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Palladium-Catalyzed Aminocyclization–Coupling Cascades: Preparation of Dehydrotryptophan Derivatives and Computational Study

  • Belén Vaz
    Belén Vaz
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    More by Belén Vaz
  • Claudio Martínez
    Claudio Martínez
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
  • Francisco Cruz
    Francisco Cruz
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
  • J. Gabriel Denis
    J. Gabriel Denis
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
  • Ángel R. de Lera
    Ángel R. de Lera
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
  • José M. Aurrecoechea*
    José M. Aurrecoechea
    Departamento de Química Orgánica e Inorgánica, Facultad de Ciencia y Tecnología, Universidad del País Vasco UPV/EHU, Apartado 644, 48080 Bilbao, Spain
    *E-mail: [email protected] (J.M.A.).
  • , and 
  • Rosana Álvarez*
    Rosana Álvarez
    Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    *E-mail: [email protected] (R.A.).
Cite this: J. Org. Chem. 2021, 86, 13, 8766–8785
Publication Date (Web):June 14, 2021
https://doi.org/10.1021/acs.joc.1c00636

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Abstract

Dehydrotryptophan derivatives have been prepared by palladium-catalyzed aminocyclization-Heck-type coupling cascades starting from o-alkynylaniline derivatives and methyl α-aminoacrylate. Aryl, alkyl (primary, secondary, and tertiary), and alkenyl substituents have been introduced at the indole C-2 position. Further variations at the indole benzene ring, as well as the C-2-unsubstituted case, have all been demonstrated. In the case of C-2 aryl substitution, the preparation of the o-alkynylaniline substrate by Sonogashira coupling and the subsequent cyclization–coupling cascade have been performed in a one-pot protocol with a single catalyst. DFT calculations have revealed significant differences in the reaction profiles of these reactions relative to those involving methyl acrylate or methacrylate, and between the reactions of the free anilines and their corresponding carbamates. Those calculations suggest that the nature of the alkene and of the acid HX released in the HX/alkene exchange step that precedes C–C bond formation could be responsible for the experimentally observed differences in reaction efficiencies.

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Introduction

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Palladium complexes are extensively utilized as catalysts in nucleophilic additions to unsaturated systems (1) as well as in cross-coupling reactions. (2) These two abilities have been combined in heterocyclization–coupling cascades involving nucleophile-tethered unsaturated systems and suitable coupling agents (Scheme 1a). In this manner, the cascade strategy has provided a practical access to heterocyclic systems with an appended alkene, alkyne, or aryl group, depending on whether heterocyclization is strategically designed to be followed by Heck-, (3−30) Sonogashira- (31−41) or Suzuki-type (7,42−46) couplings, respectively. (47) Compared with an alternative two-step protocol where a precursor is functionalized (typically as halide) before performing a palladium-catalyzed coupling, (2) the use of those reaction cascades provides a more direct, expeditious and convergent method, as they use simpler acyclic substrates as starting materials and do not require the isolation of a cyclic functionalized intermediate. (47) Taking the case of an alkene coupling agent as example, in mechanistic terms the cascade reaction can be thought of as proceeding via Pd(II)-promoted nucleopalladation and alkene complexation steps leading to a typical Heck reaction intermediate Pd(II) complex (Scheme 1b). However, relative to the conventional coupling reaction from a prefunctionalized precursor, the cascade reaction features two important distinctions. Thus, oxidative conditions are needed to regenerate the Pd(II) species that promote the heterocyclization from the Pd(0) generated during the coupling and, after intramolecular nucleopalladation, an acid molecule HX has to be released and exchanged for the coupling partner. As a result, in addition to the ligand ability of the alkene coupling partner, the acidity of HX becomes also an important consideration. Perhaps not surprisingly, cycloisomerization of the acyclic starting material, a well-established Pd-catalyzed transformation, (48) has often been reported as a side-reaction, particularly in the case of alkyne-tethered substrates. (5,6,11,17,27,42) Within the context of Scheme 1b, one particular field of application of cascade reactions has been the preparation of 3-alkenyl indoles by Pd-catalyzed aminocyclization-Heck-type coupling between 2-alkynylanilines and alkenes. (14,21,27) It was envisaged that the application of this methodology to the particular use of an α-acetamidoacrylate as the alkene partner would be advantageous in the preparation of the expected dehydrotryptophan products (Scheme 1c). These compounds have attracted interest as precursors of the important family of tryptophan derivatives, (49−63) and also because of their presence in natural and non-natural substances with potential use in therapeutic applications. (64−71) Access to dehydrotryptophans has been gained, among other methodologies, (65) via Heck reaction of preformed 3-haloindoles (72,73) and α-acetamidoacrylate derivatives. (74−78) In this contribution, we report a more direct access to dehydrotryptophans from acyclic 2-alkynylaniline and α-acetamidoacrylate substrates using a Pd-catalyzed aminocyclization–Heck-type-coupling cascade. Additionally, with a combination of experimental and computational data, we have inquired into the effects of the alkene, phosphine ligand, and the aniline precursor on the overall efficiency of the cascade coupling reaction, and on the competition between coupling and cycloisomerization.

Scheme 1

Scheme 1. Palladium-catalyzed Oxidative Heterocyclization–Coupling Cascades and Application to the Preparation of Dehydrotrytophans

Results and Discussion

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Initially, the reaction conditions previously developed for related reactions with acrylate esters (14) were tested on methyl α-acetamidoacrylate (3) and representative o-alkynylaniline substrates 1 variable at the terminal alkynyl position (aryl or alkyl). The corresponding carbamates 2 were also tried since on occasion their use had proven more advantageous. (27) Results are shown in Table 1. Thus, heating o-alkynylaniline 1a derived from p-tolylacetylene with an excess (6 equiv) of alkene 3 in DMF in the presence of a catalytic amount of PdCl2 and KI (0.5 equiv) under an air atmosphere provided the expected dehydrotryptophan product 4a in moderate yield (entry 1). Cycloisomerization of the starting N-unsubstituted alkynylaniline 1a was found to be an important side-reaction leading to the formation of the 3-unsubstituted indole 6a. The use of a phosphine ligand had been found beneficial in cases where cycloisomerization was a problem, (14) and this was also the case here, as the use of PdCl2(PPh3)2 (entry 2) resulted in a considerable increase in the yield of 4a (63%) and a much more favorable 4a/6a ratio (4:1). Other phosphines were also tested but gave inferior overall results (entries 3–4). For example, with (p-MeOC6H4)3P a further increase of the 4a/6a ratio was observed (perhaps pointing to a possible effect of the phosphine electron-donating ability) but at the expense of an overall lower yield of 4a (entry 3). The use of Pd(OAc)2 in place of PdCl2 was also less effective (entry 5). Next, the reaction conditions of entry 2 were applied to alkynylanilines 1b and 1c with alkyl groups at the terminal alkynyl position, but the results were much less successful (entries 6 and 7). Finally, the reactions of carbamates 2 were tested (entries 8–10). Relative to the N-unsubstituted anilines 1, carbamates 2 were less reactive, as indicated by longer reaction times (entries 8 and 9) and complete lack of reactivity in the case of the t-Bu-substituted substrate 2c (entry 10). Nevertheless, when reactive enough, carbamates led to the best results in terms of both yield and selectivity (72% for 5a, entry 8), as the formation of a 3-unsubstituted indole analogous to 6 was not observed in those cases. In the case of the alkyl-substituted substrate 2b partial carbamate cleavage took place, resulting in the formation of the N-unsubstituted indole 4b, in addition to the corresponding carbamate 5b. (79) In any case, the overall yield of cyclization–coupling (58%) was a substantial improvement over the result of entry 6.
Table 1. Survey of Reaction Conditions for Aminocyclization–Heck Coupling Between o-Alkynylaniline Derivatives 1 and 2 and Methyl α-Acetamidoacrylate (3)a
Entry1R1, R2[Pd], Lt (h)4a/5aYield of 4/5b45/6 Ratioc
11aH, p-tolylPdCl2184a391:1
21aH, p-tolylPdCl2(PPh3)274a634:1
31aH, p-tolylPdCl2, (p-MeOC6H4)3P184a545:1
41aH, p-tolylPdCl2, (o-furyl)3P184a332:1
51aH, p-tolylPd(OAc)2, PPh3184a362:1
61bH, n-hexylPdCl2(PPh3)244b20d
71cH, tert-butylPdCl2(PPh3)254c43d
82aCO2Et, p-tolylPdCl2(PPh3)2315a72only5a
92bCO2Et, n-hexylPdCl2(PPh3)2314b, 5b18, 40only 4b, 5b
102cCO2Et, tert-butylPdCl2(PPh3)243e
a

Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph.D. Thesis, Universidade de Vigo, 2019. Reaction conditions: Alkynylaniline derivative 1 or 2, alkene 3 (6 equiv), a Pd complex (5 mol %), a phosphine ligand (where appropriate, 10 mol %), and KI (0.5 equiv) were heated in DMF (10 mL/mmol) at 100 °C under air for the indicated time.

b

Isolated yield (%).

c

Measured in the crude reaction mixture.

d

Not determined due to signal overlap.

e

No reaction.

Preparation of N-Unsubstituted Dehydrotryptophans

The extension of the cascade reaction to other carbamate substrates 2 was then studied. Additionally, the possibility of incorporating the preparation of the alkynyl carbamate substrate 2 into a one-pot protocol to perform a Sonogashira-cyclization–coupling sequence was sought. In this manner, the dehydrotryptophan derivatives would be prepared from 2-iodoarylcarbamates 7, terminal alkynes 8, and alkene 3 in a one-pot Pd-catalyzed sequence, (21) using a single catalyst, without isolation of the Sonogashira intermediate 2 (Table 2). In practice, it was found that only alkynes with terminal aryl substituents took part effectively. The resulting aryl-substituted dehydrotryptophan products are endowed with particular interest, as the 2-phenylindole moiety is considered a privileged structure in medicinal chemistry. (80) In the event, iodides 7, arylalkynes 8, and alkene 3 were reacted under typical Sonogashira conditions under argon, until complete consumption of the starting aryl iodide, whereupon air was allowed into the system and the mixture was heated to 120 °C (Table 2). Under these conditions, the expected dehydrotryptophan carbamate products 5 were formed, but it was noticed that, in line with previous observations (Table 1, entry 9), partial carbamate cleavage took place to yield also variable amounts of the N-unsubstituted dehydrotryptophans 4. (79) As a result, the experimental procedure was modified to include a carbamate-cleaving step. Accordingly, after a simple workup, the crude dehydrotryptophan product mixture (5 and 4) was treated with tert-butylamine (81) to complete the conversion of 5 into 4. This three-step procedure afforded dehydrotryptophan products 4 in good overall yields without the need for purification of intermediates. It was also found advantageous to use a polymer-bound PPh3. (82) In this manner, a simple filtration facilitated the removal of catalyst residues that otherwise made chromatographic purification of some of the products difficult. As shown in Table 2, the procedure is effective for a variety of substituted arylalkynes 8 and 2-iodoarylcarbamates 7. Electron-donating and electron-withdrawing substituents were tolerated in both sets of reactants, and the presence of bromine substituents at alternative positions of the aryl group of 7 did not interfere with the desired reaction sequence (entries 4 and 5).
Table 2. Preparation of 2-Aryldehydrotryptophans 4a, 4dn (R2 = Ar) from 2-Iodoarylcarbamates 7a
Entry7R3R4R2t (h)b4Yield of 4c
17aHHp-tolyl6, 31, 44a62
27aHH(p-MeO)C6H46, 30, 44d73
37aHH(p-CO2Me)C6H46, 40, 44e59
47bBrHp-tolyl5, 41, 34f68
57cHBrp-tolyl4, 40, 34g62
67dCO2MeHp-tolyl4, 40, 34h49
77eOMeHp-tolyl4, 40, 34i55
87aHH(m-Cl)C6H421, 48, 64j58
97aHH(m-F)C6H421, 48, 54k50
107aHH(m-OMe)C6H421, 48, 44l59
117aHH(3,4-diF)C6H321, 48, 54m58
127aHH3-thienyl21, 48, 54n51
a

Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph. D. Thesis, Universidade de Vigo, 2019. Reaction conditions. Step 1: Iodide 7, alkene 3 (6 equiv), alkyne 8 (2 equiv), PdCl2 (5 mol %), polymer-bound PPh3 (10 mol % of PPh3 relative to 7), CuI (20 mol %), Et3N (4.5 equiv) in DMF (10 mL/mmol) at 60 °C under Ar. Step 2:120 °C under air. Step 3: t-BuNH2 (30 equiv), MeOH (21 mL/mmol), reflux.

b

Reaction times for steps 1–3.

c

Isolated yield (%).

As indicated above, the one-pot Sonogashira-cyclization–coupling sequence did not provide satisfactory results when applied to alkyl-substituted terminal alkynes. Alternatively, a cyclization–coupling–carbamate-cleavage protocol was efficient with such alkynes (Scheme 2). Still, these alkynyl carbamates had a rather sluggish reactivity in the Pd-catalyzed process, resulting in long reaction times and recovery of some starting material. This prompted the use of a higher Pd load (10 mol %), and in the case of the c-hexyl-substituted substrate 2o, a higher temperature (120 °C) was also needed for practical results. As shown in Scheme 2, both primary- and secondary-alkyl groups, as well as an alkenyl substituent, were successfully used to afford the corresponding N-unsubstituted dehydrotryptophans (4b, 4o, and 4p) after carbamate deprotection.

Scheme 2

Scheme 2. Preparation of 2-Alkyldehydrotryptophans from 2-Alkynylaniline Carbamates

aReaction conditions: (i) alkene 3 (6 equiv), PdCl2(PPh3) 2 (10 mol %), KI (0.5 equiv), DMF, air, 100 °C (2b and 2p) or 120 °C (2o). (ii) t-BuNH2 (30 equiv), MeOH, 90 °C.

Preparation of N-(PMB)dehydrotryptophans

To explore also the possibility of using Csp3-substituents at the aniline N atom, p-methoxybenzyl (PMB) dehydrotryptophans were targeted as representative of the interesting subclass of benzyl-substituted indoles (83−86) (Table 3). In line with the results of Scheme 2, modifications of the reaction conditions were introduced in order to improve the performance of these aniline substrates. This implied increasing again the catalyst loading to 10 mol % and, for consistent results, also incorporating triphenylphosphine oxide (TPPO, 10 mol %) as an additive. (87)
Table 3. Preparation of 2-Alkyl- and 2-Alkenyldehydrotryptophans 10 from N-(PMB)-2-Alkynylanilines 9a
Entry9R1R2t (h)10Yieldb of 10
19aHn-hexyl1510a40
29bHCH2OAc510b41
39cHc-hexyl1610c50
49dHtert-butyl2410dc82c
59eHC(Me)2CH2OTBDPS2010e72
69fHC(Me)2OH1610f41
79gHcyclohexenyl2310g67
89hMetert-butyl1810h53
99iCO2Metert-butyl1710i48
109jMecyclohexenyl1910j50
a

Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph.D. Thesis, Universidade de Vigo, 2019. Reaction conditions: N-PMB-2-alkynylaniline 9, alkene 3 (6 equiv), PdCl2(PPh3)2 (10 mol %), TPPO (10 mol %), and KI (0.5 equiv) in DMF (10 mL/mmol) under air.

b

Isolated yield (%).

c

A 3-unsubstituted indole 11d (R1 = H; R2 = t-Bu) was also obtained in 17% yield.

As displayed in Table 3, the reaction has been applied to substrates 9 with primary-, secondary-, and tertiary-alkyl groups at the alkynyl terminal position. Additionally, both protected and unprotected carbinol-type substituents were tolerated at that position, leading to the expected 2-indolylmethanols (88) in moderate yields (entries 2, 5–6), and the incorporation of a cyclohexenyl substituent was also successful (entries 7 and 10). The particular examples of entries 4–6 and 8–9 provide a precedent for the introduction of tertiary alkyl groups, prevalent in natural and otherwise interesting dehydrotryptophan derivarives. (64−67,69) Furthermore, the reaction could also be applied to the triethylsilyl (TES)-substituted substrate 9k (Scheme 3) to yield a C-2-unsubstituted dehydrotryptophan 12 as a result of an aminocyclization–alkenylation cascade and concomitant desilylation. The use of a silyl substituent as a H surrogate was prompted by unsuccessful attempts to use directly simple o-ethynylaniline featuring a terminal alkyne. In general, some cycloisomerization of the starting alkynylaniline, with formation of the uncoupled 3-unsubstituted indoles (11), was observed as a side reaction in the cases shown in Table 3. For example, the 2-(tert-butyl) derivative 11d (R1 = H; R2 = t-Bu) was isolated in 17% yield (entry 4, Table 3), and the formation of analogous products could also be inferred in the remaining entries of Table 3 (and Scheme 3) from inspection of the 1H NMR of the crude products (singlet at δ 6.3–6.8), although these products were not further characterized.

Scheme 3

Scheme 3. Preparation of a 2-Unsubstituted Dehydrotryptophan Derivative
In all the cases under study (Tables 13 and Schemes 23) the exocyclic trisubstituted double bond of dehydrotryptophans 4, 10, and 12 was generated with high stereoselectivity, as only one geometric isomer was isolated. The configuration was determined to be Z in product 10c by X-ray analysis (see Figure S1 in Supporting Information), and the same geometry was assigned by analogy to the remaining products. This result is in line with previous literature examples where the formation of the (Z)-isomers of dehydrotryptophans was also reported in Heck-type reactions between indole and α-aminoacrylate derivatives. (58,74,76,78)

Formation of Cycloisomerization Products

Relative to the related heterocyclization–coupling reactions of 2-alkynylanilines with n-butyl acrylate and methyl methacrylate (α-unsubstituted- and α-Me-substituted analogs, respectively, of acrylate 3), (14) the α-acetamidoacrylate reactions appear to be less effective, as indicated by their often lower isolated yields and higher incidence of cycloisomerization products (the main observed side reaction for N-unsubstituted and N-PMB-substituted anilines; see also Table 4 below), although that type of product was not observed in the carbamate series (Tables 12 and Scheme 2). The relative importance of that competing cycloisomerization reaction is also strongly dependent on the presence or absence of PPh3, as seen in Table 1. In order to have a more precise picture of the alkene- and phosphine-dependence of the coupling/cycloisomerization ratio, we have run some control experiments that have enabled comparisons, under the same reaction conditions, between α-acetamidoacrylate (3), n-butyl acrylate, and methyl methacrylate. These results are displayed in Table 4, where entries 1, 2, and 7 have been taken from Table 1.
Table 4. Effect of the Alkene and PPh3 on Yields and Coupling/Cycloisomerization Ratiosa
entryYR2[Pd]T (° C)t (h)4, 1314Yield of 4, 1314b4 or 1314/6 Ratioc
1NHAcp-tolylPdCl2100184a391:1
2NHAcp-tolylPdCl2(PPh3)210074a634:1
3Hp-tolylPdCl2802013ae561.4:1d,e
4Hp-tolylPdCl21002013ae85only 13ae
5Hp-tolylPdCl2(PPh3)2801913ae90only 13ae
6Hp-tolylPdCl2(PPh3)21001813ae91only 13ae
7NHAcn-hexylPdCl2(PPh3)210044b20f
8Hn-hexylPdCl2(PPh3)21001813be52only 13be
9Mep-tolylPdCl2(PPh3)2602014e67only 14e
10gNHAcp-tolylPdCl2(PPh3)210020gg 
11gNHAcp-tolylPdCl210020gg 
12hNHAcp-tolyl 1004hh 
a

Reaction conditions: Unless otherwise indicated, 1a or 1b, a Pd complex (5 mol %), KI (0.5 equiv) and alkene (6 equiv) in DMF under air atmosphere.

b

Isolated yield (%).

c

Measured in the crude reaction mixture.

d

Ratio of isolated yields.

e

Reference (14).

f

Not determined due to signal overlap.

g

Reaction run in the absence of alkene. The cycloisomerization product 6a was obtained in 28% yield (entry 10) or 15% yield (entry 11).

h

Experiment run in the absence of alkene and Pd catalyst: No reaction.

The results in Table 4 confirm that, under comparable conditions, cycloisomerization is a more important competing side reaction in the α-acetamidoacrylate case relative to the other acrylates. Notably, the disubstituted alkene of entry 9 reacts without observable formation of cycloisomerization products. It is also apparent that the effect of the phosphine ligand PPh3 on cycloisomerization is not exclusive of α-acetamidoacrylates. Thus, while cycloisomerization is subdued in the α-acetamidoacrylate reaction in the presence of PPh3 (entries 1 and 2), it appears to be completely suppressed with the simpler acrylates under similar reaction conditions (see entry 3 vs entries 5 and 9). Control reactions in the absence of alkene showed that the 3-unsubstituted indole 6a was formed (albeit in a low 15–28% yield) (89) (Table 4, entries 10–11) but was not detected when the Pd catalyst was also omitted (Table 4, entry 12). This indicated that, at least in part, cycloisomerization is a Pd-catalyzed reaction.

Computational Studies

In order to gain further insights into the above-mentioned differences in reactivity, we have studied computationally the aminocyclization–coupling reactions using DFT methods. We have evaluated the effect of the alkene and PPh3 ligand on the energetics of the reaction pathway, as well as the differences between N-unsubstituted 2-alkynylanilines and their corresponding carbamates. The expected catalytic cycle is shown in Scheme 4, where product formation is the result of four major steps, namely cyclization (intramolecular aminopalladation), HCl/alkene exchange, carbopalladation (insertion), and β-hydride elimination (BHE). To complete the catalytic cycle, oxidation of the Pd(0) released by reductive elimination (RE) of HCl after BHE regenerates the Pd(II) species needed to activate the C–C triple bond and reinitiate the cycle.

Scheme 4

Scheme 4. Expected Catalytic Cycle
According to this general scheme, we have compared the reaction profiles of cyclization–coupling cascades involving palladium complexes B originating from o-alkynylaniline derivatives A, variable at the nitrogen and alkynyl substituents (R1 and R2, respectively), and acrylate esters where variations were introduced at Cα (substituent Y). For reactions run in the absence of PPh3, the vacant position at Pd has been filled with a molecule of solvent (DMF). (90) A summary of results is displayed in Table 5, where the energy differences (ΔG, kcal/mol) between species (intermediates and transition states) have been collected for cyclization, HCl/alkene exchange, insertion, BHE, and RE steps starting from complex B. Full energy profiles are displayed in Figures 12 and S3 (see Supporting Information).

Figure 1

Figure 1. (a) Reaction profile starting from complexes B derived from Aa (R1 = H, R2 = Ph in Scheme 4) and methyl α-acetamidoacrylate (Y = NHAc) or methyl acrylate (Y = H) in a reaction promoted by PdCl2/L (L = PPh3 or DMF) [energy values in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]. (b) Ground state structures of intermediates involved in the reaction profile.

Figure 2

Figure 2. (a) Reaction profile starting from complexes B derived from Aa-carb (R1 = CO2Me, R2 = Ph, L = PPh3 in Scheme 4) and methyl α-acetamidoacrylate in a reaction promoted by PdCl2(PPh3)2 [energy values in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]. (b) 3-D structures of TSs, as representative of those involved in the different series.

Table 5. Energy Differences [in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)] for the Stepwise Transformation of B to G
    AminopalladationHCl/alkene exchangeCarbopalladationRotation-BHEHCl RE
entryR1, R2LYΔG#B–CΔG°B–CΔG°C–DΔG#D–EΔG°D–EΔG#C–EΔG#E–FΔG°E–FΔG#F–GΔG°F–G
1H, PhPPh3H18.7–10.1–0.77.5–27.26.828.218.47.30.3
2H, PhDMFH13.9–33.610.512.7–14.823.215.26.217.312.9
3H, PhPPh3Me18.7–10.12.26.7–23.08.9    
4H, PhPPh3NHAc18.7–10.16.016.9–26.022.926.5a18.34.41.3
5H, MePPh3NHAc19.1–9.07.716.6–32.824.329.924.24.9–2.9
6H, t-BuPPh3NHAc17.8–8.210.014.9–32.624.929.124.53.5–1.8
7CO2Me, PhPPh3NHAc20.49.2–6.318.1–27.110.8b31.124.12.7–1.9
8CO2Me, t-BuPPh3NHAc21.812.52.916.3–28.619.230.226.22.1–4.9
a

27.0 kcal/mol from the lowest energy intermediate Erot (see Figure 1).

b

18.1 kcal/mol from D (see Figure 2).

Formation of palladium complexes B from o-alkynylaniline derivatives A and PdCl2(PPh3)2 is an endergonic process in all cases (15.6–16.8 kcal/mol; see also Tables S2–S4 in Supporting Information), and almost insensitive to substituent effects. However, it is noticed that this estimate is probably realistic only in the early stages of the reaction, when PPh3 has to be displaced from Pd by the o-alkynylaniline A. Indeed, under the experimental oxidative conditions, some PPh3 is oxidized to the corresponding triphenylphosphine oxide (TPPO), (91,92) and this should make complexation of the o-alkynylaniline A more favorable, as TPPO is a weaker Pd-ligand than PPh3. In any event, the activated triple bond and internal amino group of B then engage in a 5-endo-dig cyclization leading to zwitterions C (where the palladium trans geometry is maintained) with moderate activation energies, which are in the range 17.8–21.8 kcal/mol, with the exception of the phosphine-free cyclization, which has a significantly lower cyclization barrier (13.9 kcal/mol). It is interesting that this step appears to be insensitive to the steric bulk of the t-Bu group in the N-unsubstituted series. On the other hand, carbamates have somewhat higher barriers (by 1.7 and 4 kcal/mol, for R2 = Ph and t-Bu, respectively) than the corresponding amines. However, a much more substantial difference is observed in the reaction energies, as the cyclization of the carbamate substrates (B, R1 = CO2Me) proceeds uphill (by 9.2–12.5 kcal/mol) whereas for the N-unsubstituted substrates (B, R1 = H) the cyclizations are all exergonic (by 8.2–33.6 kcal/mol). Again, differences are noticed between the PPh3-ligated complexes (B, L = PPh3), which maintain cyclization exergonicity within a narrow range (8.2–10.1 kcal/mol), and the much more favorable phosphine-free case (B, L = DMF; ΔG°B–C = −33.6 kcal/mol). Those calculated differences between N-unsubstituted anilines and their carbamates are understood as a consequence of the effect of the electron-withdrawing group on N that, relative to the unsubstituted aniline (B, R1 = H), renders the carbamate (B, R1 = CO2Me) a less reactive nucleophile and reduces the stability of the zwitterionic cyclization product C (R1 = CO2Me). In any case, from zwitterions C the loss of HCl is accompanied by the incorporation of an alkene molecule to arrive at intermediates D, where the alkene ligand occupies the position of the released chloride anion. Complexes D are the starting point for the C–C-bond forming carbopalladation step eventually leading to the coupling product. Some interesting information emerges from the HCl/alkene exchange data. Thus, for reactions catalyzed by PdCl2(PPh3)2, methyl acrylate (Y = H, cf. entry 1, Table 5) and methyl methacrylate (Y = Me, cf. entry 3) have a more favorable HCl/alkene exchange energy than the corresponding methyl α-acetamidoacrylate (Y = NHAc, cf. entries 4–6), indicating that the former have a higher affinity for that particular palladium moiety. This exchange is also more favorable for carbamates, relative to the N-unsubstituted anilines; for example, for the carbamate of entry 7 (R2 = Ph, Y = NHAc) HCl/alkene exchange is exergonic (by 6.3 kcal/mol), whereas in the corresponding aniline it is endergonic by approximately the same amount (6.0 kcal/mol, cf. entry 4). It is reasonable to expect that, in this case, the same substituent effects discussed above would make the carbamate zwitterion C (R1 = CO2Me) more acidic, leading to a more favorable HCl/alkene exchange. A final note on this step has to do with the phosphine-free complex (C, L = DMF, cf. entry 2), where the exchange is found to be much less favorable (by 11.2 kcal/mol) than in the corresponding PPh3-ligated case (C, L = PPh3, cf. entry 1); however, these latter data would be difficult to interpret in the foregoing context of substituent effects because both the acidity of C and the affinity of the HCl-free Pd complex for the alkene are affected by the change at L in this case.
Next, from complexes D carbopalladation leads to intermediates E, which display a trans-relationship between the Cl–Pd and newly formed σ–Pd-Cα bonds, while the 5-membered indole π-system occupies the remaining vacant position at Pd. This step is predicted to be very exergonic in all cases and irreversible, as a result. However, differences are clearly observed in the activation energies. Thus, both methyl acrylate and methyl methacrylate are predicted to have substantially lower insertion barriers when compared with methyl α-acetamidoacrylate (cf. entries 1 and 3 vs 4–8). From the carbopalladation product E, an energy sink, the reaction proceeds to the BHE TS by detachment of the indole π-ligand from palladium and Cα–Cβ rotation to first reach rot-E (Figures 12 and S3) and allow the interaction between palladium and one of the C–H bonds at the original alkene’s β-position. The overall activation energy for BHE leading to the experimentally obtained Z-isomer is relatively high (26.5–31.1 kcal/mol), again with the exception of the PPh3-free complex (L = DMF, ΔG#E-F = 15.2 kcal/mol, entry 2), whereas the barrier for the unobserved E-isomer is 7 kcal/mol higher in the calculated case (R1 = H; R2 = Ph; L = PPh3; Y = NHAc) (see Table S5 in Supporting Information). The BHE step is reversible in all cases, and in this scenario, product release and completion of the catalytic cycle require a relatively facile and irreversible regeneration of the starting PdX2 catalyst. (93) According to the literature, (93,94) this could take place from HPdX by initial rate-determining H atom abstraction by O2 (HAA pathway) or an alternative reductive elimination of HX, followed by facile oxidation by O2 of the resulting Pd(0) species (HXRE pathway), leading in both cases to the formation of a Pd(II) hydroperoxide intermediate. While the actual oxidation mechanism has not been subject to study in our particular system, in the context of the more generally considered HXRE mechanism (93) we have determined that reductive elimination of HCl from complexes F (L = PPh3), where the H and Cl atoms already have the required cis arrangement, has indeed a relatively low activation energy (2.7–7.3 kcal/mol, Table 5, Figures 12 and S3). Furthermore, the subsequent Pd(0) oxidation is expected to be facilitated by the participation of molecular iodine formed from the KI additive under the oxidizing (air) reaction conditions. (14,95)
The analysis of the data in Table 5, Figures 12 and S3 (Supporting Information) reveals that the carbamate reactions transit through a higher energy pathway than the N-unsubstituted cases, and this would be in line with the experimental observation of a longer reaction time required for substrate 2a relative to 1a (Table 1). Nevertheless, the carbamate reactions are higher yielding than those of their corresponding amines, possibly because the former benefit from an exergonic HCl/alkene exchange (with the exception of the t-Bu-substituted case; see below) between the zwitterion C and the key insertion precursor D. As a result, intermediate D (that leads irreversibly to E) is much more populated than C, while the insertion barrier is kept lower than that of the N-unsubstituted aniline (18.1 kcal/mol from D vs 22.9 kcal/mol from C, entries 7 and 4, respectively; Table 5). On the other hand, the lack of reactivity of the t-Bu-substituted carbamate 2c (entry 10, Table 1) could be ascribed to the endergonicity of both cyclization and HCl/alkene exchange steps, resulting in a total insertion barrier of 31.7 kcal/mol starting from B. This, together with a similarly high barrier for BHE (30.2 kcal/mol, entry 8, Table 1) would lead to a slow reaction.
Further examination of Tables 45 also indicates that cycloisomerization of the starting alkynylaniline derivative, leading to products 6, is absent in cases with low insertion energy and/or favorable HCl/alkene exchange energy. As suggested in the literature, (96) protodepalladation is a possible cycloisomerization mechanism and, in the context of the catalytic cycle of Scheme 4, this could be taking place from an intermediate of an undetermined structure, originating from C or D. (97) In this scenario, reactions of n-butyl acrylate or methyl methacrylate, with low insertion activation energies, would be expected to compete more efficiently with that cycloisomerization pathway than those of α-acetamidoacrylates, where insertion has a much higher barrier. (98) As for the effect of PPh3, it is noticed that protodepalladation would be dependent on the availability of HCl (released upon formation of D and also after BHE), which is in turn limited by its consumption during the final Pd(0) oxidation (Scheme 4), and possibly by interaction with TPPO produced as a result of PPh3 air oxidation. (91,92) In fact, the formation of the hydrochloride HClTPPO (99) from TPPO and HCl is a very favorable process, calculated to release 13.7 kcal/mol. As a result, TPPO could have a regulatory effect on the available amount of HCl. Interestingly, upon following the reaction of 1a and 3 by HPLC-MS, it was found that the ratio 4a/6a increased as the reaction progressed (and presumably more HClTPPO was formed). (92) This possible regulatory role of TPPO could explain its beneficial effect in the reactions of N-PMB derivatives (Table 3), as indicated above, and perhaps also the higher incidence of cycloisomerization in the PPh3-free reactions (entries 1 and 3 in Tables 1 and 4, respectively), where that regulatory effect is absent.

Conclusions

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The preparation of structurally diverse dehydrotryptophans has been developed using palladium-catalyzed oxidative aminocyclization–coupling cascade reactions involving 2-alkynylaniline derivatives and methyl α-acetamidoacrylate. In this direct manner, moderate-to-high yields of products are realized and, relative to alternative strategies, the isolation and purification of intermediates is minimized. The method is effective for the preparation of the indolyl N-unsubstituted dehydrotryptophans (through the corresponding carbamates), as well as for N-PMB derivatives. Aryl, alkenyl, and alkyl (primary, secondary, and tertiary) substituents have all been incorporated at the indole C-2 position, and the presence of both electron-donating and electron-withdrawing groups at the aniline benzene ring has been shown to be well tolerated. DFT calculations have been performed on these and related reactions using model methyl acrylates. The computed data indicate that the presence of the amino substituent on the alkene tends to disfavor both HCl/alkene exchange and alkene insertion steps, whereas the presence of PPh3 and the use of a carbamate of the alkynylaniline have the opposite effect. These findings are in line with the experimentally observed higher incidence of competing cycloisomerization in those cases where HCl/alkene exchange and alkene insertion are disfavored (use of α-acetamidoacrylates, absence of PPh3, and use of N-unsubstituted alkynylanilines).

Computational Details

All calculations were carried out using the Gaussian 09 program package (100) and ωB97XD functional developed by Chai and Head-Gordon. (101) The def2SVPP basis set developed by Ahlrichs and co-workers was used for nonmetals and LANL2DZ for Pd. (102) Single-point energy calculations were carried out with a triple ζ basis (def2TZVPP) for all atoms. (103) The SMD model (104) was used to include the solvent (DMF) in both optimizations and single-point calculations. The nature of the different saddle points were determined by the number of imaginary frequencies, and these structures were connected via IRC. All 3D representations were created using the Chemcraft software. (105)

Experimental Section

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General Information

THF and MeOH were dried using a Puresolv solvent purification system. Commercial DMF (≥99.8%) was kept over 4 Å MS. A polymer-bound PPh3 (100–200 mesh; 1.6 mmol/g PPh3 loading; diphenylphosphino polystyrene cross-linked with divinylbenzene) was purchased from Aldrich. All other reagents were commercial compounds of the highest purity available. For reactions that require heating we used the Heat-On block system of radleys. New compounds were fully characterized by their 1H and 13C NMR, IR, and HRMS spectral properties. Unless otherwise indicated, routine NMR spectra were obtained at 25 °C on a Bruker ARX-400 spectrometer (400.16 MHz for 1H and 100.62 MHz for 13C) using CDCl3, acetone-d6, CD3OD, and DMSO-d6 as solvents and internal reference (CDCl3 δ 7.26 for 1H and δ 77.0 for 13C, acetone-d6 δ 2.05 for 1H and δ 29.84 for 13C, CD3OD δ 3.31 for 1H and δ 49.0 for 13C, DMSO-d6 δ 2.50 for 1H and δ 39.5 for 13C). Chemical shifts (δ) are reported in ppm, and coupling constants (J) are given in hertz (Hz). The proton spectra are reported as follows: multiplicity, coupling constant J, number of protons. The DEPT sequence was routinely used for 13C multiplicity assignment. Additionally, a combination of COSY, HSQC, and HMBC NMR experiments were used for structural assignments. Infrared spectra (IR) data were obtained from a thin film deposited onto a NaCl glass and were measured on a Jasco FT/IR 4100 in the interval between 4000 and 600 cm–1 with a 4 cm–1 resolution; data include only characteristic absorptions. Electrospray ionization (ESI) mass spectra were obtained on a micrOTOF focus mass spectrometer (Bruker Daltonics) using an ApolloII (ESI) source with a voltage of 4500 V applied to the capillary. Electron impact (EI) mass spectra were obtained on a Hewlett-Packard HP59970 instrument operating at 70 eV. For UPLC-QTOF, chromatographic separation was done with an Acquity UPLC BEH C18 1.7 μm, 50 mm × 2.1 mm column, and H2O/HCO2H (99.9:0.1, v/v) or MeOH/HCO2H (99.9:0.1, v/v) as eluent mixture; the ionization source was electrospray in positive mode (ESI+) with a voltage of 15 V; the range of masses in acquisition was 50–1200 u in SCAN mode. Flash-column chromatography was carried out in an automated system, using silica gel (230–400 mesh), cyano-functionalized silica gel (CN-silica gel, 20 to 40 μm particle size, spherical) or C18-derivatized silica gel (C18-silica, 40 to 63 μm, particle size). Analytical thin layer chromatography (TLC) was performed on aluminum plates with Merck Kieselgel 60F254 and visualized by UV irradiation (254 nm). Melting points were measured in a Büchi B-540 apparatus in open capillary tubes.

X-ray Crystallographic Analysis of 10c

The crystals were grown in hexane/EtOAc by warming for 2 days at 5–7 °C. Crystallographic data were collected on a Bruker Smart 1000 CCD diffractometer at CACTI (Universidade de Vigo) at 20 °C using graphite monochromated Mo Kα radiation (λ = 0.71073 Å), and were corrected for Lorentz and polarization effects. The software SMART1 was used for collecting frames of data, indexing reflections, and the determination of lattice parameters and SAINT2 for integration of intensity of reflections and scaling and SADABS3 for empirical absorption correction. The structure (Figure 1) was solved by direct methods using the program SHELXS97.4. Non-hydrogen atoms were refined with anisotropic thermal parameters by full-matrix least-squares calculations on F2 using the program SHELXL97.5. Hydrogen atoms were inserted at calculated positions and constrained with isotropic thermal parameters. The crystallographic data of 10c were deposited in the Cambridge Crystallographic Data Centre with the deposition number CCDC 1939395.

Carbamate Preparation from o-Iodoanilines. General Procedure

To a suspension of K2CO3 (0.36 g, 2.61 mmol) and the appropriate 2-iodoaniline (2.01 mmol) in THF (10 mL) at 0 °C was added dropwise ethyl chloroformate (0.23 mL, 2.41 mmol), and the mixture was stirred either at room temperature or at 80 °C for 12–22 h. The reaction mixture was poured over H2O (10 mL), and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 and dried (Na2SO4). The solvent was evaporated, and the residue was purified by flash-column chromatography (silica gel; solvent A, hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B) to afford the product.

Ethyl (4-Bromo-2-iodophenyl)carbamate (7b) (27,106)

Following the general procedure for carbamate formation described above, the reaction of 4-bromo-2-iodoaniline (0.50 g, 1.68 mmol), ethyl chloroformate (0.19 mL, 2.01 mmol), and K2CO3 (0.30 g, 2.18 mmol) in THF (8.4 mL) at 80 °C for 19 h provided 0.55 g (88%) 7b as a white solid. Mp: 105–106 °C (hexane/EtOAc). (106)

Ethyl (5-Bromo-2-iodophenyl)carbamate (7c). (106)

To a cooled (0 °C) solution of 5-bromo-2-iodoaniline (1.5 g, 5.03 mmol) in pyridine (6.6 mL) was added ethyl chloroformate (0.67 mL, 7.05 mmol). The mixture was warmed up to 25 °C and stirred for 20 h. The reaction was poured into a mixture of EtOAc and brine (100 mL, 1:1 v/v). The layers were separated, the aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed successively with a saturated aqueous solution of CuSO4 (2×) and brine (2×) and dried (Na2SO4). The solvent was evaporated, and the residue was purified by flash-column chromatography (silica gel, 95:5 hexane/EtOAc) to afford 1.80 g (97%) of 7c as a white solid. Mp 108–109 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.30 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.3, 2.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ppm. (106)13C{1H} NMR (100.62 MHz, CDCl3): δ 153.2, 139.8, 139.7, 128.0, 123.5, 122.9, 86.3, 62.0, 14.6 ppm. FTIR (NaCl): ν 3291 (s, N–H), 1690 (s, C═O), 1565 (s), 1518 (s), 1075 (s, C–Br) cm–1.

Methyl 4-[(Ethoxycarbonyl)amino]-3-iodobenzoate (7d). (107)

Following the general procedure for carbamate formation described above the reaction of methyl 4-amino-3-iodobenzoate (0.78 g, 2.82 mmol), ethyl chloroformate (0.32 mL, 3.38 mmol), and K2CO3 (0.51 g, 3.66 mmol) in THF (14.1 mL) at 80 °C for 12 h provided 0.98 g (69%) of 7d as a white solid. Mp: 113–114 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.40 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.96 (dd, J = 8.7, 2.0 Hz, 1H), 7.16 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 165.3, 153.0, 142.5, 140.4, 130.9, 126.2, 118.4, 87.1, 62.0, 52.3, 14.5 ppm. FTIR (NaCl): ν 3380 (s, N–H), 2976 (m, C–H), 1748 (s, C═O), 1709 (s, C═O), 1520 (s), 1242 (s), 759 (s, C–Br) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C11H13INO4 349.9884; found 349.9889.

Ethyl (2-Iodo-4-methoxyphenyl)carbamate (7e)

Following the general procedure for carbamate formation described above the reaction of 2-iodo-4-methoxyaniline (0.20 g, 0.80 mmol), ethyl chloroformate (0.09 mL, 0.96 mmol), and K2CO3 (0.14 g, 1.04 mmol) in THF (4 mL) at 25 °C for 22 h afforded 0.21 g (81%) of 7e as a white solid. Mp: 79–80 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.81 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 2.9 Hz, 1H), 6.90 (dd, J = 9.0, 2.9 1H), 6.65 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 156.4, 154.0), 132.1, 123.9, 122.2, 115.1, 90.9, 61.6, 55.8, 14.7) ppm. FTIR (NaCl): ν 3279 (s, N–H), 2978 (w), 2938 (w), 2904 (w), 2838 (w), 1697 (s, C═O), 1528 (s, N–C═O), 1401 (w), 1283 (s, C–O–C), 1240 (s, C–O), 1216 (s, C–O), 1034 (w), 1024 (w), 854 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C10H13INO3 321.9935; found 321.9931.

tert-Butyl[(2,2-dimethylbut-3-yn-1-yl)oxy]diphenylsilane (8n)

To a cooled (0 °C) solution of 4-hydroxy-3,3-dimethylbutan-2-one (108) (5.5 g, 47 mmol) in DMF (95 mL), TBDPSCl (18.5 mL, 71 mmol) and imidazole (8.1 g, 118 mmol) were added. The resulting mixture was stirred at 25 °C for 20 h under argon. Then, the mixture was poured over a 1:1 NaHCO3 (sat)/water solution, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with water (3×), dried (Na2SO4), and concentrated. The residue was purified by flash-column chromatography (silica gel, 95: hexane/EtOAc) to afford 8.0 g (68%) of the silyl ether 4-[(tert-butyldiphenylsilyl)oxy]-3,3-dimethylbutan-2-one. 1H NMR (400.16 MHz, CDCl3): δ 7.68–7.62 (m, 4H), 7.48–7.36 (m, 6H), 3.65 (s, 2H), 2.18 (s, 3H), 1.13 (s, 6H), 1.06 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 213.0, 135.8 (4×), 133.3 (2×), 129.9 (2×), 127.8 (4×), 70.9, 50.0, 27.0 (3×), 26.2, 21.7 (2×), 19.4 ppm. FTIR (NaCl): ν 2961 (m, C–H), 2932 (m, C–H), 2859 (m, C–H), 1710 (s), 1472 (m), 1427 (m), 1392 (m), 1360 (m), 1109 (s), 703 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H31O2Si 355.2088; found 355.2082. This material was processed as follows: n-BuLi (1.77 M in hexanes, 1.2 mL, 2.07 mmol) was added to a cooled (0 °C) solution of diisopropylamine (0.307 mL, 2.17 mmol) in THF (3.9 mL), and the resulting mixture was stirred at 0 °C for 30 min. Then, this solution was cooled down to −78 °C, and a solution of 4-[(tert-butyldiphenylsilyl)oxy]-3,3-dimethylbutan-2-one (1.00 g, 1.97 mmol) in THF (2.0 mL) was added. After stirring for 1 h at the same temperature, diethyl chlorophosphate (0.314 mL, 2.17 mmol) was added, and the reaction mixture was allowed to warm up to 25 °C over a period of 90 min. Then, a second LDA solution was prepared by the addition of n-BuLi (1.77 M in hexanes, 2.5 mL, 4.44 mmol) to a solution of diisopropylamine (0.642 mL, 4.54 mmol) in THF (3.9 mL) at 0 °C and further stirring for 30 min at the same temperature. Then, the previous reaction mixture was added to this freshly prepared LDA solution at −78 °C, and stirring was continued at this temperature for 1 h. After additional stirring for 1 h at 25 °C, the reaction mixture was quenched at 0 °C by the addition of a saturated aqueous solution of NH4Cl. Then Et2O was added, the layers were separated, and the aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 and dried (Na2SO4), and the solvent was evaporated. The residue was purified by flash-column chromatography (silica gel, gradient from hexane to 95:5 hexane/EtOAc) to afford 0.34 g (52%) of 8n as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.72–7.66 (m, 4H), 7.46–7.35 (m, 6H), 3.52 (s, 2H), 2.08 (s, 1H), 1.26 (s, 6H), 1.08 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 135.9 (4×), 133.8 (2×), 129.8 (2×), 127.8 (4×), 90.6, 71.8, 68.4, 33.7, 27.0 (3×), 25.7 (2×), 19.6. FTIR (NaCl): ν 3066 (m, C–H), 2948 (m, C–H), 2929 (m, C–H), 1690 (s), 1632 (m), 1466 (m), 1387 (m), 1247 (m), 1107 (s), 746 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H29OSi 337.1982; found 337.1984.

Preparation of 2-Alkynylaniline Derivatives 2 and 9 by Sonogashira Reaction

Procedure A: In a typical experiment, to a solution of an appropriate o-iodoaniline derivative (0.29 mmol) and alkyne 8 (1.18 mmol) in Et3N (0.2 mL) and DMF (2.9 mL) were added PdCl2(PPh3)2 (4.2 mg, 0.006 mmol) and CuI (2.3 mg, 0.012 mmol), and the mixture was stirred at 25 °C under argon. After reaction completion, a saturated aqueous solution of NH4Cl was added, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), and the solvent was evaporated. The residue was purified by flash-column chromatography to afford product 2 or 9. Procedure B: In a typical experiment, to a solution of an appropriate o-iodoaniline derivative (1.18 mmol) and alkyne 8 (4.72 mmol) in Et3N (2.6 mL) were added PdCl2(PPh3)2 (16.8 mg, 0.024 mmol) and CuI (4.6 mg, 0.024 mmol), and the mixture was stirred at 25 °C under argon. It then proceeded as in procedure A to afford product 2 or 9. Procedure C: In a typical experiment, to a solution of an appropriate o-iodoaniline derivative (0.29 mmol) and alkyne 8 (0.35 mmol) in Et3N (0.6 mL) and DMF (0.3 mL) were added PdCl2(PPh3)2 (4.2 mg, 0.006 mmol) and CuI (0.6 mg, 0.003 mmol), and the mixture was stirred at 25 °C under argon. It then proceeded as in procedure A to afford product 2 or 9. Procedure D: In a typical experiment, to a solution an appropriate o-iodoaniline derivative (0.34 mmol) and alkyne 8 (0.69 mmol) in a mixture of THF/Et3N (6.4 mL, 4:1 v/v) were added PdCl2(PPh3)2 (4.8 mg, 0.007 mmol) and CuI (2.6 mg, 0.014 mmol), and the mixture was stirred at 25 °C under argon. It then proceeded as in procedure A to afford product 2 or 9.

Ethyl [2-(Oct-1-yn-1-yl)phenyl]carbamate (2b)

The Sonogashira Procedure A was followed from ethyl (2-iodophenyl)carbamate (27,107) (7a) (500 mg, 1.72 mmol) and oct-1-yne (8b) (1.0 mL, 6.87 mmol) (reaction time 20 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 413 mg (88%) of 2b as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 8.13 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H, NH), 7.34 (dd, J = 7.7, 1.5 Hz, 1H), 7.32–7.22 (m, 1H), 6.95 (td, J = 7.6, 1.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 1.70–1.57 (m, 2H), 1.54–1.43 (m, 2H), 1.37–1.31 (m, 7H), 0.92 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 153.4, 139.1, 131.7, 128.9, 122.3, 117.4, 112.2, 97.8, 75.9, 61.4, 31.5, 28.7 (2×), 22.7, 19.7, 14.7, 14.2 ppm. FTIR (NaCl): ν 3398 (s, N–H), 2956 (w), 2931 (w), 2858 (w), 1741 (s, C═O), 1580 (s), 1521 (s), 1452 (s), 1230 (w), 1210 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C17H24NO2 274.1803; found 274.1802.

Ethyl [2-(3,3-Dimethylbut-1-yn-1-yl)phenyl]carbamate (2c)

The Sonogashira Procedure B was followed from 7a (27,107) (200 mg, 0.69 mmol) and tert-butylacetylene (8c) (0.10 mL, 0.83 mmol) (reaction time 3 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 90:10 A/B), 165 mg (98%) of 2c as a colorless oil. 1H NMR (400.16 MHz, CDCl3): δ 8.12 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.32 (ddd, J = 7.7, 1.6, 0.5 Hz, 1H), 7.26 (dddd, J = 8.2, 7.4, 1.6, 0.5 Hz, 1H), 6.94 (td, J = 7.6, 1.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.37 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 153.4, 139.0, 131.3, 128.9, 122.2, 117.4, 112.1, 106.0, 74.5, 61.3, 31.1 (3×), 28.4, 14.6 ppm. FTIR (NaCl): ν 3399 (m, N–H), 2970 (m, C–H), 1742 (s, C═O), 1582 (m), 1522 (s), 1454 (m), 1216 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C15H20NO2 246.1488; found 246.1486.

Ethyl [2-Cyclohexyl)ethynyl)phenyl]carbamate (2o)

The Sonogashira Procedure A was followed from 7a (27,107) (500 mg, 1.72 mmol) and 1-ethynylcyclohexane (8k) (0.90 mL, 6.87 mmol) (reaction time 20 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 357 mg (77%) of 2o as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 8.11 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H, NH), 7.34 (dd, J = 7.9, 1.4 Hz, 1H), 7.29–7.24 (m, 1H), 6.95 (td, J = 7.6, 1.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.70 (tt, J = 8.4, 3.7 Hz, 1H), 1.98–1.84 (m, 2H), 1.80–1.74 (m, 2H), 1.64–1.52 (m, 3H), 1.47–1.36 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 153.5, 139.1, 131.5, 128.9, 122.3, 117.4, 112.2, 101.9, 75.9, 61.4, 32.7 (2×), 29.8, 25.9 (2×), 24.8, 14.7 ppm. FTIR (NaCl): ν 3395 (s, N–H), 2979 (w), 2930 (s), 2854 (s), 1741 (s, C═O), 1581 (s), 1521 (s), 1451(s), 1307 (w), 1227 (s), 1207 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C17H22NO2 272.1646; found 272.1645.

Ethyl [2-Cyclohex-1-en-1-ylethynyl)phenyl]carbamate (2p)

The Sonogashira Procedure A was followed from 7a (27,107) (500 mg, 1.72 mmol) and 1-ethynylcyclohex-1-ene (8l) (0.81 mL, 6.87 mmol) (reaction time 20 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 460 mg (99%) of 2p as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 8.15 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 7.7, 1.7 Hz, 2H), 7.33–7.27 (m, 1H), 6.99 (tt, J = 7.6, 1.0 Hz, 1H), 6.32–6.25 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (ddt, J = 5.9, 4.4, 2.4 Hz, 2H), 2.23–2.15 (m, 2H), 1.77–1.69 (m, 2H), 1.69–1.62 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 153.4, 138.9, 136.2, 131.6, 129.3, 122.4, 120.3, 117.6, 111.9, 98.3, 81.7, 61.4, 29.3, 25.9, 22.4, 21.5, 14.7 ppm. FTIR (NaCl): ν 3398 (s, N–H), 2979 (w), 2932 (m), 2859 (w), 2837 (w), 1740 (s, C═O), 1579 (m), 1520 (s), 1452 (m), 1208 (s), 1060 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C17H20NO2 270.1488; found 270.1489.

N-(4-Methoxybenzyl)-2-(oct-1-yn-1-yl)aniline (9a)

The Sonogashira Procedure A was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (100 mg, 0.29 mmol) and 8b (0.174 mL, 1.18 mmol) at 60 °C (reaction time 16 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 52 mg (55%) of 9a as an oil. 1H NMR (400.16 MHz, CDCl3): δ 7.30 (d, J = 8.7 Hz, 2H), 7.27 (dd, J = 7.5, 1.5 Hz, 1H), 7.12 (ddd, J = 7.7, 7.0, 1.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H), 2.45 (t, J = 7.0 Hz, 2H), 1.63–1.53 (m, 2H), 1.47–1.37 (m, 2H), 1.33–1.23 (m, 4H), 0.90 (t, J = 7.0 Hz 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.9, 148.8, 132.0, 131.4, 129.2, 128.6 (2×), 116.5, 114.1 (2×), 109.8, 108.7, 96.4, 77.2, 55.4, 47.4, 31.5, 29.0, 28.7, 22.7, 19.8, 14.2 ppm. FTIR (NaCl): ν 3396 (m, N–H), 2924 (s, C–H), 2858 (s, C–H), 1605 (m), 1508 (s), 1246 (s), 741 (m) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H28NO 322.2165; found 322.2161.

3-[2-(4-Methoxybenzylamino)phenyl]prop-2-yn-1-yl Acetate (9b)

The Sonogashira Procedure B was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (400 mg, 1.18 mmol) and prop-2-yn-1-yl acetate (8m) (0.468 mL, 4.72 mmol) in Et3N (2.6 mL) (reaction time 24 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 170 mg (47%) of 9b as a yellow solid. Mp: 59–60 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.31 (dd, J = 7.5, 1.5 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.16 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.1 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 5.05 (br s, 1H), 4.92 (s, 2H), 4.36 (s, 2H), 3.80 (s, 3H), 2.09 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 170.4, 158.9, 149.4, 132.6, 131.1, 130.6, 128.4 (2×), 116.4, 114.1 (2×), 110.0, 106.3, 89.0, 83.6, 55.3, 53.1, 47.1, 20.9 ppm. FTIR (NaCl): ν 3398 (m, N–H), 3000 (w, C–H), 2936 (w), 2836 (w), 2223 (w, C≡C), 1741 (s, C═O), 1507 (s), 1229 (s), 1028 (s), 743 (m) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO3 310.1438; found 310.1429.

2-(Cyclohexylethynyl)-N-(4-methoxybenzyl)aniline (9c)

The Sonogashira Procedure C was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (100 mg, 0.29 mmol) and 8k (0.046 mL, 0.35 mmol) (reaction time 24h) to afford, after purification by flash-column chromatography (silica gel; solvent A, hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B), 58 mg (62%) of 9c as an oil. 1H NMR (400.16 MHz, CDCl3): δ 7.31 (d, J = 8.7 Hz, 2H), 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.13 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.1 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.95 (br s, 1H), 4.34 (s, 2H), 3.81 (s, 3H), 2.66 (tt, J = 8.6, 3.8 Hz, 1H), 1.88–1.79 (m, 2H), 1.75–1.64 (m, 2H), 1.58–1.45 (m, 3H), 1.40–1.26 (m, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 159.0, 148.8, 131.8, 131.4, 129.1, 128.6 (2×), 116.5, 114.1 (2×), 109.7, 108.7, 100.6, 77.2), 55.4, 47.5, 32.9 (2×), 29.9, 26.0 (2×), 24.8 ppm. FTIR (NaCl): ν 3400 (m, N–H), 3006 (m, C–H), 2928 (s, C–H), 2851 (s, C–H), 1603 (s), 1508 (s), 1454 (s), 1246 (s), 744 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H26NO 320.2009; found 320.2004.

2-(3,3-Dimethylbut-1-yn-1-yl)-N-(4-methoxybenzyl)aniline (9d)

The Sonogashira Procedure B was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (100 mg, 0.29 mmol) and 8c (0.044 mL, 0.35 mmol) (reaction time 4 h) to afford, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 100:0 to 80:20 A/B) 84 mg (98%) of 9d as a yellow solid. Mp: 30–31 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 7.28 (dd, J = 7.5, 1.5 Hz, 1H), 7.14 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.63 (td, J = 7.5, 1.1 Hz, 1H), 6.59 (dd, J = 8.2, 1.0 Hz, 1H), 4.92 (s, 1H), 4.35 (s, 2H), 3.82 (s, 3H), 1.32 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.9, 148.7, 131.7, 131.4, 129.2, 128.5 (2×), 116.5, 114.1 (2×), 109.8, 108.6, 104.9, 75.7, 55.4, 47.5, 31.4 (3×) 28.4 ppm. FTIR (NaCl): ν 3401 (m, N–H), 3064 (m, C–H), 2967 (s, C–H), 2903 (m, C–H), 2841 (m, C–H), 1607 (s), 1579 (s), 1506 (s), 1457 (s), 1247 (s), 741 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H24NO 294.1852; found 294.1850.

2-{4-[(tert-Butyldiphenylsilyl)oxy]-3,3-dimethylbut-1-yn-1-yl}-N-(4-methoxybenzyl)aniline (9e)

The Sonogashira Procedure C was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (500 mg, 1.47 mmol) and 8n (595 mg, 1.77 mmol) (reaction time 48 h) to afford, after purification by flash-column chromatography (C18-silica gel; solvent A, acetonitrile; solvent B, water; gradient from 70:30 to 100:0 A/B), 580 mg (72%) of 9e as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.72–7.66 (m, 4H), 7.44–7.37 (m, 2H), 7.38–7.30 (m, 4H), 7.25–7.19 (m, 3H), 7.10 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.59 (td, J = 7.5, 1.1 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.94 (br s, 1H), 4.26 (d, J = 3.9 Hz, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 1.30 (s, 6H), 1.07 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 148.8, 135.8 (4×), 133.7, 131.9, 131.4 (2×), 129.8 (2×), 129.3, 128.3 (2×), 127.8 (4×), 116.4, 114.1 (2×), 109.8, 108.4, 102.2, 77.4, 72.1, 55.4, 47.3, 34.8, 27.0 (3×), 26.1 (2×), 19.6 ppm. FTIR (NaCl): ν 3398 (w, N–H), 3067 (w, C–H), 2960 (s, C–H), 2927 (s, C–H), 2863 (s, C–H), 1606 (m), 1509 (s), 1464 (m), 1246 (m), 1106 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C36H42NO2Si 548.2979; found 548.2995.

4-[2-(4-Methoxybenzylamino)phenyl]-2-methylbut-3-yn-2-ol (9f)

The Sonogashira Procedure D was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (400 mg, 1.18 mmol) and 2-methylbut-3-yn-2-ol (8o) (0.23 mL, 2.36 mmol) (reaction time 12 h) to afford, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 80:20 A/B), 340 mg (98%) of 9f as a brown oil. 1H NMR (400.16 MHz, CDCl3): δ 7.31–7.25 (m, 3H), 7.18–7.12 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.62 (td, J = 7.5, 1.0 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.87 (br s, 1H, NH), 4.34 (s, 2H), 3.81 (s, 3H), 1.60 (s, 6H), 1.53 (br s, 1H, OH) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 148.8, 132.1, 131.1, 129.9, 128.3 (2×), 116.5, 114.1 (2×), 110.0, 107.1, 100.1, 78.9, 65.8, 55.3, 47.2, 31.7, 31.1 ppm. FTIR (NaCl): ν 3600–3000 (br, O–H), 2979 (m, C–H), 2932 (m, C–H), 2835 (m, C–H), 1509 (s), 1248 (s), 1173 (s), 772 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C19H22NO2 296.1645; found 296.1639.

2-(Cyclohex-1-en-1-ylethynyl)-N-(4-methoxybenzyl)aniline (9g)

The Sonogashira Procedure B was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (100 mg, 0.29 mmol) and 8l (0.042 mL, 0.35 mmol) (reaction time 6 h) to afford, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 100:0 to 80:20 A/B), 91 mg (98%) of 9g as a yellow solid. Mp: 38–39 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.29 (d, J = 8.7 Hz, 2H), 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.12 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.15 (tt, J = 3.9, 1.8 Hz, 1H), 5.00 (br s, 1H), 4.35 (s, 2H), 3.81 (s, 3H), 2.23–2.17 (m, 2H), 2.17–2.10 (m, 2H), 1.72–1.57 (m, 4H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.9, 148.6, 134.9, 132.0, 131.3, 129.6, 128.5 (2×), 120.9, 116.7, 114.2 (2×), 110.0, 108.3, 97.4, 83.3, 55.4, 47.4, 29.6, 25.9, 22.5, 21.7 ppm. FTIR (NaCl): ν 3400 (m, N–H), 2926 (s, C–H), 2853 (s, C–H), 2190 (w, C≡C), 1601 (m), 1507 (s), 1454 (m), 1244 (s), 1034 (m), 747 (m) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H24NO [(M+H)+] 318.1852; found 318.1857.

2-(3,3-Dimethylbut-1-yn-1-yl)-N-(4-methoxybenzyl)-4-methylaniline (9h)

The Sonogashira Procedure D was followed from 2-iodo-N-(4-methoxybenzyl)-4-methylaniline (110) (710 mg, 2.04 mmol) and 8c (0.50 mL, 4.07 mmol) (reaction time 16 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, acetonitrile; solvent B, water; gradient from 50:50 to 100:0 A/B), 593 mg (95%) of 9h as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.29 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.94–6.89 (m, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.3 Hz, 1H), 4.72 (t, J = 5.5 Hz, 1H, NH), 4.30 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.18 (s, 3H), 1.28 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 146.6, 139.3, 132.1, 131.6, 129.8, 128.5 (2×), 125.6, 114.0 (2×), 109.9, 108.5, 104.5, 75.7, 55.4, 47.7, 31.4 (3×), 20.3 ppm. FTIR (NaCl): ν 3397 (w, N–H), 2965 (w), 2925 (w), 2864 (w), 2834 (w), 1511 (s), 1248 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H26NO 308.2009; found 308.2011.

Methyl 3-(3,3-Dimethylbut-1-yn-1-yl)-4-[(4-methoxybenzyl)amino]benzoate (9i)

The Sonogashira Procedure D was followed from methyl 3-iodo-4-[(4-methoxybenzyl)amino]benzoate (109) (500 mg, 1.26 mmol) and 8c (0.31 mL, 2.52 mmol) (reaction time 16 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 90:10 A/B), 428 mg (95%) of 9i as a brown oil. 1H NMR (400.16 MHz, CDCl3): δ 7.95 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.5, 1.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 8.7 Hz, 1H), 5.29 (t, J = 5.3 Hz, 1H, NH), 4.37 (d, J = 5.3 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 1.28 (s 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 167.0, 159.1, 151.7, 133.7, 131.3, 130.2, 128.5 (2×), 117.8, 114.4, 114.2 (2×), 108.6, 108.0, 105.4, 74.6, 55.4, 51.7, 47.0, 31.2 (3×) ppm. FTIR (NaCl): ν 3397 (m, N–H), 2967 (w), 2900 (w), 2866 (w), 2837 (w), 1709 (s, C═O), 1604 (s), 1514 (s), 1302 (s), 1249 (s), 1176 (w), 1131 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H26NO3 352.1910; found 352.1907.

2-(Cyclohex-1-en-1-ylethynyl)-N-(4-methoxybenzyl)-4-methylaniline (9j)

The Sonogashira Procedure D was followed from 2-iodo-N-(4-methoxybenzyl)-4-methylaniline (110) (600 mg, 1.70 mmol) and 8l (0.40 mL, 3.40 mmol) (reaction time 16 h) to afford, after purification by flash-column chromatography (silica gel; solvent A, acetonitrile; solvent B, water; gradient from 50:50 to 100:0 A/B), 231 mg (41%) 9j as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.29 (d, J = 8.8 Hz, 2H), 7.16–7.09 (m, 1H), 6.93 (ddd, J = 8.3, 2.2, 0.8 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.3 Hz, 1H), 6.15 (tt, J = 3.9, 1.8 Hz, 1H), 4.82 (br s, 1H, NH), 4.33 (s, 2H), 3.81 (s, 3H), 2.24–2.17 (m, 5H), 2.14 (tdd, J = 6.1, 4.0, 2.1 Hz, 2H), 1.72–1.59 (m, 4H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 146.5, 134.7, 132.2, 131.6, 130.2, 128.4 (2×), 125.6, 120.8, 114.1 (2×), 110.1, 108.2, 97.1, 83.5, 55.4, 47.5, 29.6, 25.9, 22.5, 21.6, 20.3 ppm. FTIR (NaCl): ν 3398 (w, N–H), 3021 (w), 2928 (w), 2857 (w), 2834 (w), 1611 (w), 1509 (s), 1437 (w), 1246 (m), 1034 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H26NO 332.2004; found 332.2008.

N-(4-Methoxybenzyl)-2-[(triethylsilyl)ethynyl]aniline (9k)

The Sonogashira Procedure D was followed from 2-iodo-N-(4-methoxybenzyl)aniline (109) (400 mg, 1.18 mmol) and triethyl(ethynyl)silane (8p) (0.42 mL, 2.36 mmol) (reaction time 12 h) to afford, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 95:5 to 90:10 A/B), 214 mg (52%) of 9k as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.21–7.13 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.65–6.56 (m, 2H), 4.97 (br s, 1H, NH), 4.31 (s, 2H), 3.81 (s, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.62 (q, J = 7.9 Hz, 6H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 159.1, 149.4, 132.2, 131.0, 130.2, 128.8 (2×), 116.4, 114.2 2×), 109.7, 107.8, 103.3, 97.9, 55.4, 47.5, 7.6 (3×), 4.6 (3×) ppm. FTIR (NaCl): ν 3398 (s, N–H), 2953 (s, C–H), 2933 (m, C–H), 2909 (m, C–H), 2873 (m, C–H), 2834 (w, C–H), 2141 (w, C≡C), 1602 (s), 1510 (s), 1458 (s), 1249 (s), 1038 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H30NOSi 352.2091; found 352.2085.

Preparation of Dehydrotryptophans 4ac or 5ab from 1ac or 2ab and 3 (Table 1)

In a typical experiment, to a solution of the appropriate alkynylaniline derivative 1 or 2 (0.24 mmol) and methyl α-acetamidoacrylate (3) (207.2 mg, 1.45 mmol) in DMF (2.4 mL) were added PdCl2(PPh3)2 (8.5 mg, 0.012 mmol) and KI (20.0 mg, 0.121 mmol). The resulting mixture was stirred at 100 °C with the flask open to air. After reaction completion, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), and the solvent was evaporated. The residue was purified by flash-column chromatography to afford products 4 and/or 5.

Methyl (Z)-2-Acetamido-3-[2-(p-tolyl)-1H-indol-3-yl]acrylate (4a)

The reaction of 2-(p-tolylethynyl)aniline (1a) (14,111) (50.0 mg, 0.24 mmol) and methyl 2-acetamidoacrylate (3) (207.2 mg, 1.45 mmol) in 7 h afforded, after purification by flash-column chromatography (CN-silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 100:0 to 50:50 A/B), 50.4 mg (63%) of 4a and 9.8 mg (20%) of 6a. (111,112) Data for 4a: Yellow solid. Mp: 158–159 °C (hexane/EtOAc). 1H NMR (400.16 MHz, Acetone-d6): δ 10.88 (s, 1H), 8.40 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.44 (dt, J = 8.0, 1.0 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.18 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.10 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.74 (s, 3H), 2.39 (s, 3H), 1.82 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, Acetone-d6): δ 169.0, 166.4, 140.3, 139.2, 137.6, 130.4, 130.2 (2×), 129.4 (2×), 127.8, 126.0, 125.7, 123.1, 121.4, 120.9, 112.4, 108.2, 52.2, 22.8, 21.3 ppm. FTIR (NaCl): ν 3284 (br, m, N–H), 3013 (m, C═C), 2950 (m, C–H), 2866 (m, C–H), 1680 (s, C═O), 1671 (s, C═O), 1507 (s), 1246 (s), 754 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O3 349.1547; found 349.1546.

Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b)

The reaction of 2-(oct-1-yn-1-yl)aniline (113) (1b) (40.3 mg, 0.20 mmol) and 3 (171.8 mg, 1.20 mmol) in DMF (2.0 mL) in 4 h afforded, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 20:80 A/B) 14.0 mg (20%) of 4b as a brown solid. Mp: 122–123 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.65 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.29–7.26 (m, 1H), 7.17–7.06 (m, 2H), 6.95 (s, 1H), 3.87 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 2.04 (s, 3H), 1.64–1.51 (m, 2H), 1.38–1.20 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.4, 166.2, 143.6, 135.9, 125.9, 125.9, 122.0, 120.8, 120.6, 120.4, 111.4, 107.4, 52.5, 31.7, 29.4, 29.1, 26.8, 23.5, 22.7, 14.2 ppm. FTIR (NaCl): ν 3271 (s, N–H), 2924 (s, C–H), 2858 (m), 1674 (s, C═O), 1625 (s, C═O), 1460 (s), 1239 (s), 749 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H27N2O3 343.2016; found 343.2027.

Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1H-indol-3-yl]acrylate (4c)

The reaction of 2-(3,3-dimethylbut-1-yn-1-yl)aniline (113) (1c) (34.7 mg, 0.20 mmol) and 3 (171.8 mg, 1.20 mmol) in 5 h afforded, after purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 20:80 A/B), 27.0 mg (20%) of 4c as a white solid. Mp: 107–108 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.65 (s, 1H), 7.59 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.14 (ddd, J = 8.1, 7.0, 1.3 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H), 3.87 (s, 3H), 1.88 (s, 3H), 1.47 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.8, 165.7, 147.6, 134.3, 126.3, 125.4, 124.3, 121.9, 120.6, 119.8, 111.2, 104.8, 52.6, 33.4, 30.3 (3×), 23.3 ppm. FTIR (NaCl): ν 3321 (s, N–H), 2967 (s, C–H), 1709 (s, C═O), 1674 (s, C═O), 1432 (s), 1257 (s), 752 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C18H23N2O3 315.1703; found 315.1701.

Ethyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-(p-tolyl)-1H-indole-1-carboxylate (5a)

The reaction of ethyl [2-(p-tolylethynyl)phenyl]carbamate (114) (2a) (50.0 mg, 0.18 mmol) and 3 (153.7 mg, 1.07 mmol) for 31 h afforded, after purification by flash-column chromatography (CN-silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 100:0 to 50:50 A/B), 54.2 mg (72%) of 5a as a yellow solid. Mp: 85–86 °C (hexane/EtOAc). 1H NMR (400.16 MHz, Acetone-d6): δ 8.62 (s, 1H), 8.22 (dt, J = 8.4, 0.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.42–7.33 (m, 3H), 7.33–7.23 (m, 3H), 6.89 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 2.41 (s, 3H), 1.84 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, Acetone-d6): δ 168.7, 165.8, 151.9, 140.4, 139.0, 137.4, 130.8 (2×), 130.8, 129.2 (2×), 128.8, 127.8, 125.4, 123.9, 123.3, 121.4, 116.7, 116.0, 63.9, 52.4, 22.8, 21.4, 13.8 ppm. FTIR (NaCl): ν 3400–3200 (m, N–H), 2991 (m, C–H), 2955 (m, C–H), 1727 (s, C═O), 1681 (s, C═O), 1508 (m), 1221 (s), 751 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C24H25N2O5 421.1758; found 421.1749.

Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b) and Ethyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-hexyl-1H-indole-1-carboxylate (5b)

The reaction of 2b (48.9 mg, 0.18 mmol) and 3 (153.7 mg, 1.07 mmol) in 31 h afforded, after purification by flash-column chromatography (CN-silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 95:5 to 0:100 A/B), 29.8 mg (40%) of 5b and 11.2 mg (18%) of 4b.
Data for 5b: Pale yellow solid. Mp: 136–137 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.11 (d, J = 8.3, 1H), 7.33–7.28 (m, 2H), 7.26 (dd, J = 8.3, 1.5 Hz, 1H), 7.20 (td, J = 7.4, 1.1 Hz, 1H), 6.87 (s, 1H), 4.51 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.02 (app t, J = 7.7 Hz, 2H), 1.91 (s, 3H), 1.66–1.56 (m, 2H), 1.50 (t, J = 7.1 Hz, 3H), 1.42–1.26 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.3, 165.3, 151.6, 142.7, 136.1, 126.9, 126.8, 124.3, 123.3, 122.0, 119.8, 116.0, 113.9, 63.6, 52.8, 31.7, 29.9, 29.5, 28.0, 23.3, 22.8, 14.4, 14.2 ppm. FTIR (NaCl): ν 3263 (m, N–H), 2954 (w, C–H), 2928(w, C–H), 2856 (w, C–H), 1735 (s, C═O), 1457 (m), 1325 (m), 1223 (m), 1122 (w), 756 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H31N2O5 415.2227; found 415.2238.

Preparation of 2-Aryldehydrotryptophans 4a and 4dn from o-Iodoaryl Carbamates 7, Alkynes 8, and Alkene 3 (Table 2)

In a typical experiment, to a solution of an o-iodoaryl carbamate 7 (0.21 mmol), an alkyne 8 (0.41 mmol), and 3 (177 mg, 1.24 mmol) in DMF (2.1 mL, previously degassed with freeze–thaw cycles under argon) were added PdCl2 (1.8 mg, 0.010 mmol), polymer-bound PPh3 (13.1 mg, 1.6 mmol/g PPh3 loading, 0.021 mmol of PPh3), CuI (7.9 mg, 0.041 mmol), and Et3N (0.129 mL, 0.93 mmol). The resulting mixture was stirred at 60 °C under argon. After reaction completion, air was allowed into the system, and the mixture was stirred at 120 °C. Then, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and filtered over silica gel (230–400 mesh). After removal of the solvent by evaporation, the residue was dissolved in methanol (4.3 mL) in the presence of tert-butylamine (0.64 mL, 6.1 mmol), and the mixture was heated at reflux. The solvent was removed under reduced pressure, and the crude product was purified by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 20:80 to 0:100 A/B) to afford products 4a and 4dn. Reaction times are those given in Table 2.

Methyl (Z)-2-Acetamido-3-[2-(p-tolyl)-1H-indol-3-yl]acrylate (4a)

Starting from ethyl (2-iodophenyl)carbamate (7a) (27,107) (60 mg, 0.21 mmol) and p-tolylacetylene (8a) (0.052 mL, 0.41 mmol) afforded 44 mg (62%) of 4a.

Methyl (Z)-2-Acetamido-3-[2-(4-methoxyphenyl)-1H-indol-3-yl]acrylate (4d)

Starting from 7a (27,107) (60 mg, 0.21 mmol) and 1-ethynyl-4-methoxybenzene (8d) (55 mg, 0.41 mmol) afforded 55 mg (73%) of 4d as a solid. Mp: 165–166 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 8.84 (s, 1H), 7.53–7.48 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.18–7.09 (m, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.89 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 1.85 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.0, 166.0, 160.1, 139.3, 136.3, 129.9 (2×), 126.9, 125.7, 124.6, 122.8, 122.7, 120.8, 120.2, 114.6 (2×), 111.5, 107.5, 55.5, 52.6, 23.3 ppm. FTIR (NaCl): ν 3500–3100 (br, s, N–H), 3012 (m, C–H), 2950 (m, C–H), 2837 (m, C–H), 1706 (s, C═O), 1670 (s, C═O), 1611 (m), 1502 (s), 1250 (s), 752 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O4 365.1496; found 365.1489.

Methyl (Z)-4-[3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-1H-indol-2-yl]benzoate (4e)

Starting from 7a (27,107) (60.0 mg, 0.21 mmol) and methyl 4-ethynylbenzoate (8e) (66.0 mg, 0.41 mmol) afforded 48.0 mg (59%) of 4e as a yellow solid. Mp: 111–112 °C (hexane/EtOAc). 1H NMR (400.16 MHz, DMSO-d6): δ 12.05 (s, 1H), 9.38 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.22 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.09 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 1.70 (s, 3H). 13C{1H} NMR (100.62 MHz, DMSO-d6): δ 168.5, 165.9, 165.4, 137.3, 136.8, 136.4, 129.5 (2×), 128.8, 128.5 (2×), 126.2, 125.4, 124.4, 122.8, 120.5, 120.1, 111.9, 108.2, 52.3, 51.9, 22.3 ppm. FTIR (NaCl): ν 3500–3100 (br, m, N–H), 3009 (m, C–H), 2949 (m, C–H), 1713 (s, C═O), 1670 (s, C═O), 1435 (m), 1276 (s), 751 (s) cm–1. HRMS (ESI) [M + H]+: calcd for C22H21N2O5 393.1445; found 393.1433.

Methyl (Z)-2-Acetamido-3-[5-bromo-2-(p-tolyl)-1H-indol-3-yl]acrylate (4f)

Starting from 7b (27,106) (200 mg, 0.54 mmol) and 8a (0.137 mL, 1.08 mmol) afforded 157 mg (68%) of 4f as a yellow solid. Mp: 163–164 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD): δ 7.62 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 (dd, J = 8.6, 1.8 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 1.91 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD): δ 172.4, 167.4, 143.4, 140.3, 136.8, 130.5 (2×), 130.1, 129.9 (2×), 129.4, 129.1, 126.0, 124.2, 123.9, 114.4, 114.2, 107.7, 52.8, 22.5, 21.3 ppm. FTIR (NaCl): ν 3400–3100 (br, m, N–H), 3013 (w, C═C), 2949 (w, C–H), 1684 (s, C═O), 1672 (s, C═O), 1433 (s), 1245 (s), 753 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H2079BrN2O3 427.0652; found 427.0637.

Methyl (Z)-2-Acetamido-3-[6-bromo-2-(p-tolyl)-1H-indol-3-yl]acrylate (4g)

Starting from 7c (106) (200 mg, 0.54 mmol) and 8a (0.137 mL, 1.08 mmol) afforded 144 mg (62%) of 4g as a yellow solid. Mp: 157–158 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD): δ 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 3.72 (s, 3H), 2.28 (s, 3H), 1.76 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD): δ 172.1, 167.4, 142.3, 140.0, 138.8, 130.4 (2×), 130.1, 129.6 (2×), 129.1, 126.8, 124.3, 124.0), 122.6, 116.6, 115.4, 108.0, 52.8, 22.5, 21.4 ppm. FTIR (NaCl): ν 3500–3100 (br, m, N–H), 3017 (m, C═C), 2953 (m, C–H), 1685 (s, C═O), 1671 (s, C═O), 1434 (m), 1246 (s), 757 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H2079BrN2O3 427.0652; found 427.0644.

Methyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-(p-tolyl)-1H-indole-5-carboxylate (4h)

Starting from 7d (107) (200 mg, 0.57 mmol) and 8a (0.145 mL, 1.15 mmol) afforded 115 mg (49%) of 4h as a yellow solid. Mp: 244–245 °C (hexane/EtOAc). 1H NMR (400.16 MHz, DMSO-d6): δ 12.27 (s, 1H), 9.56 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.82 (dd, J = 8.5, 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.18 (s, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 2.39 (s, 3H), 1.85 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6): δ 168.8, 167.0, 165.6, 141.5, 139.1, 138.6, 129.5 (2×), 128.7 (2×), 128.3, 125.6, 124.8, 124.0, 123.5), 123.0, 121.3, 111.6), 107.6, 51.9, 51.7, 22.2, 20.9 ppm. FTIR (NaCl): ν 3600–2900 (s, br, N–H), 3040 (w, C–H), 2963 (w, C–H), 2257 (w), 2126 (w), 1708 (s, C═O), 1664 (s, C═O), 1243 (m), 1025 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C23H23N2O5 407.1602; found 407.1601.

Methyl (Z)-2-Acetamido-3-[5-methoxy-2-(p-tolyl)-1H-indol-3-yl]acrylate (4i)

Starting from 7e (200 mg, 0.62 mmol) and 8a (0.158 mL, 1.25 mmol) afforded 130 mg (55%) of 4i as a solid. Mp: 179–180 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD): δ 7.54 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.35 (s, 3H), 1.87 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD): δ 172.4, 167.5, 155.9, 142.3, 139.6, 133.1, 130.7, 130.4 (2×), 130.2, 129.6 (2×), 128.5, 123.4, 113.6, 113.3, 107.9, 103.5, 56.2, 52.7, 22.7, 21.3 ppm. FTIR (NaCl): ν 3400–3100 (br, s, N–H), 3010 (m, C–H), 2950 (m, C–H), 2840 (s, C–H), 1701 (s, C═O), 1668 (s, C═O), 1624 (s), 1488 (s), 1256 (s), 754 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H23N2O4 379.1652; found 379.1660.

Methyl (Z)-2-Acetamido-3-[2-(3-chlorophenyl)-1H-indol-3-yl]acrylate (4j)

Starting from 7a (27,107) (75.0 mg, 0.26 mmol) and 8d (0.063 mL, 0.52 mmol) afforded 55 mg (58%) of 4j as a foam. 1H NMR (400.16 MHz, CD3OD, 323 K): δ 7.90 (s, 1H), 7.55–7.53 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.45–7.41 (m, 3H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H), 1.80 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.1, 167.4, 139.3, 138.3, 135.7, 135.6, 131.4, 129.3 (2×), 128.6, 128.3, 127.8, 124.7, 123.9, 121.5 (2×), 112.8, 109.1, 52.8, 22.4 ppm. FTIR (NaCl): ν 3263 (s, N–H), 3058 (w), 3001 (w), 2950 (w), 1704 (s, C═O), 1669 (s, C═O), 1435 (s), 1243 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H18ClN2O3 [(M+H)+] 369.1000; found 369.1000.

Methyl (Z)-2-Acetamido-3-[2-(3-fluorophenyl)-1H-indol-3yl]acrylate (4k)

Starting from 7a (27,107) (75.0 mg, 0.26 mmol) and 8e (0.060 mL, 0.52 mmol) afforded 45.0 mg (50%) of 4k as a foam. 1H NMR (400.16 MHz, CD3OD, 323 K): δ 7.90 (s, 1H), 7.53–7.41 (m, 4H), 7.38 (ddd, J = 10.0, 2.6, 1.5 Hz, 1H), 7.23–7.08 (m, 3H), 3.82 (s, 3H), 1.80 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.2, 167.4, 164.2 (1JCF = 245.1 Hz), 139.5, 138.3, 135.9 (3JCF = 8.3 Hz), 131.7 (3JCF = 8.6 Hz), 128.8, 127.8, 125.8 (4JCF = 3.0 Hz), 124.7, 123.9, 121.5 (2×), 116.3 (2JCF = 18.3 Hz), 116.1 (2JCF = 16.8 Hz), 112.7, 109.0, 52.8, 22.4 ppm. FTIR (NaCl): ν 3260 (s, N–H), 3050 (w), 3029 (w), 2950 (w), 1698 (s, C═O), 1669 (s, C═O), 1436 (s), 1270 (s), 1243 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H18FN2O3 353.1298; found 353.1296.

Methyl (Z)-2-Acetamido-3-[2-(3-methoxyphenyl)-1H-indol-3-yl]acrylate (4l)

Starting from 7a (27,107) (75.0 mg, 0.26 mmol) and 1-ethynyl-3-methoxybenzene (8f) (0.065 mL, 0.52 mmol) afforded 55.0 mg (59%) of 4l as a foam. 1H NMR (400.16 MHz, DMSO-d6, 333 K): δ 9.23 (s, 1H), 7.50–7.42 (m, 3H), 7.32 (s, 1H), 7.23–7.16 (m, 3H), 7.09 (d, J = 8.1 Hz, 1H), 7.08–6.99 (m, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 1.77 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.3, 165.4, 159.2, 138.9, 136.3, 132.9, 129.6, 126.0, 125.6, 124.2, 122.0, 120.8, 120.3, 119.7, 114.0, 113.8, 111.5, 107.0, 55.0, 51.6, 22.1 ppm. FTIR (NaCl): ν 3274 (s, N–H), 3058 (w), 3006 (w), 2951 (w), 2836 (w), 1708 (s, C═O), 1670 (s, C═O), 1491 (s), 1435 (s), 1240.0 (s), 1042 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O4 365.1480; found 365.1496.

Methyl (Z)-2-Acetamido-3-[2-(3,4-difluorophenyl)-1H-indol-3-yl]acrylate (4m)

Starting from 7a (27,107) (75.0 mg, 0.26 mmol) and 4-ethynyl-1,2-difluorobenzene (8g) (0.062 mL, 0.52 mmol) afforded 55.0 mg (58%) of 4m as a foam. 1H NMR (400.16 MHz, DMSO-d6, 333 K): δ 9.22 (s, 1H), 7.69–7.54 (m, 2H), 7.45 (dd, J = 7.6, 7.0 Hz, 3H), 7.26 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 3.73 (s, 3H), 1.72 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.1, 165.2, 146.3 (1JCF = 245.4 Hz), 149.2 (1JCF = 246.0 Hz), 136.3 (3JCF = 8.5 Hz), 129.4, 129.3, 126.1, 125.3 (2×), 124.3, 122.4, 120.2, 119.9, 117.8 (2JCF = 17.4 Hz), 116.9 (2JCF = 18.1 Hz), 111.6, 107.5, 51.6, 22.0 ppm. FTIR (NaCl): ν 3264 (s, N–H), 3058 (w), 3019 (w), 2952 (w), 1707 (s, C═O), 1669 (s, C═O), 1513 (s), 1456 (s), 1436 (s), 1277 (s), 1242 (s), 1202 (w), 1118 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H17F2N2O3 371.1184; found 371.1201.

Methyl (Z)-2-Acetamido-3-[2-(3,4-thiophen-2-yl)-1H-indol-3-yl]acrylate (4n)

Starting from 7a (27,107) (75.0 mg, 0.26 mmol) and 3-ethynylthiophene (8h) (0.051 mL, 0.52 mmol) afforded 45.0 mg (51%) of 4n as a foam. 1H NMR (400.16 MHz, DMSO-d6, 333 K): δ 9.22 (s, 1H), 7.73 (s, 2H), 7.53–7.33 (m, 4H), 7.17 (q, J = 7.3 Hz, 1H), 7.06 (q, J = 7.2 Hz, 1H), 3.74 (s, 3H), 1.82 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.5, 165.4, 136.1, 134.8), 132.4, 127.0, 126., 125.8, 125.1, 124.4, 124.2, 121.2, 120.3, 119.7, 111.3, 106.7, 51.6, 22.2 ppm. FTIR (NaCl): ν 3275 (s, N–H), 3105 (w), 3055 (w), 3008 (w), 2950 (w), 1704 (s, C═O), 1669 (s, C═O), 1514 (w), 1434 (s), 1243 (s), 1131 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C18H17N2O3S 341.0938; found 341.0954.

Preparation of 2-Alkyldehydrotryptophans 4b, 4o, and 4p from o-Alkynylaryl Carbamates 2 and Alkene 3 (Scheme 2)

The following procedure is representative: To a solution of 2 (0.20 mmol) and 3 (170.9 mg, 1.19 mmol) in DMF (2.0 mL) were added PdCl2(PPh3)2 (14.0 mg, 0.020 mmol) and KI (16.5 mg, 0.099 mmol). The resulting mixture was stirred at 100 °C (2b, 45 h; 2p, 45 h) or 120 °C (2o, 44 h) with the flask opened to air. After reaction completion, water was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and filtered through a pad of Celite, and the solvent was evaporated. The residue was dissolved in MeOH (4.2 mL) in the presence of tert-butylamine (0.63 mL, 6.0 mmol), and the mixture was heated to 90 °C (2b, 16 h; 2o, 18 h; 2p, 45 h). The solvent was removed under reduced pressure, and the crude product was purified by flash-column chromatography (silica gel, hexane/EtOAc gradient) to afford product 4b, 4o, or 4p.

Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b)

Starting from 2b (60.0 mg, 0.22 mmol), purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 20:80 A/B) afforded 33.7 mg (45%) of 4b.

Methyl (Z)-2-Acetamido-3-(2-cyclohexyl-1H-indol-3-yl)acrylate (4o)

Starting from 2o (54.0 mg, 0.20 mmol), purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 0:100 A/B) afforded 43.8 mg (65%) of 4o as a yellow foam. 1H NMR (400.16 MHz, CD3OD): δ 7.67 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.02 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.82 (s, 3H), 2.94 (tt, J = 12.2, 3.3 Hz, 1H), 1.97 (s, 3H), 1.93–1.85 (m, 4H), 1.83–1.77 (m, 1H), 1.65 (qd, J = 12.8, 3.6 Hz, 2H), 1.48 (qt, J = 12.8, 3.2 Hz, 2H), 1.43–1.29 (m, 1H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD): δ 172.8, 167.8, 149.4, 137.8, 129.9, 127.1, 122.5, 121.9, 121.3, 121.0, 112.2, 106.5, 52.7, 37.9, 33.8 (2×), 27.6 (2×), 27.1, 22.6 ppm. FTIR (NaCl): ν 3281 (s, N–H), 2930 (s, C–H), 2853 (s), 1670 (s), 1625 (s) 1455 (s), 1434 (s), 1247 (s), 1223 (s), 751 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H25N2O3 341.1860; found 341.1859.

Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-yl)-1H-indol-3-yl]acrylate (4p)

Starting from 2p (60.0 mg, 0.22 mmol), purification by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 0:100 A/B) afforded 51.7 mg (68%) of 4p as a yellow foam. 1H NMR (400.16 MHz, CDCl3, 323 K): δ 8.44 (s, 1H), 7.48 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.92 (s, 1H), 6.14–6.10 (m, 1H), 3.87 (s, 3H), 2.40–2.34 (m, 2H), 2.32–2.24 (m, 2H), 1.97 (s, 3H), 1.83–1.74 (m, 2H), 1.73–1.67 (m, 2H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3, 323 K): δ 168.3, 165.9, 141.6, 135.4, 132.8, 129.3, 128.7, 126.3, 122.7, 122.5, 120.6, 120.2, 111.4, 106.8, 52.6, 27.4, 26.0, 23.5, 22.6, 21.9 ppm. FTIR (NaCl): ν 3400–3200 (s, N–H), 3011 (w), 2936 (w), 2865 (w), 2829 (w), 1683 (s, C═O), 1666 (s, C═O), 1495 (w), 1435 (w), 1247 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H23N2O3 339.1703; found 339.1705.

Preparation of Dehydrotryptophans 10 from N-PMB-o-Alkynylanilines 9 (Table 3 and Scheme 3)

In a typical procedure, to a solution of an o-alkynylaniline 9 (0.22 mmol) and 3 (188 mg, 1.32 mmol) in DMF (2.1 mL) were added PdCl2(PPh3)2 (15.4 mg, 0.022 mmol), TPPO (6.1 mg, 0.022 mmol), and KI (18.2 mg, 0.11 mmol), and the mixture was stirred at 100 °C for 5–24 h (see Table 3 for details) with the flask opened to air. After reaction completion, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), and the solvent was evaporated. The residue was purified by flash-column chromatography (silica gel, solvent A: hexane; solvent B: EtOAc; gradient from 20:80 to 80:20 A/B) to afford products 10.

Methyl (Z)-2-Acetamido-3-(2-hexyl-1-(4-methoxybenzyl)-1H-indol-3-yl)acrylate (10a)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9a (70 mg, 0.22 mmol) afforded 40 mg (40%) of 10a as a pale brown solid. Mp: 128–129 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD, 323 K): δ 7.64 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.13–7.05 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.35 (s, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 2.83 (t, J = 7.8 Hz, 2H), 1.97 (s, 3H), 1.54–1.43 (m, 2H), 1.39–1.30 (m, 2H), 1.30–1.20 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.5, 167.8, 160.6, 146.1, 138.8, 130.9, 129.4, 128.4 (2×), 126.8, 122.9, 122.4, 121.8, 121.5, 115.3 (2×), 111.3, 109.0, 55.8, 52.7, 47.2, 32.5, 30.9, 30.0, 26.1, 23.4, 22.7, 14.3 ppm. FTIR (NaCl): ν 3400–3200 (br, m, N–H), 2933 (s, C–H), 1711 (s, C═O), 1678 (s), 1514 (s), 1250 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C28H35N2O4 463.2591; found 463.2595.

Methyl (Z)-2-Acetamido-3-[2-(acetoxymethyl)-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10b)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9b (50 mg, 0.16 mmol) afforded 30 mg (41%) of 10b as a solid. Mp: 139–140 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD, 323 K): δ 7.83 (s, 1H), 7.72 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.20 (ddd, J = 8.3, 7.6, 1.2 Hz, 1H), 7.12 (app t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.43 (s, 2H), 5.30 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 1.93 (s, 3H), 1.83 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.5, 172.0, 167.3, 160.6, 139.1, 136.2, 130.8, 128.4 (2×), 127.4, 126.4, 125.7, 124.3, 122.2, 121.8, 115.2 (2×), 112.1, 111.7, 56.7, 55.8, 52.8, 47.6, 22.6, 20.4 ppm. FTIR (NaCl): ν 3500–3200 (br, m, N–H), 3004 (w, C–H), 2947 (w, C–H), 1731 (s, C═O), 1681 (s, C═O), 1514 (s), 1246 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C25H27N2O6 451.1864, found 451.1870.

(Z)-2-Acetamido-3-[2-cyclohexyl-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10c)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9c (70 mg, 0.22 mmol) afforded 50 mg (50%) of 10c as a white solid. Mp: 176–177 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.60 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24–7.19 (m, 1H), 7.16–7.07 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.76 (br s, 1H), 5.34 (s, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 2.93–2.80 (m, 1H), 1.93 (s, 3H), 1.84–1.78 (m, 2H), 1.77–1.68 (m, 5H), 1.30–1.21 (m, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.6, 165.8, 159.1, 146.2, 136.7, 129.5, 127.3 (2×), 125.5, 125.1, 123.6, 121.9, 120.6, 120.2, 114.4 (2×), 110.2, 106.2, 55.4, 52.6, 46.8, 37.7, 32.2 (2×), 27.1 (2×), 25.9, 23.4 ppm. FTIR (NaCl): ν 3400–3100 (w, N–H), 3009 (m, C–H), 2931 (s, C–H), 2852 (m, C–H), 1716 (s, C═O), 1679 (s, C═O), 1511 (s), 1249 (s), 750 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C28H33N2O4 461.2435; found 461.2453.

Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10d) and 2-(tert-Butyl)-1-(4-methoxybenzyl)-1H-indole (11d)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9d (50 mg, 0.17 mmol) afforded 61 mg (82%) of 10d and 17 mg (17%) of 11d. Data for 10d: Yellow solid. Mp: 82–83 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.63 (s, 1H), 7.25–7.21 (m, 1H), 7.10–7.02 (m, 2H), 7.02–6.96 (m, 1H), 6.80 (app. s, 4H), 6.65 (s, 1H), 5.59 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 1.82 (s, 3H), 1.50 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.5, 165.6, 158.8, 146.2, 137.7, 129.6, 127.3, 126.8 (2×), 125.6, 125.3, 122.2, 120.5, 119.5, 114.2 (2×), 110.6, 105.7, 55.3, 52.6, 48.9, 34.7, 32.0 (3×), 23.3 ppm. FTIR (NaCl): ν 3400–3100 (m, N–H), 3000 (m, C–H), 2962 (m, C–H), 1716 (s, C═O), 1678 (s, C═O), 1510 (s), 1470 (s), 1249 (s), 753 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C26H31N2O4 435.2278; found 435.2279. Data for 11d: White solid. Mp: 135–136 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.62–7.54 (m, 1H), 7.10–6.98 (m, 3H), 6.85–6.75 (m, 4H), 6.41 (d, J = 0.8 Hz, 1H), 5.56 (s, 2H), 3.76 (s, 3H), 1.44 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.7, 149.3, 138.4, 130.3, 127.6, 126.9 (2×), 121.2, 120.1, 119.7, 114.1 (2×), 110.1, 98.7, 55.3, 48.2, 32.6, 30.8 (3×) ppm. FTIR (NaCl): ν 3041 (w, C–H), 2964 (s, C–H), 2871 (w, C–H), 1607 (w), 1512 (s), 1466 (s), 1244 (s), 1175 (m), 738 (m) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C20H24NO 294.1852; found 294.1856.

Methyl (Z)-2-Acetamido-3-{2-[1-(tert-butyldiphenylsilyloxyl)-2-methylpropan-2-yl]-1-(4-methoxybenzyl)-1H-indol-3-yl}acrylate (10e)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9e (50 mg, 0.091 mmol) afforded 45 mg (72%) of 10e as a yellow oil. 1H NMR (400.16 MHz, CD3OD, 323 K): δ 7.77 (s, 1H), 7.46–7.42 (m, 4H), 7.41–7.32 (m, 3H), 7.24–7.22 (m, 5H), 7.06–6.95 (m, 3H), 6.72–6.67 (m, 4H), 5.36 (s, 2H), 3.88 (s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 1.73 (s, 3H), 1.49 (s, 6H), 1.01 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.3, 167.2, 160.2, 144.8, 139.4, 136.8 (4×), 134.7, 131.2, 130.8 (2×), 128.7 (4×), 127.8 (2×), 127.7, 126.9, 126.8, 123.1, 121.1, 120.7, 115.1 (2×), 115.0, 111.2, 109.5, 72.8, 55.8, 52.7, 49.9, 41.8, 27.6 (2×), 27.5 (3×), 22.4, 20.1 ppm. FTIR (NaCl): ν 3074 (w, C–H), 2994 (m, C–H), 2922 (m, C–H), 2858 (m, C–H), 1697 (s, C═O), 1683 (s, C═O), 1513 (s), 1250 (s), 1111 (s), 1086 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C42H49N2O5Si 689.3405, found 689.3379.

Methyl (Z)-2-Acetamido-3-[2-(2-hydroxypropan-2-yl)-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10f)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9f (50 mg, 0.17 mmol) afforded 30 mg (41%) of 10f as a brown solid. Mp: 86–87 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.58–7.50 (m, 1H), 7.18–7.11 (m, 4H), 6.84–6.76 (m, 4H), 6.19 (br s, 1H, NH), 5.39 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.23 (br s, 1H, OH), 1.88 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 170.7, 169.6, 159.2, 138.9, 137.9, 129.6, 127.5, 126.9 (2×), 126.6, 122.6, 122.5, 120.3, 118.3, 114.5 (2×), 110.6, 102.4, 74.6, 55.4, 53.1, 47.9, 30.6, 28.8, 23.2 (CH3) ppm. FTIR (NaCl): ν 3500–3100 (s, O–H), 2934 (m, C–H), 2928 (m, C–H), 2837 (m, C–H), 1748 (s, C═O), 1672 (s, C═O), 1513 (s), 1465 (s), 1248 (s), 1034 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C25H29N2O5 437.2071; found 437.2065.

Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10g)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9g (50 mg, 0.158 mmol) afforded 48 mg (67%) of 10g as a solid. Mp: 59–60 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.57–7.49 (m, 1H), 7.43 (s, 1H), 7.18–7.10 (m, 3H), 6.98–6.90 (m, 3H), 6.80 (d, J = 8.4 Hz, 2H), 5.91 (s, 1H), 5.24 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 2.27–2.19 (m, 2H), 2.14–2.07 (m, 2H), 2.02 (s, 3H), 1.77–1.64 (m, 4H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.3, 165.9, 158.9, 146.0, 136.9, 134.2, 129.5, 129.3, 127.3 (2×), 126.1, 125.6, 122.3, 121.6, 120.7, 120.6, 114.2 (2×), 110.8, 107.7, 55.3, 52.4, 47.4, 29.7, 25.6, 23.3, 22.6, 21.7 ppm. FTIR (NaCl): ν 3500–3100 (br, m, N–H), 3006 (m, C–H), 2936 (s, C–H), 2840 (m, C–H), 1708 (s, C═O), 1678 (s, C═O), 1513 (s), 1250 (s), 750 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C28H31N2O4 459.2278; found 459.2296.

Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1-(4-methoxybenzyl)-5-methyl-1H-indol-3-yl]acrylate (10h)

Starting from 9h (60 mg, 0.20 mmol) afforded 46 mg (53%) of 10h as a foam. 1H NMR (400.16 MHz, CDCl3, 323 K): δ 7.61 (s, 1H), 7.01 (s, 1H), 6.89 (d, J = 1.2 Hz, 2H), 6.80 (s, 4H), 6.60 (s, 1H), 5.56 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 2.38 (s, 3H), 1.83 (s, 3H), 1.49 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3, 323 K): δ 165.7, 158.9, 146.3, 136.2, 129.9, 129.8, 128.2, 126.8 (2×), 125.8, 125.7, 123.8, 119.2, 114.1, 114.3 (2×), 110.4, 105.3, 55.4, 52.5, 48.9, 34.7, 32.0 (3×), 23.1, 21.4 ppm. FTIR (NaCl): ν 3327 (s, N–H), 2996 (w), 2955 (w), 2874 (w), 2837 (w), 1719 (s, C═O), 1676 (s, C═O), 1513 (s), 1249 (s), 1181 (w), 1036 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C27H33N2O4 449.2422; found 449.2434.

Methyl (Z)-2-Acetamido-)-3-[2-(tert-butyl)-5-methoxycarbonyl-1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10i)

Starting from 9i (90 mg, 0.26 mmol) afforded 60 mg (48%) of 10i as a foam. 1H NMR (400.16 MHz, CDCl3, 323 K): δ 7.98 (d, J = 2.3 Hz, 1H), 7.76 (s, 1H), 7.74 (dd, J = 8.6, 1.6 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.79–6.76 (m, 4H), 5.60 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.75 (s, 3H), 1.75 (s, 3H), 1.54 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3, 323 K): δ 168.2, 165.7, 159.0, 147.6, 140.5, 132.3, 129.9, 129.2, 128.7, 128.6, 126.8 (2×), 124.8, 123.5, 123.3, 114.4 (2×), 110.4, 55.4, 52.7, 51.9, 49.2, 34.9, 31.8 (3×), 23.1 ppm. FTIR (NaCl): ν 3332 (w, N–H), 2952 (w), 2919 (w), 2841 (w), 1715 (s, C═O), 1513 (w), 1436 (w), 1274 (s), 1248 (s), 1181 (w), 1132 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C28H33N2O6 493.2327; found 493.2333.

Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-5-methyl-1H-indol-3-yl]acrylate (10j)

Starting from 9j (75 mg, 0.23 mmol) afforded 53 mg (50%) of 10j as a foam. 1H NMR (400.16 MHz, DMSO-d6, 333 K): δ 9.23 (s, 1H, NH), 7.34 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.03–6.93 (m, 3H), 6.84 (d, J = 8.7 Hz, 2H), 5.86 (t, J = 3.8 Hz, 1H), 5.26 (s, 2H), 3.70 (s, 3H), 2.36 (s, 3H), 2.24–2.18 (m, 2H), 2.10–2.03 (m, 2H), 1.91 (s, 3H), 1.66–1.61 (m, 4H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.4, 168.3, 165.6, 158.3, 145.8, 134.9, 133.1, 129.6, 128.6, 128.4, 127.5 (2×), 126.3, 125.2, 123.0, 120.9, 113.8 (2×), 110.4, 106.7, 54.9, 51.5, 46.4, 29.3, 24.8, 22.3, 22.0, 21.0, 20.9 ppm. FTIR (NaCl): ν 2931 (s, N–H), 2856 (w), 2836 (w), 1710 (s, C═O), 1665 (s, C═O), 1512 (s), 1415 (s), 1249 (s), 1175 (w), 1035 (w) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C29H33N2O4, 473.2412; found 473.2434.

Methyl (Z)-2-Acetamido-3-[1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (12)

Following the procedure for the preparation of N-PMB-dehydrotryptophans 10, starting from 9k (25 mg, 0.071 mmol) afforded 20 mg (75%) of the desilylated 12. Mp: 180–181 °C (hexane/EtOAc). 1H NMR (400.16 MHz, DMSO-d6): δ 9.63 (s, 1H, NH), 7.64 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.08 (app t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 3.68 (s, 6H), 2.08 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6): δ 169.7, 165.7, 159.0, 137.8, 132.4, 130.5, 128.0 (2×), 127.8, 127.1, 123.9, 121.6, 120.7, 119.6, 114.5 (2×), 110.9, 106.4, 55.5, 52.6, 45.7, 23.0 ppm. FTIR (NaCl): ν 3001 (w, C–H), 2925 (s, C–H), 2853 (s, C–H), 1690 (s, C═O), 1674 (s, C═O), 1514 (s), 1333 (s), 1251 (s), 1032 (s) cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C22H23N2O4 379.1652; found 379.1644.

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  • X-ray data; monitoring of reaction progress by HPLC-MS; copies of 1H NMR and 13C NMR spectra; computational data (PDF)

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  • Authors
    • Belén Vaz - Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    • Claudio Martínez - Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    • Francisco Cruz - Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    • J. Gabriel Denis - Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain
    • Ángel R. de Lera - Departamento de Química Orgánica, Facultad de Química (CINBIO) and Instituto de Investigación Biomédica de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, SpainOrcidhttps://orcid.org/0000-0001-6896-9078
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors thank the Spanish Ministerio de Economía y Competitividad (MINECO) (grant number CTQ2012-37734), Fondos Europeos para el Desarrollo Regional (FEDER), and the Universidad del País Vasco UPV/EHU (PES18/89) for financial support. We also thank Universidad de Vigo for technical support (NMR facilities, HRMS and X-ray analyses). We are grateful to the Centro de Supercomputación de Galicia (CESGA) for generous allocation of computing resources. (115)

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  • Abstract

    Scheme 1

    Scheme 1. Palladium-catalyzed Oxidative Heterocyclization–Coupling Cascades and Application to the Preparation of Dehydrotrytophans

    Scheme 2

    Scheme 2. Preparation of 2-Alkyldehydrotryptophans from 2-Alkynylaniline Carbamates

    aReaction conditions: (i) alkene 3 (6 equiv), PdCl2(PPh3) 2 (10 mol %), KI (0.5 equiv), DMF, air, 100 °C (2b and 2p) or 120 °C (2o). (ii) t-BuNH2 (30 equiv), MeOH, 90 °C.

    Scheme 3

    Scheme 3. Preparation of a 2-Unsubstituted Dehydrotryptophan Derivative

    Scheme 4

    Scheme 4. Expected Catalytic Cycle

    Figure 1

    Figure 1. (a) Reaction profile starting from complexes B derived from Aa (R1 = H, R2 = Ph in Scheme 4) and methyl α-acetamidoacrylate (Y = NHAc) or methyl acrylate (Y = H) in a reaction promoted by PdCl2/L (L = PPh3 or DMF) [energy values in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]. (b) Ground state structures of intermediates involved in the reaction profile.

    Figure 2

    Figure 2. (a) Reaction profile starting from complexes B derived from Aa-carb (R1 = CO2Me, R2 = Ph, L = PPh3 in Scheme 4) and methyl α-acetamidoacrylate in a reaction promoted by PdCl2(PPh3)2 [energy values in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]. (b) 3-D structures of TSs, as representative of those involved in the different series.

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