, 83% in two steps) as a white solid; ¹H NMR (300 MHz, CDCl₃) δ 6.77–6.65 (m, 3H), 5.39 (m, 1H), 3.76 (s, 3H), 2.87–2.79 (m, 1H), 2.53–2.50 (m, 2H), 2.21–2.18 (m, 2H), 1.92–1.82 (m, 2H), 1.72 (s, 3H), 1.09 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.1, 147.7, 133.7, 123.1, 121.7, 117.9, 114.5, 113.7, 75.9, 55.8, 42.1, 35.6, 26.4, 24.2, 20.1, 16.5; HRMS (EI) m/z: [M]⁺ calcd for C₁₆H₂₀O₂ 244.1458; found 244.1439.

(4S,9S)-1-Butyl-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6e]

According to the general procedure, the reaction of 1,5-enyne (E)-5b (14c) (95.7 mg, 0.31 mmol) with InI₃ (7.1 mg, 0.016 mmol), tributylindium (0.217 mmol), and Pd(PPh₃)₄ (17.5 mg, 0.016 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), trans-6e (71.9 mg, 81% two steps) as a white solid; mp 48–50 °C; ¹H NMR (300 MHz, CDCl₃) δ 6.78–6.72 (m, 2H), 6.66 (d, J = 2.7 Hz, 1H), 5.39 (m, 1H), 3.76 (s, 3H), 2.85 (d, J = 11.0 Hz, 1H), 2.54–2.50 (m, 2H), 2.21 (m, 2H), 2.06–1.81 (m, 4H), 1.41–1.26 (m, 4H), 1.09 (s, 3H), 0.92 (t, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 153.0, 147.7, 137.7, 123.1, 120.8, 117.9, 114.4, 113.8, 76.1, 55.8, 40.7, 35.6, 33.5, 30.7, 26.2, 24.2, 22.6, 16.6, 14.2; IR (neat) ν_max 2929, 2856, 1493, 1224, 1148, 1081, 1041 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₁₉H₂₆O₂ 286.1927; found: 286.1923.

5′,7′-Dimethoxy-3-phenyl-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8d)

According to the general procedure, the reaction of 1,5-enyne 7c (95.2 mg, 0.19 mmol) with InI₃ (4.9 mg, 0.010 mmol), triphenylindium (0.13 mmol), and Pd(PPh₃)₄ (11.0 mg, 0.010 mmol) afforded, after purification by column chromatography (5% EtOAc/hexanes), 8d (56.7 mg, 61% in two steps) as a white solid; mp 125–127 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.70–7.67 (m, 2H), 7.41–7.39 (m, 2H), 7.32–7.21 (m, 5H), 6.35 (d, J = 2.5 Hz, 1H), 6.18 (d, J = 2.5 Hz, 1H), 6.13 (q, J = 3.4, 2.4 Hz, 1H), 4.21–4.08 (m, 2H), 3.76 (s, 6H), 3.37 (dd, J = 17.2, 3.3 Hz, 1H), 3.12 (q, J = 11.9 Hz, 2H), 2.73–2.67 (m, 1H), 2.39 (s, 3H), 2.30 (d, J = 17.3 Hz, 3H), 1.26 (m, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.8, 158.9, 143.7, 142.6, 135.7, 134.6, 133.2, 129.8, 128.3, 127.9, 126.8, 125.5, 123.0, 122.6, 102.2, 98.6, 55.4, 55.3, 52.5, 50.0, 37.7, 34.0, 27.2, 22.8, 21.7; IR (neat) ν_max 2932, 2841, 1608, 1460, 1340, 1164, 1055, 831 cm^–1; HRMS (EI) m/z: [M]⁺ calcd for C₂₉H₃₁NO₄S 489.1968; found 489.1976.

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Corresponding Authors
- Enrique Gómez-Bengoa - Departamento de Química Orgánica I, Universidad del País Vasco UPV/EHU, 20009 Donostia-San, Sebastián; https://orcid.org/0000-0002-8753-3760; Email: [email protected]
- José Pérez Sestelo - Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain; https://orcid.org/0000-0001-7036-6217; Email: [email protected]
Authors
- Ramón E. Millán - Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain
- Jaime Rodríguez - Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain; https://orcid.org/0000-0001-5348-6970
- Luis A. Sarandeses - Centro de Investigacións Científicas Avanzadas (CICA) and Departamento de Química, Universidade da Coruña, E-15071 A Coruña, Spain; https://orcid.org/0000-0003-1114-7107
Notes
The authors declare no competing financial interest.

Acknowledgments

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Dedicated to the memory of Prof. Kilian Muñiz. We thank the Spanish Ministerio de Ciencia, Innovación y Universidades (PGC2018-097792-B-I00 and PID 2019-110008GB-I00), Xunta de Galicia (GRC2018/039), IZO-SGI SGIker of UPV/EHU, and EDRF funds for financial and human support.

References

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This article references 28 other publications.

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Fuerstner, Alois
Accounts of Chemical Research (2014), 47 (3), 925-938CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. During the last century, conceptual advances in organometallic chem. were often rapidly embraced by target oriented synthesis. Feedback provided by such preparative scrutiny has greatly benefitted method development; particularly prominent are examples from the entire cross coupling arena, as well as olefin metathesis. Seen against this backdrop, it is somewhat surprising that the explosive growth of research into π-acid catalysis has not yet yielded a matching no. of implementations into the synthesis of structurally complex targets of biol. significance. In contrast to the massive output of methodol. and mechanistic investigations, few studies illustrate the strategic use of gold, silver, or platinum catalysis in late stages of such multistep endeavors. These elaborate and highly precious compds. demand utmost confidence in the reliability and robustness of the method to be applied. In this Account, we analyze the possible reasons for this imbalance, after a short summary of the conceptual basis of carbophilic activation of π-bonds with the aid of soft transition metal cations or complexes. We pinpoint mechanistic subtleties, which, at least in part, produce a great deal of structural diversity but can jeopardize predictive power. With the advances in the understanding of π-acid catalyzed processes in general, however, this uncertainty is gradually vanishing and the entire field is transitioning from comprehension to prediction. This is expected to foster advanced applications, while recent progress in asym. gold catalysis further improves the preparative significance. The presented work in this Account illustrates our own commitment to the field as well as our growing confidence in the maturity of platinum and gold catalysis. The carbophilic activation of π-bonds, particularly of alkynes, provides a method to manipulate functional groups that is orthogonal to traditional carbonyl chem. We illustrate this notion by presenting a new approach to hydroxypyrone derivs. that has enabled the total synthesis of the fragile polyunsatd. cyclophane deriv. neurymenolide A. The synthesis of the pyrrole alkaloid streptorubin by an enyne cycloisomerization is equally instructive. In addn., different manifestations of transannular hydroxyl addn. reactions across alkyne partners mark the late stages of our conquests of amphidinolide F, polycavernoside A, and spirastrellolide F. Together with a few model studies and a personal selection of recent highlights from other groups, these examples augur well for future applications of π-acid catalysts in the realm of target oriented synthesis.
(e) Geier, M. J.; Gagné, M. R. Diastereoselective Pt Catalyzed Cycloisomerization of Polyenes to Polycycles. J. Am. Chem. Soc. 2014, 136, 3032– 3035, DOI: 10.1021/ja500656k
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Diastereoselective Pt Catalyzed Cycloisomerization of Polyenes to Polycycles
Geier, Michael J.; Gagne, Michel R.
Journal of the American Chemical Society (2014), 136 (8), 3032-3035CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Application of a tridentate NHC contg. pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates, e.g. I, to the their polycyclic counterparts, e.g. II.
(f) Toullec, P. Y.; Michelet, V. Chiral Cationic Platinum Complexes: New Catalysts for the Activation of Carbon-Carbon Multiple Bonds Towards Nucleophilic Enantioselective Attack. Curr. Org. Chem. 2010, 14, 1245– 1253, DOI: 10.2174/138527210791330431
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Chiral cationic platinum complexes. New catalysts for the activation of carbon-carbon multiple bonds towards nucleophilic enantioselective attack
Toullec, Patrick Y.; Michelet, Veronique
Current Organic Chemistry (2010), 14 (12), 1245-1253CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
A review. The concept of π-acid catalysis has emerged as a powerful principle for the chemists to create diversity and originality from simple mols. Carbophilic late transition metals such as gold or platinum have appeared as fascinating catalysts able to activate alkenes, alkynes and other unsatd. derivs. towards anti nucleophilic addn. via complexation on a single empty coordination site. Tunable chiral square-planar cationic platinum complexes created by combination of a mono- and a bidentate ligand appear as a new class of highly promising asym. catalytic systems. This highlight intends to stress the potential applications in enantioselective catalytic reactions assocd. with a variety of chiral cationic tricoordinated platinum complexes recently described in the literature.
(g) Mascareñas, J. L.; Varela, I.; López, F. Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions. Acc. Chem. Res. 2019, 52, 465– 479, DOI: 10.1021/acs.accounts.8b00567
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5g
Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions
Mascarenas, Jose L.; Varela, Ivan; Lopez, Fernando
Accounts of Chemical Research (2019), 52 (2), 465-479CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. Cycloaddn. reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Esp. appealing are formal cycloaddns. promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chem. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via std. oxidative addn. or reductive elimination processes. Curiously, metals of the third row like platinum and, esp., gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addn. or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddn. reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing no. of reports that exploit the peculiar reactivities of allenes and derivs. In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloaddns. of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddn. processes. Esp. relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties assocd. with the transfer of stereochem. information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered. This Account is organized considering the no. of atoms engaged in the annulation process, and when possible, we present the results in a chronol. order.
6
For some leading references, see:
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6a
Gold-Catalyzed Assembly of Heterobicyclic Systems
Zhang, Liming; Kozmin, Sergey A.
Journal of the American Chemical Society (2005), 127 (19), 6962-6963CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An efficient gold-catalyzed double cyclization of 1,5-enynes gave a range of heterobicyclic compds., including oxabicyclo[3.2.1]octenes, azabicyclo[3.2.1]octenes, oxaspiro[5.4]decene, azaspiro[5.4]decene, oxaspiro[5.5]undecene, oxabicyclo[4.3.0]nonene, azabicyclo[4.3.0]nonene, and oxabicyclo[4.4.0]decene. The mechanism of this reaction is proposed to involve a chemoselective gold-based alkyne activation, carbocyclization, intramol. nucleophilic addn., followed by protodemetalation. The most notable aspect of this process is the efficient and diastereospecific interception of the reactive intermediate of the initial 6-endo-dig (or 5-endo-dig) cyclization with either oxygen- or nitrogen-based nucleophiles.
(b) Lim, C.; Kang, J.-E.; Lee, J.-E.; Shin, S. Gold-Catalyzed Tandem C–C and C–O Bond Formation: A Highly Diastereoselective Formation of Cyclohex-4-ene-1,2-diol Derivatives. Org. Lett. 2007, 9, 3539– 3542, DOI: 10.1021/ol071402f
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6b
Gold-catalyzed tandem C-C and C-O bond formation: a highly diastereoselective formation of cyclohex-4-ene-1,2-diol derivatives
Lim, Choongmin; Kang, Ji-Eun; Lee, Ji-Eun; Shin, Seunghoon
Organic Letters (2007), 9 (18), 3539-3542CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
An efficient gold(I)-catalyzed tandem cyclization of tert-Bu carbonate derivs. of hex-1-en-5-yn-3-ol where nucleophilic participation of the O-Boc group appears to intercept a carbocationic (or cyclopropyl carbene) Au intermediate was reported. This protocol led to densely functionalized cyclohexene-3,4-diol derivs. where 1,2- or 1,2,3-stereocenters are controlled in a highly diastereoselective fashion.
(c) Fürstner, A. Gold and Platinum Catalysis-a Convenient Tool for Generating Molecular Complexity. Chem. Soc. Rev. 2009, 38, 3208– 3221, DOI: 10.1039/b816696j
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6c
Gold and platinum catalysis-a convenient tool for generating molecular complexity
Fuerstner, Alois
Chemical Society Reviews (2009), 38 (11), 3208-3221CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
This review intends to familiarize the reader with the essence of π-acid catalysis, in particular with reactions or reaction cascades effected by gold and platinum complexes. Even though materialized in apparently different reactivity modes, such noble metal catalyzed processes can be easily rationalized on the basis of a uniform mechanistic scheme that is outlined in detail. The resulting increase in mol. complexity is illustrated by selected natural product total syntheses and the formation of various intricate non-natural compds. (106 refs.).
(d) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity. Chem. Rev. 2015, 115, 9028– 9072, DOI: 10.1021/cr500691k
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6d
Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity
Dorel, Ruth; Echavarren, Antonio M.
Chemical Reviews (Washington, DC, United States) (2015), 115 (17), 9028-9072CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. In this review, the authors cover reactions of alkynes activated by gold(I) complexes, including recent applications of these transformations in the synthesis of natural products. The main focus is on the application of gold(I)-catalyzed reactions of alkynes in org. synthesis, and the reactions are organized mechanistically. Reactions of gold(I)-activated alkenes and allenes, as well as gold(III)-activated alkynes, are not covered in this review.
(e) Li, Y.; Li, W.; Zhang, J. Gold-Catalyzed Enantioselective Annulations. Chem. – Eur. J. 2017, 23, 467– 512, DOI: 10.1002/chem.201602822
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6e
Gold-Catalyzed Enantioselective Annulations
Li, Yangyan; Li, Wenbo; Zhang, Junliang
Chemistry - A European Journal (2017), 23 (3), 467-512CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This review summarized the methods to construct chiral cyclic compds. by gold-catalyzed enantioselective annulations reported since 2005. The review was organized according to the general annulation types catalyzed by chiral gold complexes or chiral gold salts, which have four main types (cycloaddns., cyclizations of C-C multiple bonds with tethered nucleophiles, cycloisomerization or cyclization of enynes, and tandem annulations), as well as some other strategies. The general reaction mechanisms of each subcategory, key intermediates for some unusual transformations, and the application of several novel ligands and chiral goldsalts were also discussed.
(f) Marín-Luna, M.; Nieto Faza, O.; Silva López, C. Gold-Catalyzed Homogeneous (Cyclo)isomerization Reactions. Front. Chem. 2019, 7, 296, DOI: 10.3389/fchem.2019.00296
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Gold-catalyzed homogeneous (Cyclo)isomerization reactions
Marin-Luna, Marta; Faza, Olalla Nieto; Lopez, Carlos Silva
Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 296CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
A review summarizes the most recent contributions in which Au(I)- and/or Au(III)-catalysts mediate intramol. (cyclo)isomerization transformations of unsatd. species, which commonly feature allene or alkyne motifs, and organize them depending on the substrate and the reaction type. Au is currently one of the most used metals in organometallic catalysis. The ability of Au to activate unsatd. groups in different modes, together with its tolerance to a wide range of functional groups and reaction conditions, turns Au-based complexes into efficient and highly sought after catalysts. Natural products and relevant compds. with biol. and pharmaceutical activity are often characterized by complex mol. structures. (Cyclo)isomerization reactions are often a useful strategy for the generation of this mol. complexity from synthetically accessible reactants.
(g) Virumbrales, C.; Suárez-Pantiga, S.; Marín-Luna, M.; Silva López, C.; Sanz, R. Unlocking the 5-exo Pathway with the Au^I-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes. Chem. – Eur. J. 2020, 26, 8443– 8451, DOI: 10.1002/chem.202001296
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6g
Unlocking the 5-exo Pathway with the AuI-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes
Virumbrales, Cintia; Suarez-Pantiga, Samuel; Marin-Luna, Marta; Silva Lopez, Carlos; Sanz, Roberto
Chemistry - A European Journal (2020), 26 (38), 8443-8451CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes was described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne played a crucial role on the regiochem. outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes was synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addn., mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity obsd. between both E/Z geometrical isomers as well as for the stereochem. outcome of the reaction.
(h) Mies, T.; White, A. J. P.; Parsons, P. J.; Barrett, A. G. M. Biomimetic Syntheses of Analogs of Hongoquercin A and B by Late-Stage Derivatization. J. Org. Chem. 2021, 86, 1802– 1817, DOI: 10.1021/acs.joc.0c02638
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6h
Biomimetic syntheses of analogs of Hongoquercin A and B by late-stage derivatization
Mies, Thomas; White, Andrew J. P.; Parsons, Philip J.; Barrett, Anthony G. M.
Journal of Organic Chemistry (2021), 86 (2), 1802-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The Hongoquercins are tetracyclic meroterpenoid natural products with the trans-transoid decalin-dihydrobenzopyran ring system, which display a range of different bioactivities. In this study, the syntheses of a range of Hongoquercins using gold-catalyzed enyne cyclization reactions and further derivatization are described. The parent enyne resorcylate precursors were synthesized biomimetically from the corresponding dioxanone keto ester via regioselective acylation, Tsuji-Trost allylic decarboxylative rearrangement, and aromatization. The dioxanone keto ester 12 was prepd. in 6 steps from geraniol using allylic functionalization and alkyne synthesis.
7
(a) Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. Skeletal Reorganization of Enynes to 1-Vinylcycloalkenes Catalyzed by GaCl₃. J. Am. Chem. Soc. 2002, 124, 10294– 10295, DOI: 10.1021/ja0274554
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7a
Skeletal Reorganization of Enynes to 1-Vinylcycloalkenes Catalyzed by GaCl3
Chatani, Naoto; Inoue, Hiroki; Kotsuma, Taiichi; Murai, Shinji
Journal of the American Chemical Society (2002), 124 (35), 10294-10295CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The GaCl3-catalyzed transformation of enynes, e.g. I, into 1-vinylcycloalkenes, e.g. II, is the first example of the skeletal reorganization of enynes catalyzed by typical metal complexes. The process is simple and provides a diverse range of vinylcycloalkenes in good to high yields (66-87%). The reaction of enynes with a monosubstituent at the terminal olefinic carbon proceeds in a stereospecific manner with respect to the geometry of the olefin moiety. This skeletal rearrangement proceeds efficiently even with enynes, bearing two substituents at the olefinic terminal carbon, which were previously known as unsuitable substrates for similar transformations.
(b) Tang, S.; Monot, J.; El-Hellani, A.; Michelet, B.; Guillot, R.; Bour, C.; Gandon, V. Cationic Gallium(III) Halide Complexes: a New Generation of π-Lewis Acids. Chem. – Eur. J. 2012, 18, 10239– 10243, DOI: 10.1002/chem.201201202
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7b
Cationic Gallium(III) Halide Complexes: a New Generation of π-Lewis Acids
Tang, Shun; Monot, Julien; El-Hellani, Ahmad; Michelet, Bastien; Guillot, Regis; Bour, Christophe; Gandon, Vincent
Chemistry - A European Journal (2012), 18 (33), 10239-10243, S10239/1-S10239/17CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The combination of (NHC)GaX3 complexes and AgSbF6 advantageously replaces hygroscopic GaX3 salts. While the peculiar selectivity of the salts is maintained, the air-stable NHC adducts allow better yields at lower temps. and faster reaction times. Catalytic amts. as low as 1 mol % can be used, which is not possible with simple gallium(III) halides. Besides, a "silver-free" protocol based on the use of well-defined cationic gallium halides has been developed. The advantages of having one metal instead of two in the reaction mixt. have been clearly recognized in the field of gold catalysis. This paves the way for further developments in Ga(III) catalysis in general, and in (asym.) π-acid catalysis in particular. The synthesis of air- and moisture-stable, and yet active, cationic gallium species is also a goal actively pursued in authors lab.
(c) Strom, K. R.; Impastato, A. C.; Moy, K. J.; Landreth, A. J.; Snyder, J. K. Gallium(III)-Promoted Halocyclizations of 1,6-Diynes. Org. Lett. 2015, 17, 2126– 2129, DOI: 10.1021/acs.orglett.5b00716
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7c
Gallium(III)-Promoted Halocyclizations of 1,6-Diynes
Strom, Kyle R.; Impastato, Anna C.; Moy, Kenneth J.; Landreth, Adrian J.; Snyder, John K.
Organic Letters (2015), 17 (9), 2126-2129CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Cyclization of 1,6-diynes promoted by stoichiometric Ga(III) halides produces vinyl halides I [ R1 = H, Me, Et, Ph, CH2SiMe3; R2 = H, 4-OMe, 4-Cl, etc.; A = O, NTs; X = Br, I, Cl] in good to excellent yields. Under acidic conditions, initially formed iodocyclization products undergo in situ Friedel-Crafts cyclizations, giving access to iodoindenopyridines II [R1 = H, Me, Et; R2 = H, 4-OMe, 4-Cl, etc.; A = O, NTs]. Application of the vinyl halides in cross-coupling reactions has been explored, and mechanistic aspects of the cyclization are discussed.
8
(a) Kita, Y.; Yata, T.; Nishimoto, Y.; Chiba, K.; Yasuda, M. Selective Oxymetalation of Terminal Alkynes Via 6-endo Cyclization: Mechanistic Investigation and Application to the Efficient Synthesis of 4-Substituted Isocoumarins. Chem. Sci. 2018, 9, 6041– 6052, DOI: 10.1039/C8SC01537F
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8a
Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins
Kita, Yuji; Yata, Tetsuji; Nishimoto, Yoshihiro; Chiba, Kouji; Yasuda, Makoto
Chemical Science (2018), 9 (28), 6041-6052CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
Herein, a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position was reported. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decompn. of terminal alkynes, resp. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallog. anal. The theor. calcn. of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodn. control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the at. characters of indium, boron and their ligands would contribute to such a regioselective switch. and metalated isocoumarins were applied to org. synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups and palladium-catalyzed cross coupling of organometallic species with org. halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.
(b) Kang, K.; Nishimoto, Y.; Yasuda, M. Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -Stannane Nucleophiles. J. Org. Chem. 2019, 84, 13345– 13363, DOI: 10.1021/acs.joc.9b01505
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8b
Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -stannane Nucleophiles
Kang, Kyoungmin; Nishimoto, Yoshihiro; Yasuda, Makoto
Journal of Organic Chemistry (2019), 84 (21), 13345-13363CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The authors achieved regio- and stereoselective carboindation of terminal and internal alkynyl ethers using InI3 and organosilicon or -stannane nucleophiles to synthesize (Z)-β-alkoxyalkenylindiums. The carbometalation regio- and stereoselectively proceeded in anti-addn. fashion, which was confirmed by x-ray diffraction anal. of (Z)-β-alkoxyalkenylindium products. Theor. calcn. on the carboindation of alkynyl ethers to elucidate the effect of an alkoxy group was conducted in parallel with calcns. on a C analog of the alkynyl ether. Reaction profiles and computational data of carboindation suggest that the alkoxy group enhances the interaction between InI3 and an alkyne moiety and reduces the activation energy. Many types of C nucleophiles such as silyl ketene acetals, silyl ketene imines, a silyl cyanide, an alkynyl stannane, and an allylic stannane were applicable to the present reaction system to give highly functionalized metalated enol ethers (β-alkoxyalkenylindiums). The prepd. β-alkoxyalkenylindiums were transformed to various functionalized tetrasubstituted enol ethers by iodination followed by Suzuki coupling. The synthesis of a seven-membered ring compd. contg. a phenol ether moiety was accomplished using a sequential process that included the present stereoselective carboindation.
(c) Tani, T.; Sohma, Y.; Tsuchimoto, T. Zinc/Indium Bimetallic Lewis Acid Relay Catalysis for Dehydrogenative Silylation/Hydrosilylation Reaction of Terminal Alkynes with Bis(hydrosilane)s. Adv. Synth. Catal. 2020, 362, 4098– 4108, DOI: 10.1002/adsc.202000501
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8c
Zinc/Indium Bimetallic Lewis Acid Relay Catalysis for Dehydrogenative Silylation/Hydrosilylation Reaction of Terminal Alkynes with Bis(hydrosilane)s
Tani, Tomohiro; Sohma, Yudai; Tsuchimoto, Teruhisa
Advanced Synthesis & Catalysis (2020), 362 (19), 4098-4108CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
When mixed with two different Lewis acid catalysts of Zn and In, terminal alkynes react with bis(hydrosilane)s to selectively provide 1,1-disilylalkenes from among several possible products, by way of a sequential dehydrogenative silylation/intramol. hydrosilylation reaction. Adding a pyridine base is crucial in this reaction; a switch as a catalyst of the Zn Lewis acid is turned on by forming a Zn-pyridine-base complex. A range of the 1,1-disilylalkenes can be obtained by a combination of aryl and aliph. terminal alkynes plus aryl-, heteroaryl-, and naphthyl-tethered bis(hydrosilane)s. The 1,1-disilylalkene prepd. here is available as a reagent for further transformations by using its C-Si or C:C bond. The former includes Hiyama cross-coupling, Bi-catalyzed ether formation, and iododesilylation; the latter includes double alkylation and epoxidn. Mechanistic studies clarified the role of the two Lewis acids: the Zn-pyridine-base complex catalyzes the dehydrogenative silylation as a 1st stage, and, following on this, the In Lewis acid catalyzes the ring-closing hydrosilylation as a 2nd stage, thus leading to the 1,1-disilylalkene.
(d) Vayer, M.; Bour, C.; Gandon, V. Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds Under π-Acid Catalysis. Eur. J. Org. Chem. 2020, 2020, 5350– 5357, DOI: 10.1002/ejoc.202000623
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8d
Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds Under π-Acid Catalysis
Vayer, Marie; Bour, Christophe; Gandon, Vincent
European Journal of Organic Chemistry (2020), 2020 (33), 5350-5357CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
The reactivity of 7-alkynycycloheptatrienes tethered to an aryl group under π-acid catalysis has been studied. A variety of useful cyclic products were synthesized via Au(I)-catalyzed skeletal reorganization, Cu(II)-catalyzed hydroarylation, or Broensted acid-catalyzed tandem hydroarylation/Friedel-Crafts reaction. We also report a rare type of skeletal reorganization involving the 1,3-acetonide tether in the presence of a univalent cationic Ga(I)+ complex.
(e) Tian, J.; Chen, Y.; Vayer, M.; Djurovic, A.; Guillot, R.; Guermazi, R.; Dagorne, S.; Bour, C.; Gandon, V. Exploring the Limits of π-Acid Catalysis Using Strongly Electrophilic Main Group Metal Complexes: the Case of Zinc and Aluminium. Chem. – Eur. J. 2020, 26, 12831– 12838, DOI: 10.1002/chem.202001376
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8e
Exploring the Limits of π-Acid Catalysis Using Strongly Electrophilic Main Group Metal Complexes: The Case of Zinc and Aluminum
Tian, Jiaxin; Chen, Yan; Vayer, Marie; Djurovic, Alexandre; Guillot, Regis; Guermazi, Refka; Dagorne, Samuel; Bour, Christophe; Gandon, Vincent
Chemistry - A European Journal (2020), 26 (56), 12831-12838CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The catalytic activity of cationic NHC-Zn(II) and NHC-Al(III) (NHC=N-heterocyclic carbene) complexes in reactions that require the electrophilic activation of soft C-C π bonds has been studied. The former proved able to act as a soft π-Lewis acid in a variety of transformations. The benefit of the bulky IPr NHC ligand was demonstrated by comparison with simple ZnX2 salts. The tested NHC-Al(III) catalyst is not able to activate C-C π bonds but simple AlX2+ ions were found potent in some cases.
9
For some revisions see:
(a) Augé, J.; Lubin-Germain, N.; Uziel, J. Recent Advances in Indium-Promoted Organic Reactions. Synthesis 2007, 2007, 1739– 1764, DOI: 10.1055/s-2007-983703
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(b) Pathipati, S. R.; van der Werf, A.; Selander, N. Indium(III)-Catalyzed Transformations of Alkynes: Recent Advances in Carbo- and Heterocyclization Reactions. Synthesis 2017, 49, 4931– 4941, DOI: 10.1055/s-0036-1588555
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Indium(III)-Catalyzed Transformations of Alkynes: Recent Advances in Carbo- and Heterocyclization Reactions
Pathipati, Stalin R.; van der Werf, Angela; Selander, Nicklas
Synthesis (2017), 49 (22), 4931-4941CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
A review. The use of a well-chosen catalyst is instrumental for the development of more efficient, economical and environmentally friendly reactions. In recent decades, indium-based catalysts have proven to be competitive and useful alternatives to transition-metal catalysts such as silver and gold. In this short review, we present some of the recent advances in indium(III)-catalyzed transformations of alkynes, with a focus on cyclization reactions: (1 )introduction, (2) terminal alkynes as nucleophiles, (3) nucleophilic addns. to alkynes, (4) carbo- and heterocyclization reactions, (4.1) carbocyclization, (4.2) oxygen-based heterocycles, (4.3) nitrogen-based heterocycles, (4.4) sulfur-based heterocycles, (5) conclusion.
(c) Sestelo, J. P.; Sarandeses, L. A.; Martínez, M. M.; Alonso-Marañón, L. Indium(III) as π-Acid Catalyst for the Electrophilic Activation of Carbon–Carbon Unsaturated Systems. Org. Biomol. Chem. 2018, 16, 5733– 5747, DOI: 10.1039/C8OB01426D
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Araki, S.; Hirashita, T. Comprehensive Organometallic Chemistry III; Crabtree, R. H.; Mingos, D. M. P., Eds.; Elsevier: Oxford, 2007; Vol. 9, pp 649– 722.
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(a) Cintas, P. Synthetic Organoindium Chemistry: What Makes Indium So Appealing?. Synlett 1995, 1995, 1087– 1096, DOI: 10.1055/s-1995-5192
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(b) Frost, C. G.; Hartley, J. P. New Applications of Indium Catalysts in Organic Synthesis. Mini-Rev. Org. Chem. 2004, 1, 1– 7, DOI: 10.2174/1570193043489006
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11b
New applications of indium catalysts in organic synthesis
Frost, C. G.; Hartley, J. P.
Mini-Reviews in Organic Chemistry (2004), 1 (1), 1-7CODEN: MOCIBT; ISSN:1570-193X. (Bentham Science Publishers Ltd.)
A review. Indium(III) salts as Lewis acid catalysts in org. syntheses are discussed. The stability of the salts as coordination active centers in substoichiometric quantities is discussed in terms of various reaction mechanisms. The stability of the In salts in water allows aq. recycling and often the use of water as a reaction solvent. Reactions described include arom. functionalization, cycloaddn. reactions, conjugate addns. and multi-component coupling reactions.
(c) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Indium Salt-Promoted Organic Reactions. Curr. Org. Chem. 2003, 7, 1661– 1689, DOI: 10.2174/1385272033486251
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11c
Indium salt-promoted organic reactions
Fringuelli, Francesco; Piermatti, Oriana; Pizzo, Ferdinando; Vaccaro, Luigi
Current Organic Chemistry (2003), 7 (16), 1661-1689CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
A review. The use of indium salts as catalysts and mediators in nucleophilic addn. reactions (with or without ring opening), cyclization (Diels-Alder, Biginelli, Prins, etc.), arom. electrophilic substitution, nucleophilic substitution, coupling, redn., rearrangement and polymn. reactions, reported in the period from 2000 and the first half of 2002, is reviewed. InCl3, InBr3, InI3, InCl, InBr, InI, In(OTf)3 (Tf = F3CSO2), and In(NTf)3 are the most commonly used indium salts used. The use of indium salts, generally, allows the reaction to be carried out under mild conditions, in high yields and with high selectivity. Sometimes, an aq. medium can be used and the catalyst can be reused.
(d) Yadav, J. S.; Antony, A.; George, J.; Subba Reddy, B. V. Recent Developments in Indium Metal and Its Salts in Organic Synthesis. Eur. J. Org. Chem. 2010, 2010, 591– 605, DOI: 10.1002/ejoc.200900895
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(f) Singh, M. S.; Raghuvanshi, K. Recent Advances in InCl₃-Catalyzed One-Pot Organic Synthesis. Tetrahedron 2012, 68, 8683– 8697, DOI: 10.1016/j.tet.2012.06.099
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11f
Recent advances in InCl3-catalyzed one-pot organic synthesis
Singh, Maya Shankar; Raghuvanshi, Keshav
Tetrahedron (2012), 68 (42), 8683-8697CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
A review was given on recent progress in a large variety of InCl3-catalyzed/mediated reactions performed in solvent and/or under solvent-free conditions. The review is organized starting with the introduction of org. synthesis via multicomponent reactions, followed by advantages of InCl3 as catalyst, and an overview of the org. reactions that were traditionally conducted under InCl3 catalysis.
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For representative examples, see:
(a) Mamane, V.; Hannen, P.; Fürstner, A. Synthesis of Phenanthrenes and Polycyclic Heteroarenes by Transition-Metal Catalyzed Cycloisomerization Reactions. Chem. – Eur. J. 2004, 10, 4556– 4575, DOI: 10.1002/chem.200400220
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12a
Synthesis of phenanthrenes and polycyclic heteroarenes by transition-metal catalyzed cycloisomerization reactions
Mamane, Victor; Hannen, Peter; Fuerstner, Alois
Chemistry - A European Journal (2004), 10 (18), 4556-4575CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Readily available biphenyl derivs. contg. an alkyne unit at one of their ortho-positions were converted into substituted phenanthrenes, e.g., I, on exposure to catalytic amts. of either PtCl2, AuCl, AuCl3, GaCl3 or InCl3 in toluene. This 6-endo-dig cyclization likely proceeded through initial π-complexation of the alkyne unit followed by interception of the resulting η2-metal species by the adjacent arene ring. The reaction was inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product. Moreover, it was readily extended to the heterocyclic series as exemplified by the prepn. of benzoindoles, benzocarbazoles, naphthothiophenes, as well as bridgehead nitrogen heterocycles such as pyrrolo[1,2-a]quinolines, e.g., II. Depending on the chosen catalyst, biaryls bearing halo-alkyne units can either be converted into the corresponding 10-halo-phenanthrenes or into the isomeric 9-halo-phenanthrenes; in the latter case, the concomitant 1,2-halide shift was best explained by assuming a metal vinylidene species as the reactive intermediate. The scope of this method for the prepn. of polycyclic arenes was illustrated by the total synthesis of a series of polyoxygenated phenanthrenes that were close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring sym. dimer.
(b) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Regio- and Stereoselective Generation of Alkenylindium Compounds From Indium Tribromide, Alkynes, and Ketene Silyl Acetals. Angew. Chem., Int. Ed. 2009, 48, 4577– 4580, DOI: 10.1002/anie.200901417
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12b
Regio- and Stereoselective Generation of Alkenylindium Compounds from Indium Tribromide, Alkynes, and Ketene Silyl Acetals
Nishimoto, Yoshihiro; Moritoh, Ryosuke; Yasuda, Makoto; Baba, Akio
Angewandte Chemie, International Edition (2009), 48 (25), 4577-4580, S4577/1-S4577/27CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
InBr3 promotes the addn. of ketene silyl acetals to monosubstituted alkynes to afford 2,2-disubstituted alkenylindium compds. in high regio- and stereoselectivity. In addn., the alkenylindium derivs. have been subsequently coupled with iodobenzene in the presence of a palladium catalyst. Thus, InBr3 mediated reaction of PhC≡CH with Me2C:C(OMe)(OSiMe3) in CH2Cl2 followed by washing with hexane/CD3CN gave a mixt. of Br2InCH:CPhCMe2CO2Me (6) and BrIn(CH:CPhCMe2CO2Me)2. The crystal structures of 6 and 7 and their hydrolysis to give Me 2,2-dimethyl-3-phenyl-3-butenoate is described.
(c) Antoniotti, S.; Dalla, V.; Duñach, E. Metal Triflimidates: Better Than Metal Triflates as Catalysts in Organic Synthesis-the Effect of a Highly Delocalized Counteranion. Angew. Chem., Int. Ed. 2010, 49, 7860– 7888, DOI: 10.1002/anie.200906407
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12c
Metal triflimidates. Better than metal triflates as catalysts in organic synthesis. The effect of a highly delocalized counteranion
Antoniotti, Sylvain; Dalla, Vincent; Dunach, Elisabet
Angewandte Chemie, International Edition (2010), 49 (43), 7860-7888CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The continuously increasing need for novel and selective methods in org. synthesis to aid drug discovery and to address environmental concerns is a const. source of stimulation to develop novel and more efficient reaction systems. This often resulted in a focus on transition metals, ligands, and additives, with much less attention paid to the counterion(s) of the metal cation. Recently, metal salts with one or more triflimidate counterion(s) appeared as a unique class of catalysts that display outstanding σ- and π-Lewis acid character. The highly delocalized nature of the triflimidate counterion, combined with its high steric hindrance results in virtually no nucleophilic behavior and an extremely high pos. charge d. on the metal cation, thus enhancing its Lewis acid character. Consequently, these metal triflimidates often outperform their metal halide or triflate analogs. This review described general methods for the prepn. of metal triflimidate salts and their use as catalysts.
(d) Tsuchimoto, T.; Kanbara, M. Reductive Alkylation of Indoles with Alkynes and Hydrosilanes Under Indium Catalysis. Org. Lett. 2011, 13, 912– 915, DOI: 10.1021/ol1029673
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12d
Reductive Alkylation of Indoles with Alkynes and Hydrosilanes under Indium Catalysis
Tsuchimoto, Teruhisa; Kanbara, Mitsutaka
Organic Letters (2011), 13 (5), 912-915CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Under Indium catalysis, diverse alkylindoles were successfully prepd. with a flexible combination of indoles and alkynes in the presence of hydrosilanes. In addn. to the hydrosilane, carbon nucleophiles are also available. This new method generates alkylindoles, e.g. I, in yields over 70% with a broad scope of functional group compatibility.
(e) Kumar, A.; Li, Z.; Sharma, S. K.; Parmar, V. S.; Van der Eycken, E. V. Switching the Regioselectivity via Indium(III) and Gold(I) Catalysis: a Post-Ugi Intramolecular Hydroarylation to Azepino- and Azocino-[c,d]indolones. Chem. Commun. 2013, 49, 6803– 6805, DOI: 10.1039/c3cc42704h
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Switching the regioselectivity via indium(III) and gold(I) catalysis: a post-Ugi intramolecular hydroarylation to azepino- and azocino-[c,d]indolones
Kumar, Amit; Li, Zhenghua; Sharma, Sunil K.; Parmar, Virinder S.; Van der Eycken, Erik V.
Chemical Communications (Cambridge, United Kingdom) (2013), 49 (60), 6803-6805CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A post-Ugi indium(III)- and gold(I)-mediated regioselective intramol. hydroarylation for the synthesis of azepino- and azocino-[c,d]indolones is described.
(f) Michelet, B.; Colard-Itte, J.-R.; Thiery, G.; Guillot, R.; Bour, C.; Gandon, V. Dibromoindium(III) Cations as a π-Lewis Acid: Characterization of [IPr·InBr₂][SbF₆] and Its Catalytic Activity Towards Alkynes and Alkenes. Chem. Commun. 2015, 51, 7401– 7404, DOI: 10.1039/C5CC00740B
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Dibromoindium(III) cations as a π-Lewis acid: characterization of [IPr·InBr2][SbF6] and its catalytic activity towards alkynes and alkenes
Michelet, Bastien; Colard-Itte, Jean-Remy; Thiery, Guillaume; Guillot, Regis; Bour, Christophe; Gandon, Vincent
Chemical Communications (Cambridge, United Kingdom) (2015), 51 (34), 7401-7404CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
[IPr·InBr2][SbF6] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has been synthesized and characterized in the solid state. This complex proved to be a very active catalyst for hydroarylations, transfer hydrogenations, and cycloisomerizations.
(g) Yonekura, K.; Yoshimura, Y.; Akehi, M.; Tsuchimoto, T. A Heteroarylamine Library: Indium-Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines. Adv. Synth. Catal. 2018, 360, 1159– 1181, DOI: 10.1002/adsc.201701452
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12g
A Heteroarylamine Library: Indium-Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines
Yonekura, Kyohei; Yoshimura, Yasuhiro; Akehi, Mizuri; Tsuchimoto, Teruhisa
Advanced Synthesis & Catalysis (2018), 360 (6), 1159-1181CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
Under indium Lewis acid catalysis, electron-rich five-membered heteroaryl electrophiles fused with/without a benzene ring were found to couple with amines to produce heteroarylamines with broad structural diversity. The heteroarylamine formation proceeds through the cleavage of a heteroaryl-OMe bond by the nucleophilic attack of the amine based on the nucleophilic arom. substitution (SNAr) reaction. In contrast to the corresponding traditional SNAr amination, the present SNAr-based heteroaryl amination can be performed without relying on both heteroaryl electrophiles with electron-withdrawing groups and nucleophilicity-enhanced metal amides. High compatibility towards the functional groups such as NO2, Br, I, CF3, CN, CO2Et, pyridyl, thiazolyl, C=C, and OH groups was obsd., thus showing the practicality and reliability of this method. Mechanistic studies indicated that a carbon-indium bond is likely to be formed on the heteroaryl ring during the process.
(h) de Orbe, M. E.; Zanini, M.; Quinonero, O.; Echavarren, A. M. Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with Allylsilanes Through a Concealed Rearrangement. ACS Catal. 2019, 9, 7817– 7822, DOI: 10.1021/acscatal.9b02314
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12h
Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with Allylsilanes through a Concealed Rearrangement
de Orbe, M. Elena; Zanini, Margherita; Quinonero, Ophelie; Echavarren, Antonio M.
ACS Catalysis (2019), 9 (9), 7817-7822CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
The gold(I)-catalyzed reaction of bromoalkynes with allylsilanes gives 1,4-enynes in a formal cross-coupling reaction. Mechanistic studies revealed the involvement of gold(I) vinylidenes or vinylidenephenonium gold(I) cations depending on the substituent on the bromoalkyne. In the case of bromo arylalkynes, the vinylidenephenonium gold(I) cations lead to 1,4-enynes via a 1,2-aryl rearrangement. The same reactivity has been obsd. in the presence of InBr3.
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For some reviews see:
(a) Echavarren, A. M.; Nevado, C. Non-Stabilized Transition Metal Carbenes as Intermediates in Intramolecular Reactions of Alkynes with Alkenes. Chem. Soc. Rev. 2004, 33, 431– 436, DOI: 10.1039/b308768a
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13a
Non-stabilized transition metal carbenes as intermediates in intramolecular reactions of alkynes with alkenes
Echavarren, Antonio M.; Nevado, Cristina
Chemical Society Reviews (2004), 33 (7), 431-436CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. In this tutorial review we summarize the two major pathways followed in the reaction of alkenes with alkynes catalyzed by electrophilic transition metals. If the metal coordinates simultaneously to the alkyne and the alkene, an oxidative cyclometallation can ensue to give a metallacyclopentene, which usually evolves by β-hydrogen elimination to give Alder-ene cycloisomerization derivs. On the other hand, coordination of the metal to the alkyne promotes the attack of the alkene to give metal cyclopropyl carbenes.
(b) Jiménez-Núñez, E.; Echavarren, A. M. Gold-Catalyzed Cycloisomerizations of Enynes: a Mechanistic Perspective. Chem. Rev. 2008, 108, 3326– 3350, DOI: 10.1021/cr0684319
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13b
Gold-Catalyzed Cycloisomerizations of Enynes: A Mechanistic Perspective
Jimenez-Nunez, Eloisa; Echavarren, Antonio M.
Chemical Reviews (Washington, DC, United States) (2008), 108 (8), 3326-3350CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. Homogeneous catalysis by gold is a relatively young area of research that has grown very rapidly in the last 3-4 years. Since excellent comprehensive reviews of gold chem. have already been published recently, this review will cover gold-catalyzed cycloisomerization reactions of 1,n-enynes in detail, with a focus on their mechanisms. Cyclizations with concomitant addn. of nucleophiles to 1,n-enynes are also covered, as these reactions shed light on the general mechanism of cyclizations of enynes. These reactions are domino-type transformations in which two bonds (C-C/C-X or two C-C) are consecutively formed.
(c) Toullec, P. Y.; Michelet, V. Cycloisomerization of 1,n-Enynes via Carbophilic Activation. Top. Curr. Chem. 2011, 302, 31– 80
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13c
Cycloisomerization of 1,n-enynes via carbophilic activation
Toullec, Patrick Yves; Michelet, Veronique
Topics in Current Chemistry (2011), 302 (Computational Mechanisms of Au and Pt Catalyzed Reactions), 31-80CODEN: TPCCAQ; ISSN:0340-1022. (Springer GmbH)
A review. Metal-catalyzed cycloisomerization of 1,n-enynes has appeared as a highly attractive methodol. for the synthesis of original carbocyclic compds. and heterocyclic compds. This chapter intends to propose an overview of the recent advances in 1,n-enynes cycloisomerization reactions in the presence of carbophilic transition metals. The recent mechanistic insights, the enantioselective versions, and the applications in total synthesis are highlighted. Topics thus discussed included carbophilic Lewis acids and their reactivity principles, enyne cycloisomerization reaction on the absence of nucleophiles, formation of dienes, Conia ene-type reactions, formation of bicyclic compds., domino-ene cycloisomerization and nucleophilic addn. reaction, oxygen nucleophiles, carbon nucleophiles, nitrogen nucleophiles, etc.
(d) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Transition Metal Catalyzed Cycloisomerizations of 1,n-Allenynes and -Allenenes. Chem. Rev. 2011, 111, 1954– 1993, DOI: 10.1021/cr100376w
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13d
Transition Metal Catalyzed Cycloisomerizations of 1,n-Allenynes and -Allenenes
Aubert, Corinne; Fensterbank, Louis; Garcia, Pierre; Malacria, Max; Simonneau, Antoine
Chemical Reviews (Washington, DC, United States) (2011), 111 (3), 1954-1993CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review was given summarizing advances in the cycloisomerization of 1,n-allenynes and 1,n-allenenes. Herein, cycloisomerization refers to the formation of new C-C bonds to accomplish the assembly of carbocyclic or heterocyclic rings for precursors contg. heteroatom-based tethers.
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(a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Mercuric Triflate-Catalyzed Tandem Cyclization Leading to Polycarbocycles. Org. Lett. 2005, 7, 451– 453, DOI: 10.1021/ol047472t
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14a
Mercuric Triflate-Catalyzed Tandem Cyclization Leading to Polycarbocycles
Imagawa, Hiroshi; Iyenaga, Tomoaki; Nishizawa, Mugio
Organic Letters (2005), 7 (3), 451-453CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
We developed Hg(OTf)2-catalyzed cyclization of (E)-1,3-dimethoxy-5-(4-methyl-3-nonen-7-ynyl)benzene leading to the formation of (4aS*,10aS*)-3,4,4a,9,10,10a-hexahydro-5,7-dimethoxy-1,4a-dimethylphenanthrene I in 98% yield with up to 100 catalytic turnovers. This is the first mercuric salt-catalyzed biomimetic tandem cyclization.
(b) Pradal, A.; Chen, Q.; Faudot dit Bel, P.; Toullec, P. Y.; Michelet, V. Gold-Catalyzed Cycloisomerization of Functionalized 1,5-Enynes – an Entry to Polycyclic Framework. Synlett 2012, 2012, 74– 79, DOI: 10.1055/s-0031-1289867
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(c) Rong, Z.; Echavarren, A. M. Broad Scope Gold(I)-Catalysed Polyenyne Cyclisations for the Formation of Up to Four Carbon-Carbon Bonds. Org. Biomol. Chem. 2017, 15, 2163– 2167, DOI: 10.1039/C7OB00235A
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14c
Broad scope gold(I)-catalysed polyenyne cyclisations for the formation of up to four carbon-carbon bonds
Rong, Zhouting; Echavarren, Antonio M.
Organic & Biomolecular Chemistry (2017), 15 (10), 2163-2167CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
The polycyclization of polyenynes catalyzed by gold(I) has been extended for the first time to the simultaneous formation of up to four carbon-carbon bonds, leading to steroid-like mols. with high stereoselectivity in a single step with low catalyst loadings. In addn. to terminal alkynes, bromoalkynes can also be used as initiators of polyene cyclizations, giving rise to synthetically useful cyclic bromoalkenes.
(d) Lu, X.-L.; Lyu, M.-Y.; Peng, X.-S.; Wong, H. N. C. Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers by Hydride Transfer. Angew. Chem., Int. Ed. 2018, 57, 11365– 11368, DOI: 10.1002/anie.201806842
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14d
Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers by Hydride Transfer
Lu, Xiao-Lin; Lyu, Mao-Yun; Peng, Xiao-Shui; Wong, Henry N. C.
Angewandte Chemie, International Edition (2018), 57 (35), 11365-11368CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A novel gold-catalyzed tandem protocol, initiated by hydride transfer in the presence of catalytic (C6F5)3PAuCl/AgSbF6, for the formation of fused polycyclic ring systems has been achieved. This tandem reaction provides rapid access to various fused polycyclic species in a single chem. operation, leading to stereospecific formation of two carbon-carbon bonds and three rings.
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Miyanohana, Y.; Chatani, N. Skeletal Reorganization of Enynes Catalyzed by InCl₃. Org. Lett. 2006, 8, 2155– 2158, DOI: 10.1021/ol060606d
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Skeletal Reorganization of Enynes Catalyzed by InCl3
Miyanohana, Yuhei; Chatani, Naoto
Organic Letters (2006), 8 (10), 2155-2158CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The skeletal reorganization of enynes is achieved by the presence of InCl3 as the catalyst. The reaction of enynes having a terminal acetylenic moiety proceeds in a stereospecific manner to give 1-vinylcycloalkenes. The reaction of enynes contg. an alkyl group on the acetylenic terminal carbon resulted in a new type of skeletal reorganization to give 1-allylcycloalkenes, formation of which involves a double cleavage of the C-C double bond and the triple bond.
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(a) Surendra, K.; Qiu, W.; Corey, E. J. A Powerful New Construction of Complex Chiral Polycycles by an Indium(III)-Catalyzed Cationic Cascade. J. Am. Chem. Soc. 2011, 133, 9724– 9726, DOI: 10.1021/ja204142n
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16a
A Powerful New Construction of Complex Chiral Polycycles by an Indium(III)-Catalyzed Cationic Cascade
Surendra, Karavadhi; Qiu, Wenwei; Corey, E. J.
Journal of the American Chemical Society (2011), 133 (25), 9724-9726CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
InI3 and InBr3 have been found to be effective catalysts for the π activation of C≡C bonds to initiate the conversion of chiral propargylic alcs. or silyl ethers to polycyclic products in excellent yields and with high stereoselectivity. The method was applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. The power and scope of the method were illustrated by a variety of examples. E.g., pentacycle I (R = SiMe2CMe3) was prepd. with 76% yield by cyclization of diene II (R = SiMe2CMe3) using InBr3 in CH2Cl2.
(b) Surendra, K.; Corey, E. J. Diiodoindium(III) Cation, InI₂⁺, a Potent Yneophile. Generation and Application to Cationic Cyclization by Selective π-Activation of C≡C. J. Am. Chem. Soc. 2014, 136, 10918– 10920, DOI: 10.1021/ja506502p
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16b
Diiodoindium(III) Cation, InI2+, a Potent Yneophile. Generation and Application to Cationic Cyclization by Selective π-Activation of C≡C
Surendra, Karavadhi; Corey, E. J.
Journal of the American Chemical Society (2014), 136 (31), 10918-10920CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The removal of the iodide ion from indium triiodide by means of reactive Ag(I) salts leads to the formation of the highly reactive ligandless cation InI2+, which is unusual in having two vacant low-lying p-orbitals. This bivalent Lewis acidity leads to an esp. high affinity for the two orthogonal π-bonds of carbon-carbon triple bonds. Consequently, the double-coordinating InI2+ is an esp. effective reagent for the selective activation of C≡C and the catalytic initiation of cationic cyclization processes. A no. of such reactions are described to demonstrate synthetic utility.
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For some representative references, see:
(a) Pérez, I.; Pérez Sestelo, J.; Sarandeses, L. A. Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction of Indium Organometallics with Organic Electrophiles. J. Am. Chem. Soc. 2001, 123, 4155– 4160, DOI: 10.1021/ja004195m
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17a
Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction of Indium Organometallics with Organic Electrophiles
Perez, Ignacio; Perez Sestelo, Jose; Sarandeses, Luis A.
Journal of the American Chemical Society (2001), 123 (18), 4155-4160CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The novel metal-catalyzed cross-coupling reaction of indium organometallics R3In (R = Ph, H2C:CH, PhC≡C, Me3SiC≡C, Bu, Me, c-C3H5, Me3SiCH2) (I) with org. electrophiles such as aryl iodides, bromides, and chlorides, alkenyl triflates, benzyl bromide, and acyl chlorides is described. I are efficiently prepd. from the corresponding lithium or magnesium organometallics by reaction with indium trichloride. The cross-coupling reaction of I with aryl halides and pseudohalides, vinyl triflates, benzyl bromides, and acid chlorides proceeds under palladium catalysis in excellent yields and with high chemoselectivity. I (R = Ph, Bu) also react with 4-methylphenyl chloride in the presence of bis(triphenylphosphine)nickel dichloride to give 4-MeC6H4R in 74 and 83% yields. In cross-coupling reactions, I transfer all three of the org. groups attached to the metal, requiring only 34 mol% of the trialkylindium reagents. The feasibility of using I in reactions with different electrophiles, along with the high yields and chemoselectivities obtained, reveals indium organometallics to be useful alternatives to other organometallics in cross-coupling reactions.
(b) Caeiro, J.; Pérez Sestelo, J.; Sarandeses, L. A. Enantioselective Nickel-Catalyzed Cross-Coupling Reactions of Trialkynylindium Reagents with Racemic Secondary Benzyl Bromides. Chem. – Eur. J. 2008, 14, 741– 746, DOI: 10.1002/chem.200701035
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17b
Enantioselective nickel-catalyzed cross-coupling reactions of trialkynylindium reagents with racemic secondary benzyl bromides
Caeiro, Jorge; Perez Sestelo, Jose; Sarandeses, Luis A.
Chemistry - A European Journal (2008), 14 (2), 741-746CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The first enantioselective sp-sp3 cross-coupling reaction between alkynyl organometals and racemic benzyl bromides is reported. The coupling is performed at room temp. by using NiBr2·diglyme and (S)-(iPr)-Pybox as the catalytic system and trialkynylindium reagents as nucleophiles. The reaction is stereoconvergent, both enantiomers of the racemic benzyl bromide are converted into one enantiomer of the product, and stereospecific. The reaction takes place efficiently in good yields and with high atom economy, as the triorganoindium reagents transfer the three org. groups attached to indium (only 40 mol % of R3In is used).
(c) Mato, M.; Pérez-Caaveiro, C.; Sarandeses, L. A.; Pérez Sestelo, J. Ferrocenylindium Reagents in Palladium-Catalyzed Cross-Coupling Reactions: Asymmetric Synthesis of Planar Chiral 2-Aryl Oxazolyl and Sulfinyl Ferrocenes. Adv. Synth. Catal. 2017, 359, 1388– 1393, DOI: 10.1002/adsc.201601397
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17c
Ferrocenylindium Reagents in Palladium-Catalyzed Cross-Coupling Reactions: Asymmetric Synthesis of Planar Chiral 2-Aryl Oxazolyl and Sulfinyl Ferrocenes
Mato, Mauro; Perez-Caaveiro, Cristina; Sarandeses, Luis A.; Perez Sestelo, Jose
Advanced Synthesis & Catalysis (2017), 359 (8), 1388-1393CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
The prepn. of ferrocenylindium species and palladium-catalyzed cross-coupling reactions for the synthesis of monosubstituted and planar chiral 1,2-disubstituted ferrocenes is described. Triferrocenylindium reagents (Fc3In) are efficiently prepd. in a one-pot procedure from ferrocenes by lithiation and transmetallation to indium using InCl3. The palladium-catalyzed cross-coupling reactions of Fc3In (40 mol%) with a variety of org. electrophiles (aryl, heteroaryl, benzyl, alkenyl and acyl halides) in THF at 80° overnight provided a wide variety of monosubstituted ferrocenes in good to excellent yields. This methodol. allowed the stereoselective synthesis of planar chiral 2-aryl-1-oxazolylferrocenes and 2-aryl-1-sulfinylferrocenes, which are of interest in asym. catalysis.
(d) Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Synthesis of Bench-Stable Solid Triorganoindium Reagents and Reactivity in Palladium-Catalyzed Cross-Coupling Reactions. Chem. Commun. 2018, 54, 1453– 1456, DOI: 10.1039/C7CC09344F
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17d
Synthesis of bench-stable solid triorganoindium reagents and reactivity in palladium-catalyzed cross-coupling reactions
Gil-Negrete, Jose M.; Perez Sestelo, Jose; Sarandeses, Luis A.
Chemical Communications (Cambridge, United Kingdom) (2018), 54 (12), 1453-1456CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Bench-stable solid triorganoindium compds. were prepd. by coordination with 4-(dimethylamino)pyridine (DMAP). The solid R3In(DMAP) complexes were obtained from the corresponding soln. of R3In in quant. yield and was stored for up to several weeks. These reagents showed excellent reactivity in palladium-catalyzed cross-coupling reactions with org. electrophiles.
(e) Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines. J. Org. Chem. 2019, 84, 9778– 9785, DOI: 10.1021/acs.joc.9b00928
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17e
Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines
Gil-Negrete, Jose M.; Perez Sestelo, Jose; Sarandeses, Luis A.
Journal of Organic Chemistry (2019), 84 (15), 9778-9785CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Triorganoindium reagents react with tetrahydroisoquinolines (THIQs) in the presence of Ph3CBF4 as an oxidant to afford 1-substituted THIQs. The reaction proceeds in good yields at rt using 50 mol % triorganoindium reagent with a variety of org. groups. 1H NMR studies show the generation of an iminium ion intermediate, supporting a two-step mechanism based on THIQ oxidn. and R3In nucleophilic addn. This reaction was applied to the synthesis of the alkaloid nuciferine in three steps.
18
(a) Alonso-Marañón, L.; Martínez, M. M.; Sarandeses, L. A.; Pérez Sestelo, J. Indium-Catalyzed Intramolecular Hydroarylation of Aryl Propargyl Ethers. Org. Biomol. Chem. 2015, 13, 379– 387, DOI: 10.1039/C4OB02033B
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18a
Indium-catalyzed intramolecular hydroarylation of aryl propargyl ethers
Alonso-Maranon, Lorena; Martinez, M. Montserrat; Sarandeses, Luis A.; Sestelo, Jose Perez
Organic & Biomolecular Chemistry (2015), 13 (2), 379-387CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Indium(III) halides catalyze efficiently the intramol. hydroarylation (IMHA) of aryl propargyl ethers. The reaction proceeds regioselectively with terminal and internal alkynes bearing electron-rich and electron-deficient substituents in the benzenes and alkynes affording only the 6-endo dig cyclization product. Addnl., a sequential indium-catalyzed IMHA and palladium-catalyzed Sonogashira coupling can be performed in one reaction vessel. Expts. with deuterium support a mechanism through electrophilic arom. substitution.
(b) Alonso-Marañón, L.; Sarandeses, L. A.; Martínez, M. M.; Pérez Sestelo, J. Sequential In-Catalyzed Intramolecular Hydroarylation and Pd-Catalyzed Cross-Coupling Reactions Using Bromopropargyl Aryl Ethers and Amines. Org. Chem. Front. 2017, 4, 500– 505, DOI: 10.1039/C6QO00721J
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18b
Sequential In-catalyzed intramolecular hydroarylation and Pd-catalyzed cross-coupling reactions using bromopropargyl aryl ethers and amines
Alonso-Maranon, Lorena; Sarandeses, Luis A.; Martinez, M. Montserrat; Perez Sestelo, Jose
Organic Chemistry Frontiers (2017), 4 (4), 500-505CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
A sequential one-pot indium-catalyzed intramol. hydroarylation (IMHA) of bromopropargyl aryl ethers and amines, and palladium-catalyzed cross-coupling reaction using triorganoindium reagents was developed. In this transformation, the IMHA of 3-bromo-2-propynyl aryl ethers under indium(III) catalysis, proceeded regioselectively through a 6-endo dig pathway to afford 4-bromo-2H-chromenes and subsequent palladium-catalyzed cross-coupling with triorganoindium reagents gave 4-substituted-2H-chromenes I [R1 = R3 = H; R2 = OMe; R4 = Bu, Ph, 2-thienyl, etc.; X = O] in one-pot. This sequential transformation was further extended for the synthesis of 4-substituted-1-tosyl-1,2-dihydroquinolines I [R1 = R2 = R3 = H, OMe; R4 = Me, Bu, Ph, etc.; X = N-Ts] from 3-bromo-2-propynyl-N-tosylanilines. The dual-catalyzed procedure took place efficiently showing the efficiency of these organometallics and providing the compatibility of indium and palladium in catalysis.
(c) Alonso-Marañón, L.; Sarandeses, L. A.; Martínez, M. M.; Pérez Sestelo, J. Synthesis of Fused Chromenes by the Indium(III)-Catalyzed Cascade Hydroarylation/Cycloisomerization Reactions of Polyyne-Type Aryl Propargyl Ethers. Org. Chem. Front. 2018, 5, 2308– 2312, DOI: 10.1039/C8QO00457A
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18c
Synthesis of fused chromenes by the indium(III)-catalyzed cascade hydroarylation/cycloisomerization reactions of polyyne-type aryl propargyl ethers
Alonso-Maranon, Lorena; Sarandeses, Luis A.; Martinez, M. Montserrat; Perez Sestelo, Jose
Organic Chemistry Frontiers (2018), 5 (15), 2308-2312CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
Fused 2H-chromenes were prepd. by the cascade hydroarylation/cycloisomerization reactions of polyyne-type aryl propargyl ethers using indium(III) catalysis. The transformation proceeded with 6-endo-dig regioselectivity using InBr3 (5 mol%). The method was extended to triynes allowing the formation of three bonds in one pot. Indium(III) also catalyzed the hydroamination/hydroarylation cascade reaction of o-aryldiynyl anilines to form fused carbazoles.
(d) Alonso-Marañón, L.; Martínez, M. M.; Sarandeses, L. A.; Gómez-Bengoa, E.; Pérez Sestelo, J. Indium(III)-Catalyzed Synthesis of Benzo[b]Furans by Intramolecular Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights. J. Org. Chem. 2018, 83, 7970– 7980, DOI: 10.1021/acs.joc.8b00829
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18d
Indium(III)-Catalyzed Synthesis of Benzo[b]furans by Intramolecular Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights
Alonso-Maranon, Lorena; Martinez, M. Montserrat; Sarandeses, Luis A.; Gomez-Bengoa, Enrique; Perez Sestelo, Jose
Journal of Organic Chemistry (2018), 83 (15), 7970-7980CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Indium(III) halides catalyze the hydroalkoxylation reaction of ortho-alkynylphenols to afford benzo[b]furans in good yields. The reaction proceeds with 5-endo-dig regioselectivity with a variety of phenols functionalized at the arene and alkyne moieties in high yields using InI3 (5 mol %) in DCE. Exptl. and computational studies support a mechanism based on the indium(III) π-Lewis acid activation of the alkyne followed by nucleophilic addn. of the phenol and final protodemetalation to afford the corresponding benzo[b]furan. DFT calcns. suggest that dimer In2I6 is the catalytic species through a novel double coordination with the alkyne and the hydroxyl group.
19
Using ¹H-¹H COSY, edited-HSQC and HMBC experiments, we were able to assign all protons and carbons for (trans)-4f. Key signals to deduce the trans-fused bicyclic system were protons H-6 (δ_H 2.21 ppm, td, J = 11.2, 11.2, 2.2 Hz) and H-5 (δ_H 2.02 ppm, bt, J = 11.5 Hz), which clearly show an antiperiplanar relationship between them (see the SI on page S40–S42).
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20
Toullec, P. Y.; Blarre, T.; Michelet, V. Mimicking Polyolefin Carbocyclization Reactions: Gold-Catalyzed Intramolecular Phenoxycyclization of 1,5-Enynes. Org. Lett. 2009, 11, 2888– 2891, DOI: 10.1021/ol900864n
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Mimicking Polyolefin Carbocyclization Reactions: Gold-Catalyzed Intramolecular Phenoxycyclization of 1,5-Enynes
Toullec, Patrick Yves; Blarre, Thomas; Michelet, Veronique
Organic Letters (2009), 11 (13), 2888-2891CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
PPh3AuNTf2 promotes highly efficient intramol. phenoxycyclization reactions on 1,5-enynes under mild conditions. The original tricyclic and functionalized heterocycles were isolated in good to excellent yields. The 6-endo cyclization process is predominant and operates via a biomimetic cascade cation-olefin process. The efficiency of this system was further demonstrated in the cycloisomerization reaction of a 1,5,9-dienyne, I.
21
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22
(a) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P. Organoindium Reagents: the Preparation and Application in Organic Synthesis. Chem. Rev. 2013, 113, 271– 401, DOI: 10.1021/cr300051y
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Organoindium Reagents: The Preparation and Application in Organic Synthesis
Shen, Zhi-Liang; Wang, Shun-Yi; Chok, Yew-Keong; Xu, Yun-He; Loh, Teck-Peng
Chemical Reviews (Washington, DC, United States) (2013), 113 (1), 271-401CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. The intent of this review is to provide an overview of the prepn. and application of organoindium reagents in org. synthesis.
(b) Zhao, K.; Shen, L.; Shen, Z.-L.; Loh, T.-P. Transition Metal-Catalyzed Cross-Coupling Reactions Using Organoindium Reagents. Chem. Soc. Rev. 2017, 46, 586– 602, DOI: 10.1039/C6CS00465B
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Transition metal-catalyzed cross-coupling reactions using organoindium reagents
Zhao, Kai; Shen, Liang; Shen, Zhi-Liang; Loh, Teck-Peng
Chemical Society Reviews (2017), 46 (3), 586-602CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. This review focuses on the recent develpments in the prepn. of organoindium reagents and its use in the subsequent transition metal-catalyzed cross-coupling reactions with various electrophiles. These cross-coupling reactions employing organoindium reagents exhibited remarkable chemo- and stereoselectivity. In addn., the versatility and significance of transition metal catalyzed cross-couplings of organoindium reagents are further highlighted by their applications in org. synthesis and materials science.
23
Sotorríos, L.; Demertzidou, V. P.; Zografos, A. L.; Gómez-Bengoa, E. DFT Studies on Metal-Catalyzed Cycloisomerization of trans-1,5-Enynes to Cyclopropane Sesquiterpenoids. Org. Biomol. Chem. 2019, 17, 5112– 5120, DOI: 10.1039/C9OB00890J
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DFT studies on metal-catalyzed cycloisomerization of trans-1,5-enynes to cyclopropane sesquiterpenoids
Sotorrios, Lia; Demertzidou, Vera P.; Zografos, Alexandros L.; Gomez-Bengoa, Enrique
Organic & Biomolecular Chemistry (2019), 17 (20), 5112-5120CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
We have recently described the synthesis of strained carbocyclic sesquiterpenoid motifs through a highly regioselective cycloisomerization of common enyne acetates, in the presence of platinum(II) and gold(I) chlorides as catalysts. In this work, the mechanisms of these cyclization reactions have been studied by means of DFT methods. At the outset of the reactions, the propargyl substrates suffer 1,2- or 1,3-acetate rearrangements, which compete for the formation of a metal-carbene or a vinyl-metal species, resp. These intermediates are the resting states of the cycles towards the formation of lindenane or myliol core structures. The DFT studies have revealed the energetics of the two migration processes, as well as the reasons for some of the key exptl. observations, such as the syn/anti preference in the formation of the cyclopropane rings, the different reactivities of substrates contg. furan or lactone moieties, and the different outcomes of the reactions when Pt(II) and Au(I) salts are used.
24
All structures were optimized using Gaussian 16 with the B3LYP/6-31G(d,p) method for C, H, and O and SDD basis set for In and I. Final energies were refined at the M06/def2tzvpp level of theory in toluene. For more details, see the Supporting Information.
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25
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The 1:1 complex of o,o'-dichloro-R-BINOL and SbCl5 initiates the enantioselective cationic polycyclization of polyunsatd. substrates at a predictable π-bond which may be either terminal or, as shown herein, internal (e.g., I → II). The extension of this powerful construction to internal π-bonds expands the scope of this method and opens up very short pathways to numerous chiral polycyclic mols., including natural products and their analogs. Esp. simple synthetic routes are disclosed that provide access to dysideapalaunic acid, dehydroabietic acid, and epi-podocarpic acid and illustrate the value of this enantioselective approach.
26
Corey, E. J.; Seibel, W. L. First stekeospecific synthesis of E-γ-bisabolene. A method for the concurrent generation of a ring and a tetrasubstituted exocyclic double bond. Tetrahedron Lett. 1986, 27, 905– 908, DOI: 10.1016/S0040-4039(00)84133-7
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A short stereospecific synthesis of E-γ-bisabolene (I) from an acyclic acetylenic precursor [either II or III (R = SiMe2CMe3)] is described.
27
Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Bräse, S. Enantioselective Intramolecular Friedel–Crafts-Type α-Arylation of Aldehydes. J. Am. Chem. Soc. 2009, 131, 2086– 2087, DOI: 10.1021/ja809405c
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Nicolaou, K. C.; Reingruber, Rudiger; Sarlah, David; Brase, Stefan
Journal of the American Chemical Society (2009), 131 (6), 2086-2087CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Enantioselective organo-SOMO catalysis has, in the last two years, been the subject of considerable development and exploration. A no. of new and unique transformations have been reported, such as α-allylation, α-oxyamination, α-enolation, and α-vinylation of aldehydes. Herein, we report a modification of this activation mode that involves the intramol. Friedel-Crafts-type α-arylation of aldehydes carrying electron-donating groups on their arom. nucleus and its application to the total synthesis of demethyl calamenene, I, a potent cytotoxic agent against human adenocarcinoma A 549.
28
Mostafa, M. A. B.; Grafton, M. W.; Wilson, C.; Sutherland, A. A one-pot, three-step process for the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and ruthenium(II)-catalysis. Org. Biomol. Chem. 2016, 14, 3284– 3297, DOI: 10.1039/C6OB00165C
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A one-pot, three-step process for the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and ruthenium(II)-catalysis
Mostafa, Mohamed A. B.; Grafton, Mark. W.; Wilson, Claire; Sutherland, Andrew
Organic & Biomolecular Chemistry (2016), 14 (12), 3284-3297CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes has been attained using a one-pot multi-bond forming process. A four-step synthetic route was developed for the efficient synthesis of a series of C-7 substituted hept-2-en-6-yn-1-ols, RC=CCH2CH2CH=CHCH2OH (R = H, CH3, C6H5, 4-H3COC6H4, 4-O2NC6H4). These compds. were then investigated as substrates for a one-pot, three-step tandem process involving a palladium(II)-catalyzed Overman rearrangement, a ruthenium(II)-catalyzed ring closing enyne metathesis reaction followed by a hydrogen bond directed Diels-Alder reaction. The optimization of the one-pot process has allowed the rapid prepn. of a library of aminobicyclo[4.3.0]nonanes with significant mol. complexity and up to four stereogenic centers.

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Abstract
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Scheme 1
Scheme 1. Indium(III)-Catalyzed Electrophilic Activation of Alkynes
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Scheme 2
Scheme 2. Sequential One-Pot In-Catalyzed 1,5-Enyne Cycloisomerization and Pd-Catalyzed Cross-Coupling Reaction with (E)-5b
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Scheme 3
Scheme 3. General Plausible Mechanism for the In(III)-Catalyzed Cascade Cycloisomerization Reaction of 1,5-Enynes 1a–d and 3a–f
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Scheme 4
Scheme 4. DFT-Calculated Mechanism of the Reaction of (Z)-1a and (E)-1a for the Selective Formation of INT2-cis and -trans
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Scheme 5
Scheme 5. DFT-Calculated Isomerization Process between the Intermediates INT1-cis and INT1-trans
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Scheme 6
Scheme 6. DFT-Calculated Mechanism of the Reaction of (Z)-1d and (E)-1d under Curtin–Hammett Conditions
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References
This article references 28 other publications.
1. 1
  (a) Ye, F.; Ge, Y.; Spannenberg, A.; Neumann, H.; Beller, M. The Role of Allyl Ammonium Salts in Palladium-Catalyzed Cascade Reactions Towards the Synthesis of Spiro-Fused Heterocycles. Nat. Commun. 2020, 11, 5383 DOI: 10.1038/s41467-020-19110-3
  1a
  The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles
  Ye, Fei; Ge, Yao; Spannenberg, Anke; Neumann, Helfried; Beller, Matthias
  Nature Communications (2020), 11 (1), 5383CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
  Two general and efficient cascade procedures for the synthesis of spiro-fused heterocycles, e.g., I, and II [R = C(O)OEt, C(O)Ph, CCPh, CN, etc.; R1 = H, Ph, F, Me; R2 = tert-Bu, Me, Ph, F, etc.; R3 = Ph, n-pentyl; X = O, NTs] were described. This transformation combines selective nucleophilic substitution (SN2'), palladium-catalyzed Heck and C-H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts is key to the success of the transformations. The synthetic utility of these methodologies is showcased by the prepn. of 48 spiro-fused dihydrobenzofurans and indolines, e.g., I, and II including a variety of fluorinated derivs.
  and references therein.
  (b) Catalytic Cascade Reactions; Xu, P. F.; Wang, W., Eds; Wiley: Hoboken, New Jersey, 2014.
  There is no corresponding record for this reference.
2. 2
  For some reviews see:
  (a) Barrett, A. G. M.; Ma, T.-K.; Mies, T. Recent Developments in Polyene Cyclizations and Their Applications in Natural Product Synthesis. Synthesis 2019, 51, 67– 82, DOI: 10.1055/s-0037-1610382
  2a
  Recent Developments in Polyene Cyclizations and Their Applications in Natural Product Synthesis
  Barrett, Anthony G. M.; Ma, Tsz-Kan; Mies, Thomas
  Synthesis (2019), 51 (1), 67-82CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
  A review. Cascade polyene cyclization reactions are highly efficient and elegant bioinspired transformations that involve simultaneous multiple bond constructions to rapidly generate complex polycyclic mols. This review summarizes the most prominent work on a variety of cationic and radical cascade cyclizations and their applications in natural product synthesis published between 2014 and 2018.
  (b) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Enzyme Mechanisms for Polycyclic Triterpene Formation. Angew. Chem., Int. Ed. 2000, 39, 2812– 2833, DOI: 10.1002/1521-3773(20000818)39:16<2812::AID-ANIE2812>3.0.CO;2-#
  2b
  Enzyme mechanisms for polycyclic triterpene formation
  Wendt, K. Ulrich; Schulz, Georg E.; Corey, Elias J.; Liu, David R.
  Angewandte Chemie, International Edition (2000), 39 (16), 2812-2833CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
  Review with 105 refs. on the mechanisms by which triterpene cyclases transform olefins into complex and biol. important polycyclic products fueling nearly half a century of intense research. Recent chem. and biol. studies, together with previous findings, provide intriguing new insights into the enzymic mechanism of triterpene formation and form a surprisingly detailed picture of these elegant catalysts. It can be concluded that the role of the oxidosqualene cyclases involves protection of the intermediate carbocation against addn. of water or deprotonation by base, thereby allowing the shift of the hydride and Me groups along a thermodynamically and kinetically favorable cascade. Key questions in the areas of structural biol., site-directed mutagenesis, and directed evolution are apparent, now that the first structure of a triterpene cyclase is known.
  (c) Yoder, R. A.; Johnston, J. N. A Case Study in Biomimetic Total Synthesis: Polyolefin Carbocyclizations to Terpenes and Steroids. Chem. Rev. 2005, 105, 4730– 4756, DOI: 10.1021/cr040623l
  2c
  A Case Study in Biomimetic Total Synthesis: Polyolefin Carbocyclizations to Terpenes and Steroids
  Yoder, Ryan A.; Johnston, Jeffrey N.
  Chemical Reviews (Washington, DC, United States) (2005), 105 (12), 4730-4756CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review on polycarbocyclization of squalene and oxidosqualene to terpenes and steroids.
3. 3
  Representative examples:
  (a) Corey, E. J.; Lee, J. Enantioselective Total Synthesis of Oleanolic Acid, Erythrodiol, β-Amyrin, and Other Pentacyclic Triterpenes From a Common Intermediate. J. Am. Chem. Soc. 1993, 115, 8873– 8874, DOI: 10.1021/ja00072a064
  3a
  Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other pentacyclic triterpenes from a common intermediate
  Corey, E. J.; Lee, Jaemoon
  Journal of the American Chemical Society (1993), 115 (19), 8873-4CODEN: JACSAT; ISSN:0002-7863.
  The first enantioselective total synthesis of several key members of the β-amyrin series of triterpenes, including I (R = Me, CH2OH, CO2H), from 7-methoxy-1-tetralone via aegiceradienol (II) is described.
  (b) Corey, E. J.; Lin, S. A Short Enantioselective Total Synthesis of Dammarenediol II. J. Am. Chem. Soc. 1996, 118, 8765– 8766, DOI: 10.1021/ja9620806
  3b
  A Short Enantioselective Total Synthesis of Dammarenediol II
  Corey, E. J.; Lin, Shouzhong
  Journal of the American Chemical Society (1996), 118 (36), 8765-8766CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Dammarenediol II (I) has been obtained by total synthesis for the first time by the following sequence of reactions. The chiral starting material II (R = OAc, R 1 = OH, R2 = α-OH) is readily available by a recently developed catalytic enantio- and position-selective dihydroxylation reaction and is readily transformed into epoxyfarnesyl bromide II (R = Br, R1R2 = β-O). Two component coupling of II (R = Br, R1R2 = β-O) and MeOCH2CHMeN:C(SiMe2CMe3)Me produced II (R = CH2COSiMe2CMe3, R1R2 = β-O) which, by a three component coupling with 2-lithiopropene and 2-(2-iodoethyl)-2-methyl-1,3-dithiolane, afforded II [R = CH2C(OSiMe2CMe3):CMe(CH2)3-(2-methyl-1,3-dithiolan-2-yl), R1R2 = β-O] stereospecifically. Cation-olefin cyclization of II [R = CH2C(OSiMe2CMe3):CMe(CH2)3-(2-methyl-1,3-dithiolan-2-yl), R1R2 = β-O] led to III which could be converted to IV by aldol cyclization. Conversion of IV to I was accomplished as shown. The brevity and stereochem. control of this synthesis are noteworthy.
  (c) Huang, A. X.; Xiong, Z.; Corey, E. J. An Exceptionally Short and Simple Enantioselective Total Synthesis of Pentacyclic Triterpenes of the β-Amyrin Family. J. Am. Chem. Soc. 1999, 121, 9999– 10003, DOI: 10.1021/ja992411p
  3c
  An Exceptionally Short and Simple Enantioselective Total Synthesis of Pentacyclic Triterpenes of the β-Amyrin Family
  Huang, Alan X.; Xiong, Zhaoming; Corey, E. J.
  Journal of the American Chemical Society (1999), 121 (43), 9999-10003CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A new and very direct enantioselective total synthesis of members of the β-amyrin family of pentacyclic triterpenes has been developed starting with an acylsilane I, 2-propenyl lithium, and cyclohexenylmethyl bromide, which were assembled to form tetraene II. Cationic cyclization of II and silylation afforded III, which after vinyl triflate formation was cyclized via a Cu(I) intermediate to form the TBS ether of aegiceradienol IV, a versatile intermediate that is readily converted into natural β-amyrins such as β-amyrin and oleanolic acid. The C(14)-diastereomer of aegiceradienol was also synthesized from the C(14)-diastereomer using an intramol. Stille reaction for the closure of ring D.
  (d) Surendra, K.; Corey, E. J. Rapid and Enantioselective Synthetic Approaches to Germanicol and Other Pentacyclic Triterpenes. J. Am. Chem. Soc. 2008, 130, 8865– 8869, DOI: 10.1021/ja802730a
  3d
  Rapid and Enantioselective Synthetic Approaches to Germanicol and Other Pentacyclic Triterpenes
  Surendra, Karavadhi; Corey, E. J.
  Journal of the American Chemical Society (2008), 130 (27), 8865-8869CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Two exceedingly short synthetic routes to the key intermediate I for the synthesis of the pentacyclic triterpene germanicol have been developed. In the first, the (S)-epoxide of farnesyl bromide is transformed in just three steps to the tetracyclic intermediate II, which is converted to chiral I by treatment with polyphosphoric acid. The second synthetic route to I involves the coupling of the (S)-epoxide III with vinyl iodide IV to give bicycle V and two-stage acid-catalyzed cyclization of V to form I. During the course of this work we have also discovered a very unusual intramol. 1,5-proton shift from a carbocation to a C-C double bond. The details of the process have been confirmed by 2H-labeling expts.
  (e) Surendra, K.; Corey, E. J. A Short Enantioselective Total Synthesis of the Fundamental Pentacyclic Triterpene Lupeol. J. Am. Chem. Soc. 2009, 131, 13928– 13929, DOI: 10.1021/ja906335u
  3e
  A Short Enantioselective Total Synthesis of the Fundamental Pentacyclic Triterpene Lupeol
  Surendra, Karavadhi; Corey, E. J.
  Journal of the American Chemical Society (2009), 131 (39), 13928-13929CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Nonracemic lupeol I (R = H) is prepd. enantioselectively using the stereoselective cyclization of epoxide II (TIPS = triisopropylsilyl) to dienone III and a subsequent stereoselective cyclization of tetracyclic alc. IV (R = TBS; TBS = tert-butyldimethylsilyl) to I (R = TBS) as the key steps. Triflic acid-mediated rearrangement of I (R = H) gives a mixt. of pentacyclic triterpenes; the change in the distribution of triterpenes with increasing reaction time is discussed.
  (f) Bartels, F.; Hong, Y. J.; Ueda, D.; Weber, M.; Sato, T.; Tantillo, D. J.; Christmann, M. Bioinspired Synthesis of Pentacyclic Onocerane Triterpenoids. Chem. Sci. 2017, 8, 8285– 8290, DOI: 10.1039/C7SC03903D
  3f
  Bioinspired synthesis of pentacyclic onocerane triterpenoids
  Bartels, Florian; Hong, Young J.; Ueda, Daijiro; Weber, Manuela; Sato, Tsutomu; Tantillo, Dean J.; Christmann, Mathias
  Chemical Science (2017), 8 (12), 8285-8290CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  The first chem. synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymic studies.
4. 4
  (a) Fürstner, A.; Davies, P. W. Catalytic Carbophilic Activation: Catalysis by Platinum and Gold π Acids. Angew. Chem., Int. Ed. 2007, 46, 3410– 3449, DOI: 10.1002/anie.200604335
  4a
  Catalytic carbophilic activation: catalysis by platinum and gold π acids
  Fuerstner, Alois; Davies, Paul W.
  Angewandte Chemie, International Edition (2007), 46 (19), 3410-3449CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The ability of platinum and gold catalysts to effect powerful atom-economic transformations has led to a marked increase in their utilization. The quite remarkable correlation of their catalytic behavior with the available structural data, coordination chem., and organometallic reactivity patterns, including relativistic effects, allows the underlying principles of catalytic carbophilic activation by π acids to be formulated. The spectrum of reactivity extends beyond their utility as catalytic and benign alternatives to conventional stoichiometric π acids. The resulting reactivity profile allows this entire field of catalysis to be rationalized, and brings together the apparently disparate electrophilic metal carbene and nonclassical carbocation explanations. The advances in coupling, cycloisomerization, and structural reorganization - from the design of new transformations to the improvement to known reactions - are highlighted in this Review. The application of platinum- and gold-catalyzed transformations in natural product synthesis is also discussed.
  (b) Yamamoto, Y. From σ- to π-Electrophilic Lewis Acids. Application to Selective Organic Transformations. J. Org. Chem. 2007, 72, 7817– 7831, DOI: 10.1021/jo070579k
  4b
  From σ- to π-Electrophilic Lewis Acids. Application to Selective Organic Transformations
  Yamamoto, Yoshinori
  Journal of Organic Chemistry (2007), 72 (21), 7817-7831CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A review. Computed enthalpies of formation for various Lewis acid complexes with representative unsatd. compds. (aldehydes, imines, alkynes, and alkenes) provide a means to evaluate the applicability of a particular catalyst in a catalytic reaction. As expected, main group Lewis acids such as BX3 show much stronger complexes with heteroatoms than with carbon-carbon multiple bonds (σ-electrophilic Lewis acids). Gold(I) and copper(I) salts with non-nucleophilic anions increase the relative strength of coordination to the carbon-carbon multiple bonds (π-electrophilic Lewis acids). As representative examples for the use of σ-electrophilic Lewis acids in org. synthesis, the Lewis acid mediated allylation reactions of aldehydes and imines with allylic organometallic reagents which give the corresponding homoallyl alcs. and amines, resp., are mentioned. The allylation method is applied for the synthesis of polycyclic ether marine natural products, such as hemibrevetoxin B, gambierol, and brevetoxin B. As representative examples for the use of π-electrophilic Lewis acids in org. synthesis, the Zr-, Hf-, or Al-catalyzed trans-stereoselective hydro- and carbosilylation/stannylation of alkynes is mentioned. This method is extended to σ-π chelation controlled redn. and allylation of certain alkynylaldehydes. Gold- and copper-catalyzed benzannulation of ortho-alkynylaldehydes (and ketones) with alkynes (and alkenes) is discovered, which proceeds through the reverse electron demand Diels-Alder type [4 + 2] cycloaddn. catalyzed by the π-electrophilic Lewis acids. This reaction is applied for the short synthesis of (+)-ochromycinone. Palladium and platinum catalysts act as a σ- and/or π-electrophilic catalyst depending on substrates and reaction conditions.
  (c) Sethofer, S. G.; Mayer, T.; Toste, F. D. Gold(I)-Catalyzed Enantioselective Polycyclization Reactions. J. Am. Chem. Soc. 2010, 132, 8276– 8277, DOI: 10.1021/ja103544p
  4c
  Gold(I)-Catalyzed Enantioselective Polycyclization Reactions
  Sethofer, Steven G.; Mayer, Timo; Toste, F. Dean
  Journal of the American Chemical Society (2010), 132 (24), 8276-8277CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A series of enantioselective polycyclization reactions, catalyzed by a cationic bis(phosphine) gold complexes [[μ-[1,1'-[1,1'-binaphthalene]-2,2'-diylbis[1,1-diphenylphosphine-κP]]]dichlorobis[gold] derivs.] are reported here. Polycyclization reactions which employ an alkyne as an initiating group, begin with a gold-promoted 6-exo-dig cyclization and can be terminated with a variety of nucleophiles including carboxylic acids, phenols, sulfonamides, and electron-rich aryl groups. This method allows for the prepn. of up to four bonds in a single operation with excellent diastereoselectivity and enantioselectivity.
5. 5
  For recent key feature article, see:
  (a) Ríos, P.; Rodríguez, A.; Conejero, S. Enhancing the Catalytic Properties of Well-Defined Electrophilic Platinum Complexes. Chem. Commun. 2020, 56, 5333– 5349, DOI: 10.1039/D0CC01438A
  5a
  Enhancing the catalytic properties of well-defined electrophilic platinum complexes
  Rios Pablo; Rodriguez Amor; Conejero Salvador
  Chemical communications (Cambridge, England) (2020), 56 (40), 5333-5349 ISSN:.
  Platinum complexes have been often considered as the least reactive of the group 10 triad metals. Slow kinetics are behind this lack of reactivity but, still, some industrially relevant catalytic process are dominated by platinum compounds and sometimes different selectivities can be found in comparison to Ni or Pd. Nevertheless, during the last years, it has been reported that the catalytic behaviour of well-defined platinum derivatives can be improved through a judicious choice of their electronic and steric properties, leading to highly electrophilic or low-electron count platinum systems. In this feature article, we highlight some catalytic processes in which well-defined electrophilic platinum complexes or coordinatively unsaturated systems play an important role in their catalytic activity.
  Some representative references:
  (b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. PtCl₂-Catalyzed Conversion of 1,6- and 1,7-Enynes to 1-Vinylcycloalkenes. Anomalous Bond Connection in Skeletal Reorganization of Enynes. Organometallics 1996, 15, 901– 903, DOI: 10.1021/om950832j
  5b
  PtCl2-Catalyzed Conversion of 1,6- and 1,7-Enynes to 1-Vinylcycloalkenes. Anomalous Bond Connection in Skeletal Reorganization of Enynes
  Chatani, Naoto; Furukawa, Naoyuki; Sakurai, Hitoshi; Murai, Shinji
  Organometallics (1996), 15 (3), 901-3CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  The treatment of 1,6-enynes and 1,7-enynes with a catalytic amt. of PtCl2 in toluene at 80 °C resulted in skeletal reorganization (cyclorearrangement) of the enynes to give 1-vinylcyloalkenes in high yields. A deuterium labeling expt. indicates that two mechanistic paths are operating for the cyclorearrangement. For example, the cyclization and rearrangement of (2-propenyl)(2-propynyl)propanedioic acid di-Et ester gave 3-ethenyl-3-cyclopentene-1,1-dicarboxylic acid di-Et ester (86% yield). The cyclization and rearrangement of (3-butenyl)(2-propynyl)propanedioic acid di-Et ester gave 3-ethenyl-3-cyclohexene-1,1-dicarboxylic acid di-Et ester (40% yield). The cyclization of (E)-cinnamyl propargyl ether gave 7-phenyl-3-oxabicyclo[4.1.0]hept-4-ene (9% yield) and polymn. products. The nature and position of substituents affect the reaction course. Anomalous carbon-carbon bond formation is attained selectively in the reaction of 1,6-enynes having an ester group at the terminal acetylenic carbon.
  (c) Oi, S.; Tsukamoto, I.; Miyano, S.; Inoue, Y. Cationic Platinum-Complex-Catalyzed Skeletal Reorganization of Enynes. Organometallics 2001, 20, 3704– 3709, DOI: 10.1021/om010316v
  5c
  Cationic Platinum-Complex-Catalyzed Skeletal Reorganization of Enynes
  Oi, Shuichi; Tsukamoto, Issei; Miyano, Sotaro; Inoue, Yoshio
  Organometallics (2001), 20 (17), 3704-3709CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  The skeletal reorganization of 1,6-enynes into 1-vinylcyclopentenes was catalyzed by a cationic platinum complex under extremely mild conditions. Thus, [Pt(dppp)(PhCN)2](BF4)2 catalyzed cyclization of CH2:CHCH2C(E2)CH2C≡CMe (E = CO2Et) gave 74% vinylcyclopentene I in 28:72 E:Z ratio. The unusual rearrangement of the carbon skeleton, involving the cleavage of both the double and triple carbon-carbon bonds, was obsd. in certain cases and confirmed by 13C- and 2H-labeling expts. Reaction mechanisms describing the rearrangement of carbocations are proposed.
  (d) Fürstner, A. From Understanding to Prediction: Gold- and Platinum-Based Π-Acid Catalysis for Target Oriented Synthesis. Acc. Chem. Res. 2014, 47, 925– 938, DOI: 10.1021/ar4001789
  5d
  From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis
  Fuerstner, Alois
  Accounts of Chemical Research (2014), 47 (3), 925-938CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. During the last century, conceptual advances in organometallic chem. were often rapidly embraced by target oriented synthesis. Feedback provided by such preparative scrutiny has greatly benefitted method development; particularly prominent are examples from the entire cross coupling arena, as well as olefin metathesis. Seen against this backdrop, it is somewhat surprising that the explosive growth of research into π-acid catalysis has not yet yielded a matching no. of implementations into the synthesis of structurally complex targets of biol. significance. In contrast to the massive output of methodol. and mechanistic investigations, few studies illustrate the strategic use of gold, silver, or platinum catalysis in late stages of such multistep endeavors. These elaborate and highly precious compds. demand utmost confidence in the reliability and robustness of the method to be applied. In this Account, we analyze the possible reasons for this imbalance, after a short summary of the conceptual basis of carbophilic activation of π-bonds with the aid of soft transition metal cations or complexes. We pinpoint mechanistic subtleties, which, at least in part, produce a great deal of structural diversity but can jeopardize predictive power. With the advances in the understanding of π-acid catalyzed processes in general, however, this uncertainty is gradually vanishing and the entire field is transitioning from comprehension to prediction. This is expected to foster advanced applications, while recent progress in asym. gold catalysis further improves the preparative significance. The presented work in this Account illustrates our own commitment to the field as well as our growing confidence in the maturity of platinum and gold catalysis. The carbophilic activation of π-bonds, particularly of alkynes, provides a method to manipulate functional groups that is orthogonal to traditional carbonyl chem. We illustrate this notion by presenting a new approach to hydroxypyrone derivs. that has enabled the total synthesis of the fragile polyunsatd. cyclophane deriv. neurymenolide A. The synthesis of the pyrrole alkaloid streptorubin by an enyne cycloisomerization is equally instructive. In addn., different manifestations of transannular hydroxyl addn. reactions across alkyne partners mark the late stages of our conquests of amphidinolide F, polycavernoside A, and spirastrellolide F. Together with a few model studies and a personal selection of recent highlights from other groups, these examples augur well for future applications of π-acid catalysts in the realm of target oriented synthesis.
  (e) Geier, M. J.; Gagné, M. R. Diastereoselective Pt Catalyzed Cycloisomerization of Polyenes to Polycycles. J. Am. Chem. Soc. 2014, 136, 3032– 3035, DOI: 10.1021/ja500656k
  5e
  Diastereoselective Pt Catalyzed Cycloisomerization of Polyenes to Polycycles
  Geier, Michael J.; Gagne, Michel R.
  Journal of the American Chemical Society (2014), 136 (8), 3032-3035CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Application of a tridentate NHC contg. pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates, e.g. I, to the their polycyclic counterparts, e.g. II.
  (f) Toullec, P. Y.; Michelet, V. Chiral Cationic Platinum Complexes: New Catalysts for the Activation of Carbon-Carbon Multiple Bonds Towards Nucleophilic Enantioselective Attack. Curr. Org. Chem. 2010, 14, 1245– 1253, DOI: 10.2174/138527210791330431
  5f
  Chiral cationic platinum complexes. New catalysts for the activation of carbon-carbon multiple bonds towards nucleophilic enantioselective attack
  Toullec, Patrick Y.; Michelet, Veronique
  Current Organic Chemistry (2010), 14 (12), 1245-1253CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
  A review. The concept of π-acid catalysis has emerged as a powerful principle for the chemists to create diversity and originality from simple mols. Carbophilic late transition metals such as gold or platinum have appeared as fascinating catalysts able to activate alkenes, alkynes and other unsatd. derivs. towards anti nucleophilic addn. via complexation on a single empty coordination site. Tunable chiral square-planar cationic platinum complexes created by combination of a mono- and a bidentate ligand appear as a new class of highly promising asym. catalytic systems. This highlight intends to stress the potential applications in enantioselective catalytic reactions assocd. with a variety of chiral cationic tricoordinated platinum complexes recently described in the literature.
  (g) Mascareñas, J. L.; Varela, I.; López, F. Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions. Acc. Chem. Res. 2019, 52, 465– 479, DOI: 10.1021/acs.accounts.8b00567
  5g
  Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions
  Mascarenas, Jose L.; Varela, Ivan; Lopez, Fernando
  Accounts of Chemical Research (2019), 52 (2), 465-479CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. Cycloaddn. reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Esp. appealing are formal cycloaddns. promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chem. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via std. oxidative addn. or reductive elimination processes. Curiously, metals of the third row like platinum and, esp., gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addn. or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddn. reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing no. of reports that exploit the peculiar reactivities of allenes and derivs. In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloaddns. of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddn. processes. Esp. relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties assocd. with the transfer of stereochem. information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered. This Account is organized considering the no. of atoms engaged in the annulation process, and when possible, we present the results in a chronol. order.
6. 6
  For some leading references, see:
  (a) Zhang, L.; Kozmin, S. A. Gold-Catalyzed Assembly of Heterobicyclic Systems. J. Am. Chem. Soc. 2005, 127, 6962– 6963, DOI: 10.1021/ja051110e
  6a
  Gold-Catalyzed Assembly of Heterobicyclic Systems
  Zhang, Liming; Kozmin, Sergey A.
  Journal of the American Chemical Society (2005), 127 (19), 6962-6963CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An efficient gold-catalyzed double cyclization of 1,5-enynes gave a range of heterobicyclic compds., including oxabicyclo[3.2.1]octenes, azabicyclo[3.2.1]octenes, oxaspiro[5.4]decene, azaspiro[5.4]decene, oxaspiro[5.5]undecene, oxabicyclo[4.3.0]nonene, azabicyclo[4.3.0]nonene, and oxabicyclo[4.4.0]decene. The mechanism of this reaction is proposed to involve a chemoselective gold-based alkyne activation, carbocyclization, intramol. nucleophilic addn., followed by protodemetalation. The most notable aspect of this process is the efficient and diastereospecific interception of the reactive intermediate of the initial 6-endo-dig (or 5-endo-dig) cyclization with either oxygen- or nitrogen-based nucleophiles.
  (b) Lim, C.; Kang, J.-E.; Lee, J.-E.; Shin, S. Gold-Catalyzed Tandem C–C and C–O Bond Formation: A Highly Diastereoselective Formation of Cyclohex-4-ene-1,2-diol Derivatives. Org. Lett. 2007, 9, 3539– 3542, DOI: 10.1021/ol071402f
  6b
  Gold-catalyzed tandem C-C and C-O bond formation: a highly diastereoselective formation of cyclohex-4-ene-1,2-diol derivatives
  Lim, Choongmin; Kang, Ji-Eun; Lee, Ji-Eun; Shin, Seunghoon
  Organic Letters (2007), 9 (18), 3539-3542CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  An efficient gold(I)-catalyzed tandem cyclization of tert-Bu carbonate derivs. of hex-1-en-5-yn-3-ol where nucleophilic participation of the O-Boc group appears to intercept a carbocationic (or cyclopropyl carbene) Au intermediate was reported. This protocol led to densely functionalized cyclohexene-3,4-diol derivs. where 1,2- or 1,2,3-stereocenters are controlled in a highly diastereoselective fashion.
  (c) Fürstner, A. Gold and Platinum Catalysis-a Convenient Tool for Generating Molecular Complexity. Chem. Soc. Rev. 2009, 38, 3208– 3221, DOI: 10.1039/b816696j
  6c
  Gold and platinum catalysis-a convenient tool for generating molecular complexity
  Fuerstner, Alois
  Chemical Society Reviews (2009), 38 (11), 3208-3221CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  This review intends to familiarize the reader with the essence of π-acid catalysis, in particular with reactions or reaction cascades effected by gold and platinum complexes. Even though materialized in apparently different reactivity modes, such noble metal catalyzed processes can be easily rationalized on the basis of a uniform mechanistic scheme that is outlined in detail. The resulting increase in mol. complexity is illustrated by selected natural product total syntheses and the formation of various intricate non-natural compds. (106 refs.).
  (d) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity. Chem. Rev. 2015, 115, 9028– 9072, DOI: 10.1021/cr500691k
  6d
  Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity
  Dorel, Ruth; Echavarren, Antonio M.
  Chemical Reviews (Washington, DC, United States) (2015), 115 (17), 9028-9072CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. In this review, the authors cover reactions of alkynes activated by gold(I) complexes, including recent applications of these transformations in the synthesis of natural products. The main focus is on the application of gold(I)-catalyzed reactions of alkynes in org. synthesis, and the reactions are organized mechanistically. Reactions of gold(I)-activated alkenes and allenes, as well as gold(III)-activated alkynes, are not covered in this review.
  (e) Li, Y.; Li, W.; Zhang, J. Gold-Catalyzed Enantioselective Annulations. Chem. – Eur. J. 2017, 23, 467– 512, DOI: 10.1002/chem.201602822
  6e
  Gold-Catalyzed Enantioselective Annulations
  Li, Yangyan; Li, Wenbo; Zhang, Junliang
  Chemistry - A European Journal (2017), 23 (3), 467-512CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This review summarized the methods to construct chiral cyclic compds. by gold-catalyzed enantioselective annulations reported since 2005. The review was organized according to the general annulation types catalyzed by chiral gold complexes or chiral gold salts, which have four main types (cycloaddns., cyclizations of C-C multiple bonds with tethered nucleophiles, cycloisomerization or cyclization of enynes, and tandem annulations), as well as some other strategies. The general reaction mechanisms of each subcategory, key intermediates for some unusual transformations, and the application of several novel ligands and chiral goldsalts were also discussed.
  (f) Marín-Luna, M.; Nieto Faza, O.; Silva López, C. Gold-Catalyzed Homogeneous (Cyclo)isomerization Reactions. Front. Chem. 2019, 7, 296, DOI: 10.3389/fchem.2019.00296
  6f
  Gold-catalyzed homogeneous (Cyclo)isomerization reactions
  Marin-Luna, Marta; Faza, Olalla Nieto; Lopez, Carlos Silva
  Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 296CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
  A review summarizes the most recent contributions in which Au(I)- and/or Au(III)-catalysts mediate intramol. (cyclo)isomerization transformations of unsatd. species, which commonly feature allene or alkyne motifs, and organize them depending on the substrate and the reaction type. Au is currently one of the most used metals in organometallic catalysis. The ability of Au to activate unsatd. groups in different modes, together with its tolerance to a wide range of functional groups and reaction conditions, turns Au-based complexes into efficient and highly sought after catalysts. Natural products and relevant compds. with biol. and pharmaceutical activity are often characterized by complex mol. structures. (Cyclo)isomerization reactions are often a useful strategy for the generation of this mol. complexity from synthetically accessible reactants.
  (g) Virumbrales, C.; Suárez-Pantiga, S.; Marín-Luna, M.; Silva López, C.; Sanz, R. Unlocking the 5-exo Pathway with the Au^I-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes. Chem. – Eur. J. 2020, 26, 8443– 8451, DOI: 10.1002/chem.202001296
  6g
  Unlocking the 5-exo Pathway with the AuI-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes
  Virumbrales, Cintia; Suarez-Pantiga, Samuel; Marin-Luna, Marta; Silva Lopez, Carlos; Sanz, Roberto
  Chemistry - A European Journal (2020), 26 (38), 8443-8451CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes was described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne played a crucial role on the regiochem. outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes was synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addn., mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity obsd. between both E/Z geometrical isomers as well as for the stereochem. outcome of the reaction.
  (h) Mies, T.; White, A. J. P.; Parsons, P. J.; Barrett, A. G. M. Biomimetic Syntheses of Analogs of Hongoquercin A and B by Late-Stage Derivatization. J. Org. Chem. 2021, 86, 1802– 1817, DOI: 10.1021/acs.joc.0c02638
  6h
  Biomimetic syntheses of analogs of Hongoquercin A and B by late-stage derivatization
  Mies, Thomas; White, Andrew J. P.; Parsons, Philip J.; Barrett, Anthony G. M.
  Journal of Organic Chemistry (2021), 86 (2), 1802-1817CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The Hongoquercins are tetracyclic meroterpenoid natural products with the trans-transoid decalin-dihydrobenzopyran ring system, which display a range of different bioactivities. In this study, the syntheses of a range of Hongoquercins using gold-catalyzed enyne cyclization reactions and further derivatization are described. The parent enyne resorcylate precursors were synthesized biomimetically from the corresponding dioxanone keto ester via regioselective acylation, Tsuji-Trost allylic decarboxylative rearrangement, and aromatization. The dioxanone keto ester 12 was prepd. in 6 steps from geraniol using allylic functionalization and alkyne synthesis.
7. 7
  (a) Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. Skeletal Reorganization of Enynes to 1-Vinylcycloalkenes Catalyzed by GaCl₃. J. Am. Chem. Soc. 2002, 124, 10294– 10295, DOI: 10.1021/ja0274554
  7a
  Skeletal Reorganization of Enynes to 1-Vinylcycloalkenes Catalyzed by GaCl3
  Chatani, Naoto; Inoue, Hiroki; Kotsuma, Taiichi; Murai, Shinji
  Journal of the American Chemical Society (2002), 124 (35), 10294-10295CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The GaCl3-catalyzed transformation of enynes, e.g. I, into 1-vinylcycloalkenes, e.g. II, is the first example of the skeletal reorganization of enynes catalyzed by typical metal complexes. The process is simple and provides a diverse range of vinylcycloalkenes in good to high yields (66-87%). The reaction of enynes with a monosubstituent at the terminal olefinic carbon proceeds in a stereospecific manner with respect to the geometry of the olefin moiety. This skeletal rearrangement proceeds efficiently even with enynes, bearing two substituents at the olefinic terminal carbon, which were previously known as unsuitable substrates for similar transformations.
  (b) Tang, S.; Monot, J.; El-Hellani, A.; Michelet, B.; Guillot, R.; Bour, C.; Gandon, V. Cationic Gallium(III) Halide Complexes: a New Generation of π-Lewis Acids. Chem. – Eur. J. 2012, 18, 10239– 10243, DOI: 10.1002/chem.201201202
  7b
  Cationic Gallium(III) Halide Complexes: a New Generation of π-Lewis Acids
  Tang, Shun; Monot, Julien; El-Hellani, Ahmad; Michelet, Bastien; Guillot, Regis; Bour, Christophe; Gandon, Vincent
  Chemistry - A European Journal (2012), 18 (33), 10239-10243, S10239/1-S10239/17CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The combination of (NHC)GaX3 complexes and AgSbF6 advantageously replaces hygroscopic GaX3 salts. While the peculiar selectivity of the salts is maintained, the air-stable NHC adducts allow better yields at lower temps. and faster reaction times. Catalytic amts. as low as 1 mol % can be used, which is not possible with simple gallium(III) halides. Besides, a "silver-free" protocol based on the use of well-defined cationic gallium halides has been developed. The advantages of having one metal instead of two in the reaction mixt. have been clearly recognized in the field of gold catalysis. This paves the way for further developments in Ga(III) catalysis in general, and in (asym.) π-acid catalysis in particular. The synthesis of air- and moisture-stable, and yet active, cationic gallium species is also a goal actively pursued in authors lab.
  (c) Strom, K. R.; Impastato, A. C.; Moy, K. J.; Landreth, A. J.; Snyder, J. K. Gallium(III)-Promoted Halocyclizations of 1,6-Diynes. Org. Lett. 2015, 17, 2126– 2129, DOI: 10.1021/acs.orglett.5b00716
  7c
  Gallium(III)-Promoted Halocyclizations of 1,6-Diynes
  Strom, Kyle R.; Impastato, Anna C.; Moy, Kenneth J.; Landreth, Adrian J.; Snyder, John K.
  Organic Letters (2015), 17 (9), 2126-2129CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Cyclization of 1,6-diynes promoted by stoichiometric Ga(III) halides produces vinyl halides I [ R1 = H, Me, Et, Ph, CH2SiMe3; R2 = H, 4-OMe, 4-Cl, etc.; A = O, NTs; X = Br, I, Cl] in good to excellent yields. Under acidic conditions, initially formed iodocyclization products undergo in situ Friedel-Crafts cyclizations, giving access to iodoindenopyridines II [R1 = H, Me, Et; R2 = H, 4-OMe, 4-Cl, etc.; A = O, NTs]. Application of the vinyl halides in cross-coupling reactions has been explored, and mechanistic aspects of the cyclization are discussed.
8. 8
  (a) Kita, Y.; Yata, T.; Nishimoto, Y.; Chiba, K.; Yasuda, M. Selective Oxymetalation of Terminal Alkynes Via 6-endo Cyclization: Mechanistic Investigation and Application to the Efficient Synthesis of 4-Substituted Isocoumarins. Chem. Sci. 2018, 9, 6041– 6052, DOI: 10.1039/C8SC01537F
  8a
  Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins
  Kita, Yuji; Yata, Tetsuji; Nishimoto, Yoshihiro; Chiba, Kouji; Yasuda, Makoto
  Chemical Science (2018), 9 (28), 6041-6052CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  Herein, a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position was reported. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decompn. of terminal alkynes, resp. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallog. anal. The theor. calcn. of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodn. control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the at. characters of indium, boron and their ligands would contribute to such a regioselective switch. and metalated isocoumarins were applied to org. synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups and palladium-catalyzed cross coupling of organometallic species with org. halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.
  (b) Kang, K.; Nishimoto, Y.; Yasuda, M. Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -Stannane Nucleophiles. J. Org. Chem. 2019, 84, 13345– 13363, DOI: 10.1021/acs.joc.9b01505
  8b
  Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -stannane Nucleophiles
  Kang, Kyoungmin; Nishimoto, Yoshihiro; Yasuda, Makoto
  Journal of Organic Chemistry (2019), 84 (21), 13345-13363CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The authors achieved regio- and stereoselective carboindation of terminal and internal alkynyl ethers using InI3 and organosilicon or -stannane nucleophiles to synthesize (Z)-β-alkoxyalkenylindiums. The carbometalation regio- and stereoselectively proceeded in anti-addn. fashion, which was confirmed by x-ray diffraction anal. of (Z)-β-alkoxyalkenylindium products. Theor. calcn. on the carboindation of alkynyl ethers to elucidate the effect of an alkoxy group was conducted in parallel with calcns. on a C analog of the alkynyl ether. Reaction profiles and computational data of carboindation suggest that the alkoxy group enhances the interaction between InI3 and an alkyne moiety and reduces the activation energy. Many types of C nucleophiles such as silyl ketene acetals, silyl ketene imines, a silyl cyanide, an alkynyl stannane, and an allylic stannane were applicable to the present reaction system to give highly functionalized metalated enol ethers (β-alkoxyalkenylindiums). The prepd. β-alkoxyalkenylindiums were transformed to various functionalized tetrasubstituted enol ethers by iodination followed by Suzuki coupling. The synthesis of a seven-membered ring compd. contg. a phenol ether moiety was accomplished using a sequential process that included the present stereoselective carboindation.
  (c) Tani, T.; Sohma, Y.; Tsuchimoto, T. Zinc/Indium Bimetallic Lewis Acid Relay Catalysis for Dehydrogenative Silylation/Hydrosilylation Reaction of Terminal Alkynes with Bis(hydrosilane)s. Adv. Synth. Catal. 2020, 362, 4098– 4108, DOI: 10.1002/adsc.202000501
  8c
  Zinc/Indium Bimetallic Lewis Acid Relay Catalysis for Dehydrogenative Silylation/Hydrosilylation Reaction of Terminal Alkynes with Bis(hydrosilane)s
  Tani, Tomohiro; Sohma, Yudai; Tsuchimoto, Teruhisa
  Advanced Synthesis & Catalysis (2020), 362 (19), 4098-4108CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  When mixed with two different Lewis acid catalysts of Zn and In, terminal alkynes react with bis(hydrosilane)s to selectively provide 1,1-disilylalkenes from among several possible products, by way of a sequential dehydrogenative silylation/intramol. hydrosilylation reaction. Adding a pyridine base is crucial in this reaction; a switch as a catalyst of the Zn Lewis acid is turned on by forming a Zn-pyridine-base complex. A range of the 1,1-disilylalkenes can be obtained by a combination of aryl and aliph. terminal alkynes plus aryl-, heteroaryl-, and naphthyl-tethered bis(hydrosilane)s. The 1,1-disilylalkene prepd. here is available as a reagent for further transformations by using its C-Si or C:C bond. The former includes Hiyama cross-coupling, Bi-catalyzed ether formation, and iododesilylation; the latter includes double alkylation and epoxidn. Mechanistic studies clarified the role of the two Lewis acids: the Zn-pyridine-base complex catalyzes the dehydrogenative silylation as a 1st stage, and, following on this, the In Lewis acid catalyzes the ring-closing hydrosilylation as a 2nd stage, thus leading to the 1,1-disilylalkene.
  (d) Vayer, M.; Bour, C.; Gandon, V. Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds Under π-Acid Catalysis. Eur. J. Org. Chem. 2020, 2020, 5350– 5357, DOI: 10.1002/ejoc.202000623
  8d
  Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds Under π-Acid Catalysis
  Vayer, Marie; Bour, Christophe; Gandon, Vincent
  European Journal of Organic Chemistry (2020), 2020 (33), 5350-5357CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The reactivity of 7-alkynycycloheptatrienes tethered to an aryl group under π-acid catalysis has been studied. A variety of useful cyclic products were synthesized via Au(I)-catalyzed skeletal reorganization, Cu(II)-catalyzed hydroarylation, or Broensted acid-catalyzed tandem hydroarylation/Friedel-Crafts reaction. We also report a rare type of skeletal reorganization involving the 1,3-acetonide tether in the presence of a univalent cationic Ga(I)+ complex.
  (e) Tian, J.; Chen, Y.; Vayer, M.; Djurovic, A.; Guillot, R.; Guermazi, R.; Dagorne, S.; Bour, C.; Gandon, V. Exploring the Limits of π-Acid Catalysis Using Strongly Electrophilic Main Group Metal Complexes: the Case of Zinc and Aluminium. Chem. – Eur. J. 2020, 26, 12831– 12838, DOI: 10.1002/chem.202001376
  8e
  Exploring the Limits of π-Acid Catalysis Using Strongly Electrophilic Main Group Metal Complexes: The Case of Zinc and Aluminum
  Tian, Jiaxin; Chen, Yan; Vayer, Marie; Djurovic, Alexandre; Guillot, Regis; Guermazi, Refka; Dagorne, Samuel; Bour, Christophe; Gandon, Vincent
  Chemistry - A European Journal (2020), 26 (56), 12831-12838CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The catalytic activity of cationic NHC-Zn(II) and NHC-Al(III) (NHC=N-heterocyclic carbene) complexes in reactions that require the electrophilic activation of soft C-C π bonds has been studied. The former proved able to act as a soft π-Lewis acid in a variety of transformations. The benefit of the bulky IPr NHC ligand was demonstrated by comparison with simple ZnX2 salts. The tested NHC-Al(III) catalyst is not able to activate C-C π bonds but simple AlX2+ ions were found potent in some cases.
9. 9
  For some revisions see:
  (a) Augé, J.; Lubin-Germain, N.; Uziel, J. Recent Advances in Indium-Promoted Organic Reactions. Synthesis 2007, 2007, 1739– 1764, DOI: 10.1055/s-2007-983703
  There is no corresponding record for this reference.
  (b) Pathipati, S. R.; van der Werf, A.; Selander, N. Indium(III)-Catalyzed Transformations of Alkynes: Recent Advances in Carbo- and Heterocyclization Reactions. Synthesis 2017, 49, 4931– 4941, DOI: 10.1055/s-0036-1588555
  9b
  Indium(III)-Catalyzed Transformations of Alkynes: Recent Advances in Carbo- and Heterocyclization Reactions
  Pathipati, Stalin R.; van der Werf, Angela; Selander, Nicklas
  Synthesis (2017), 49 (22), 4931-4941CODEN: SYNTBF; ISSN:1437-210X. (Georg Thieme Verlag)
  A review. The use of a well-chosen catalyst is instrumental for the development of more efficient, economical and environmentally friendly reactions. In recent decades, indium-based catalysts have proven to be competitive and useful alternatives to transition-metal catalysts such as silver and gold. In this short review, we present some of the recent advances in indium(III)-catalyzed transformations of alkynes, with a focus on cyclization reactions: (1 )introduction, (2) terminal alkynes as nucleophiles, (3) nucleophilic addns. to alkynes, (4) carbo- and heterocyclization reactions, (4.1) carbocyclization, (4.2) oxygen-based heterocycles, (4.3) nitrogen-based heterocycles, (4.4) sulfur-based heterocycles, (5) conclusion.
  (c) Sestelo, J. P.; Sarandeses, L. A.; Martínez, M. M.; Alonso-Marañón, L. Indium(III) as π-Acid Catalyst for the Electrophilic Activation of Carbon–Carbon Unsaturated Systems. Org. Biomol. Chem. 2018, 16, 5733– 5747, DOI: 10.1039/C8OB01426D
  There is no corresponding record for this reference.
10. 10
  Araki, S.; Hirashita, T. Comprehensive Organometallic Chemistry III; Crabtree, R. H.; Mingos, D. M. P., Eds.; Elsevier: Oxford, 2007; Vol. 9, pp 649– 722.
  There is no corresponding record for this reference.
11. 11
  (a) Cintas, P. Synthetic Organoindium Chemistry: What Makes Indium So Appealing?. Synlett 1995, 1995, 1087– 1096, DOI: 10.1055/s-1995-5192
  There is no corresponding record for this reference.
  (b) Frost, C. G.; Hartley, J. P. New Applications of Indium Catalysts in Organic Synthesis. Mini-Rev. Org. Chem. 2004, 1, 1– 7, DOI: 10.2174/1570193043489006
  11b
  New applications of indium catalysts in organic synthesis
  Frost, C. G.; Hartley, J. P.
  Mini-Reviews in Organic Chemistry (2004), 1 (1), 1-7CODEN: MOCIBT; ISSN:1570-193X. (Bentham Science Publishers Ltd.)
  A review. Indium(III) salts as Lewis acid catalysts in org. syntheses are discussed. The stability of the salts as coordination active centers in substoichiometric quantities is discussed in terms of various reaction mechanisms. The stability of the In salts in water allows aq. recycling and often the use of water as a reaction solvent. Reactions described include arom. functionalization, cycloaddn. reactions, conjugate addns. and multi-component coupling reactions.
  (c) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Indium Salt-Promoted Organic Reactions. Curr. Org. Chem. 2003, 7, 1661– 1689, DOI: 10.2174/1385272033486251
  11c
  Indium salt-promoted organic reactions
  Fringuelli, Francesco; Piermatti, Oriana; Pizzo, Ferdinando; Vaccaro, Luigi
  Current Organic Chemistry (2003), 7 (16), 1661-1689CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
  A review. The use of indium salts as catalysts and mediators in nucleophilic addn. reactions (with or without ring opening), cyclization (Diels-Alder, Biginelli, Prins, etc.), arom. electrophilic substitution, nucleophilic substitution, coupling, redn., rearrangement and polymn. reactions, reported in the period from 2000 and the first half of 2002, is reviewed. InCl3, InBr3, InI3, InCl, InBr, InI, In(OTf)3 (Tf = F3CSO2), and In(NTf)3 are the most commonly used indium salts used. The use of indium salts, generally, allows the reaction to be carried out under mild conditions, in high yields and with high selectivity. Sometimes, an aq. medium can be used and the catalyst can be reused.
  (d) Yadav, J. S.; Antony, A.; George, J.; Subba Reddy, B. V. Recent Developments in Indium Metal and Its Salts in Organic Synthesis. Eur. J. Org. Chem. 2010, 2010, 591– 605, DOI: 10.1002/ejoc.200900895
  There is no corresponding record for this reference.
  (f) Singh, M. S.; Raghuvanshi, K. Recent Advances in InCl₃-Catalyzed One-Pot Organic Synthesis. Tetrahedron 2012, 68, 8683– 8697, DOI: 10.1016/j.tet.2012.06.099
  11f
  Recent advances in InCl3-catalyzed one-pot organic synthesis
  Singh, Maya Shankar; Raghuvanshi, Keshav
  Tetrahedron (2012), 68 (42), 8683-8697CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  A review was given on recent progress in a large variety of InCl3-catalyzed/mediated reactions performed in solvent and/or under solvent-free conditions. The review is organized starting with the introduction of org. synthesis via multicomponent reactions, followed by advantages of InCl3 as catalyst, and an overview of the org. reactions that were traditionally conducted under InCl3 catalysis.
12. 12
  For representative examples, see:
  (a) Mamane, V.; Hannen, P.; Fürstner, A. Synthesis of Phenanthrenes and Polycyclic Heteroarenes by Transition-Metal Catalyzed Cycloisomerization Reactions. Chem. – Eur. J. 2004, 10, 4556– 4575, DOI: 10.1002/chem.200400220
  12a
  Synthesis of phenanthrenes and polycyclic heteroarenes by transition-metal catalyzed cycloisomerization reactions
  Mamane, Victor; Hannen, Peter; Fuerstner, Alois
  Chemistry - A European Journal (2004), 10 (18), 4556-4575CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Readily available biphenyl derivs. contg. an alkyne unit at one of their ortho-positions were converted into substituted phenanthrenes, e.g., I, on exposure to catalytic amts. of either PtCl2, AuCl, AuCl3, GaCl3 or InCl3 in toluene. This 6-endo-dig cyclization likely proceeded through initial π-complexation of the alkyne unit followed by interception of the resulting η2-metal species by the adjacent arene ring. The reaction was inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product. Moreover, it was readily extended to the heterocyclic series as exemplified by the prepn. of benzoindoles, benzocarbazoles, naphthothiophenes, as well as bridgehead nitrogen heterocycles such as pyrrolo[1,2-a]quinolines, e.g., II. Depending on the chosen catalyst, biaryls bearing halo-alkyne units can either be converted into the corresponding 10-halo-phenanthrenes or into the isomeric 9-halo-phenanthrenes; in the latter case, the concomitant 1,2-halide shift was best explained by assuming a metal vinylidene species as the reactive intermediate. The scope of this method for the prepn. of polycyclic arenes was illustrated by the total synthesis of a series of polyoxygenated phenanthrenes that were close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring sym. dimer.
  (b) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Regio- and Stereoselective Generation of Alkenylindium Compounds From Indium Tribromide, Alkynes, and Ketene Silyl Acetals. Angew. Chem., Int. Ed. 2009, 48, 4577– 4580, DOI: 10.1002/anie.200901417
  12b
  Regio- and Stereoselective Generation of Alkenylindium Compounds from Indium Tribromide, Alkynes, and Ketene Silyl Acetals
  Nishimoto, Yoshihiro; Moritoh, Ryosuke; Yasuda, Makoto; Baba, Akio
  Angewandte Chemie, International Edition (2009), 48 (25), 4577-4580, S4577/1-S4577/27CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  InBr3 promotes the addn. of ketene silyl acetals to monosubstituted alkynes to afford 2,2-disubstituted alkenylindium compds. in high regio- and stereoselectivity. In addn., the alkenylindium derivs. have been subsequently coupled with iodobenzene in the presence of a palladium catalyst. Thus, InBr3 mediated reaction of PhC≡CH with Me2C:C(OMe)(OSiMe3) in CH2Cl2 followed by washing with hexane/CD3CN gave a mixt. of Br2InCH:CPhCMe2CO2Me (6) and BrIn(CH:CPhCMe2CO2Me)2. The crystal structures of 6 and 7 and their hydrolysis to give Me 2,2-dimethyl-3-phenyl-3-butenoate is described.
  (c) Antoniotti, S.; Dalla, V.; Duñach, E. Metal Triflimidates: Better Than Metal Triflates as Catalysts in Organic Synthesis-the Effect of a Highly Delocalized Counteranion. Angew. Chem., Int. Ed. 2010, 49, 7860– 7888, DOI: 10.1002/anie.200906407
  12c
  Metal triflimidates. Better than metal triflates as catalysts in organic synthesis. The effect of a highly delocalized counteranion
  Antoniotti, Sylvain; Dalla, Vincent; Dunach, Elisabet
  Angewandte Chemie, International Edition (2010), 49 (43), 7860-7888CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The continuously increasing need for novel and selective methods in org. synthesis to aid drug discovery and to address environmental concerns is a const. source of stimulation to develop novel and more efficient reaction systems. This often resulted in a focus on transition metals, ligands, and additives, with much less attention paid to the counterion(s) of the metal cation. Recently, metal salts with one or more triflimidate counterion(s) appeared as a unique class of catalysts that display outstanding σ- and π-Lewis acid character. The highly delocalized nature of the triflimidate counterion, combined with its high steric hindrance results in virtually no nucleophilic behavior and an extremely high pos. charge d. on the metal cation, thus enhancing its Lewis acid character. Consequently, these metal triflimidates often outperform their metal halide or triflate analogs. This review described general methods for the prepn. of metal triflimidate salts and their use as catalysts.
  (d) Tsuchimoto, T.; Kanbara, M. Reductive Alkylation of Indoles with Alkynes and Hydrosilanes Under Indium Catalysis. Org. Lett. 2011, 13, 912– 915, DOI: 10.1021/ol1029673
  12d
  Reductive Alkylation of Indoles with Alkynes and Hydrosilanes under Indium Catalysis
  Tsuchimoto, Teruhisa; Kanbara, Mitsutaka
  Organic Letters (2011), 13 (5), 912-915CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Under Indium catalysis, diverse alkylindoles were successfully prepd. with a flexible combination of indoles and alkynes in the presence of hydrosilanes. In addn. to the hydrosilane, carbon nucleophiles are also available. This new method generates alkylindoles, e.g. I, in yields over 70% with a broad scope of functional group compatibility.
  (e) Kumar, A.; Li, Z.; Sharma, S. K.; Parmar, V. S.; Van der Eycken, E. V. Switching the Regioselectivity via Indium(III) and Gold(I) Catalysis: a Post-Ugi Intramolecular Hydroarylation to Azepino- and Azocino-[c,d]indolones. Chem. Commun. 2013, 49, 6803– 6805, DOI: 10.1039/c3cc42704h
  12e
  Switching the regioselectivity via indium(III) and gold(I) catalysis: a post-Ugi intramolecular hydroarylation to azepino- and azocino-[c,d]indolones
  Kumar, Amit; Li, Zhenghua; Sharma, Sunil K.; Parmar, Virinder S.; Van der Eycken, Erik V.
  Chemical Communications (Cambridge, United Kingdom) (2013), 49 (60), 6803-6805CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A post-Ugi indium(III)- and gold(I)-mediated regioselective intramol. hydroarylation for the synthesis of azepino- and azocino-[c,d]indolones is described.
  (f) Michelet, B.; Colard-Itte, J.-R.; Thiery, G.; Guillot, R.; Bour, C.; Gandon, V. Dibromoindium(III) Cations as a π-Lewis Acid: Characterization of [IPr·InBr₂][SbF₆] and Its Catalytic Activity Towards Alkynes and Alkenes. Chem. Commun. 2015, 51, 7401– 7404, DOI: 10.1039/C5CC00740B
  12f
  Dibromoindium(III) cations as a π-Lewis acid: characterization of [IPr·InBr2][SbF6] and its catalytic activity towards alkynes and alkenes
  Michelet, Bastien; Colard-Itte, Jean-Remy; Thiery, Guillaume; Guillot, Regis; Bour, Christophe; Gandon, Vincent
  Chemical Communications (Cambridge, United Kingdom) (2015), 51 (34), 7401-7404CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  [IPr·InBr2][SbF6] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has been synthesized and characterized in the solid state. This complex proved to be a very active catalyst for hydroarylations, transfer hydrogenations, and cycloisomerizations.
  (g) Yonekura, K.; Yoshimura, Y.; Akehi, M.; Tsuchimoto, T. A Heteroarylamine Library: Indium-Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines. Adv. Synth. Catal. 2018, 360, 1159– 1181, DOI: 10.1002/adsc.201701452
  12g
  A Heteroarylamine Library: Indium-Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines
  Yonekura, Kyohei; Yoshimura, Yasuhiro; Akehi, Mizuri; Tsuchimoto, Teruhisa
  Advanced Synthesis & Catalysis (2018), 360 (6), 1159-1181CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Under indium Lewis acid catalysis, electron-rich five-membered heteroaryl electrophiles fused with/without a benzene ring were found to couple with amines to produce heteroarylamines with broad structural diversity. The heteroarylamine formation proceeds through the cleavage of a heteroaryl-OMe bond by the nucleophilic attack of the amine based on the nucleophilic arom. substitution (SNAr) reaction. In contrast to the corresponding traditional SNAr amination, the present SNAr-based heteroaryl amination can be performed without relying on both heteroaryl electrophiles with electron-withdrawing groups and nucleophilicity-enhanced metal amides. High compatibility towards the functional groups such as NO2, Br, I, CF3, CN, CO2Et, pyridyl, thiazolyl, C=C, and OH groups was obsd., thus showing the practicality and reliability of this method. Mechanistic studies indicated that a carbon-indium bond is likely to be formed on the heteroaryl ring during the process.
  (h) de Orbe, M. E.; Zanini, M.; Quinonero, O.; Echavarren, A. M. Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with Allylsilanes Through a Concealed Rearrangement. ACS Catal. 2019, 9, 7817– 7822, DOI: 10.1021/acscatal.9b02314
  12h
  Gold- or Indium-Catalyzed Cross-Coupling of Bromoalkynes with Allylsilanes through a Concealed Rearrangement
  de Orbe, M. Elena; Zanini, Margherita; Quinonero, Ophelie; Echavarren, Antonio M.
  ACS Catalysis (2019), 9 (9), 7817-7822CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  The gold(I)-catalyzed reaction of bromoalkynes with allylsilanes gives 1,4-enynes in a formal cross-coupling reaction. Mechanistic studies revealed the involvement of gold(I) vinylidenes or vinylidenephenonium gold(I) cations depending on the substituent on the bromoalkyne. In the case of bromo arylalkynes, the vinylidenephenonium gold(I) cations lead to 1,4-enynes via a 1,2-aryl rearrangement. The same reactivity has been obsd. in the presence of InBr3.
13. 13
  For some reviews see:
  (a) Echavarren, A. M.; Nevado, C. Non-Stabilized Transition Metal Carbenes as Intermediates in Intramolecular Reactions of Alkynes with Alkenes. Chem. Soc. Rev. 2004, 33, 431– 436, DOI: 10.1039/b308768a
  13a
  Non-stabilized transition metal carbenes as intermediates in intramolecular reactions of alkynes with alkenes
  Echavarren, Antonio M.; Nevado, Cristina
  Chemical Society Reviews (2004), 33 (7), 431-436CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. In this tutorial review we summarize the two major pathways followed in the reaction of alkenes with alkynes catalyzed by electrophilic transition metals. If the metal coordinates simultaneously to the alkyne and the alkene, an oxidative cyclometallation can ensue to give a metallacyclopentene, which usually evolves by β-hydrogen elimination to give Alder-ene cycloisomerization derivs. On the other hand, coordination of the metal to the alkyne promotes the attack of the alkene to give metal cyclopropyl carbenes.
  (b) Jiménez-Núñez, E.; Echavarren, A. M. Gold-Catalyzed Cycloisomerizations of Enynes: a Mechanistic Perspective. Chem. Rev. 2008, 108, 3326– 3350, DOI: 10.1021/cr0684319
  13b
  Gold-Catalyzed Cycloisomerizations of Enynes: A Mechanistic Perspective
  Jimenez-Nunez, Eloisa; Echavarren, Antonio M.
  Chemical Reviews (Washington, DC, United States) (2008), 108 (8), 3326-3350CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. Homogeneous catalysis by gold is a relatively young area of research that has grown very rapidly in the last 3-4 years. Since excellent comprehensive reviews of gold chem. have already been published recently, this review will cover gold-catalyzed cycloisomerization reactions of 1,n-enynes in detail, with a focus on their mechanisms. Cyclizations with concomitant addn. of nucleophiles to 1,n-enynes are also covered, as these reactions shed light on the general mechanism of cyclizations of enynes. These reactions are domino-type transformations in which two bonds (C-C/C-X or two C-C) are consecutively formed.
  (c) Toullec, P. Y.; Michelet, V. Cycloisomerization of 1,n-Enynes via Carbophilic Activation. Top. Curr. Chem. 2011, 302, 31– 80
  13c
  Cycloisomerization of 1,n-enynes via carbophilic activation
  Toullec, Patrick Yves; Michelet, Veronique
  Topics in Current Chemistry (2011), 302 (Computational Mechanisms of Au and Pt Catalyzed Reactions), 31-80CODEN: TPCCAQ; ISSN:0340-1022. (Springer GmbH)
  A review. Metal-catalyzed cycloisomerization of 1,n-enynes has appeared as a highly attractive methodol. for the synthesis of original carbocyclic compds. and heterocyclic compds. This chapter intends to propose an overview of the recent advances in 1,n-enynes cycloisomerization reactions in the presence of carbophilic transition metals. The recent mechanistic insights, the enantioselective versions, and the applications in total synthesis are highlighted. Topics thus discussed included carbophilic Lewis acids and their reactivity principles, enyne cycloisomerization reaction on the absence of nucleophiles, formation of dienes, Conia ene-type reactions, formation of bicyclic compds., domino-ene cycloisomerization and nucleophilic addn. reaction, oxygen nucleophiles, carbon nucleophiles, nitrogen nucleophiles, etc.
  (d) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Transition Metal Catalyzed Cycloisomerizations of 1,n-Allenynes and -Allenenes. Chem. Rev. 2011, 111, 1954– 1993, DOI: 10.1021/cr100376w
  13d
  Transition Metal Catalyzed Cycloisomerizations of 1,n-Allenynes and -Allenenes
  Aubert, Corinne; Fensterbank, Louis; Garcia, Pierre; Malacria, Max; Simonneau, Antoine
  Chemical Reviews (Washington, DC, United States) (2011), 111 (3), 1954-1993CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review was given summarizing advances in the cycloisomerization of 1,n-allenynes and 1,n-allenenes. Herein, cycloisomerization refers to the formation of new C-C bonds to accomplish the assembly of carbocyclic or heterocyclic rings for precursors contg. heteroatom-based tethers.
14. 14
  (a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Mercuric Triflate-Catalyzed Tandem Cyclization Leading to Polycarbocycles. Org. Lett. 2005, 7, 451– 453, DOI: 10.1021/ol047472t
  14a
  Mercuric Triflate-Catalyzed Tandem Cyclization Leading to Polycarbocycles
  Imagawa, Hiroshi; Iyenaga, Tomoaki; Nishizawa, Mugio
  Organic Letters (2005), 7 (3), 451-453CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  We developed Hg(OTf)2-catalyzed cyclization of (E)-1,3-dimethoxy-5-(4-methyl-3-nonen-7-ynyl)benzene leading to the formation of (4aS*,10aS*)-3,4,4a,9,10,10a-hexahydro-5,7-dimethoxy-1,4a-dimethylphenanthrene I in 98% yield with up to 100 catalytic turnovers. This is the first mercuric salt-catalyzed biomimetic tandem cyclization.
  (b) Pradal, A.; Chen, Q.; Faudot dit Bel, P.; Toullec, P. Y.; Michelet, V. Gold-Catalyzed Cycloisomerization of Functionalized 1,5-Enynes – an Entry to Polycyclic Framework. Synlett 2012, 2012, 74– 79, DOI: 10.1055/s-0031-1289867
  There is no corresponding record for this reference.
  (c) Rong, Z.; Echavarren, A. M. Broad Scope Gold(I)-Catalysed Polyenyne Cyclisations for the Formation of Up to Four Carbon-Carbon Bonds. Org. Biomol. Chem. 2017, 15, 2163– 2167, DOI: 10.1039/C7OB00235A
  14c
  Broad scope gold(I)-catalysed polyenyne cyclisations for the formation of up to four carbon-carbon bonds
  Rong, Zhouting; Echavarren, Antonio M.
  Organic & Biomolecular Chemistry (2017), 15 (10), 2163-2167CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  The polycyclization of polyenynes catalyzed by gold(I) has been extended for the first time to the simultaneous formation of up to four carbon-carbon bonds, leading to steroid-like mols. with high stereoselectivity in a single step with low catalyst loadings. In addn. to terminal alkynes, bromoalkynes can also be used as initiators of polyene cyclizations, giving rise to synthetically useful cyclic bromoalkenes.
  (d) Lu, X.-L.; Lyu, M.-Y.; Peng, X.-S.; Wong, H. N. C. Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers by Hydride Transfer. Angew. Chem., Int. Ed. 2018, 57, 11365– 11368, DOI: 10.1002/anie.201806842
  14d
  Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers by Hydride Transfer
  Lu, Xiao-Lin; Lyu, Mao-Yun; Peng, Xiao-Shui; Wong, Henry N. C.
  Angewandte Chemie, International Edition (2018), 57 (35), 11365-11368CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A novel gold-catalyzed tandem protocol, initiated by hydride transfer in the presence of catalytic (C6F5)3PAuCl/AgSbF6, for the formation of fused polycyclic ring systems has been achieved. This tandem reaction provides rapid access to various fused polycyclic species in a single chem. operation, leading to stereospecific formation of two carbon-carbon bonds and three rings.
15. 15
  Miyanohana, Y.; Chatani, N. Skeletal Reorganization of Enynes Catalyzed by InCl₃. Org. Lett. 2006, 8, 2155– 2158, DOI: 10.1021/ol060606d
  15
  Skeletal Reorganization of Enynes Catalyzed by InCl3
  Miyanohana, Yuhei; Chatani, Naoto
  Organic Letters (2006), 8 (10), 2155-2158CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The skeletal reorganization of enynes is achieved by the presence of InCl3 as the catalyst. The reaction of enynes having a terminal acetylenic moiety proceeds in a stereospecific manner to give 1-vinylcycloalkenes. The reaction of enynes contg. an alkyl group on the acetylenic terminal carbon resulted in a new type of skeletal reorganization to give 1-allylcycloalkenes, formation of which involves a double cleavage of the C-C double bond and the triple bond.
16. 16
  (a) Surendra, K.; Qiu, W.; Corey, E. J. A Powerful New Construction of Complex Chiral Polycycles by an Indium(III)-Catalyzed Cationic Cascade. J. Am. Chem. Soc. 2011, 133, 9724– 9726, DOI: 10.1021/ja204142n
  16a
  A Powerful New Construction of Complex Chiral Polycycles by an Indium(III)-Catalyzed Cationic Cascade
  Surendra, Karavadhi; Qiu, Wenwei; Corey, E. J.
  Journal of the American Chemical Society (2011), 133 (25), 9724-9726CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  InI3 and InBr3 have been found to be effective catalysts for the π activation of C≡C bonds to initiate the conversion of chiral propargylic alcs. or silyl ethers to polycyclic products in excellent yields and with high stereoselectivity. The method was applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. The power and scope of the method were illustrated by a variety of examples. E.g., pentacycle I (R = SiMe2CMe3) was prepd. with 76% yield by cyclization of diene II (R = SiMe2CMe3) using InBr3 in CH2Cl2.
  (b) Surendra, K.; Corey, E. J. Diiodoindium(III) Cation, InI₂⁺, a Potent Yneophile. Generation and Application to Cationic Cyclization by Selective π-Activation of C≡C. J. Am. Chem. Soc. 2014, 136, 10918– 10920, DOI: 10.1021/ja506502p
  16b
  Diiodoindium(III) Cation, InI2+, a Potent Yneophile. Generation and Application to Cationic Cyclization by Selective π-Activation of C≡C
  Surendra, Karavadhi; Corey, E. J.
  Journal of the American Chemical Society (2014), 136 (31), 10918-10920CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The removal of the iodide ion from indium triiodide by means of reactive Ag(I) salts leads to the formation of the highly reactive ligandless cation InI2+, which is unusual in having two vacant low-lying p-orbitals. This bivalent Lewis acidity leads to an esp. high affinity for the two orthogonal π-bonds of carbon-carbon triple bonds. Consequently, the double-coordinating InI2+ is an esp. effective reagent for the selective activation of C≡C and the catalytic initiation of cationic cyclization processes. A no. of such reactions are described to demonstrate synthetic utility.
17. 17
  For some representative references, see:
  (a) Pérez, I.; Pérez Sestelo, J.; Sarandeses, L. A. Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction of Indium Organometallics with Organic Electrophiles. J. Am. Chem. Soc. 2001, 123, 4155– 4160, DOI: 10.1021/ja004195m
  17a
  Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction of Indium Organometallics with Organic Electrophiles
  Perez, Ignacio; Perez Sestelo, Jose; Sarandeses, Luis A.
  Journal of the American Chemical Society (2001), 123 (18), 4155-4160CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The novel metal-catalyzed cross-coupling reaction of indium organometallics R3In (R = Ph, H2C:CH, PhC≡C, Me3SiC≡C, Bu, Me, c-C3H5, Me3SiCH2) (I) with org. electrophiles such as aryl iodides, bromides, and chlorides, alkenyl triflates, benzyl bromide, and acyl chlorides is described. I are efficiently prepd. from the corresponding lithium or magnesium organometallics by reaction with indium trichloride. The cross-coupling reaction of I with aryl halides and pseudohalides, vinyl triflates, benzyl bromides, and acid chlorides proceeds under palladium catalysis in excellent yields and with high chemoselectivity. I (R = Ph, Bu) also react with 4-methylphenyl chloride in the presence of bis(triphenylphosphine)nickel dichloride to give 4-MeC6H4R in 74 and 83% yields. In cross-coupling reactions, I transfer all three of the org. groups attached to the metal, requiring only 34 mol% of the trialkylindium reagents. The feasibility of using I in reactions with different electrophiles, along with the high yields and chemoselectivities obtained, reveals indium organometallics to be useful alternatives to other organometallics in cross-coupling reactions.
  (b) Caeiro, J.; Pérez Sestelo, J.; Sarandeses, L. A. Enantioselective Nickel-Catalyzed Cross-Coupling Reactions of Trialkynylindium Reagents with Racemic Secondary Benzyl Bromides. Chem. – Eur. J. 2008, 14, 741– 746, DOI: 10.1002/chem.200701035
  17b
  Enantioselective nickel-catalyzed cross-coupling reactions of trialkynylindium reagents with racemic secondary benzyl bromides
  Caeiro, Jorge; Perez Sestelo, Jose; Sarandeses, Luis A.
  Chemistry - A European Journal (2008), 14 (2), 741-746CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The first enantioselective sp-sp3 cross-coupling reaction between alkynyl organometals and racemic benzyl bromides is reported. The coupling is performed at room temp. by using NiBr2·diglyme and (S)-(iPr)-Pybox as the catalytic system and trialkynylindium reagents as nucleophiles. The reaction is stereoconvergent, both enantiomers of the racemic benzyl bromide are converted into one enantiomer of the product, and stereospecific. The reaction takes place efficiently in good yields and with high atom economy, as the triorganoindium reagents transfer the three org. groups attached to indium (only 40 mol % of R3In is used).
  (c) Mato, M.; Pérez-Caaveiro, C.; Sarandeses, L. A.; Pérez Sestelo, J. Ferrocenylindium Reagents in Palladium-Catalyzed Cross-Coupling Reactions: Asymmetric Synthesis of Planar Chiral 2-Aryl Oxazolyl and Sulfinyl Ferrocenes. Adv. Synth. Catal. 2017, 359, 1388– 1393, DOI: 10.1002/adsc.201601397
  17c
  Ferrocenylindium Reagents in Palladium-Catalyzed Cross-Coupling Reactions: Asymmetric Synthesis of Planar Chiral 2-Aryl Oxazolyl and Sulfinyl Ferrocenes
  Mato, Mauro; Perez-Caaveiro, Cristina; Sarandeses, Luis A.; Perez Sestelo, Jose
  Advanced Synthesis & Catalysis (2017), 359 (8), 1388-1393CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The prepn. of ferrocenylindium species and palladium-catalyzed cross-coupling reactions for the synthesis of monosubstituted and planar chiral 1,2-disubstituted ferrocenes is described. Triferrocenylindium reagents (Fc3In) are efficiently prepd. in a one-pot procedure from ferrocenes by lithiation and transmetallation to indium using InCl3. The palladium-catalyzed cross-coupling reactions of Fc3In (40 mol%) with a variety of org. electrophiles (aryl, heteroaryl, benzyl, alkenyl and acyl halides) in THF at 80° overnight provided a wide variety of monosubstituted ferrocenes in good to excellent yields. This methodol. allowed the stereoselective synthesis of planar chiral 2-aryl-1-oxazolylferrocenes and 2-aryl-1-sulfinylferrocenes, which are of interest in asym. catalysis.
  (d) Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Synthesis of Bench-Stable Solid Triorganoindium Reagents and Reactivity in Palladium-Catalyzed Cross-Coupling Reactions. Chem. Commun. 2018, 54, 1453– 1456, DOI: 10.1039/C7CC09344F
  17d
  Synthesis of bench-stable solid triorganoindium reagents and reactivity in palladium-catalyzed cross-coupling reactions
  Gil-Negrete, Jose M.; Perez Sestelo, Jose; Sarandeses, Luis A.
  Chemical Communications (Cambridge, United Kingdom) (2018), 54 (12), 1453-1456CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Bench-stable solid triorganoindium compds. were prepd. by coordination with 4-(dimethylamino)pyridine (DMAP). The solid R3In(DMAP) complexes were obtained from the corresponding soln. of R3In in quant. yield and was stored for up to several weeks. These reagents showed excellent reactivity in palladium-catalyzed cross-coupling reactions with org. electrophiles.
  (e) Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines. J. Org. Chem. 2019, 84, 9778– 9785, DOI: 10.1021/acs.joc.9b00928
  17e
  Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines
  Gil-Negrete, Jose M.; Perez Sestelo, Jose; Sarandeses, Luis A.
  Journal of Organic Chemistry (2019), 84 (15), 9778-9785CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Triorganoindium reagents react with tetrahydroisoquinolines (THIQs) in the presence of Ph3CBF4 as an oxidant to afford 1-substituted THIQs. The reaction proceeds in good yields at rt using 50 mol % triorganoindium reagent with a variety of org. groups. 1H NMR studies show the generation of an iminium ion intermediate, supporting a two-step mechanism based on THIQ oxidn. and R3In nucleophilic addn. This reaction was applied to the synthesis of the alkaloid nuciferine in three steps.
18. 18
  (a) Alonso-Marañón, L.; Martínez, M. M.; Sarandeses, L. A.; Pérez Sestelo, J. Indium-Catalyzed Intramolecular Hydroarylation of Aryl Propargyl Ethers. Org. Biomol. Chem. 2015, 13, 379– 387, DOI: 10.1039/C4OB02033B
  18a
  Indium-catalyzed intramolecular hydroarylation of aryl propargyl ethers
  Alonso-Maranon, Lorena; Martinez, M. Montserrat; Sarandeses, Luis A.; Sestelo, Jose Perez
  Organic & Biomolecular Chemistry (2015), 13 (2), 379-387CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Indium(III) halides catalyze efficiently the intramol. hydroarylation (IMHA) of aryl propargyl ethers. The reaction proceeds regioselectively with terminal and internal alkynes bearing electron-rich and electron-deficient substituents in the benzenes and alkynes affording only the 6-endo dig cyclization product. Addnl., a sequential indium-catalyzed IMHA and palladium-catalyzed Sonogashira coupling can be performed in one reaction vessel. Expts. with deuterium support a mechanism through electrophilic arom. substitution.
  (b) Alonso-Marañón, L.; Sarandeses, L. A.; Martínez, M. M.; Pérez Sestelo, J. Sequential In-Catalyzed Intramolecular Hydroarylation and Pd-Catalyzed Cross-Coupling Reactions Using Bromopropargyl Aryl Ethers and Amines. Org. Chem. Front. 2017, 4, 500– 505, DOI: 10.1039/C6QO00721J
  18b
  Sequential In-catalyzed intramolecular hydroarylation and Pd-catalyzed cross-coupling reactions using bromopropargyl aryl ethers and amines
  Alonso-Maranon, Lorena; Sarandeses, Luis A.; Martinez, M. Montserrat; Perez Sestelo, Jose
  Organic Chemistry Frontiers (2017), 4 (4), 500-505CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  A sequential one-pot indium-catalyzed intramol. hydroarylation (IMHA) of bromopropargyl aryl ethers and amines, and palladium-catalyzed cross-coupling reaction using triorganoindium reagents was developed. In this transformation, the IMHA of 3-bromo-2-propynyl aryl ethers under indium(III) catalysis, proceeded regioselectively through a 6-endo dig pathway to afford 4-bromo-2H-chromenes and subsequent palladium-catalyzed cross-coupling with triorganoindium reagents gave 4-substituted-2H-chromenes I [R1 = R3 = H; R2 = OMe; R4 = Bu, Ph, 2-thienyl, etc.; X = O] in one-pot. This sequential transformation was further extended for the synthesis of 4-substituted-1-tosyl-1,2-dihydroquinolines I [R1 = R2 = R3 = H, OMe; R4 = Me, Bu, Ph, etc.; X = N-Ts] from 3-bromo-2-propynyl-N-tosylanilines. The dual-catalyzed procedure took place efficiently showing the efficiency of these organometallics and providing the compatibility of indium and palladium in catalysis.
  (c) Alonso-Marañón, L.; Sarandeses, L. A.; Martínez, M. M.; Pérez Sestelo, J. Synthesis of Fused Chromenes by the Indium(III)-Catalyzed Cascade Hydroarylation/Cycloisomerization Reactions of Polyyne-Type Aryl Propargyl Ethers. Org. Chem. Front. 2018, 5, 2308– 2312, DOI: 10.1039/C8QO00457A
  18c
  Synthesis of fused chromenes by the indium(III)-catalyzed cascade hydroarylation/cycloisomerization reactions of polyyne-type aryl propargyl ethers
  Alonso-Maranon, Lorena; Sarandeses, Luis A.; Martinez, M. Montserrat; Perez Sestelo, Jose
  Organic Chemistry Frontiers (2018), 5 (15), 2308-2312CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  Fused 2H-chromenes were prepd. by the cascade hydroarylation/cycloisomerization reactions of polyyne-type aryl propargyl ethers using indium(III) catalysis. The transformation proceeded with 6-endo-dig regioselectivity using InBr3 (5 mol%). The method was extended to triynes allowing the formation of three bonds in one pot. Indium(III) also catalyzed the hydroamination/hydroarylation cascade reaction of o-aryldiynyl anilines to form fused carbazoles.
  (d) Alonso-Marañón, L.; Martínez, M. M.; Sarandeses, L. A.; Gómez-Bengoa, E.; Pérez Sestelo, J. Indium(III)-Catalyzed Synthesis of Benzo[b]Furans by Intramolecular Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights. J. Org. Chem. 2018, 83, 7970– 7980, DOI: 10.1021/acs.joc.8b00829
  18d
  Indium(III)-Catalyzed Synthesis of Benzo[b]furans by Intramolecular Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights
  Alonso-Maranon, Lorena; Martinez, M. Montserrat; Sarandeses, Luis A.; Gomez-Bengoa, Enrique; Perez Sestelo, Jose
  Journal of Organic Chemistry (2018), 83 (15), 7970-7980CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Indium(III) halides catalyze the hydroalkoxylation reaction of ortho-alkynylphenols to afford benzo[b]furans in good yields. The reaction proceeds with 5-endo-dig regioselectivity with a variety of phenols functionalized at the arene and alkyne moieties in high yields using InI3 (5 mol %) in DCE. Exptl. and computational studies support a mechanism based on the indium(III) π-Lewis acid activation of the alkyne followed by nucleophilic addn. of the phenol and final protodemetalation to afford the corresponding benzo[b]furan. DFT calcns. suggest that dimer In2I6 is the catalytic species through a novel double coordination with the alkyne and the hydroxyl group.
19. 19
  Using ¹H-¹H COSY, edited-HSQC and HMBC experiments, we were able to assign all protons and carbons for (trans)-4f. Key signals to deduce the trans-fused bicyclic system were protons H-6 (δ_H 2.21 ppm, td, J = 11.2, 11.2, 2.2 Hz) and H-5 (δ_H 2.02 ppm, bt, J = 11.5 Hz), which clearly show an antiperiplanar relationship between them (see the SI on page S40–S42).
  There is no corresponding record for this reference.
20. 20
  Toullec, P. Y.; Blarre, T.; Michelet, V. Mimicking Polyolefin Carbocyclization Reactions: Gold-Catalyzed Intramolecular Phenoxycyclization of 1,5-Enynes. Org. Lett. 2009, 11, 2888– 2891, DOI: 10.1021/ol900864n
  20
  Mimicking Polyolefin Carbocyclization Reactions: Gold-Catalyzed Intramolecular Phenoxycyclization of 1,5-Enynes
  Toullec, Patrick Yves; Blarre, Thomas; Michelet, Veronique
  Organic Letters (2009), 11 (13), 2888-2891CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  PPh3AuNTf2 promotes highly efficient intramol. phenoxycyclization reactions on 1,5-enynes under mild conditions. The original tricyclic and functionalized heterocycles were isolated in good to excellent yields. The 6-endo cyclization process is predominant and operates via a biomimetic cascade cation-olefin process. The efficiency of this system was further demonstrated in the cycloisomerization reaction of a 1,5,9-dienyne, I.
21. 21
  Capon, R. J. Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier: New York, 1995; Vol. 15, pp 289– 326.
  There is no corresponding record for this reference.
22. 22
  (a) Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P. Organoindium Reagents: the Preparation and Application in Organic Synthesis. Chem. Rev. 2013, 113, 271– 401, DOI: 10.1021/cr300051y
  22a
  Organoindium Reagents: The Preparation and Application in Organic Synthesis
  Shen, Zhi-Liang; Wang, Shun-Yi; Chok, Yew-Keong; Xu, Yun-He; Loh, Teck-Peng
  Chemical Reviews (Washington, DC, United States) (2013), 113 (1), 271-401CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. The intent of this review is to provide an overview of the prepn. and application of organoindium reagents in org. synthesis.
  (b) Zhao, K.; Shen, L.; Shen, Z.-L.; Loh, T.-P. Transition Metal-Catalyzed Cross-Coupling Reactions Using Organoindium Reagents. Chem. Soc. Rev. 2017, 46, 586– 602, DOI: 10.1039/C6CS00465B
  22b
  Transition metal-catalyzed cross-coupling reactions using organoindium reagents
  Zhao, Kai; Shen, Liang; Shen, Zhi-Liang; Loh, Teck-Peng
  Chemical Society Reviews (2017), 46 (3), 586-602CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. This review focuses on the recent develpments in the prepn. of organoindium reagents and its use in the subsequent transition metal-catalyzed cross-coupling reactions with various electrophiles. These cross-coupling reactions employing organoindium reagents exhibited remarkable chemo- and stereoselectivity. In addn., the versatility and significance of transition metal catalyzed cross-couplings of organoindium reagents are further highlighted by their applications in org. synthesis and materials science.
23. 23
  Sotorríos, L.; Demertzidou, V. P.; Zografos, A. L.; Gómez-Bengoa, E. DFT Studies on Metal-Catalyzed Cycloisomerization of trans-1,5-Enynes to Cyclopropane Sesquiterpenoids. Org. Biomol. Chem. 2019, 17, 5112– 5120, DOI: 10.1039/C9OB00890J
  23
  DFT studies on metal-catalyzed cycloisomerization of trans-1,5-enynes to cyclopropane sesquiterpenoids
  Sotorrios, Lia; Demertzidou, Vera P.; Zografos, Alexandros L.; Gomez-Bengoa, Enrique
  Organic & Biomolecular Chemistry (2019), 17 (20), 5112-5120CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  We have recently described the synthesis of strained carbocyclic sesquiterpenoid motifs through a highly regioselective cycloisomerization of common enyne acetates, in the presence of platinum(II) and gold(I) chlorides as catalysts. In this work, the mechanisms of these cyclization reactions have been studied by means of DFT methods. At the outset of the reactions, the propargyl substrates suffer 1,2- or 1,3-acetate rearrangements, which compete for the formation of a metal-carbene or a vinyl-metal species, resp. These intermediates are the resting states of the cycles towards the formation of lindenane or myliol core structures. The DFT studies have revealed the energetics of the two migration processes, as well as the reasons for some of the key exptl. observations, such as the syn/anti preference in the formation of the cyclopropane rings, the different reactivities of substrates contg. furan or lactone moieties, and the different outcomes of the reactions when Pt(II) and Au(I) salts are used.
24. 24
  All structures were optimized using Gaussian 16 with the B3LYP/6-31G(d,p) method for C, H, and O and SDD basis set for In and I. Final energies were refined at the M06/def2tzvpp level of theory in toluene. For more details, see the Supporting Information.
  There is no corresponding record for this reference.
25. 25
  Surendra, K.; Rajendar, G.; Corey, E. J. Useful Catalytic Enantioselective Cationic Double Annulation Reactions Initiated at an Internal π-Bond: Method and Applications. J. Am. Chem. Soc. 2014, 136, 642– 645, DOI: 10.1021/ja4125093
  25
  Useful Catalytic Enantioselective Cationic Double Annulation Reactions Initiated at an Internal π-Bond: Method and Applications
  Surendra, Karavadhi; Rajendar, Goreti; Corey, E. J.
  Journal of the American Chemical Society (2014), 136 (2), 642-645CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The 1:1 complex of o,o'-dichloro-R-BINOL and SbCl5 initiates the enantioselective cationic polycyclization of polyunsatd. substrates at a predictable π-bond which may be either terminal or, as shown herein, internal (e.g., I → II). The extension of this powerful construction to internal π-bonds expands the scope of this method and opens up very short pathways to numerous chiral polycyclic mols., including natural products and their analogs. Esp. simple synthetic routes are disclosed that provide access to dysideapalaunic acid, dehydroabietic acid, and epi-podocarpic acid and illustrate the value of this enantioselective approach.
26. 26
  Corey, E. J.; Seibel, W. L. First stekeospecific synthesis of E-γ-bisabolene. A method for the concurrent generation of a ring and a tetrasubstituted exocyclic double bond. Tetrahedron Lett. 1986, 27, 905– 908, DOI: 10.1016/S0040-4039(00)84133-7
  26
  First stereospecific synthesis of E-γ-bisabolene. A method for the concurrent generation of a ring and a tetrasubstituted exocyclic double bond
  Corey, E. J.; Seibel, William L.
  Tetrahedron Letters (1986), 27 (8), 905-8CODEN: TELEAY; ISSN:0040-4039.
  A short stereospecific synthesis of E-γ-bisabolene (I) from an acyclic acetylenic precursor [either II or III (R = SiMe2CMe3)] is described.
27. 27
  Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Bräse, S. Enantioselective Intramolecular Friedel–Crafts-Type α-Arylation of Aldehydes. J. Am. Chem. Soc. 2009, 131, 2086– 2087, DOI: 10.1021/ja809405c
  27
  Enantioselective Intramolecular Friedel-Crafts-Type α-Arylation of Aldehydes
  Nicolaou, K. C.; Reingruber, Rudiger; Sarlah, David; Brase, Stefan
  Journal of the American Chemical Society (2009), 131 (6), 2086-2087CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Enantioselective organo-SOMO catalysis has, in the last two years, been the subject of considerable development and exploration. A no. of new and unique transformations have been reported, such as α-allylation, α-oxyamination, α-enolation, and α-vinylation of aldehydes. Herein, we report a modification of this activation mode that involves the intramol. Friedel-Crafts-type α-arylation of aldehydes carrying electron-donating groups on their arom. nucleus and its application to the total synthesis of demethyl calamenene, I, a potent cytotoxic agent against human adenocarcinoma A 549.
28. 28
  Mostafa, M. A. B.; Grafton, M. W.; Wilson, C.; Sutherland, A. A one-pot, three-step process for the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and ruthenium(II)-catalysis. Org. Biomol. Chem. 2016, 14, 3284– 3297, DOI: 10.1039/C6OB00165C
  28
  A one-pot, three-step process for the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes using consecutive palladium(II)- and ruthenium(II)-catalysis
  Mostafa, Mohamed A. B.; Grafton, Mark. W.; Wilson, Claire; Sutherland, Andrew
  Organic & Biomolecular Chemistry (2016), 14 (12), 3284-3297CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes has been attained using a one-pot multi-bond forming process. A four-step synthetic route was developed for the efficient synthesis of a series of C-7 substituted hept-2-en-6-yn-1-ols, RC=CCH2CH2CH=CHCH2OH (R = H, CH3, C6H5, 4-H3COC6H4, 4-O2NC6H4). These compds. were then investigated as substrates for a one-pot, three-step tandem process involving a palladium(II)-catalyzed Overman rearrangement, a ruthenium(II)-catalyzed ring closing enyne metathesis reaction followed by a hydrogen bond directed Diels-Alder reaction. The optimization of the one-pot process has allowed the rapid prepn. of a library of aminobicyclo[4.3.0]nonanes with significant mol. complexity and up to four stereogenic centers.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c00825.
- Copies of ¹H and ¹³C{¹H} NMR spectra (PDF)
- jo1c00825_si_001.pdf (6.61 MB)
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Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-EnynesClick to copy article linkArticle link copied!

The Journal of Organic Chemistry

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Abstract

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Introduction

Scheme 1

Results and Discussion

Scheme 2

Mechanistic Studies

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Conclusions

Experimental Section

General Methods

(E)-1,3-Dimethoxy-5-[(3-methyloct-2-en-6-yn-1-yl)oxy]benzene [(E)-1b] (14a)

(E)-1-[(7-Bromo-3-methylhept-2-en-6-yn-1-yl)oxy]-3,5-dimethoxybenzene [(E)-1c]

(E)-[(3-Methylhept-2-en-6-yn-1-yl)oxy]benzene [(E)-1d]

(Z)-1,3-Dimethoxy-5-[(3-methylhept-2-en-6-yn-1-yl)oxy]benzene [(Z)-1a]

(Z)-1-[(7-Bromo-3-methylhept-2-en-6-yn-1-yl)oxy]-3,5-dimethoxybenzene [(Z)-1c]

(Z)-[(3-Methylhept-2-en-6-yn-1-yl)oxy]benzene [(Z)-1d]

(E)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methyloct-2-en-6-yn-1-yl)benzenesulfonamide [(E)-3b]

(E)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methyl-7-phenylhept-2-en-6-yn-1-yl)benzenesulfonamide [(E)-3c]

(E)-N-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide [(E)-3d] (14c)

(E)-4-Methyl-N-(3-methylhept-2-en-6-yn-1-yl)-N-phenylbenzenesulfonamide [(E)-3e]

(Z)-N-(3,5-Dimethoxyphenyl)-4-methyl-N-(3-methylhept-2-en-6-yn-1-yl)benzenesulfonamide [(Z)-3a]

(Z)-N-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide [(Z)-3d]

(Z)-4-Methyl-N-(3-methylhept-2-en-6-yn-1-yl)-N-phenylbenzenesulfonamide [(Z)-3e]

(E)-N-(3,5-Dimethoxyphenyl)-N-(hept-2-en-6-yn-1-yl)-4-methylbenzenesulfonamide [(E)-3f]

(Z)-4-Methoxy-2-(3-methylhept-2-en-6-yn-1-yl)phenol [(Z)-5a]

(Z)-2-(7-Bromo-3-methylhept-2-en-6-yn-1-yl)-4-methoxyphenol [(Z)-5b]

General Procedure for In(III)-Catalyzed Cascade Cycloisomerization Reactions of 1,5-Enynes

(6aS*,10aS*)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2a] (14c)

Scale-Up Experiment for (trans)-2a

(4aS*,9aS*)-6,8-Dimethoxy-4a-methyl-4,4a,9,9a-tetrahydro-3H-xanthene (I)

2-(But-3-yn-1-yl)-5,7-dimethoxy-2-methylchromane (II)

(6aS*,10aS*)-1,3-Dimethoxy-7,10a-dimethyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2b] (14a)

(6aS*,10aS*)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2c]

(6aR*,10aS*)-10a-Methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2d]

(6aR*,10aS*)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2a]

(6aR*,10aS*)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2c]

(6aS*,10aS*)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4a] (14c)

(6aS*,10aS*)-1,3-Dimethoxy-7,10a-dimethyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4b]

(6aR*,10aS*)-1,3-Dimethoxy-10a-methyl-7-phenyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4c]

(6aS*,10aS*)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4d] (14c)

(6aR*,10aS*)-10a-Methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4e]

(6aR*,10aS*)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4a]

(6aR*,10aS*)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4d]

(6aS*,10aS*)-1,3-Dimethoxy-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4f]

(4S*,9S*)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6a] (20)

(4S*,9R*)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6b] (14c)

(4S*,9R*)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6a]

(4S*,9S*)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6b]

5′,7′-Dimethoxyspiro[cyclohexane-1,4′-isochroman]-3-ene (8a) (14c)

5′,7′-Dimethoxy-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8b) (14c)

3-Bromo-5′,7′-dimethoxy-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8c) (14c)

General Procedure for the One-Pot Sequential Indium-Catalyzed Cycloisomerization and Palladium-Catalyzed Cross-Coupling Reactions of (E)-5b and 7c

(4S*,9S*)-7-Methoxy-4-methyl-1-phenyl-4,9-tetrahydro-3H-xanthene [trans-6c] (20)

(4S*,9S*)-7-Methoxy-1,4-dimethyl-4,9-tetrahydro-3H-xanthene [trans-6d] (20)

(4S*,9S*)-1-Butyl-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6e]

5′,7′-Dimethoxy-3-phenyl-2′-tosyl-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-isoquinolin]-3-ene (8d)

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Abstract

Scheme 1

Scheme 2

Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-Enynes
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(6aS,10aS)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2a] (14c)

(4aS,9aS)-6,8-Dimethoxy-4a-methyl-4,4a,9,9a-tetrahydro-3H-xanthene (I)

(6aS,10aS)-1,3-Dimethoxy-7,10a-dimethyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2b] (14a)

(6aS,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [trans-2c]

(6aR,10aS)-10a-Methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2d]

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2a]

(6aR,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-6a,9,10,10a-tetrahydro-6H-benzo[c]chromene [cis-2c]

(6aS,10aS)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4a] (14c)

(6aS,10aS)-1,3-Dimethoxy-7,10a-dimethyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4b]

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-7-phenyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4c]

(6aS,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4d] (14c)

(6aR,10aS)-10a-Methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4e]

(6aR,10aS)-1,3-Dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4a]

(6aR,10aS)-7-Bromo-1,3-dimethoxy-10a-methyl-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [cis-4d]

(6aS,10aS)-1,3-Dimethoxy-5-tosyl-5,6,6a,9,10,10a-hexahydrophenanthridine [trans-4f]

(4S,9S)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6a] (20)

(4S,9R)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6b] (14c)

(4S,9R)-7-Methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6a]

(4S,9S)-1-Bromo-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [cis-6b]

(4S,9S)-7-Methoxy-4-methyl-1-phenyl-4,9-tetrahydro-3H-xanthene [trans-6c] (20)

(4S,9S)-7-Methoxy-1,4-dimethyl-4,9-tetrahydro-3H-xanthene [trans-6d] (20)

(4S,9S)-1-Butyl-7-methoxy-4-methyl-4,9-tetrahydro-3H-xanthene [trans-6e]