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Dearomative Spirocyclization of Tryptamine-Derived Isocyanides via Iron-Catalyzed Carbene Transfer
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Dearomative Spirocyclization of Tryptamine-Derived Isocyanides via Iron-Catalyzed Carbene Transfer
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  • Thomas R. Roose
    Thomas R. Roose
    Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
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  • Finn McSorley
    Finn McSorley
    Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
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  • Bryan Groenhuijzen
    Bryan Groenhuijzen
    Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
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  • Jordy M. Saya
    Jordy M. Saya
    Organic Chemistry, Aachen-Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Urmonderbaan 22, 6167 KD Geleen, Netherlands
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  • Bert U. W. Maes*
    Bert U. W. Maes
    Organic Synthesis Division, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.s
    *E-mail: [email protected]
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    Orcidhttps://orcid.org/0000-0003-0431-7606
  • Romano V. A. Orrù*
    Romano V. A. Orrù
    Organic Chemistry, Aachen-Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Urmonderbaan 22, 6167 KD Geleen, Netherlands
    *E-mail: [email protected]
    More by Romano V. A. Orrù
    Orcidhttps://orcid.org/0000-0003-1142-6798
  • Eelco Ruijter*
    Eelco Ruijter
    Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
    *E-mail: [email protected]
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    Orcidhttps://orcid.org/0000-0002-1105-3947
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The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2023, 88, 24, 17345–17355
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https://doi.org/10.1021/acs.joc.3c02160
Published December 4, 2023

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Abstract

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Tryptamine-derived isocyanides are valuable building blocks in the construction of spirocyclic indolenines and indolines via dearomatization of the indole moiety. We report the Bu4N[Fe(CO)3NO]-catalyzed carbene transfer of α-diazo esters to 3-(2-isocyanoethyl)indoles, leading to ketenimine intermediates that undergo spontaneous dearomative spirocyclization. The utility of this iron-catalyzed carbene transfer/spirocyclization cascade was demonstrated by its use as a key step in the formal total synthesis of monoterpenoid indole alkaloids (±)-aspidofractinine, (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy-N-acetylcylindrocarine.

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Introduction

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Functionalized isocyanides have proven valuable building blocks in organic chemistry. Tethering the isocyanide moiety to other reactive functionalities provides great opportunities for the development of novel cascade and multicomponent processes. (1) For example, 3-(2-isocyanoethyl)indoles (1, Scheme 1a) have recently attracted considerable interest, as they allow for the facile construction of (polycyclic) spiroindol(en)ines 2 (2−5) through dearomatization of the indole moiety. (6) These spiroindolenines/indolines (2) are of considerable relevance as these motifs occur in, e.g., medicinally relevant compounds, (7) such as Sky kinase inhibitor 5 (7a) and monoterpenoid indole alkaloids of the Aspidosperma and Strychnos types (Scheme 1b). (8) Notably, strategies toward construction of these natural products often involve dearomatization of the indole moiety. (9) Several strategies for the dearomative spirocyclization of 3-(2-isocyanoethyl)indoles 1 have been reported, (3−5) which differ in the transformation of the isocyano moiety providing different functionalities allowing spirocyclization (Scheme 2a). The first strategy (I) relies on trapping the isocyano moiety by an electrophile, resulting in nitrilium ion 7. Subsequently, this intermediate is trapped in an intramolecular fashion by the indole C3 position.

Scheme 1

Scheme 1. Dearomative Spirocyclization of 3-(2-Isocyanoethyl)indoles
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Scheme 2

Scheme 2. Strategies for Dearomatization of 3-(2-Isocyanoethyl)indoles
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Multiple electrophiles have been applied in the formation of spirocyclic indolenines and indolines. (3) Moreover, our group has demonstrated that using NIS as electrophile, 3-(2-isocyanoethyl) indoles 1 could be applied in the formal total synthesis of (±)-aspidofractinine. (3g) A less explored strategy (II) involves transition-metal-catalyzed imidoylative cross-coupling, (10) which proceeds via imidoylpalladium intermediate 8 (Scheme 2a). (5) The third strategy (III) proceeds via heteroallene 9, which can be accessed via selective transition-metal-catalyzed carbene (Y = CR6) or nitrene transfer (Y = N) to the isocyanide moiety, (11) followed by nucleophilic addition of the C3-position of the indole to the heteroallene (Scheme 2a). (4) Although one base-metal-catalyzed example is reported for the nitrene transfer to isocyanide 1, (4b) no base-metal-catalyzed carbene transfers to 3-(2-isocyanoethyl)indoles (1) have been reported.
In 2020, Chen and co-workers reported the dearomative spirocyclization of isocyanides 1 using strategy III, proceeding via ketenimine intermediate 9 (Y = CR6, Scheme 2a). (4a) They described the Pd-catalyzed carbene transfer to isocyanide 1 in the construction of spiroindolenine 15 and polycyclic spiroindolines 16 (Scheme 2b). Although this method displays a broad scope, a high loading of the precious palladium catalyst (10–15%) is required. In addition, despite obtaining pentacyclic scaffold 17 (resembling the core of monoterpenoid indole alkaloids), the authors could not obtain the correct relative stereochemistry at the C–E ring junction, which should be cis-fused as in, e.g., aspidospermidine (3, Scheme 1b).
Shifting from Pd-catalyzed processes to base metals, such as iron, is highly desired, due to their high abundancy on Earth and low cost. Recently, our group developed an iron-catalyzed carbene transfer reaction to isocyanides for the construction of multiple heterocycles. (12) The ferrate complex, Bu4N[Fe(CO)3NO] (also known as the Hieber anion), (13) was demonstrated to effectively catalyze the transfer of carbenes (14) to isocyanides to give a ketenimine intermediate. In this work, we demonstrate for the first time that the Hieber anion can be employed to catalyze a dearomative spirocyclization of 3-(2-isocyanoethyl)indoles (1). The process proceeds via carbene transfer to the isocyanide moiety (Scheme 3b) to afford spiroindolenines 19 as potential synthetic intermediates in the total synthesis of indole alkaloids.

Results and Discussion

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We started our investigation using isocyanide 1a and ethyl diazoacetate (22) as model reactants for optimization (Table 1). Various iron-based catalysts (entries 1–6) were found to be inferior to the Bu4N[Fe(CO)3NO] as a catalyst of the reaction (entry 7). The addition of phosphine ligands negatively affected the reaction (entries 8 and 9).
Table 1. Optimization of the Fe-Catalyzed Carbene Transfer to 3-(2-Isocyanoethyl)indole 1a
Entry[Fe]-cat.Additive (mol %)SolventYield of 23a (%)a
1Fe(CO)5 DCE92
2Fe (Pc) DCE21c
3Fe(TPP)Cl DCE18c
4Fe(TPP)ClZn (50)DCEtracec
5Fe(ClO4)2·4H2OTMEDA (6) NaBarF (6)DCEtraced
6Fe(ClO4)2·4H2ODPPE (6) NaBarF (6)DCEtraced
7Bu4N[Fe(CO)3NO] DCE98 (96b)
8Bu4N[Fe(CO)3NO]PPh3 (6)DCE89
9Bu4N[Fe(CO)3NO]P(2-Fur)3 (6)DCE86
10Bu4N[Fe(CO)3NO] DCE22d,e
11  DCE0
12Bu4N[Fe(CO)3NO] dioxane70
13Bu4N[Fe(CO)3NO] CH3CN89
14Bu4N[Fe(CO)3NO] PhMe66
15Bu4N[Fe(CO)3NO] DMF85
16Bu4N[Fe(CO)3NO] i-PrOH56
a

Reactions performed on a 0.5 mmol scale of 1a and 0.6 mmol of 22. Yields are determined by 1H NMR analysis using 2,5-dimethylfuran as internal standard.

b

Isolated yield.

c

Full conversion of ethyl diazoacetate (22) prior to full conversion of isocyanide 1a.

d

No full conversion of isocyanide 1a observed by TLC analysis after 22–24 h at 80 °C.

e

Reaction performed at 60 °C.

Furthermore, performing the reaction at lower temperature afforded the product in low yield with slow conversion (entry 10). In addition, the reaction was found to proceed in several solvents (entries 12–16), albeit not as efficiently as in DCE. Thus, we opted to continue with the conditions in entry 7, affording spiroindolenine 23a in 96% isolated yield.
With the optimal conditions in hand, we started to investigate the scope of the Fe-catalyzed carbene transfer/spirocyclization cascade with regard to C2-substituted indole isocyanides 1b–p (Scheme 3). Aliphatic substituents were generally well tolerated, affording indolenine 23b (R2 = Me) in good yield. A slower conversion and lower yields were observed with increasing bulk of the aliphatic substituent (23c, R2 = t-Bu, Scheme 3). Decoration of the indole benzene ring with several substituents at different positions afforded spiroindolenines 23d–i in good to excellent yield. In addition, the reaction allowed the presence of aromatic indole substituents (R2) including a 2-naphthyl group, and the corresponding indolenines (23j–n) were obtained in good yield. To our delight, even the use of a 2-bromoindole isocyanide 1o (R2 = Br) afforded 23o in good yield, providing an imidoyl halide as a functional handle at the C2-position. (15) In addition, the tautomerized bis-β-enamino ester 23p was obtained in moderate yield starting from 2-(2-methoxy-2-oxoethyl)indole isocyanide 1p (R2 = CH2CO2Me).

Scheme 3

Scheme 3. Scope for C2-Substituted 3-(2-Isocyanoethyl)indoles and Substituted α-Diazo Estersa
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aReaction conditions: Bu4N[Fe(CO)3NO] (0.025 mmol), 1 (0.5 mmol), and 18 (0.6 mmol) in DCE (2 mL) at 80 °C under N2.

After investigation of the isocyanide scope, the scope of diazo compounds was briefly explored (Scheme 3). We started with the use of diazo precursors for donor–acceptor carbenes (18a, R3 = Ph, R4 = Me), which afforded the products 23aa and 23ba in only trace amounts. In contrast, in the analogous Pd-catalyzed reaction, these carbenes were converted to indolenines 23aa and 23ba in good to excellent yield. (4a) A similar limitation in scope of α-diazo esters was observed in the recently reported iron-catalyzed intermolecular carbene transfer to isocyanides, where we used amidines to trap the ketenimine intermediate. (12) Next, we employed diethyl 2-diazosuccinate (18b) of the acceptor-type carbene class, which was reacted with isocyanides 1a and 1b to give the corresponding spiroindolenines 23ab and 23bb in moderate yield. Extending the carbon chain to diethyl 2-diazoglutarate (18c) afforded only a trace amount of product 23bc as judged by 1H NMR analysis of the crude product. In addition, the use of α-diazo ester 18e (R3 = COMe, R4 = Me) from the acceptor–acceptor class did afford spiroindolenine 23be, albeit in low yield. Finally, we employed α-diazo ester 18d (R3 = E-CH = CHCO2Me, R4 = Me) in combination with isocyanide 1a, which would allow for a carbene transfer/spirocyclization/Mannich cascade affording tetracyclic spiroindoline 24 as described by Chen et al. (Scheme 1b). (4a) Unfortunately, with [Fe(CO)3NO]Bu4N as catalyst this cascade did not occur.
In addition to the isocyanide scope bearing a C2 indole substituent, we explored the scope of the C2-unsubstituted isocyanides, where R2 = H (Scheme 4). Based on previous work, (3g,16) we envisioned that the corresponding spiroindolines, containing an imine functionality, are relatively less stable compared to their corresponding C2-substituted counterparts. Fortunately, the obtained spiroindolenine 25a with the benchmark substrate (1a) is relatively stable upon isolation and column chromatography. However, the stability of the spiroindolenine derived from isocyanides 1q–x differs significantly depending on the substitution pattern on the indole moiety (R1). For example, the spiroindolenine derived from isocyanide 1q (R1 = 5-OMe) could not be isolated and fully degraded upon isolation. Therefore, we decided to in situ transform all C2-unsubstituted spiroindolenines 23 to the more stable spiroindolines 25q–x via a one-pot spirocyclization/reduction sequence (Scheme 4). After a brief optimization (Table S3) we were able to isolate benchmark spiroindoline 25a in 77% yield using NaBH4 as the reducing agent (method A). Various C5-substituted indole isocyanides (1q–v) were converted to the corresponding spiroindolines 25q–v in moderate to good yield (Scheme 4). Next, we investigated tryptamine-derived isocyanides bearing a substituent on the ethylene linker (1w, 1x). Initially, low yields were observed for spiroindolines 25w and 25x employing NaBH4 reductant (method A). Gratifyingly, changing to slightly different conditions (method B) using NaBH3CN as the hydride source, spiroindolenines 25w and 25x could be isolated in reasonable yield.

Scheme 4

Scheme 4. Scope for C2-Unsubstituted 3-(2-Isocyanoethyl)indolesa
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aReaction conditions: Bu4N[Fe(CO)3NO] (0.025 mmol), 1 (0.5 mmol), and 22 (0.6 mmol) in 1,2-DCE (2 mL) at 80 °C under N2 until full conversion of 1. Method A: Solution was cooled to 0 °C and diluted with MeOH (2 mL), and NaBH4 (0.525 mmol) was added. Method B: Solution was cooled to 0 °C, and MeOH (2 mL). NaBH3CN (0.525 mmol) and a few drops of AcOH were added.

bExtra portion(s) of reducing agent (NaBH4/NaBH3CN) added to reach full conversion of indolenine intermediate 23 observed on TLC.

Conversion of 1w to 25w proceeded with moderate diastereoselectivity (2.2:1 dr). A slightly higher stereoinduction (3:1 dr) was observed for 25x. Advantageously, when C2-methyl-substituted isocyanide 1b was employed in the one-pot sequence, spiroindoline 25b was obtained as a single diastereomer. Based on literature precedent, (3g) the relative stereochemistry was assumed to proceed with the hydride approaching from the least hindered face.
In order to show the utility of the Fe-catalyzed carbene transfer/spirocyclization cascade methodology, we investigated the conversion of a suitably functionalized isocyanide to the core scaffold of monoterpene indole alkaloids (Scheme 5). To our delight, isocyanide 1y could be subjected to the one-pot spirocyclization/reduction sequence as the free alcohol, affording spiroindoline 25y in 66% yield as a single diastereomer on a 6.3 mmol scale. Next, the alcohol in 25y was converted to the corresponding iodide, which under the reactions conditions immediately cyclized to afford tetracycle 26 in excellent yield. Subsequent Boc-protection results in the desired scaffold 20, which can be transformed into pentacyclic 19-oxoaspidospermidine (27) as demonstrated by Saya et al. (3g) Further, Dufour et al. demonstrated that scaffold 27 can be transformed into (±)-aspidofractinine, (17) while more recently, Martin et al. also reported the conversion of indoline 27 to (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy-N-acetylcylindrocarine. (18)

Scheme 5

Scheme 5. Application of Fe-Catalyzed Carbene Transfer/Spirocyclization Cascade in Formal Total Synthesisa
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aReaction conditions: (a) Bu4N[Fe(CO)3NO] (0.63 mmol), 1y (6.3 mmol), and 22 (7.6 mmol) in DCE (25 mL), 80 °C; then NaBH4, MeOH, 0 °C; (b) imidazole (1.35 equiv), 25y (1.0 equiv), PPh3 (1.30 equiv), I2 (1.30 equiv), rt, CH2Cl2, 1 h; (c) 26 (1.0 equiv), Boc2O (10.5 equiv), DMAP (0.4 equiv), 72 h.

In conclusion, we report the use of Bu4N[Fe(CO)3NO] as catalyst in the carbene transfer/dearomative spirocyclization cascade toward spiroindolenines. In addition, the corresponding spiroindolines could be obtained via a one-pot reduction sequence. In general, the reaction displays a high functional group tolerance for the isocyanide 1. However, the Bu4N[Fe(CO)3NO]-catalyzed reaction is less tolerant of α-diazo ester input compared to the Pd-catalyzed reaction developed by Chen and co-workers. (4a) Nonetheless, using a carefully chosen C2-prefunctionalized 3-(2-isocyanoethyl)indole, we were able to apply the Bu4N[Fe(CO)3NO]-catalyzed carbene transfer/dearomative spirocyclization/reduction sequence in the formal total synthesis of the monoterpene indole alkaloids (±)-aspidofractinine, (±)-limaspermidine, (±)-aspidospermidine, and (±)-17-demethoxy-N-acetylcylindrocarine.

Experimental Section

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General Information

Unless stated otherwise, all solvents and commercially available reagents were used as purchased. Anhydrous dichloromethane, THF, DMF, and toluene were obtained via the PureSolv MD 5 Solvent Purification System. All other solvents were used as purchased from the corresponding supplier. Diazo compounds used in this work were either obtained commercially or synthesized according to the corresponding literature procedures. Caution! It should be noted that diazo compounds can be potentially explosive. Correct safety measures, such as the scale of the reaction, and careful handling are required. Use of appropriate safety gear, including a blast shield, is strongly recommended. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 600 MHz (150 MHz for 13C), Bruker Avance 500 MHz (126 MHz for 13C), and (470 MHz for 19F) or Bruker Avance 300 MHz (75.4 MHz for 13C) using the residual solvent as internal standard (1H: δ 7.26 ppm, 13C {1H}: δ 77.16 ppm for CDCl3, 1H: δ 2.50 ppm, 13C{1H}: δ 39.52 ppm for DMSO-d6). Chemical shifts (δ) are given in ppm, and coupling constants (J) are quoted in hertz (Hz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sex (sextet), sep (septet), br (broad singlet), and m (multiplet) or combinations thereof. Electrospray ionization (ESI) high-resolution mass spectrometry was carried out using a Bruker QTOF impact II instrument in positive-ion mode (capillary potential of 4500 V). Flash chromatography was performed on Silicycle Silia-P flash silica gel (particle size 40–63 μm, pore diameter 60 Å) using the indicated eluent. Thin-layer chromatography (TLC) was performed using TLC plates from Merck (SiO2, Kieselgel 60 F254 neutral, on aluminum with fluorescence indicator), and compounds were visualized by UV detection (254 nm) and KMnO4 stain. SFC-MS analysis was conducted using a Shimadzu Nexera SFC-MS equipped with a Nexera X2 SIL-30AC autosampler, Nexera UC LC-30AD SF CO2 pump, Nexera X2 LC-30AD liquid chromatograph, Nexera UC SFC-30A back pressure regulator, prominence SPD-M20A diode array detector, prominence CTO-20AC column oven, and CBM-20A system controller. A gradient of supercritical CO2 (A) and methanol (B) was used. Method: 2% B/98% A → 100% B/0% A over the course of 7 min. The flow was maintained at 2.0 mL/min, and the sample injection volume was 5 μL. Mass spectrometry analyses were performed using a Shimadzu LCMS-2020 mass spectrometer. The data were acquired in full-scan APCI mode (MS) from m/z 100 to 800 in positive ionization mode. Data was processed using Shimadzu Labsolutions 5.82.

General Procedure A: Synthesis of Spiroindolenines 23

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv). Subsequently, 1,2-DCE was added (2 mL), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of tryptamine-derived isocyanide (0.5 mmol, 1.0 equiv) and ethyl diazoacetate (22) (0.6 mmol, 1.2 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C until full conversion of the isocyanide was observed on TLC. Subsequently, the reaction mixture cooled to room temperature and directly subjected to purification by flash column chromatography, using a mixture of EtOAc:cHex as eluent.

General Procedure B: Synthesis of Spiroindolines 25

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (0.05 equiv). Subsequently, 1,2-DCE was added (0.25 M), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of tryptamine-derived isocyanide (0.5 mmol, 1.0 equiv) and ethyl diazoacetate (22) (0.6 mmol, 1.2 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C until full conversion of the isocyanide was observed on TLC. Subsequently, the reaction mixture was cooled to 0 °C and diluted with MeOH to a concentration of 0.125 M, after which NaBH4 (1.05 equiv) was added. The reaction was stirred at 0 °C until full conversion of indolenine intermediate 23 was observed on TLC. Afterward, the reaction mixture was quenched with saturated aqueous NH4Cl solution and stirred vigorously for 15 min. The aqueous layer was extracted with CH2Cl2 (3×), and the organic layers were collected, washed with brine, dried over Na2SO4, and filtered. The filtrate was collected and concentrated in vacuo. Subsequently, the crude product was subjected to flash column chromatography, using a mixture of EtOAc:cHex as eluent, to obtain the pure title compound.

General Procedure C: Synthesis of Spiroindolines 23 for Diazo Scope

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (20.6 mg, 0.025 mmol, 0.05 equiv). Subsequently, 1,2-DCE was added (2 mL), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of tryptamine-derived isocyanide (0.5 mmol, 1.0 equiv) and α-diazoacetate (18) (0.6 mmol, 1.2 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C for 22–24 h. Subsequently, the reaction mixture was cooled to room temperature and directly purified via flash column chromatography using a mixture of EtOAc:cHex as eluent to provide the title compound.

Ethyl (Z)-2-(Spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23a)

Ethyl (Z)-2-(spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-1H-indole (85.3 mg, 0.50 mmol, 1.0 equiv). The title compound was isolated via FCC using EtOAc:cHex +5% Et3N as eluent to obtain the title compound as a light-yellow oil (124 mg, 0.48 mmol, 96%). Rf = 0.30 (EtOAc:cHex = 1:9 + 5% Et3N); 1H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 7.99 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.37 (td, J = 7.5, 1.5 Hz, 1H), 7.31–7.24 (m, 2H), 4.06–3.97 (m, 2H), 3.94 (s, 1H), 3.88 (dddd, J = 10.2, 7.8, 5.0, 1.0 Hz, 1H), 3.85–3.79 (m, 1H), 2.43 (ddd, J = 12.5, 7.4, 4.9 Hz, 1H), 2.31 (ddd, J = 12.9, 7.8, 6.7 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3): δ 171.9 (CH), 170.5 (Cq), 162.0 (Cq), 155.6 (Cq), 140.1 (Cq), 128.9 (CH), 127.3 (CH), 122.3 (CH), 121.5 (CH), 77.4 (CH), 67.2 (Cq), 58.9 (CH2), 46.0 (CH2), 30.5 (CH2), 14.5 (CH3) ppm; HRMS (ESI): m/z calculated for C15H17N2O2 [M+H+] = 257.1285, found = 257.1281.

Ethyl (Z)-2-(2-Methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23b)

Ethyl (Z)-2-(2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-2-methyl-1H-indole (91.4 mg, 0.50 mmol, 1.0 equiv). The title compound was isolated as a yellow solid (112 mg, 0.41 mmol, 83%). Rf = 0.30 (cyclohexane:EtOAc 3:2); 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.94–3.79 (m, 2H), 3.88 (s, 1H), 2.39–2.29 (m, 2H), 2.27 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 181.8 (Cq), 170.8 (Cq), 164.2 (Cq), 155.2 (Cq), 142.1 (Cq), 128.8 (CH), 126.2 (CH), 122.1 (CH), 120.2 (CH), 77.1 (CH), 67.7 (Cq), 58.9 (CH2), 46.0 (CH2), 31.6 (CH2), 16.4 (CH3), 14.5 (CH3) ppm. HRMS (ESI): m/z calculated for C16H19N2O2 [M+H+] = 271.1441, found = 271.1446.

Ethyl (Z)-2-(2-(tert-Butyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23c)

Ethyl (Z)-2-(2-(tert-butyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 2-(tert-butyl)-3-(2-isocyanoethyl)-1H-indole (113.2 mg, 0.50 mmol, 1.0 equiv). The title compound was isolated as a white solid (92.0 mg, 0.294 mmol, 59%). Rf = 0.35 (cyclohexane:EtOAc 4:1); 1H NMR (500 MHz, CDCl3): δ 8.22 (s, 1H), 7.54 (dz, J = 7.7 Hz, 1H), 7.30 (ddd, J = 7.8, 5.1, 3.7 Hz, 1H), 7.18–7.14 (m, 2H), 4.06–3.91 (m, 5H), 2.89 (ddd, J = 13.5, 9.3, 7.7 Hz, 1H), 2.23 (ddd, J = 13.5, 8.0, 3.6 Hz, 1H).1.41 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 190.3 (Cq), 170.8 (Cq), 164.7 (Cq), 153.6 (Cq), 144.6 (Cq), 128.5 (CH), 126.4 (CH), 120.9 (CH), 120.3 (CH), 76.8 (CH), 68.1 (Cq), 58.8 (CH2), 46.3 (CH2), 38.1 (Cq), 30.3 (CH3), 30.3 (CH2), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C19H25N2O2 [M+H+] = 313.1911, found = 313.1914.

Ethyl (Z)-2-(5-Methoxy-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23d)

Ethyl (Z)-2-(5-methoxy-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-5-methoxy-2-methyl-1H-indole (107.3 mg, 0.50 mmol, 1.0 equiv). The title compound was isolated as a yellow waxy solid (136 mg, 0.45 mmol, 90%). Rf = 0.19 (cyclohexane:EtOAc 2:1); 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.93–3.80 (m, 2H), 3.91 (s, 1H), 3.79 (s, 3H), 2.41–2.25 (m, 2H), 2.24 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 179.7 (Cq), 170.9 (Cq), 164.3 (Cq), 158.6 (Cq), 148.7 (Cq), 143.6 (Cq), 120.5 (CH), 113.3 (CH), 108.9 (CH), 77.3 (CH), 68.0 (Cq), 59.0 (CH2), 55.8 (CH3), 46.0 (CH2), 31.8 (CH2) 16.3 (CH3), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C17H21N2O3 [M+H+] = 301.1547, found = 301.1552.

Ethyl (Z)-2-(2,5-Dimethylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23e)

Ethyl (Z)-2-(2,5-dimethylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-2,5-dimethyl-1H-indole (99.5 mg, 0.50 mmol, 1.0 equiv). The title compound was isolated as a yellow waxy solid (116 mg, 0.41 mmol, 82%). Rf = 0.24 (cHex:EtOAc 2:1); 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.94–3.81 (m, 2H), 3.90 (s, 1H), 2.39–2.27 (m, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 180.8 (Cq), 170.8 (Cq), 164.5 (Cq), 152.9 (Cq), 142.3 (Cq), 136.1 (Cq), 129.3 (CH), 122.9 (CH), 119.8 (CH), 77.1 (CH), 67.7 (Cq), 58.9 (CH2), 46.0 (CH2), 31.7 (CH2), 21.5 (CH3), 16.3 (CH3), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C17H21N2O2 [M+H+] = 285.1598, found = 285.1603.

Ethyl (Z)-2-(5-Fluoro-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23f)

Ethyl (Z)-2-(5-fluoro-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 5-fluoro-3-(2-isocyanoethyl)-2-methyl-1H-indole (101.3 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a light-yellow solid (140 mg, 0.49 mmol, 97%). Rf = 0.23 (cyclohexane:EtOAc 3:2); 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.44 (dd, J = 8.4, 4.6 Hz, 1H), 7.01 (td, J = 8.6, 2.5 Hz, 1H), 6.95 (dd, J = 7.8, 2.6 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.94–3.80 (m, 2H), 3.89 (s, 1H), 2.41–2.27 (m, 2H), 2.26 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 181.7 (Cq, d, J = 3.6 Hz), 170.7 (Cq), 163.4 (Cq), 161.5 (d, J = 245.2 Hz, Cq), 151.2 (Cq, d, J = 2.3 Hz), 143.9 (Cq, d, J = 8.8 Hz), 120.9 (CH, d, J = 8.8 Hz), 115.4 (CH, d, J = 23.6 Hz), 110.1 (CH, d, J = 25.1 Hz), 77.3 (CH), 68.2 (Cq, d, J = 2.3 Hz), 59.0 (CH2), 45.9 (CH2), 31.6 (CH2), 16.3 (CH3), 14.5 (CH3) ppm; 19F{1H} NMR (470.4 MHz, CDCl3): δ −115.90 ppm; HRMS (ESI): m/z calculated for C16H18FN2O2 [M+H+] = 289.1347, found = 289.1356.

Ethyl (Z)-2-(4-bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23g)

Ethyl (Z)-2-(4-bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 4-bromo-3-(2-isocyanoethyl)-2-methyl-1H-indole (132.0 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as light brown solid (136 mg, 0.39 mmol, 78%). Rf = 0.30 (EtOAc:cHex = 1:5); 1H NMR (500 MHz, CDCl3): δ 8.19 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 4.08–3.95 (m, 3H), 3.91–3.81 (m, 2H), 2.86 (ddd, J = 13.8, 9.7, 7.5 Hz, 1H), 2.23 (s, 3H), 2.12 (ddd, J = 13.8, 8.4, 3.4 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 183.3 (Cq), 170.8 (Cq), 161.4 (Cq), 157.4 (Cq), 140.1 (Cq), 130.5 (CH), 129.8 (CH), 119.3 (CH), 118.0 (Cq), 76.6 (CH), 69.8 (Cq), 59.0 (CH2), 46.4 (CH2), 26.7 (CH2), 16.2 (CH3), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C16H18BrN2O2 [M+H+] = 349.0546, found = 349.0555.

Ethyl (Z)-2-(5-Bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23h)

Ethyl (Z)-2-(5-bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 5-bromo-3-(2-isocyanoethyl)-2-methyl-1H-indole (132.0 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a yellow solid (124 mg, 0.35 mmol, 71%). Rf = 0.23 (cyclohexane:EtOAc 2:1); 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 4.03 (qd, J = 7.1, 1.4 Hz, 2H), 3.93–3.79 (m, 2H), 3.88 (s, 1H), 2.40–2.27 (m, 2H), 2.26 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 182.4 (Cq), 170.6 (Cq), 163.1 (Cq), 154.2 (Cq), 144.2 (Cq), 131.9 (CH), 125.6 (CH), 121.6 (CH), 119.7 (Cq), 77.4 (CH), 66.1 (Cq), 59.1 (CH2), 45.9 (CH2), 31.5 (CH2), 16.4 (CH3), 14.5 (CH3) ppm; HRMS (ESI): m/z calculated for C16H18BrN2O2 [M+H+] = 349.0546, found = 349.0553.

Ethyl (Z)-2-(7-Bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23i)

Ethyl (Z)-2-(7-bromo-2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 7-bromo-3-(2-isocyanoethyl)-2-methyl-1H-indole (132.0 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as brown solid (110 mg, 0.31 mmol, 63%). Rf = 0.23 (cyclohexane:EtOAc 2:1); 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H), 7.47 (dd, J = 7.9, 1.1 Hz, 1H), 7.16 (dd, J = 7.4, 1.0 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.93–3.81 (m, 3H), 2.43–2.25 (m, 5H), 1.16 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 183.4 (Cq), 170.7 (Cq), 163.2 (Cq), 153.6 (Cq), 143.8 (Cq), 132.2 (CH), 127.6 (CH), 121.2 (CH), 113.9 (Cq), 77.5 (CH), 69.4 (Cq), 59.0 (CH2), 45.9 (CH2), 31.6 (CH2), 16.6 (CH3), 14.5 (CH3) ppm; HRMS (ESI): m/z calculated for C16H18BrN2O2 [M+H+] = 349.0546, found = 349.0550.

Ethyl (Z)-2-(2-Phenylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23j)

Ethyl (Z)-2-(2-phenylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-2-phenyl-1H-indole (123.2 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as an off-white solid (141 mg, 0.424 mmol, 85%). Rf = 0.27 (EtOAc:cHex = 1:5); 1H NMR (500 MHz, CDCl3): δ 8.30 (s, 1H), 7.97 (dd, J = 8.0, 1.7 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.53–7.42 (m, 3H), 7.40 (td, J = 7.6, 1.3 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (s, 1H), 4.07–3.93 (m, 4H), 2.68 (dt, J = 13.1, 9.0 Hz, 1H), 2.19 (ddd, J = 13.1, 7.3, 2.7 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 178.0 (Cq), 171.0 (Cq), 165.4 (Cq), 154.0 (Cq), 144.5 (Cq), 131.8 (Cq), 131.2 (CH), 128.9 (2 x CH), 128.8 (CH), 126.8 (CH), 121.4 (CH), 121.3 (CH), 77.7 (CH), 66.6 (Cq), 59.0 (CH2), 46.3 (CH2), 33.1 (CH2), 14.5 (CH3) ppm. HRMS (ESI): m/z calculated for C21H21N2O2 [M+H+] 333.1598, found = 333.1604.

Ethyl (Z)-2-(2-(p-Tolyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23k)

Ethyl (Z)-2-(2-(p-tolyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-2-(p-tolyl)-1H-indole (130.7 mg, 0.5 mmol, 1.0 equiv). The product was purified by flash column chromatography using EtOAc:cHex = (1:4) as eluent to obtain the product as a white solid (125 mg, 0.36 mmol, 72%). Rf = 0.25 (EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3): δ 8.29 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 4.07 (s, 1H), 4.05–3.94 (m, 4H), 2.67 (dt, J = 13.2, 9.0 Hz, 1H), 2.40 (s, 3H), 2.22–2.12 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 178.0 (Cq), 171.0 (Cq), 165.5 (Cq), 154.1 (Cq), 144.5 (Cq), 141.7 (Cq), 129.6 (CH), 129.0 (Cq), 128.8 (CH), 128.7 (CH), 126.5 (CH), 121.2 (CH), 121.1 (CH), 77.6 (CH), 66.5 (Cq), 58.9 (CH2), 46.2 (CH2), 33.3 (CH2), 21.7 (CH3), 14.5 (CH3) ppm.; HRMS (ESI): m/z calculated for C22H23N2O2 [M+H+] = 347.1754, found = 347.1758.

Ethyl (Z)-2-(2-(4-Fluorophenyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23l)

Ethyl (Z)-2-(2-(4-fluorophenyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 2-(4-fluorophenyl)-3-(2-isocyanoethyl)-1H-indole (132.3 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a light-yellow solid (125 mg, 0.36 mmol, 72%). Rf = 0.25 (EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3): δ 8.29 (s, 1H), 7.98 (dd, J = 8.8, 5.4 Hz, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.39 (td, J = 7.7, 1.0 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 8.6 Hz, 2H), 4.06 (s, 1H), 4.05–3.93 (m, 4H), 2.62 (dt, J = 13.2, 9.0 Hz, 1H), 2.22–2.13 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 176.8 (Cq), 170.9 (Cq), 165.1 (Cq), 164.8 (d, J = 253.2 Hz, Cq), 153.8 (Cq), 144.4 (Cq), 130.9 (d, J = 8.6 Hz, CH), 128.9 (CH), 128.0 (Cq, d, J = 3.3 Hz), 126.7 (CH), 121.3 (2 x CH), 116.0 (d, J = 21.8 Hz, CH), 77.8 (CH), 66.5 (Cq), 59.0 (CH2), 46.2 (CH2), 33.2 (CH2), 14.5 (CH3) ppm; 19F{1H} NMR (470 MHz, CDCl3): δ −108.27 ppm; HRMS (ESI): m/z calculated for C21H20FN2O2 [M+H+] = 351.1503, found = 351.1515.

Ethyl (Z)-2-(2-(4-Chlorophenyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23m)

Ethyl (Z)-2-(2-(4-chlorophenyl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 2-(4-chlorophenyl)-3-(2-isocyanoethyl)-1H-indole (140.3 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a light-yellow solid (138 mg, 0.38 mmol, 76%). Rf = 0.21 (EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3): δ 8.28 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.46–7.37 (m, 3H), 7.30 (d, J = 7.1 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 4.05 (s, 1H), 4.06–3.93 (m, 4H), 2.62 (dt, J = 13.0, 8.9 Hz, 1H), 2.17 (dd, J = 12.9, 6.1 Hz, 2H)1.14 (t, J = 7.1 Hz, 1H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 176.8 (Cq), 170.9 (Cq), 164.9 (Cq), 153.8 (Cq), 144.5 (Cq), 137.4 (Cq), 130.1 (Cq), 130.0 (CH), 129.2 (CH), 129.0 (CH), 126.9 (CH) 121.4 (CH), 121.3 (CH), 77.8 (CH), 66.4 (Cq), 59.0 (CH2), 46.2 (CH2), 33.1 (CH2), 14.5 (CH3) ppm. HRMS (ESI): m/z calculated for C21H20ClN2O2 [M+H+] = 367.1208, found = 367.1215.

Ethyl (Z)-2-(2-(Naphthalen-2-yl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23n)

Ethyl (Z)-2-(2-(naphthalen-2-yl)spiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 3-(2-isocyanoethyl)-2-(naphthalen-2-yl)-1H-indole (148.1 mg, 0.5 mmol, 1.0 equiv). The product was purified by flash column chromatography using EtOAc:cHex = 1:4 as eluent to obtain the product as a white solid (115 mg, 0.30 mmol, 60%). Rf = 0.30 (1% Et3N in EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3) δ (ppm): 8.44–8.30 (m, 2H), 8.18 (dd, J = 8.7, 1.8 Hz, 1H), 7.95–7.89 (m, 2H), 7.87 (d, J = 7.9, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.59–7.50 (m, 2H), 7.45 (td, J = 7.5, 1.3 Hz, 1H), 7.34 (dd, J = 7.5, 1.2 Hz, 1H), 7.26 (td, J = 7.4, 1.0 Hz, 1H), 4.12 (s, 1H), 4.11–3.94 (m, 4H), 2.78 (dt, J = 13.2, 9.0 Hz, 1H), 2.24 (ddd, J = 13.1, 6.7, 3.1 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 177.9 (Cq), 170.9 (Cq), 165.4 (Cq), 154.0 (Cq), 144.7 (Cq), 134.6 (Cq), 133.0 (Cq), 129.3 (CH), 129.3 (CH), 129.2 (Cq), 128.9 (CH), 128.6 (CH), 127.8 (CH), 127.8 (CH), 126.8 (CH), 126.6 (CH), 125.3 (CH), 121.4 (CH), 121.3 (CH), 77.8 (CH), 66.6 (CHq), 58.9 (CH2), 46.3 (CH2), 33.4 (CH2), 14.5 (CH3) ppm. HRMS (ESI): m/z calculated for C25H22N2O2 [M+H+] = 383.1754, found = 383.1750.

Ethyl (Z)-2-(2-Bromospiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate (23o)

Ethyl (Z)-2-(2-bromospiro[indole-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from 2-bromo-3-(2-isocyanoethyl)-1H-indole (129.9 mg, 0.52 mmol, 1.0 equiv). The title compound was isolated as a light-yellow solid (136 mg, 0.40 mmol, 78%). Rf = 0.43 (EtOAc:cHex = 1:3); 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.35 (td, J = 7.3, 2.0 Hz, 1H), 7.30–7.22 (m, 2H), 4.10–3.94 (m, 5H), 2.53 (ddd, J = 13.1, 7.9, 5.0 Hz, 1H), 2.34 (ddd, J = 13.7, 8.1, 6.2 Hz, 1H), 1.17 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 170.6 (Cq), 164.1 (Cq), 161.9 (Cq), 154.0 (Cq), 141.8 (Cq), 129.2 (CH), 127.2 (CH) 122.3 (CH), 120.7 (CH), 78.0 (CH), 71.0 (Cq), 59.1 (CH2), 45.9 (CH2), 31.9 (CH2), 14.5 (CH3) ppm. HRMS (ESI): m/z calculated for C15H16BrN2O2 [M+H+] = 335.0390, found = 335.0388.

Ethyl (Z)-2-((Z)-2-(2-Methoxy-2-oxoethylidene)spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (23p)

Ethyl (Z)-2-((Z)-2-(2-methoxy-2-oxoethylidene)spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure A starting from methyl 2-(3-(2-isocyanoethyl)-1H-indol-2-yl)acetate (121.6 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a white solid (102 mg, 0.31 mmol, 62%). Rf = 0.28 (EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3): δ 9.66 (s, 1H), 8.06 (s, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.88 (s, 1H), 4.11 (s, 1H), 4.04 (qd, J = 7.1, 1.1 Hz, 2H), 3.82 (t, J = 6.8 Hz, 2H), 3.70 (s, 3H), 2.46–2.30 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.0 (Cq), 170.5 (Cq), 167.2 (Cq), 167.0 (Cq), 143.8 (Cq), 132.6 (Cq), 129.2 (CH), 123.4 (CH), 122.0 (CH), 109.4 (CH), 82.3 (CH), 78.8 (CH), 61.1 (Cq), 59.0 (CH2), 50.9 (CH3), 45.4 (CH2), 38.5 (CH2), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C18H21N2O4 [M+H+] = 329.1496, found = 329.1497.

Ethyl (Z)-2-(Spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25a)

Ethyl (Z)-2-(spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 3-(2-isocyanoethyl)-1H-indole (85.2 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). The title compound was isolated as a yellow solid (99 mg, 0.38 mmol, 77%). Rf = 0.25 (EtOAc:cHex 1:2); 1H NMR (500 MHz, CDCl3) δ (ppm): 7.96 (s, 1H), 7.08 (td, J = 7.6, 1.3 Hz, 1H), 7.01 (dd, J = 7.4, 1.3 Hz, 1H), 6.74 (td, J = 7.4, 1.0 Hz, 1H), 6.68 (d, J = 7.9, 1H), 4.44 (s, 1H), 4.07 (qd, J = 7.1, 3.1 Hz, 2H), 3.79 (br, 1H), 3.72–3.48 (m, 4H), 2.29–2.12 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.3 (Cq), 170.7 (Cq), 151.2 (Cq), 132.5 (Cq), 128.6 (CH), 123.7 (CH), 119.5 (CH), 110.1 (CH), 77.5 (CH), 59.4 (CH2), 58.7 (CH2), 57.3 (Cq), 45.0 (CH2), 37.2 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C15H19N2O2 [M+H+] = 259.1441, 259.1441.

Ethyl (Z)-2-(2-methylspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25b)

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv). Subsequently, 1,2-DCE was added (0.25 M), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of 3-(2-isocyanoethyl)-2-methyl-1H-indole (92.4 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C until full conversion of the isocyanide was observed on TLC. Subsequently, the reaction mixture was cooled to 0 °C and diluted with MeOH to a concentration of 0.125 M, after which NaBH3CN (32 mg, 0.51 mmol, 1.02 equiv) and a few drops of AcOH were added. The resulting mixture was stirred at 0 °C until full conversion of the spiroindolenine intermediate was observed on TLC. Subsequently, the mixture was neutralized with Na2CO3 and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3 x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. This was followed by purification via FCC using a gradient of cHex:EtOAc to obtain the title compound as a light-yellow solid (99 mg, 0.36 mmol, 73%). Rf = 0.29 (cHex:EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 7.96 (s, 1H), 7.08 (td, J = 7.6, 1.3 Hz, 1H), 7.03 (dd, J = 7.4, 1.2 Hz, 1H), 6.76 (td, J = 7.4, 0.8 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 4.25 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.86 (q, J = 6.5 Hz, 1H), 3.65–3.51 (m, 2H), 2.53–2.41 (m, 1H), 2.13 (ddd, J = 13.0, 6.6, 2.2 Hz, 1H).zf), 1.23 (d, J = 6.4 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.1 (Cq), 166.6 (Cq), 151.0 (Cq), 132.3 (Cq), 128.6 (CH), 124.0 (CH), 119.6 (CH), 110.1 (CH), 79.5 (CH), 65.5 (CH), 60.0 (Cq), 58.6 (CH2), 44.7 (CH2), 36.8 (CH2), 17.1 (CH3), 14.6 (CH3) ppm; HRMS (ESI): m/z calculated for C16H21N2O2 [M+H+] = 273.1598, found = 273.1603.

Ethyl (Z)-2-(5-methoxyspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25q)

Ethyl (Z)-2-(5-methoxyspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 3-(2-isocyanoethyl)-5-methoxy-1H-indole (100.2 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). The title compound was isolated as a light-yellow solid (81 mg, 0.28 mmol, 56%). Rf: indoline = 0.16 (cHex:EtOAc = 6:4); 1H NMR (500 MHz, CDCl3): δ 7.94 (s, 1H), 6.69–6.59 (m, 3H), 4.43 (s, 1H), 4.07 (qd, J = 7.1, 1.2 Hz, 2H), 3.72 (s, 3H), 3.68–3.48 (m, 4H), 3.26 (br, 1H), 2.29–2.11 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.3 (Cq), 170.4 (Cq), 154.3 (Cq), 144.9 (Cq), 134.2 (Cq), 114.1 (CH), 111.2 (CH), 110.1 (CH), 77.7 (CH), 59.9 (CH2), 58.8 (CH2), 58.0 (Cq), 56.0 (CH3), 45.0 (CH2), 36.9 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C16H21N2O3 [M+H+] = 289.1547, found = 289.1553.

Ethyl (Z)-2-(6-methoxyspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25r)

Ethyl (Z)-2-(6-methoxyspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 3-(2-isocyanoethyl)-6-methoxy-1H-indole (100.1 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). Extra portions of NaBH4 were added over time until full conversion of the indolenine intermediate was observed. The title compound was isolated as a light-yellow solid (97 mg, 0.34 mmol, 67%). Rf = 0.24 (cHex:EtOAc = 6:4); 1H NMR (500 MHz, CDCl3): δ 7.93 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.29 (dd, J = 8.2, 2.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 4.43 (s, 1H), 4.07 (qd, J = 7.2, 2.2 Hz, 2H), 3.78 (s, 1H), 3.75 (s, 3H), 3.67–3.50 (m, 4H), 2.26–2.10 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.4 (Cq), 171.0 (Cq), 160.9 (Cq), 152.6 (Cq), 124.9 (Cq), 124.2 (CH), 104.7 (CH), 96.5 (CH), 77.3 (CH), 59.9 (CH2), 58.8 (CH2), 56.7 (Cq), 55.5 (CH3), 45.0 (CH2), 37.3 (CH2), 14.7 (CH3) ppm. HRMS (ESI): m/z calculated for C16H21N2O3 [M+H+] = 289.1547, found = 289.1554.

Ethyl (Z)-2-(5-methylspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25s)

Ethyl (Z)-2-(5-methylspiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 3-(2-isocyanoethyl)-5-methyl-1H-indole (92.2 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). Extra portions of NaBH4 were added over time until full conversion of the indolenine intermediate was observed. The title compound was isolated as a white solid (100 mg, 0.37 mmol, 74%). Rf = 0.64 (cHex:EtOAc = 1:1); 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.83 (s, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.44 (s, 1H), 4.08 (qd, J = 7.1, 4.0 Hz, 2H), 3.72–3.50 (m, 4H), 3.47 (br, 1H), 2.27–2.12 (m, 5H), 1.22 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.4 (Cq), 170.8 (Cq), 148.7 (Cq), 132.9 (Cq), 129.2 (Cq), 129.1 (CH), 124.3 (CH), 110.3 (CH), 77.5 (CH), 59.6 (CH2), 58.7 (CH2), 57.5 (Cq), 45.0 (CH2), 37.1 (CH2), 21.0 (CH3), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C16H21N2O2 [M+H+] = 273.1598, found = 273.1597.

Ethyl (Z)-2-(5-fluorospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25t)

Ethyl (Z)-2-(5-fluorospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 5-fluoro-3-(2-isocyanoethyl)-1H-indole (94.4 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). The title compound was isolated as a light-brown solid (110 mg, 0.70 mmol, 79%). Rf = 0.25 (cHex:EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 7.94 (s, 1H), 6.78 (td, J = 8.8, 2.7 Hz, 1H), 6.73 (dd, J = 8.3, 2.6 Hz, 1H), 6.60 (dd, J = 8.5, 4.3 Hz, 1H), 4.42 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.68–3.52 (m, 4H), 3.31 (br, 1H), 2.31–2.10 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.3 (Cq), 169.9 (Cq), 157.5 (Cq, d, J = 236.6 Hz), 147.1 (Cq, d, J = 1.6 Hz), 134.2 (Cq, d, J = 7.7 Hz), 115.0 (CH, d, J = 23.5 Hz), 111.1 (CH, d, J = 24.2 Hz), 110.7 (CH, d, J = 8.2 Hz), 77.8 (CH), 59.9 (CH2), 58.9 (CH2), 57.7 (Cq), 45.0 (CH2), 37.0 (CH2), 14.7 (CH3) ppm; 19F{1H} NMR (470.4 MHz, CDCl3): δ −124.9 ppm; HRMS (ESI): m/z calculated for C15H18FN2O2 [M+H+] = 277.1347, found = 277.1346.

Ethyl (Z)-2-(5-chlorospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25u)

Ethyl (Z)-2-(5-chlorospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 5-chloro-3-(2-isocyanoethyl)-1H-indole (102.8 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv) and NaBH4 (20 mg, 0.53 mmol). The title compound was isolated as a white solid (96 mg, 0.33 mmol, 66%). Rf = 0.48 (cHex:EtOAc = 1:1); 1H NMR (500 MHz, CDCl3): δ 7.94 (s, 1H), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 4.42 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.79 (br, 1H), 3.69–3.50 (m, 4H), 2.28–2.09 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.2 (Cq), 169.9 (Cq), 149.8 (Cq), 134.3 (Cq), 128.5 (CH), 124.0 (CH), 123.9 (Cq), 110.8 (CH), 77.8 (CH), 59.7 (CH2), 58.9 (CH2), 57.3 (Cq), 45.0 (CH2), 37.2 (CH2), 14.7 (CH3) ppm. HRMS (ESI): m/z calculated for C15H18ClN2O2 [M+H+] = 293.1051, found = 293.1058.

Ethyl (Z)-2-(5-bromospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25v)

Ethyl (Z)-2-(5-bromospiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate was prepared according to general procedure B starting from 5-bromo-3-(2-isocyanoethyl)-1H-indole (124.4 mg, 0.5 mmol, 1.0 equiv), ethyl diazoacetate (0.6 mmol, 1.2 equiv), Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv), and NaBH4 (20 mg, 0.53 mmol). The title compound was isolated as a light-brown solid (102 mg, 0.30 mmol, 61%). Rf = 0.27 (cHex:EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 7.94 (s, 1H), 7.15 (dd, J = 8.3, 2.0 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 4.42 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (br, 1H), 3.68–3.50 (m, 4H), 2.24 (ddd, J = 12.8, 7.1, 4.1 Hz, 1H), 2.14 (dt, J = 12.7, 7.7 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.2 (Cq), 169.9 (Cq), 150.2 (Cq), 134.8 (Cq), 133.4 (CH), 126.8 (CH), 111.4 (CH), 110.8 (Cq), 77.8 (CH), 59.6 (CH2), 58.9 (CH2), 57.3 (Cq), 45.0 (CH2), 37.2 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C15H18BrN2O2 [M+H+] = 337.0546, found = 337.0552.

Methyl (3S,Z)-2′-(2-Ethoxy-2-oxoethylidene)spiro[indoline-3,3′-pyrrolidine]-5′-carboxylate (25w)

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.05 equiv). Subsequently, 1,2-DCE was added (0.25 M), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of 3-(1H-indol-3-yl)-2-isocyanopropanoate (114, mg, 0.50 mmol, 1.0 equiv) and ethyl diazoacetate (0.6 mmol, 1.2 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C until full conversion of the isocyanide was observed on TLC. Subsequently, the reaction mixture was cooled to 0 °C and diluted with MeOH to a concentration of 0.125 M, after which NaBH3CN (33 mg, 0.53 mmol, 1.05 equiv) and a few drops of AcOH were added. The resulting mixture was stirred at 0 °C until full conversion of the spiroindolenine intermediate was observed on TLC. Subsequently, the mixture was neutralized with Na2CO3 and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. This was followed by purification via FCC using cHex:EtOAc = 6:4 as eluent to obtain the title compound as two diastereomers separately (combined yield: 86 mg, 0.25 mmol, 50%, dr = 2.2:1). dr determined via 1H NMR of the crude product mixture. D1 (major): yellow oil (62 mg, 0.18 mmol, 36%); Rf = 0.60 (cHex:EtOAc = 6:4); 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.09 (td, J = 7.7, 1.1 Hz, 1H), 6.99 (dd, J = 7.4, 1.0 Hz, 1H), 6.75 (td, J = 7.5, 0.9 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.52 (dd, J = 8.7, 3.8 Hz, 1H), 4.49 (s, 1H), 4.08 (qd, J = 7.1, 2.2 Hz, 2H), 3.78 (s, 3H), 3.71 (d, J = 9.6 Hz, 1H), 3.52 (d, J = 9.5 Hz, 1H), 2.58–2.41 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 172.7 (Cq), 171.0 (Cq), 169.6 (Cq), 151.1 (Cq), 132.3 (Cq), 128.9 (CH), 123.5 (CH), 119.6 (CH), 110.3 (CH), 79.7 (CH), 60.5 (CH2), 59.0 (CH2), 58.7 (CH), 56.6 (Cq), 52.7 (CH3), 40.6 (CH2), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C17H21N2O4 [M+H+] = 317.1496, found = 317.1497. D2 (minor): yellow oil (24 mg, 0.07 mmol, 14%); Rf = 0.29 (cHex:EtOAc = 6:4); 1H NMR (500 MHz, CDCl3): δ 8.17 (s, 1H), 7.09 (td, J = 7.7, 1.2 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.76 (td, J = 7.5, 0.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 4.48–4.41 (m, 2H), 4.09 (qd, J = 7.2, 2.3 Hz, 2H), 3.79 (s, 3H), 3.60 (dd, J = 15.9, 9.2 Hz, 2H), 2.62 (dd, J = 13.0, 7.0 Hz, 1H), 2.23 (dd, J = 13.0, 9.0 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.8 (Cq), 170.9 (Cq), 169.0 (Cq), 151.3 (Cq), 131.2 (Cq), 129.0 (CH), 124.2 (CH), 120.0 (CH), 110.3 (CH), 79.9 (CH), 60.3 (CH2), 59.0 (CH2), 58.5 (CH), 57.4 (Cq), 52.7 (CH3), 40.7 (CH2), 14.6 (CH3) ppm. HRMS (ESI): m/z calculated for C17H21N2O4 [M+H+] = 317.1501, found = 317.1497.

Ethyl (Z)-2-((3S,4′R)-4′-(3-Methoxyphenyl)spiro[indoline-3,3′-pyrrolidin]-2′-ylidene) (25x)

To a flame-dried Schlenk flask under N2 atmosphere, charged with a stirring bean, was added Bu4N[Fe(CO)3NO] (10.3 mg, 0.025 mmol, 0.06 equiv). Subsequently, 1,2-DCE was added (0.25 M), and the mixture was stirred until the catalyst was dissolved. This was followed by the addition of 3-(2-isocyano-1-(3-methoxyphenyl)ethyl)-1H-indole (112 mg, 0.41 mmol, 1.0 equiv) and ethyl diazoacetate (0.6 mmol,1.5 equiv). The solution was placed in a preheated oil bath and stirred at 80 °C until full conversion of the isocyanide was observed on TLC. Subsequently, the reaction mixture was cooled to 0 °C and diluted with MeOH to a concentration of 0.125 M, after which NaBH3CN (33 mg, 0.53 mmol, 1.05 equiv) was added. After 30 min, NaBH3CN (31 mg, 0.50 mmol, 1.0 equiv) and a few drops of AcOH were added. The resulting mixture was stirred at 0 °C until full conversion of the spiroindolenine intermediate was observed on TLC. Subsequently, the mixture was neutralized with Na2CO3 and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. This was followed by purification via FCC using cHex:EtOAc = 2:1 as eluent to obtain both diastereomers separately (combined yield: 81 mg, 0.22 mmol, 54%, dr = 3:1). dr determined via 1H NMR of the crude product mixture. D1 (major): white solid (61 mg, 0.17 mmol, 41%); Rf = 0.44 (cHex:EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 8.09 (s, 1H), 7.20–7.13 (m, 2H), 7.10 (td, J = 7.7, 1.2 Hz, 1H), 6.84–6.75 (m, 2H), 6.66 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.51 (t, J = 1.8 Hz, 1H), 4.53 (s, 1H), 4.09 (q, J = 6.9 Hz, 2H), 4.00 (dd, J = 10.0, 7.3 Hz, 1H), 3.83 (dd, J = 10.3, 6.7 Hz, 1H), 3.65 (s, 3H), 3.57 (t, J = 6.9 Hz, 1H), 3.46–3.32 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.4 (Cq), 170.7 (Cq), 159.6 (Cq), 151.4 (Cq), 140.4 (Cq), 132.3 (Cq), 129.6 (CH), 128.9 (CH), 123.7 (CH), 119.9 (CH), 119.6 (CH), 113.6 (CH), 112.9 (CH), 110.4 (CH), 78.1 (CH), 61.5 (Cq), 58.8 (CH2), 55.1 (CH), 53.9 (CH2), 52.6 (CH3), 49.8 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C22H25N2O3 [M+H+] = 365.1860, found = 365.1868. D2 (minor): yellow oil (20 mg, 0.06 mmol, 13%); Rf = 0.26 (cHex: EtOAc = 2:1); 1H NMR (500 MHz, CDCl3): δ 8.11 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.95 (td, J = 7.7, 1.1 Hz, 1H), 6.67 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 6.43 (td, J = 7.5, 0.7 Hz, 1H), 6.36 (t, J = 1.9 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 4.49 (s, 1H), 4.18–4.04 (m, 2H), 4.00–3.88 (m, 2H), 3.72 (br, 1H), 3.66 (s, 2H), 3.58 (s, 3H), 3.49 (dd, J = 6.5, 3.7 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.3 (Cq), 169.2 (Cq), 159.3 (Cq), 151.8 (Cq), 141.0 (Cq), 129.1 (CH), 128.5 (CH), 128.2 (Cq), 126.3 (CH), 120.5 (CH), 118.7 (CH), 113.7 (CH), 112.9 (CH), 109.9 (CH), 79.0 (CH), 63.0 (Cq), 59.7 (CH2), 58.9 (CH2), 55.2 (CH), 51.6 (CH3), 50.9 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C22H25N2O3 [M+H+] = 365.1860, found = 365.1867.

Dimethyl (R,Z)-2-(Spiro[indole-3,3′-pyrrolidin]-2′-ylidene)succinate (23ab)

Dimethyl (R,Z)-2-(spiro[indole-3,3′-pyrrolidin]-2′-ylidene)succinate was prepared according to general procedure C starting from 3-(2-isocyanoethyl)-1H-indole (85.1 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a white solid (50 mg, 0.16 mmol, 33%). Rf = 0.22 (cHex:EtOAc = 1:1); 1H NMR (600 MHz, CDCl3): δ 8.90 (s, 1H), 8.12 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.40 (td, J = 7.6, 1.3 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.27 (td, J = 7.4, 1.1 Hz, 1H), 3.84 (dddd, J = 10.1, 7.2, 6.1, 0.9 Hz, 1H), 3.77 (dddd, J = 10.1, 7.7, 5.8, 1.0 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 3H), 2.47 (ddd, J = 12.8, 7.6, 6.1 Hz, 1H), 2.36–2.16 (m, 2H), 2.14 (ddd, J = 13.0, 7.5, 5.8 Hz, 1H) ppm; 13C{1H} NMR (150 MHz, CDCl3): δ 173.0 (Cq), 172.7 (CH), 170.5 (Cq), 160.3 (Cq), 154.6 (Cq), 140.3 (Cq), 129.1 (CH), 127.3 (CH), 122.5 (CH), 122.1 (CH), 85.4 (Cq), 67.2 (Cq), 51.6 (CH3), 51.1 (CH3), 45.4 (CH2), 32.7 (CH2), 30.7 (CH2) ppm. HRMS (ESI): m/z calculated for C17H19N2O4 [M+H+] = 315.1339, found = 315.1338.

Dimethyl (R,Z)-2-(2-Methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)succinate (23bb)

Dimethyl (R,Z)-2-(2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)succinate was prepared according to general procedure C starting from 2-(methyl)-3-(2-isocyanoethyl)-1H-indole (92.1 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a white solid (84 mg, 0.26 mmol, 51%). Rf = 0.68 (EtOAc); 1H NMR (600 MHz, CDCl3): 8.95 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.6, 1.3 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 3.86–3.75 (m, 2H), 3.60 (s, 3H), 3.37 (s, 3H), 2.31 (s, 3H), 2.30–2.19 (m, 4H). δ ppm; 13C{1H} NMR (150 MHz, CDCl3): δ 13C NMR (150 MHz, CDCl3) δ 182.4 (Cq), 172.6 (Cq), 170.7 (Cq), 161.9 (Cq), 154.6 (Cq), 142.1 (Cq), 128.9 (CH), 126.3 (CH), 122.5 (CH), 120.8 (CH), 85.3 (Cq), 67.9 (Cq), 51.4 (CH3), 51.0 (CH3), 45.2 (CH2), 34.3 (CH2), 30.4 (CH2), 16.8 (CH3) ppm. HRMS (ESI): m/z calculated for C18H21N2O4 [M+H+] = 329.1496, found = 329.1495.

Benzyl (R,Z)-2-(2-Methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)-3-oxobutanoate (23be)

Benzyl (R,Z)-2-(2-methylspiro[indole-3,3′-pyrrolidin]-2′-ylidene)-3-oxobutanoate was prepared according to general procedure C starting from 2-(methyl)-3-(2-isocyanoethyl)-1H-indole (92.1 mg, 0.5 mmol, 1.0 equiv). The title compound was isolated as a white solid (17 mg, 0.05 mmol, 9%). Rf = 0.16 (cHex:EtOAc = 3:7); 1H NMR (500 MHz, CDCl3): δ 12.02 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.7, 7.2, 2.1 Hz, 1H), 7.25–7.16 (m, 5H), 7.08–7.01 (m, 2H), 4.45 (s, 2H), 3.97–3.80 (m, 2H), 2.37 (ddd, J = 13.1, 7.6, 5.9 Hz, 1H), 2.31 (s, 3H), 2.26–2.16 (m, 4H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 196.7 (Cq), 181.5 (Cq), 168.6 (Cq), 167.0 (Cq), 155.0 (Cq), 141.7 (Cq), 136.3 (Cq), 128.8 (CH), 128.4 (CH), 128.3 (CH), 127.9 (CH), 126.0 (CH), 121.2 (CH), 120.5 (CH), 100.7 (Cq), 69.5 (Cq), 64.8 (CH2), 45.6 (CH2), 35.6 (CH2), 29.5 (CH3), 17.0 (CH3) ppm. HRMS (ESI): m/z calculated for C23H23N2O3 [M+H+] = 375.1703, found = 375.1702.

Ethyl (Z)-2-(2-(2-Hydroxyethyl)spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (25y)

2-(3-(2-Isocyanoethyl)-1H-indol-2-yl)ethan-1-ol (1.35 g, 6.33 mmol, 1.0 equiv) was added to a solution of Bu4[Fe(CO)3NO] (260 mg, 0.63 mmol, 0.10 equiv) in anhydrous 1,2-DCE (25 mL). Ethyl 2-diazoacetate (0.94 mL, 7.60 mmol, 1.2 equiv) was added, and the mixture was heated to 80 °C for 1.5 h and then allowed to cool to room temperature. The reaction was placed in an ice bath, and MeOH (10 mL) and NaBH4 (251 mg, 6.65 mmol, 1.05 equiv) were added. After complete conversion of the spiroindolenine was observed on TLC, the reaction was quenched with a saturated NH4Cl solution and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. FCC (gradient: 20% → 80% EtOAc in cyclohexane) yielded the product as a light-brown solid as a single diastereomer (1.12 g, 3.70 mmol, 59%). Rf = 0.28 (EtOAc/cyclohexane 4:1); 1H NMR (500 MHz, CDCl3): δ 7.97 (s, 1H), 7.08 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 4.30 (s, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.94–3.76 (m, 3H), 3.69–3.52 (m, 2H), 2.49 (dt, J = 13.1, 8.8 Hz,, 1H), 2.17 (ddd, J = 13.1, 7.0, 2.8 Hz, 1H), 2.03–1.87 (m, 1H), 1.84–1.49 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 171.2 (Cq), 167.0 (Cq), 150.9 (Cq), 132.3 (Cq), 128.7 (CH), 123.8 (CH), 119.6 (CH), 110.3 (CH), 79.5 (CH), 68.6 (CH), 61.9 (CH2), 60.1 (Cq), 58.7 (CH2), 44.9 (CH2), 37.0 (CH2), 33.8 (CH2), 14.7 (CH3) ppm; HRMS (ESI): m/z calculated for C17H23N2O3 [M+H+] = 303.1703, found = 303.1705.

Ethyl 2,3,5,6,6a,7-Hexahydro-1H-pyrrolo[2,3-d]carbazole-4-carboxylate (26)

To a mixture of imidazole (0.31 g, 4.6 mmol, 1.35 equiv), PPh3 (1.15 g, 4.4 mmol 1.30 equiv), and iodine (1.12 g, 4.4 mmol, 1.30 equiv) in CH2Cl2 (35 mL) was added ethyl (Z)-2-(2-(2-hydroxyethyl)spiro[indoline-3,3′-pyrrolidin]-2′-ylidene)acetate (1.02 g, 3.4 mmol, 1.0 equiv). After heating for an hour at reflux, the reaction mixture was allowed to cool to room temperature, after which MeOH (5 mL) was added causing the reaction mixture to turn to a clear solution. This solution was washed with a saturated Na2SO3 solution and subsequently extracted with CH2Cl2 (3×). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. FCC (gradient: 5% → 40% EtOAc in cyclohexane) yielded the product as a light yellow solid and as a single diastereomer (858 mg, 3.0 mmol, 88%). Rf = 0.30 (EtOAc:cHex = 1:4); 1H NMR (500 MHz, CDCl3): δ 7.53 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.65 (t, J = 7.5 Hz,1H), 6.61 (d, J = 7.8 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.94 (dd, J = 5.3, 2.9 Hz, 1H), 3.76 (td, J = 10.4, 6.1 Hz, 1H), 3.59 (ddd, J = 10.8, 9.2, 2.2 Hz, 1H), 2.42 (dt, J = 15.1, 4.5 Hz, 1H), 2.29 (dd, J = 12.0, 6.0 Hz, 1H), 2.14–2.05 (m,1H), 1.89 (ddd, J = 14.8, 10.9, 3.5 Hz, 1H), 1.75–1.59 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3): δ 169.4 (Cq), 162.8 (Cq), 150.2 (Cq), 132.8 (Cq), 128.6 (CH), 123.2 (CH), 118.8 (CH), 109.0 (CH), 89.6 (Cq), 63.7 (CH), 59.0 (CH2), 55.4 (Cq), 44.2 (CH2), 39.4 (CH2), 33.5 (CH2), 18.5 (CH2), 14.8 (CH3) ppm; HRMS (ESI): m/z calculated for C17H21N2O2 [M+H+] = 285.1597, found = 285.1598.

7-(tert-Butyl) 4-Ethyl 1,2,3,5,6,6a-Hexahydro-7H-pyrrolo[2,3-d]carbazole-4,7-dicarboxylate (20) (3g)

Ethyl 2,3,5,6,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-4-carboxylate (142 mg, 0.5 mmol, 1.0 equiv) was dissolved in anhydrous CH2Cl2 (0.5 M), followed by the addition of DMAP (12 mg, 0.1 mmol, 0.2 equiv) and Boc2O (372 mg, 1.5 mmol, 3.0 equiv). No full conversion was observed on TLC after 24 h, and an additional portion of Boc2O (164 mg, 0.75 mmol, 1.5 equiv) was added. After 48 h no full conversion was observed and additional amounts of Boc2O (372 mg, 1.5 mmol, 1.5 equiv) and DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added. Additional portions of Boc2O (372 mg, 1.5 mmol, 1.5 equiv) and DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added after 72 h and stirred until full conversion was observed. After completion of the reaction, the reaction was diluted with CH2Cl2, washed with H2O and brine, and dried over Na2SO4, followed by filtration and concentration in vacuo. The crude reaction mixture was then purified by FCC using EtOAc:cHex = 1:9 as eluent to obtain the product as a white foam (136 mg, 0.35 mmol, 71%). Characterization data is accordance with that reported in the literature. (3g) Rf = 0.26 EtOAc:cHex = 1:9); 1H NMR (600 MHz, CDCl3): δ 7.97–7.34 (m, 1H), 7.18 (s, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.90 (td, J = 7.5, 1.1 Hz, 1H), 4.46 (m, 1H), 4.11 (qd, J = 7.1, 1.3 Hz, 1H), 3.74 (td, J = 10.3, 6.3 Hz, 1H), 3.61 (t, J = 9.5 Hz, 1H), 2.48–2.38 (m, 1H), 2.26 (dd, J = 12.1, 6.1 Hz, 1H), 2.22–2.05 (m, 2H), 1.73–1.52 (m, 12H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3): (presence of rotameric signals) δ 169.3 (Cq), 162.2 (Cq), 152.0 (Cq), 142.3 (Cq), 134.4 (Cq), 128.7 (CH), 123.0 (CH), 122.7 (CH), 114.7 (CH), 89.9 (Cq), 81.1 (Cq), 66.2 (CH), 59.1 (CH2), 53.8 (Cq), 44.0 (CH2), 39.3 (CH2), 31.4 (CH2), 28.6 (CH3), 18.4 (CH2), 14.8 (CH3) ppm. HRMS (ESI): m/z calculated for C22H29N2O4 [M+H+] = 385.2122, found = 385.2127.

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The data underlying this study are available in the published article and its Supporting Information.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02160.

  • Experimental procedures, characterization data, and 1H and 13C NMR spectra for new compounds (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 1g, 1h, 1i, 1k–1n, 1p, 1x, 1y, 20, 23a, 23ab, 23b, 23ab, 23bb, 23be, 23c–23g, 23i, 23j–23o, 25a, 25b, 25q, 25r–25v, 25w_D1, 25w_D2, 25x_D1, 25x_D2, 25y, and 26 (ZIP)

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  • Corresponding Authors
  • Authors
    • Thomas R. Roose - Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
    • Finn McSorley - Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
    • Bryan Groenhuijzen - Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecular & Life Science (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
    • Jordy M. Saya - Organic Chemistry, Aachen-Maastricht Institute for Biobased Materials (AMIBM), Maastricht University, Urmonderbaan 22, 6167 KD Geleen, Netherlands
  • Author Contributions

    The manuscript was written through contributions of all authors.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was financially supported by The Netherlands Organisation for Scientific Research (NWO, ECHO) and the Fund for Scientific Research – Flanders (FWO, G0D1921N). B.U.W.M. thanks the Francqui Foundation for an appointment as Collen-Francqui professor. We also kindly thank Elwin Janssen for NMR support and H. Daniel Preschel for HRMS measurements (both VU Amsterdam).

References

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This article references 18 other publications.

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    A novel catalyst-free one-pot tandem reaction for the stereoselective construction of polycyclic spiroindolines was developed. This method offers a straightforward access to structurally diverse polycyclic spiroindoline derivs. in high yields (up to 90%) with excellent levels of diastereoselectivity.
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    (b) Wang, X.; Wang, S. Y.; Ji, S. J. Chemoselective synthesis of polycyclic spiroindolines and polysubstituted pyrroles via the domino reaction of 2-isocyanoethylindoles. J. Org. Chem. 2014, 79, 8577– 8583,  DOI: 10.1021/jo501143m
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    3b
    Chemoselective Synthesis of Polycyclic Spiroindolines and Polysubstituted Pyrroles via the Domino Reaction of 2-Isocyanoethylindoles
    Wang, Xiang; Wang, Shun-Yi; Ji, Shun-Jun
    Journal of Organic Chemistry (2014), 79 (18), 8577-8583CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Chemoselective 2-isocyanoethylindole-based domino reactions for the construction of polycyclic spiroindoline derivs., e.g., I, and polysubstituted pyrroles, e.g., II, have been developed. The reaction of 2-isocyanoethylindoles and gem-diactivated olefins lead to the polycyclic spiroindoline derivs. (up to 92% yields) in EtOH under reflux conditions. Furthermore, the three-component reaction of 2-isocyanoethylindoles with gem-diactivated olefins and secondary amines afford polysubstituted pyrroles (in moderate yields) in CH3CN under reflux conditions.
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    (c) Zhao, X.; Liu, X.; Xiong, Q.; Mei, H.; Ma, B.; Lin, L.; Feng, X. The asymmetric synthesis of polycyclic 3-spirooxindole alkaloids via the cascade reaction of 2-isocyanoethylindoles. Chem. Commun. 2015, 51, 16076– 16079,  DOI: 10.1039/C5CC06353A
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    3c
    The asymmetric synthesis of polycyclic 3-spirooxindole alkaloids via the cascade reaction of 2-isocyanoethylindoles
    Zhao, Xiaohu; Liu, Xiaohua; Xiong, Qian; Mei, Hongjiang; Ma, Baiwei; Lin, Lili; Feng, Xiaoming
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (89), 16076-16079CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A highly enantioselective dearomative cascade reaction between 2-isocyanoethylindoles and 3-alkenyl-oxindoles was realized using a chiral N,N'-dioxide-Mg(II) complex catalyst. This reaction provides a straightforward access to polycyclic 3-spirooxindoles, e.g. I, bearing cyclopenta[b]indole units with four contiguous stereocenters in excellent yields and moderate to good stereoselectivities via a Michael/Friedel-Crafts/Mannich cascade.
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    (d) Zhao, X.; Liu, X.; Mei, H.; Guo, J.; Lin, L.; Feng, X. Asymmetric Dearomatization of Indoles through a Michael/Friedel-Crafts-Type Cascade To Construct Polycyclic Spiroindolines. Angew. Chem., Int. Ed. 2015, 54, 4032– 4035,  DOI: 10.1002/anie.201410814
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    3d
    Asymmetric Dearomatization of Indoles through a Michael/Friedel-Crafts-Type Cascade To Construct Polycyclic Spiroindolines
    Zhao, Xiaohu; Liu, Xiaohua; Mei, Hongjiang; Guo, Jing; Lin, Lili; Feng, Xiaoming
    Angewandte Chemie, International Edition (2015), 54 (13), 4032-4035CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A highly efficient asym. dearomatization of indoles was realized through a cascade reaction between (2-isocyanoethyl)indoles I (R1 = H, 5-F, 6-Cl, 7-Me, etc., R2 = H; R1 = H, R2 = Me; R3 = H) and (alkylidene)malonates R4CH:C(CO2R5)2 (R4 = i-Pr, cyclohexyl, Ph, 4-FC6H4, 2-naphthyl, 3-thienyl, etc.; R5 = Me, Et, PhCH2) catalyzed by a chiral N,N'-dioxide/MgII catalyst. Fused polycyclic indolines II contg. three stereocenters were afforded in good yields with excellent diastereo- and enantioselectivities through a Michael/Friedel-Crafts/Mannich cascade. When 2-substituted (2-isocyanoethyl)indoles I (R1 = R2 = H; R3 = Me, Ph) were used, spiroindoline derivs. III were obtained through a Michael/Friedel-Crafts reaction.
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    (e) Saya, J. M.; Oppelaar, B.; Cioc, R. C.; Van Der Heijden, G.; Vande Velde, C. M. L.; Orru, R. V. A.; Ruijter, E. Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl) indoles. Chem. Commun. 2016, 52, 12482– 12485,  DOI: 10.1039/C6CC07459F
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    3e
    Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles
    Saya, Jordy M.; Oppelaar, Barry; Cioc, Razvan C.; van der Heijden, Gydo; Vande Velde, Christophe M. L.; Orru, Romano V. A.; Ruijter, Eelco
    Chemical Communications (Cambridge, United Kingdom) (2016), 52 (84), 12482-12485CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochem. complex spiroindolines from tryptamine-derived isocyanides has been reported. The reaction is facilitated by using fluorinated alcs. (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.
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    (f) Li, L.; Liu, J.; Shi, M. A highly regio-and diastereoselective four-component reaction to construct polycyclic bispiroindolines from 2-isocyanoethylindoles and isocyanates. Org. Lett. 2018, 20, 7076– 7079,  DOI: 10.1021/acs.orglett.8b03019
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    3f
    A Highly Regio- and Diastereoselective Four-Component Reaction to Construct Polycyclic Bispiroindolines from 2-Isocyanoethylindoles and Isocyanates
    Li, Longhai; Liu, Jiaxin; Shi, Min
    Organic Letters (2018), 20 (22), 7076-7079CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A one-pot multicomponent domino reaction between 2-isocyanoethylindoles and isocyanates for the diastereoselective construction of polycyclic bispiroindolines was developed. Fused polycyclic bispiroindolines contg. two contiguous spiral atoms were afforded in moderate to good yields with excellent regio- and diastereoselectivities through a four-component Ugi-type reaction (U-4CR) under mild conditions.
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    (g) Saya, J. M.; Roose, T. R.; Peek, J. J.; Weijers, B.; de Waal, T. J. S.; Vande Velde, C. M. L.; Orru, R. V. A.; Ruijter, E. Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine. Angew. Chem., Int. Ed. 2018, 57, 15232– 15236,  DOI: 10.1002/anie.201809678
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    3g
    Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine
    Saya, Jordy M.; Roose, Thomas R.; Peek, Jarryt J.; Weijers, Bram; de Waal, Thomas J. S.; Vande Velde, Christophe M. L.; Orru, Romano V. A.; Ruijter, Eelco
    Angewandte Chemie, International Edition (2018), 57 (46), 15232-15236CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chem. Nucleophilic addn. typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex mol. frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)-aspidofractinine.
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    (h) Liu, Y. L.; Mao, X. Y.; Lin, X. T.; Chen, G. S. A Zn(OTf)2 catalyzed Ugi-type reaction of 3-(2-isocyanoethyl) indoles with indole-derived ketimines: rapid access to hexacyclic spiroindolines. Org. Chem. Front. 2018, 5, 2303– 2307,  DOI: 10.1039/C8QO00382C
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    3h
    A Zn(OTf)2 catalyzed Ugi-type reaction of 3-(2-isocyanoethyl)indoles with indole-derived ketimines: rapid access to hexacyclic spiroindolines
    Liu, Yun-Lin; Mao, Xiang-Yu; Lin, Xiao-Tong; Chen, Guo-Shu
    Organic Chemistry Frontiers (2018), 5 (15), 2303-2307CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
    A Zn(OTf)2 catalyzed Ugi-type reaction of 3-(2-isocyanoethyl)indoles and indole-derived ketimines to rapidly afford hexacyclic spiroindolines I [R = H, 5-Cl, 7-Me, etc.; R1 = 13-Me, 12-F, 12-MeO, etc.; R2 = Ph, 2-thienyl, 2-naphthyl, etc.] featuring three stereocenters including two quaternary stereocenters in moderate to excellent yields (30-89%) with complete diastereoselectivity was reported. This reaction was highly efficient because two C-C and one C-N bonds as well as two new rings were created under mild reaction conditions in a single step.
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    (i) Li, X.; Xiong, Q.; Guan, M.; Dong, S.; Liu, X.; Feng, X. Divergent Synthesis of Enantioenriched β-Functional Amines via Desymmetrization of meso-Aziridines with Isocyanides. Org. Lett. 2019, 21, 6096– 6101,  DOI: 10.1021/acs.orglett.9b02242
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    3i
    Divergent Synthesis of Enantioenriched β-Functional Amines via Desymmetrization of meso-Aziridines with Isocyanides
    Li, Xiangqiang; Xiong, Qian; Guan, Mingming; Dong, Shunxi; Liu, Xiaohua; Feng, Xiaoming
    Organic Letters (2019), 21 (15), 6096-6101CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A highly enantioselective ring-opening desymmetrization of meso-aziridines with isocyanides was achieved in the presence of a chiral N,N'-dioxide/Mg(OTf)2 complex. The in situ generated chiral 1,4-zwitterionic intermediates were successfully trapped by intramol. oxygen- and carbon-based nucleophiles or exogenous H2O and TMSN3, enabling a collective synthesis of various chiral vicinal amino-oxazoles, spiroindolines, β-amino amides, and tetrazole deriv. in moderate to high yields with excellent enantioselectivities.
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    (j) Cao, W.-B.; Li, S.; Xu, M.-M.; Li, H.; Xu, X.-P.; Lan, Y.; Ji, S.-J. Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives. Angew. Chem., Int. Ed. 2020, 59, 21425– 21430,  DOI: 10.1002/anie.202008110
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    3j
    Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives
    Cao, Wen-Bin; Li, Shijun; Xu, Meng-Meng; Li, Haiyan; Xu, Xiao-Ping; Lan, Yu; Ji, Shun-Jun
    Angewandte Chemie, International Edition (2020), 59 (48), 21425-21430CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An efficient cascade reaction of tryptamine-derived isocyanides with C,N-cyclic azomethine imines is described. The polycyclic pyrrolo[2,3-c]quinoline derivs., which benefited from rearrangement process driven by hydrogen bonding, could be directly assembled in moderate to good yields (40-87%) under metal-free and mild conditions. This transformation involved four new heterocyclic rings formations and uniquely, ring opening of indole as well as ring expansion of C,N-cyclic azomethine imine [e.g., I + II → III (81%) in MeOH]. Both exptl. and DFT studies provided guidance on the in-depth insight into the reaction pathways and hydrogen bonding was identified to lower the free energy barrier in transition states. This work constitutes a rare example of tryptamine-derived isocyanide-based cascade reactions, and potentially could be a powerful synthetic strategy for accessing polycyclic analogs involved in natural products.
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    (k) Li, H.; Wu, J.; Zheng, J.; Li, W.-D. Z. Synthesis of polycyclic spiroindolines via the cascade reaction of 3-(2-isocyanoethyl) indoles. Chem. Commun. 2021, 57, 11092– 11095,  DOI: 10.1039/D1CC04576H
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    3k
    Synthesis of polycyclic spiroindolines via the cascade reaction of 3-(2-isocyanoethyl)indoles
    Li, Haizhen; Wu, Jinyu; Zheng, Jianfeng; Li, Wei-Dong Z.
    Chemical Communications (Cambridge, United Kingdom) (2021), 57 (84), 11092-11095CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Tandem reactions of the yttrium(III) catalyzed ring-opening reaction of 2,2'-diester aziridines with 3-(2-isocyanoethyl)indoles and the subsequent Friedel-Crafts/Mannich/desulfonylation were reported. A series of polycyclic spiroindolines contg. tetrahydro-β-carbolines, e.g., I, were obtained in moderate to excellent yields (56-92%) in one step under mild reaction conditions. A possible catalytic mechanism was also proposed.
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  4. 4

    Dearomatization of 3-(2-isocyanoethyl)indoles via heteroallene intermediate:

    (a) Chen, G. S.; Chen, S. J.; Luo, J.; Mao, X. Y.; Chan, A. S. C.; Sun, R. W. Y.; Liu, Y. L. Tandem cross-coupling/spirocyclization/Mannich-type reactions of 3-(2-isocyanoethyl) indoles with diazo compounds toward polycyclic spiroindolines. Angew. Chem., Int. Ed. 2020, 59, 614– 621,  DOI: 10.1002/anie.201911614
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    4a
    Tandem Cross-Coupling/Spirocyclization/Mannich-Type Reactions of 3-(2-Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines
    Chen, Guo-Shu; Chen, Shu-Jie; Luo, Jian; Mao, Xiang-Yu; Chan, Albert Sun-Chi; Sun, Raymond Wai-Yin; Liu, Yun-Lin
    Angewandte Chemie, International Edition (2020), 59 (2), 614-621CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chem., as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.
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    (b) Jiang, S.; Cao, W.-B.; Li, H.-Y.; Xu, X.-P.; Ji, S.-J. Convenient synthesis of spiroindolenines from tryptamine-derived isocyanides and organic azides by cobalt catalysis in pure water. Green Chem. 2021, 23, 2619– 2623,  DOI: 10.1039/D1GC00270H
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    4b
    Convenient synthesis of spiroindolenines from tryptamine-derived isocyanides and organic azides by cobalt catalysis in pure water
    Jiang, Shuai; Cao, Wen-Bin; Li, Hai-Yan; Xu, Xiao-Ping; Ji, Shun-Jun
    Green Chemistry (2021), 23 (7), 2619-2623CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    A Co-catalyzed coupling of 3-(2-isocyanoethyl)indoles with org. azides in pure water for accessing spiroindolenine derivs. such as I [R = n-Pr, 2-thienyl, Ts, etc.; R1 = H, 5-Me, 5-Cl, etc.; R2 = Me, cyclopropyl, 3-thienyl, etc.; R3 = H, 4'-Ph] was developed. This strategy featured mild reaction conditions, high atom-economy, excellent yields, wide substrate scopes and broad functional group tolerance. The products were obtained simply by sequential operation involving extn., concn., pptn., and filtration, without tedious column chromatog. More importantly, aq. catalytic system could be recycled at least ten times without reducing catalytic activity. The strategy provided a green and efficient method for construction of spiroindolenine derivs.
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    (c) Gu, M. Z.; Deng, Y. Q.; Zhang, X. T.; Lin, X. T.; Xu, Y. B.; Hu, X. W.; Liu, X. N.; Zheng, Y. L.; Chen, G. S.; Liu, Y. L. Cascade Cross-Coupling/Spirocyclization/Formal [4 + 2] Cycloaddition Reactions of 3-(2-Isocyanoethyl) Indoles with Aromatic Azides: Access to Polycyclic Spiroindolines Bearing A Pentasubstituted Guanidine Moiety. Adv. Synth. Catal. 2022, 364, 4427– 4432,  DOI: 10.1002/adsc.202201168
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    4c
    Cascade Cross-Coupling/Spirocyclization/Formal [4+2] Cycloaddition Reactions of 3-(2-Isocyanoethyl)Indoles with Aromatic Azides: Access to Polycyclic Spiroindolines Bearing A Pentasubstituted Guanidine Moiety
    Gu, Man-Zhen; Deng, Yan-Qiu; Zhang, Xi-Ting; Lin, Xiao-Tong; Xu, Yi-Bing; Hu, Xiao-Wei; Liu, Xin-Ni; Zheng, Yi-Lin; Chen, Guo-Shu; Liu, Yun-Lin
    Advanced Synthesis & Catalysis (2022), 364 (24), 4427-4432CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A rhodium-catalyzed cascade cross-coupling/spirocyclization/formal [4+2] cycloaddn. reaction of 3-(2-isocyanoethyl)indoles with arom. azides is developed, providing a general synthetic protocol to polycyclic spiroindolines bearing a pentasubstituted guanidine moiety with moderate to excellent yields. This transformation is highly effective since one C-C, one C=N, three C-N bonds as well as two new rings are constructed in a single step. More importantly, this work represents a new reactivity pattern of 3-(2-isocyanoethyl)indole, and thus constitutes an valuable addn. to 3-(2-isocyanoethyl)indole chem.
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  5. 5
    Tang, S.; Ding, S.; Li, D.; Li, L.; Zhao, H.; Chai, M.; Wang, J. Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl) indoles. Chem. Commun. 2021, 57, 10576– 10579,  DOI: 10.1039/D1CC03240B
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    5
    Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl)indoles
    Tang, Shi; Ding, Shumin; Li, Dan; Li, Lianjie; Zhao, Haixia; Chai, Minxue; Wang, Jian
    Chemical Communications (Cambridge, United Kingdom) (2021), 57 (81), 10576-10579CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A palladium-catalyzed construction of spiroindolines through dearomative spirocyclization of 3-(2-isocyanoethyl)indoles was developed. 2'-Aryl-, vinyl-, and alkyl-substituted spiroindolines were accessed under mild conditions with excellent functional group tolerance. C1-tethered oxindole- and indole-spiroindoline bisheterocycles were generated in high yields via alkene/allene insertion and an imidoylative spirocyclization cascade. Addnl., a tandem dearomatization of two different indoles was realized with N-(2-bromobenzoyl)indoles as the electrophilic coupling partner of 3-(2-isocyanoethyl)indoles, affording polyindoline - spiroindoline bisheterocyclic scaffolds conveniently. Under the catalysis of Pd(OAc)2 and a spinol-derived phosphoramidite ligand, chiral spiroindolines were successfully accessed with up to 95% yield and 85% ee.
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  6. 6

    Reviews on indole dearomatization:

    (a) Roche, S. P.; Youte Tendoung, J. J.; Tréguier, B. Advances in dearomatization strategies of indoles. Tetrahedron 2015, 71, 3549– 3591,  DOI: 10.1016/j.tet.2014.06.054
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    6a
    Advances in dearomatization strategies of indoles
    Roche, Stephane P.; Youte Tendoung, Jean-Jacques; Treguier, Bret
    Tetrahedron (2015), 71 (22), 3549-3591CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    A review. In this review, we will have a broader overview of indoles dearomatization through cycloaddn., arylation, protonation, alkylation, and oxidn. with several heteroatoms, with a special emphasis and comparison in each section on unprotected vs. protected indole nitrogens and asym. and/or catalytic dearomative methods and cascade reactions for the synthesis of complex alkaloids. In addn., to outline several selected dearomatization strategies in the context of complex natural product synthesis, we will also describe future perspectives in the field including prospects for development of enantioselective dearomatization processes.
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    (b) Zhuo, C. X.; Zhang, W.; You, S. L. Catalytic asymmetric dearomatization reactions. Angew. Chem., Int. Ed. 2012, 51, 12662– 12686,  DOI: 10.1002/anie.201204822
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    6b
    Catalytic asymmetric dearomatization reactions
    Zhuo Chun-Xiang; Zhang Wei; You Shu-Li
    Angewandte Chemie (International ed. in English) (2012), 51 (51), 12662-86 ISSN:.
    This Review summarizes the development of catalytic asymmetric dearomatization (CADA) reactions. The CADA reactions discussed herein include oxidative dearomatization reactions, dearomatization by Diels-Alder and related reactions, the alkylative dearomatization of electron-rich arenes, transition-metal-catalyzed dearomatization reactions, cascade sequences involving asymmetric dearomatization as the key step, and nucleophilic dearomatization reactions of pyridinium derivatives. Asymmetric dearomatization reactions with chiral auxiliaries and catalytic asymmetric reactions of dearomatized substrates are also briefly introduced. This Review intends to provide a concept for catalytic asymmetric dearomatization.
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    (c) Bariwal, J.; Voskressensky, L. G.; Van Der Eycken, E. V. Recent advances in spirocyclization of indole derivatives. Chem. Soc. Rev. 2018, 47, 3831– 3848,  DOI: 10.1039/C7CS00508C
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    6c
    Recent advances in spirocyclization of indole derivatives
    Bariwal Jitender; Voskressensky Leonid G; Van der Eycken Erik V
    Chemical Society reviews (2018), 47 (11), 3831-3848 ISSN:.
    Spiroindolines and spiroindoles are an important class of spirocyclic compounds present in a wide range of pharmaceuticals and biologically important natural alkaloids. Various spiroindolines and spiroindoles possess versatile reactivity which enables them to act as precursors for other privileged heterocycles. In view of the importance of this scaffold, many researchers focused their efforts to develop facile and mild synthetic methods for spirocyclization of indoles. However, the synthesis of spiroindolines and spiroindoles is known to be difficult due to rapid 1,2-migration to restore aromaticity. This review aims to briefly discuss the latest developments to access highly functionalized spiroindolines and spiroindoles to stimulate further research in the field to find new and efficient methodologies for accessing new spiroindolines and spiroindoles.
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    (d) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Synthesis of spirocyclic indolenines. Chem.─Eur. J. 2016, 22, 2856– 2881,  DOI: 10.1002/chem.201503835
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    6d
    Synthesis of Spirocyclic Indolenines
    James, Michael J.; O'Brien, Peter; Taylor, Richard J. K.; Unsworth, William P.
    Chemistry - A European Journal (2016), 22 (9), 2856-2881CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods was developed to generate these synthetically useful and biol. important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatization reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field were examd.
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    (e) Roche, S. P.; Porco, J. A. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem., Int. Ed. 2011, 50, 4068– 4093,  DOI: 10.1002/anie.201006017
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    6e
    Dearomatization Strategies in the Synthesis of Complex Natural Products
    Roche, Stephane P.; Porco, John A., Jr.
    Angewandte Chemie, International Edition (2011), 50 (18), 4068-4093CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, arom. scaffolds are converted to three-dimensional mol. architectures.
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  7. 7
    (a) Powell, N. A.; Kohrt, J. T.; Filipski, K. J.; Kaufman, M.; Sheehan, D.; Edmunds, J. E.; Delaney, A.; Wang, Y.; Bourbonais, F.; Lee, D. Y.; Schwende, F.; Sun, F.; McConnel, P.; Catana, C.; Chen, H.; Ohren, J.; Perrin, L. A. Novel and selective spiroindoline-based inhibitors of sky kinase. Bioorg. Med. Chem. Lett. 2012, 22, 190– 193,  DOI: 10.1016/j.bmcl.2011.11.036
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    7a
    Novel and selective spiroindoline-based inhibitors of sky kinase
    Powell, Noel A.; Kohrt, Jeffrey T.; Filipski, Kevin J.; Kaufman, Michael; Sheehan, Derek; Edmunds, Jeremy E.; Delaney, Amy; Wang, Yuli; Bourbonais, Francis; Lee, Doh-Yeel; Schwende, Frank; Sun, Fang; McConnell, Pat; Catana, Cornel; Chen, Huifen; Ohren, Jeff; Perrin, Lisa A.
    Bioorganic & Medicinal Chemistry Letters (2012), 22 (1), 190-193CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
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    (b) Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; Zou, P.; Sun, D.; Wang, S. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J. Med. Chem. 2013, 56, 5553– 5561,  DOI: 10.1021/jm4005708
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    7b
    A Potent Small-Molecule Inhibitor of the MDM2-p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice
    Zhao, Yujun; Yu, Shanghai; Sun, Wei; Liu, Liu; Lu, Jianfeng; McEachern, Donna; Shargary, Sanjeev; Bernard, Denzil; Li, Xiaoqin; Zhao, Ting; Zou, Peng; Sun, Duxin; Wang, Shaomeng
    Journal of Medicinal Chemistry (2013), 56 (13), 5553-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The authors previously reported the discovery of a class of spirooxindoles as potent and selective small-mol. inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). The authors report herein the authors' efforts to improve their pharmacokinetic properties and in vivo antitumor activity. The authors' efforts led to the identification of MI-888 as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. MI-888 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
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    (c) Kumar, N.; Hati, S.; Munshi, P.; Sen, S.; Sehrawat, S.; Singh, S. A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton. Mol. Cell. Biochem. 2017, 429, 11– 21,  DOI: 10.1007/s11010-016-2932-6
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    7c
    A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton
    Kumar, Naveen; Hati, Santanu; Munshi, Parthapratim; Sen, Subhabrata; Sehrawat, Seema; Singh, Shailja
    Molecular and Cellular Biochemistry (2017), 429 (1-2), 11-21CODEN: MCBIB8; ISSN:0300-8177. (Springer)
    Natural product-inspired libraries of mols. with diverse architectures have evolved as one of the most useful tools for discovering lead mols. for drug discovery. In comparison to conventional combinatorial libraries, these mols. have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of mols. From a successful DOS campaign of a natural product-inspired library, recently a small mol. with spiroindoline motif was identified as a potent anti-breast cancer compd. Herein we report the subcellular studies performed for this mol. on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization center. DNA ladder assay and cell cycle expts. further established the mol. as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.
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  8. 8
    (a) O’Connor, S. E.; Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 2006, 23, 532– 547,  DOI: 10.1039/b512615k
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    8a
    Chemistry and biology of monoterpene indole alkaloid biosynthesis
    O'Connor, Sarah E.; Maresh, Justin J.
    Natural Product Reports (2006), 23 (4), 532-547CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
    A review. Monoterpene indole alkaloids exhibit a diverse array of structures and biol. activities. The biosynthetic pathways for several representative terpene indole alkaloids are described in detail.
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    (b) Mohammed, A. E.; Abdul-Hameed, Z. H.; Alotaibi, M. O.; Bawakid, N. O.; Sobahi, T. R.; Abdel-Lateff, A.; Alarif, W. M. Chemical Diversity and Bioactivities of Monoterpene Indole Alkaloids (MIAs) from Six Apocynaceae Genera. Molecules 2021, 26, 488,  DOI: 10.3390/molecules26020488
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    8b
    Chemical diversity and bioactivities of monoterpene indole alkaloids (MIAs) from six Apocynaceae genera
    Mohammed, Afrah E.; Abdul-Hameed, Zainab H.; Alotaibi, Modhi O.; Bawakid, Nahed O.; Sobahi, Tariq R.; Abdel-Lateff, Ahmed; Alarif, Walied M.
    Molecules (2021), 26 (2), 488CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. By the end of the twentieth century, the interest in natural compds. as probable sources of drugs has declined and was replaced by other strategies such as mol. target-based drug discovery. However, in the recent times, natural compds. regained their position as extremely important source drug leads. Indole-contg. compds. are under clin. use which includes vinblastine and vincristine (anticancer), atevirdine (anti-HIV), yohimbine (erectile dysfunction), reserpine (antihypertension), ajmalicine (vascular disorders), ajmaline (anti-arrhythmic), vincamine (vasodilator), etc. Monoterpene Indole Alkaloids (MIAs) deserve the curiosity and attention of researchers due to their chem. diversity and biol. activities. These compds. were considered as an impending source of drug-lead. In this review 444 compds., were identified from six genera belonging to the family Apocynaceae, will be discussed. These genera (Alstonia, Rauvolfia, Kopsia, Ervatamia, and Tabernaemontana, and Rhazya) consist of 400 members and represent 20% of Apocynaceae species. Only 30 (7.5%) species were investigated, whereas the rest are promising to be investigated. Eleven bioactivities, including antibacterial, antifungal, anti-inflammatory and immunosuppressant activities, were reported. Whereas cytotoxic effect represents 47% of the reported activities. Convincingly, the genera selected in this review are a wealthy source for future anticancer drug lead.
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  9. 9
    Saya, J. M.; Ruijter, E.; Orru, R. V. A. Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization. Chem.─Eur. J. 2019, 25, 8916– 8935,  DOI: 10.1002/chem.201901130
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    9
    Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization
    Saya, Jordy M.; Ruijter, Eelco; Orru, Romano V. A.
    Chemistry - A European Journal (2019), 25 (38), 8916-8935CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic org. chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.
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  10. 10

    Reviews on imidoylative cross-coupling:

    (a) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry. Angew. Chem., Int. Ed. 2013, 52, 7084– 7097,  DOI: 10.1002/anie.201300942
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    10a
    Palladium-Catalyzed Migratory Insertion of Isocyanides: An Emerging Platform in Cross-Coupling Chemistry
    Vlaar, Tjostil; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
    Angewandte Chemie, International Edition (2013), 52 (28), 7084-7097CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Isocyanides have been important building blocks in org. synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-contg. fine chems. This review discusses all the achievements in this emerging field.
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    (b) Collet, J. W.; Roose, T. R.; Weijers, B.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Recent advances in palladium-catalyzed isocyanide insertions. Molecules 2020, 25, 4906,  DOI: 10.3390/molecules25214906
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    10b
    Recent advances in palladium-catalyzed isocyanide insertions
    Collet, Jurrien W.; Roose, Thomas R.; Weijers, Bram; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
    Molecules (2020), 25 (21), 4906CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. Isocyanides have long been known as versatile chem. reagents in org. synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C1 building blocks, whose inherent N-substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products. Recent developments in palladium catalyzed isocyanide insertion reactions have significantly expanded the scope and applicability of these imidoylative cross-couplings. This review highlights the advances made in this field over the past eight years.
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    (c) Collet, J. W.; Roose, T. R.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Base metal catalyzed isocyanide insertions. Angew. Chem., Int. Ed. 2020, 59, 540– 558,  DOI: 10.1002/anie.201905838
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    10c
    Base Metal Catalyzed Isocyanide Insertions
    Collet, Jurrien W.; Roose, Thomas R.; Ruijter, Eelco; Maes, Bert U. W.; Orru, Romano V. A.
    Angewandte Chemie, International Edition (2020), 59 (2), 540-558CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. This minireview focus on emerging base metal catalyzed reactions and highlight their potential in synthetic org. chem. Although mechanistic studies are still scarce, distinct proposed catalytic cycles were discussed and the literature is categorized according to (1) the(hetero)atom bound to and (2) the type of bonding with the transition metal in which the (formal) insertion occurs.
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  11. 11
    Roose, T. R.; Verdoorn, D. S.; Mampuys, P.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Transition metal-catalysed carbene-and nitrene transfer to carbon monoxide and isocyanides. Chem. Soc. Rev. 2022, 51, 5842– 5877,  DOI: 10.1039/D1CS00305D
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    11
    Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides
    Roose, T. R.; Verdoorn, D. S.; Mampuys, P.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A.
    Chemical Society Reviews (2022), 51 (14), 5842-5877CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Transition metal-catalyzed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compds. allowing in situ transformation towards numerous functional groups and org. compds., including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the org. chem. toolbox. This review discusses all known transition metal-catalyzed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations.
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  12. 12
    Roose, T. R.; Preschel, H. D.; Mayo Tejedor, H.; Roozee, J. C.; Hamlin, T. A.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Iron-Catalysed Carbene Transfer to Isocyanides as a Platform for Heterocycle Synthesis. Chem.─Eur. J. 2023, 29, e202203074  DOI: 10.1002/chem.202203074
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    12
    Iron-Catalysed Carbene Transfer to Isocyanides as a Platform for Heterocycle Synthesis
    Roose, Thomas R.; Preschel, H. Daniel; Mayo Tejedor, Helena; Roozee, Jasper C.; Hamlin, Trevor A.; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
    Chemistry - A European Journal (2023), 29 (9), e202203074CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An iron-catalyzed carbene transfer reaction of diazo compds. to isocyanides has been developed. The resulting ketenimines are trapped in situ with various bisnucleophiles to access a range of densely functionalized heterocycles (pyrimidinones, dihydropyrazolones, 1H-tetrazoles) in a one-pot process. The electron-rich Hieber anion ([Fe(CO)3NO]-) facilitates efficient catalytic carbene transfer from acceptor-type α-diazo carbonyl compds. to isocyanides, providing a cost-efficient and benign alternative to similar noble metal-catalyzed processes. Based on DFT calcns. a plausible reaction mechanism for activation of the α-diazo carbonyl carbene precursor and ketenimine formation is provided.
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  13. 13
    (a) Klein, J. E. M. N. The Hieber Anion [Fe(CO)3 (NO)]−. Synlett 2011, 2757– 2758,  DOI: 10.1055/s-0031-1289559
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    13a
    The hieber anion [Fe(CO)3(NO)]-
    Klein, Johannes E. M. N.
    Synlett (2011), (18), 2757-2758CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
    There is no expanded citation for this reference.
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    (b) Klein, J. E. M. N.; Miehlich, B.; Holzwarth, M. S.; Bauer, M.; Milek, M.; Khusniyarov, M. M.; Knizia, G.; Werner, H. J.; Plietker, B. The Electronic Ground State of [Fe(CO)3 (NO)]−: A Spectroscopic and Theoretical Study. Angew. Chem., Int. Ed. 2014, 53, 1790– 1794,  DOI: 10.1002/anie.201309767
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    13b
    The Electronic Ground State of [Fe(CO)3(NO)]-: A Spectroscopic and Theoretical Study
    Klein, Johannes E. M. N.; Miehlich, Burkhard; Holzwarth, Michael S.; Bauer, Matthias; Milek, Magdalena; Khusniyarov, Marat M.; Knizia, Gerald; Werner, Hans-Joachim; Plietker, Bernd
    Angewandte Chemie, International Edition (2014), 53 (7), 1790-1794CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    During the past 10 years iron-catalyzed reactions have become established in the field of org. synthesis. For example, the complex anion [Fe(CO)3(NO)]-, which was originally described by Hogsed and Hieber, shows catalytic activity in various org. reactions. This anion is commonly regarded as being isoelectronic with [Fe(CO)4]2-, which, however, shows poor catalytic activity. The spectroscopic and quantum chem. investigations presented herein reveal that the complex ferrate [Fe(CO)3(NO)]- cannot be regarded as a Fe-II species, but rather is predominantly a Fe0 species, in which the metal is covalently bonded to NO- by two π-bonds. A metal-N σ-bond is not obsd.
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    (c) Lin, C.-H.; Plietker, B. The Evolution of Fe-catalyzed Nucleophilic Activation of Acceptor-substituted Vinyl-and Arylcyclopropanes. Isr. J. Chem. 2016, 56, 409– 416,  DOI: 10.1002/ijch.201500085
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    13c
    The Evolution of Fe-catalyzed Nucleophilic Activation of Acceptor-substituted Vinyl- and Arylcyclopropanes
    Lin, Che-Hung; Plietker, Bernd
    Israel Journal of Chemistry (2016), 56 (6-7), 409-416CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Acceptor-substituted vinyl- (VCP) and arylcyclopropanes (ACP) are reactive substrates for nucleophilic activation using Bu4N[Fe(CO)3(NO)] (TBA[Fe]). In this account, the application of this catalytic strategy in traceless allylic substitution, [3+2]-cycloaddn., and Cloke-Wilson rearrangement will be presented. Addnl. information, derived from detailed spectroscopic and theor. investigations, is discussed. These results not only lead to a deeper understanding of the reactivity of the catalyst in VCP and ACP activation, but also set the stage for a new type of catalyst activation using photochem. irradn. at 415 nm.
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  14. 14

    Application of the Hieber anion in carbene transfer reactions:

    (a) Holzwarth, M. S.; Alt, I.; Plietker, B. Catalytic Activation of Diazo Compounds Using Electron-Rich, Defined Iron Complexes for Carbene-Transfer Reactions. Angew. Chem., Int. Ed. 2012, 51, 5351– 5354,  DOI: 10.1002/anie.201201409
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    14a
    Catalytic Activation of Diazo Compounds Using Electron-Rich, Defined Iron Complexes for Carbene-Transfer Reactions
    Holzwarth, Michael S.; Alt, Isabel; Plietker, Bernd
    Angewandte Chemie, International Edition (2012), 51 (22), 5351-5354, S5351/1-S5351/87CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The electron-rich Fe complex Bu4N[Fe(CO)3(NO)] efficiently catalyzes different carbene-transfer reactions. Various diazo compds. can be used. The high stability of the employed Fe complexes is demonstrated by the generation of the diazo reagent in situ and a sequential Fe-catalyzed allylic sulfenylation/Doyle-Kirmse reaction.
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    (b) Röske, A.; Alt, I.; Plietker, B. Scope and Limitations of TBA[Fe]-Catalyzed Carbene Transfer to X?H-bonds - Indication of a MechanisticDichotomy. ChemCatChem. 2019, 11, 5260– 5263,  DOI: 10.1002/cctc.201900459
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    (c) Picher, M. I.; Plietker, B. Fe-Catalyzed Selective Cyclopropanation of Enynes under Photochemical or Thermal Conditions. Org. Lett. 2020, 22, 340– 344,  DOI: 10.1021/acs.orglett.9b04521
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    14c
    Fe-Catalyzed Selective Cyclopropanation of Enynes under Photochemical or Thermal Conditions
    Picher, Marie-Idrissa; Plietker, Bernd
    Organic Letters (2020), 22 (1), 340-344CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    The nucleophilic Fe-complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the cyclopropanation of enynes to substituted propargyl cyclopropanes using diazoesters as carbene surrogates. The catalyst can be activated either thermally in the presence of catalytic amts. of 4-nitroanisole or under photochem. conditions. Cyclopropanation occurs selectively at the enyne moiety; alternative olefinic moieties remain intact.
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  • Abstract

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    Scheme 1

    Scheme 1. Dearomative Spirocyclization of 3-(2-Isocyanoethyl)indoles
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    Scheme 2

    Scheme 2. Strategies for Dearomatization of 3-(2-Isocyanoethyl)indoles
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    Scheme 3

    Scheme 3. Scope for C2-Substituted 3-(2-Isocyanoethyl)indoles and Substituted α-Diazo Estersa
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    aReaction conditions: Bu4N[Fe(CO)3NO] (0.025 mmol), 1 (0.5 mmol), and 18 (0.6 mmol) in DCE (2 mL) at 80 °C under N2.

    Scheme 4

    Scheme 4. Scope for C2-Unsubstituted 3-(2-Isocyanoethyl)indolesa
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    aReaction conditions: Bu4N[Fe(CO)3NO] (0.025 mmol), 1 (0.5 mmol), and 22 (0.6 mmol) in 1,2-DCE (2 mL) at 80 °C under N2 until full conversion of 1. Method A: Solution was cooled to 0 °C and diluted with MeOH (2 mL), and NaBH4 (0.525 mmol) was added. Method B: Solution was cooled to 0 °C, and MeOH (2 mL). NaBH3CN (0.525 mmol) and a few drops of AcOH were added.

    bExtra portion(s) of reducing agent (NaBH4/NaBH3CN) added to reach full conversion of indolenine intermediate 23 observed on TLC.

    Scheme 5

    Scheme 5. Application of Fe-Catalyzed Carbene Transfer/Spirocyclization Cascade in Formal Total Synthesisa
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    aReaction conditions: (a) Bu4N[Fe(CO)3NO] (0.63 mmol), 1y (6.3 mmol), and 22 (7.6 mmol) in DCE (25 mL), 80 °C; then NaBH4, MeOH, 0 °C; (b) imidazole (1.35 equiv), 25y (1.0 equiv), PPh3 (1.30 equiv), I2 (1.30 equiv), rt, CH2Cl2, 1 h; (c) 26 (1.0 equiv), Boc2O (10.5 equiv), DMAP (0.4 equiv), 72 h.

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      A highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochem. complex spiroindolines from tryptamine-derived isocyanides has been reported. The reaction is facilitated by using fluorinated alcs. (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.
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      A one-pot multicomponent domino reaction between 2-isocyanoethylindoles and isocyanates for the diastereoselective construction of polycyclic bispiroindolines was developed. Fused polycyclic bispiroindolines contg. two contiguous spiral atoms were afforded in moderate to good yields with excellent regio- and diastereoselectivities through a four-component Ugi-type reaction (U-4CR) under mild conditions.
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      The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chem. Nucleophilic addn. typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex mol. frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)-aspidofractinine.
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      A Zn(OTf)2 catalyzed Ugi-type reaction of 3-(2-isocyanoethyl)indoles with indole-derived ketimines: rapid access to hexacyclic spiroindolines
      Liu, Yun-Lin; Mao, Xiang-Yu; Lin, Xiao-Tong; Chen, Guo-Shu
      Organic Chemistry Frontiers (2018), 5 (15), 2303-2307CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
      A Zn(OTf)2 catalyzed Ugi-type reaction of 3-(2-isocyanoethyl)indoles and indole-derived ketimines to rapidly afford hexacyclic spiroindolines I [R = H, 5-Cl, 7-Me, etc.; R1 = 13-Me, 12-F, 12-MeO, etc.; R2 = Ph, 2-thienyl, 2-naphthyl, etc.] featuring three stereocenters including two quaternary stereocenters in moderate to excellent yields (30-89%) with complete diastereoselectivity was reported. This reaction was highly efficient because two C-C and one C-N bonds as well as two new rings were created under mild reaction conditions in a single step.
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      (i) Li, X.; Xiong, Q.; Guan, M.; Dong, S.; Liu, X.; Feng, X. Divergent Synthesis of Enantioenriched β-Functional Amines via Desymmetrization of meso-Aziridines with Isocyanides. Org. Lett. 2019, 21, 6096– 6101,  DOI: 10.1021/acs.orglett.9b02242
      3i
      Divergent Synthesis of Enantioenriched β-Functional Amines via Desymmetrization of meso-Aziridines with Isocyanides
      Li, Xiangqiang; Xiong, Qian; Guan, Mingming; Dong, Shunxi; Liu, Xiaohua; Feng, Xiaoming
      Organic Letters (2019), 21 (15), 6096-6101CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A highly enantioselective ring-opening desymmetrization of meso-aziridines with isocyanides was achieved in the presence of a chiral N,N'-dioxide/Mg(OTf)2 complex. The in situ generated chiral 1,4-zwitterionic intermediates were successfully trapped by intramol. oxygen- and carbon-based nucleophiles or exogenous H2O and TMSN3, enabling a collective synthesis of various chiral vicinal amino-oxazoles, spiroindolines, β-amino amides, and tetrazole deriv. in moderate to high yields with excellent enantioselectivities.
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      (j) Cao, W.-B.; Li, S.; Xu, M.-M.; Li, H.; Xu, X.-P.; Lan, Y.; Ji, S.-J. Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives. Angew. Chem., Int. Ed. 2020, 59, 21425– 21430,  DOI: 10.1002/anie.202008110
      3j
      Hydrogen-Bonding-Promoted Cascade Rearrangement Involving the Enlargement of Two Rings: Efficient Access to Polycyclic Quinoline Derivatives
      Cao, Wen-Bin; Li, Shijun; Xu, Meng-Meng; Li, Haiyan; Xu, Xiao-Ping; Lan, Yu; Ji, Shun-Jun
      Angewandte Chemie, International Edition (2020), 59 (48), 21425-21430CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An efficient cascade reaction of tryptamine-derived isocyanides with C,N-cyclic azomethine imines is described. The polycyclic pyrrolo[2,3-c]quinoline derivs., which benefited from rearrangement process driven by hydrogen bonding, could be directly assembled in moderate to good yields (40-87%) under metal-free and mild conditions. This transformation involved four new heterocyclic rings formations and uniquely, ring opening of indole as well as ring expansion of C,N-cyclic azomethine imine [e.g., I + II → III (81%) in MeOH]. Both exptl. and DFT studies provided guidance on the in-depth insight into the reaction pathways and hydrogen bonding was identified to lower the free energy barrier in transition states. This work constitutes a rare example of tryptamine-derived isocyanide-based cascade reactions, and potentially could be a powerful synthetic strategy for accessing polycyclic analogs involved in natural products.
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      (k) Li, H.; Wu, J.; Zheng, J.; Li, W.-D. Z. Synthesis of polycyclic spiroindolines via the cascade reaction of 3-(2-isocyanoethyl) indoles. Chem. Commun. 2021, 57, 11092– 11095,  DOI: 10.1039/D1CC04576H
      3k
      Synthesis of polycyclic spiroindolines via the cascade reaction of 3-(2-isocyanoethyl)indoles
      Li, Haizhen; Wu, Jinyu; Zheng, Jianfeng; Li, Wei-Dong Z.
      Chemical Communications (Cambridge, United Kingdom) (2021), 57 (84), 11092-11095CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Tandem reactions of the yttrium(III) catalyzed ring-opening reaction of 2,2'-diester aziridines with 3-(2-isocyanoethyl)indoles and the subsequent Friedel-Crafts/Mannich/desulfonylation were reported. A series of polycyclic spiroindolines contg. tetrahydro-β-carbolines, e.g., I, were obtained in moderate to excellent yields (56-92%) in one step under mild reaction conditions. A possible catalytic mechanism was also proposed.
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    4. 4

      Dearomatization of 3-(2-isocyanoethyl)indoles via heteroallene intermediate:

      (a) Chen, G. S.; Chen, S. J.; Luo, J.; Mao, X. Y.; Chan, A. S. C.; Sun, R. W. Y.; Liu, Y. L. Tandem cross-coupling/spirocyclization/Mannich-type reactions of 3-(2-isocyanoethyl) indoles with diazo compounds toward polycyclic spiroindolines. Angew. Chem., Int. Ed. 2020, 59, 614– 621,  DOI: 10.1002/anie.201911614
      4a
      Tandem Cross-Coupling/Spirocyclization/Mannich-Type Reactions of 3-(2-Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines
      Chen, Guo-Shu; Chen, Shu-Jie; Luo, Jian; Mao, Xiang-Yu; Chan, Albert Sun-Chi; Sun, Raymond Wai-Yin; Liu, Yun-Lin
      Angewandte Chemie, International Edition (2020), 59 (2), 614-621CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chem., as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.
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      (b) Jiang, S.; Cao, W.-B.; Li, H.-Y.; Xu, X.-P.; Ji, S.-J. Convenient synthesis of spiroindolenines from tryptamine-derived isocyanides and organic azides by cobalt catalysis in pure water. Green Chem. 2021, 23, 2619– 2623,  DOI: 10.1039/D1GC00270H
      4b
      Convenient synthesis of spiroindolenines from tryptamine-derived isocyanides and organic azides by cobalt catalysis in pure water
      Jiang, Shuai; Cao, Wen-Bin; Li, Hai-Yan; Xu, Xiao-Ping; Ji, Shun-Jun
      Green Chemistry (2021), 23 (7), 2619-2623CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      A Co-catalyzed coupling of 3-(2-isocyanoethyl)indoles with org. azides in pure water for accessing spiroindolenine derivs. such as I [R = n-Pr, 2-thienyl, Ts, etc.; R1 = H, 5-Me, 5-Cl, etc.; R2 = Me, cyclopropyl, 3-thienyl, etc.; R3 = H, 4'-Ph] was developed. This strategy featured mild reaction conditions, high atom-economy, excellent yields, wide substrate scopes and broad functional group tolerance. The products were obtained simply by sequential operation involving extn., concn., pptn., and filtration, without tedious column chromatog. More importantly, aq. catalytic system could be recycled at least ten times without reducing catalytic activity. The strategy provided a green and efficient method for construction of spiroindolenine derivs.
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      (c) Gu, M. Z.; Deng, Y. Q.; Zhang, X. T.; Lin, X. T.; Xu, Y. B.; Hu, X. W.; Liu, X. N.; Zheng, Y. L.; Chen, G. S.; Liu, Y. L. Cascade Cross-Coupling/Spirocyclization/Formal [4 + 2] Cycloaddition Reactions of 3-(2-Isocyanoethyl) Indoles with Aromatic Azides: Access to Polycyclic Spiroindolines Bearing A Pentasubstituted Guanidine Moiety. Adv. Synth. Catal. 2022, 364, 4427– 4432,  DOI: 10.1002/adsc.202201168
      4c
      Cascade Cross-Coupling/Spirocyclization/Formal [4+2] Cycloaddition Reactions of 3-(2-Isocyanoethyl)Indoles with Aromatic Azides: Access to Polycyclic Spiroindolines Bearing A Pentasubstituted Guanidine Moiety
      Gu, Man-Zhen; Deng, Yan-Qiu; Zhang, Xi-Ting; Lin, Xiao-Tong; Xu, Yi-Bing; Hu, Xiao-Wei; Liu, Xin-Ni; Zheng, Yi-Lin; Chen, Guo-Shu; Liu, Yun-Lin
      Advanced Synthesis & Catalysis (2022), 364 (24), 4427-4432CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A rhodium-catalyzed cascade cross-coupling/spirocyclization/formal [4+2] cycloaddn. reaction of 3-(2-isocyanoethyl)indoles with arom. azides is developed, providing a general synthetic protocol to polycyclic spiroindolines bearing a pentasubstituted guanidine moiety with moderate to excellent yields. This transformation is highly effective since one C-C, one C=N, three C-N bonds as well as two new rings are constructed in a single step. More importantly, this work represents a new reactivity pattern of 3-(2-isocyanoethyl)indole, and thus constitutes an valuable addn. to 3-(2-isocyanoethyl)indole chem.
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    5. 5
      Tang, S.; Ding, S.; Li, D.; Li, L.; Zhao, H.; Chai, M.; Wang, J. Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl) indoles. Chem. Commun. 2021, 57, 10576– 10579,  DOI: 10.1039/D1CC03240B
      5
      Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl)indoles
      Tang, Shi; Ding, Shumin; Li, Dan; Li, Lianjie; Zhao, Haixia; Chai, Minxue; Wang, Jian
      Chemical Communications (Cambridge, United Kingdom) (2021), 57 (81), 10576-10579CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A palladium-catalyzed construction of spiroindolines through dearomative spirocyclization of 3-(2-isocyanoethyl)indoles was developed. 2'-Aryl-, vinyl-, and alkyl-substituted spiroindolines were accessed under mild conditions with excellent functional group tolerance. C1-tethered oxindole- and indole-spiroindoline bisheterocycles were generated in high yields via alkene/allene insertion and an imidoylative spirocyclization cascade. Addnl., a tandem dearomatization of two different indoles was realized with N-(2-bromobenzoyl)indoles as the electrophilic coupling partner of 3-(2-isocyanoethyl)indoles, affording polyindoline - spiroindoline bisheterocyclic scaffolds conveniently. Under the catalysis of Pd(OAc)2 and a spinol-derived phosphoramidite ligand, chiral spiroindolines were successfully accessed with up to 95% yield and 85% ee.
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    6. 6

      Reviews on indole dearomatization:

      (a) Roche, S. P.; Youte Tendoung, J. J.; Tréguier, B. Advances in dearomatization strategies of indoles. Tetrahedron 2015, 71, 3549– 3591,  DOI: 10.1016/j.tet.2014.06.054
      6a
      Advances in dearomatization strategies of indoles
      Roche, Stephane P.; Youte Tendoung, Jean-Jacques; Treguier, Bret
      Tetrahedron (2015), 71 (22), 3549-3591CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      A review. In this review, we will have a broader overview of indoles dearomatization through cycloaddn., arylation, protonation, alkylation, and oxidn. with several heteroatoms, with a special emphasis and comparison in each section on unprotected vs. protected indole nitrogens and asym. and/or catalytic dearomative methods and cascade reactions for the synthesis of complex alkaloids. In addn., to outline several selected dearomatization strategies in the context of complex natural product synthesis, we will also describe future perspectives in the field including prospects for development of enantioselective dearomatization processes.
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      (b) Zhuo, C. X.; Zhang, W.; You, S. L. Catalytic asymmetric dearomatization reactions. Angew. Chem., Int. Ed. 2012, 51, 12662– 12686,  DOI: 10.1002/anie.201204822
      6b
      Catalytic asymmetric dearomatization reactions
      Zhuo Chun-Xiang; Zhang Wei; You Shu-Li
      Angewandte Chemie (International ed. in English) (2012), 51 (51), 12662-86 ISSN:.
      This Review summarizes the development of catalytic asymmetric dearomatization (CADA) reactions. The CADA reactions discussed herein include oxidative dearomatization reactions, dearomatization by Diels-Alder and related reactions, the alkylative dearomatization of electron-rich arenes, transition-metal-catalyzed dearomatization reactions, cascade sequences involving asymmetric dearomatization as the key step, and nucleophilic dearomatization reactions of pyridinium derivatives. Asymmetric dearomatization reactions with chiral auxiliaries and catalytic asymmetric reactions of dearomatized substrates are also briefly introduced. This Review intends to provide a concept for catalytic asymmetric dearomatization.
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      (c) Bariwal, J.; Voskressensky, L. G.; Van Der Eycken, E. V. Recent advances in spirocyclization of indole derivatives. Chem. Soc. Rev. 2018, 47, 3831– 3848,  DOI: 10.1039/C7CS00508C
      6c
      Recent advances in spirocyclization of indole derivatives
      Bariwal Jitender; Voskressensky Leonid G; Van der Eycken Erik V
      Chemical Society reviews (2018), 47 (11), 3831-3848 ISSN:.
      Spiroindolines and spiroindoles are an important class of spirocyclic compounds present in a wide range of pharmaceuticals and biologically important natural alkaloids. Various spiroindolines and spiroindoles possess versatile reactivity which enables them to act as precursors for other privileged heterocycles. In view of the importance of this scaffold, many researchers focused their efforts to develop facile and mild synthetic methods for spirocyclization of indoles. However, the synthesis of spiroindolines and spiroindoles is known to be difficult due to rapid 1,2-migration to restore aromaticity. This review aims to briefly discuss the latest developments to access highly functionalized spiroindolines and spiroindoles to stimulate further research in the field to find new and efficient methodologies for accessing new spiroindolines and spiroindoles.
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      (d) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Synthesis of spirocyclic indolenines. Chem.─Eur. J. 2016, 22, 2856– 2881,  DOI: 10.1002/chem.201503835
      6d
      Synthesis of Spirocyclic Indolenines
      James, Michael J.; O'Brien, Peter; Taylor, Richard J. K.; Unsworth, William P.
      Chemistry - A European Journal (2016), 22 (9), 2856-2881CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods was developed to generate these synthetically useful and biol. important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatization reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field were examd.
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      (e) Roche, S. P.; Porco, J. A. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem., Int. Ed. 2011, 50, 4068– 4093,  DOI: 10.1002/anie.201006017
      6e
      Dearomatization Strategies in the Synthesis of Complex Natural Products
      Roche, Stephane P.; Porco, John A., Jr.
      Angewandte Chemie, International Edition (2011), 50 (18), 4068-4093CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, arom. scaffolds are converted to three-dimensional mol. architectures.
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    7. 7
      (a) Powell, N. A.; Kohrt, J. T.; Filipski, K. J.; Kaufman, M.; Sheehan, D.; Edmunds, J. E.; Delaney, A.; Wang, Y.; Bourbonais, F.; Lee, D. Y.; Schwende, F.; Sun, F.; McConnel, P.; Catana, C.; Chen, H.; Ohren, J.; Perrin, L. A. Novel and selective spiroindoline-based inhibitors of sky kinase. Bioorg. Med. Chem. Lett. 2012, 22, 190– 193,  DOI: 10.1016/j.bmcl.2011.11.036
      7a
      Novel and selective spiroindoline-based inhibitors of sky kinase
      Powell, Noel A.; Kohrt, Jeffrey T.; Filipski, Kevin J.; Kaufman, Michael; Sheehan, Derek; Edmunds, Jeremy E.; Delaney, Amy; Wang, Yuli; Bourbonais, Francis; Lee, Doh-Yeel; Schwende, Frank; Sun, Fang; McConnell, Pat; Catana, Cornel; Chen, Huifen; Ohren, Jeff; Perrin, Lisa A.
      Bioorganic & Medicinal Chemistry Letters (2012), 22 (1), 190-193CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
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      (b) Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; Zou, P.; Sun, D.; Wang, S. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J. Med. Chem. 2013, 56, 5553– 5561,  DOI: 10.1021/jm4005708
      7b
      A Potent Small-Molecule Inhibitor of the MDM2-p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice
      Zhao, Yujun; Yu, Shanghai; Sun, Wei; Liu, Liu; Lu, Jianfeng; McEachern, Donna; Shargary, Sanjeev; Bernard, Denzil; Li, Xiaoqin; Zhao, Ting; Zou, Peng; Sun, Duxin; Wang, Shaomeng
      Journal of Medicinal Chemistry (2013), 56 (13), 5553-5561CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The authors previously reported the discovery of a class of spirooxindoles as potent and selective small-mol. inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). The authors report herein the authors' efforts to improve their pharmacokinetic properties and in vivo antitumor activity. The authors' efforts led to the identification of MI-888 as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. MI-888 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
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      (c) Kumar, N.; Hati, S.; Munshi, P.; Sen, S.; Sehrawat, S.; Singh, S. A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton. Mol. Cell. Biochem. 2017, 429, 11– 21,  DOI: 10.1007/s11010-016-2932-6
      7c
      A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton
      Kumar, Naveen; Hati, Santanu; Munshi, Parthapratim; Sen, Subhabrata; Sehrawat, Seema; Singh, Shailja
      Molecular and Cellular Biochemistry (2017), 429 (1-2), 11-21CODEN: MCBIB8; ISSN:0300-8177. (Springer)
      Natural product-inspired libraries of mols. with diverse architectures have evolved as one of the most useful tools for discovering lead mols. for drug discovery. In comparison to conventional combinatorial libraries, these mols. have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of mols. From a successful DOS campaign of a natural product-inspired library, recently a small mol. with spiroindoline motif was identified as a potent anti-breast cancer compd. Herein we report the subcellular studies performed for this mol. on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization center. DNA ladder assay and cell cycle expts. further established the mol. as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.
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    8. 8
      (a) O’Connor, S. E.; Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 2006, 23, 532– 547,  DOI: 10.1039/b512615k
      8a
      Chemistry and biology of monoterpene indole alkaloid biosynthesis
      O'Connor, Sarah E.; Maresh, Justin J.
      Natural Product Reports (2006), 23 (4), 532-547CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      A review. Monoterpene indole alkaloids exhibit a diverse array of structures and biol. activities. The biosynthetic pathways for several representative terpene indole alkaloids are described in detail.
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      (b) Mohammed, A. E.; Abdul-Hameed, Z. H.; Alotaibi, M. O.; Bawakid, N. O.; Sobahi, T. R.; Abdel-Lateff, A.; Alarif, W. M. Chemical Diversity and Bioactivities of Monoterpene Indole Alkaloids (MIAs) from Six Apocynaceae Genera. Molecules 2021, 26, 488,  DOI: 10.3390/molecules26020488
      8b
      Chemical diversity and bioactivities of monoterpene indole alkaloids (MIAs) from six Apocynaceae genera
      Mohammed, Afrah E.; Abdul-Hameed, Zainab H.; Alotaibi, Modhi O.; Bawakid, Nahed O.; Sobahi, Tariq R.; Abdel-Lateff, Ahmed; Alarif, Walied M.
      Molecules (2021), 26 (2), 488CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. By the end of the twentieth century, the interest in natural compds. as probable sources of drugs has declined and was replaced by other strategies such as mol. target-based drug discovery. However, in the recent times, natural compds. regained their position as extremely important source drug leads. Indole-contg. compds. are under clin. use which includes vinblastine and vincristine (anticancer), atevirdine (anti-HIV), yohimbine (erectile dysfunction), reserpine (antihypertension), ajmalicine (vascular disorders), ajmaline (anti-arrhythmic), vincamine (vasodilator), etc. Monoterpene Indole Alkaloids (MIAs) deserve the curiosity and attention of researchers due to their chem. diversity and biol. activities. These compds. were considered as an impending source of drug-lead. In this review 444 compds., were identified from six genera belonging to the family Apocynaceae, will be discussed. These genera (Alstonia, Rauvolfia, Kopsia, Ervatamia, and Tabernaemontana, and Rhazya) consist of 400 members and represent 20% of Apocynaceae species. Only 30 (7.5%) species were investigated, whereas the rest are promising to be investigated. Eleven bioactivities, including antibacterial, antifungal, anti-inflammatory and immunosuppressant activities, were reported. Whereas cytotoxic effect represents 47% of the reported activities. Convincingly, the genera selected in this review are a wealthy source for future anticancer drug lead.
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    9. 9
      Saya, J. M.; Ruijter, E.; Orru, R. V. A. Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization. Chem.─Eur. J. 2019, 25, 8916– 8935,  DOI: 10.1002/chem.201901130
      9
      Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization
      Saya, Jordy M.; Ruijter, Eelco; Orru, Romano V. A.
      Chemistry - A European Journal (2019), 25 (38), 8916-8935CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic org. chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.
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    10. 10

      Reviews on imidoylative cross-coupling:

      (a) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry. Angew. Chem., Int. Ed. 2013, 52, 7084– 7097,  DOI: 10.1002/anie.201300942
      10a
      Palladium-Catalyzed Migratory Insertion of Isocyanides: An Emerging Platform in Cross-Coupling Chemistry
      Vlaar, Tjostil; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
      Angewandte Chemie, International Edition (2013), 52 (28), 7084-7097CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Isocyanides have been important building blocks in org. synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-contg. fine chems. This review discusses all the achievements in this emerging field.
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      (b) Collet, J. W.; Roose, T. R.; Weijers, B.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Recent advances in palladium-catalyzed isocyanide insertions. Molecules 2020, 25, 4906,  DOI: 10.3390/molecules25214906
      10b
      Recent advances in palladium-catalyzed isocyanide insertions
      Collet, Jurrien W.; Roose, Thomas R.; Weijers, Bram; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
      Molecules (2020), 25 (21), 4906CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. Isocyanides have long been known as versatile chem. reagents in org. synthesis. Their ambivalent nature also allows them to function as a CO-substitute in palladium-catalyzed cross couplings. Over the past decades, isocyanides have emerged as practical and versatile C1 building blocks, whose inherent N-substitution allows for the rapid incorporation of nitrogeneous fragments in a wide variety of products. Recent developments in palladium catalyzed isocyanide insertion reactions have significantly expanded the scope and applicability of these imidoylative cross-couplings. This review highlights the advances made in this field over the past eight years.
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      (c) Collet, J. W.; Roose, T. R.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Base metal catalyzed isocyanide insertions. Angew. Chem., Int. Ed. 2020, 59, 540– 558,  DOI: 10.1002/anie.201905838
      10c
      Base Metal Catalyzed Isocyanide Insertions
      Collet, Jurrien W.; Roose, Thomas R.; Ruijter, Eelco; Maes, Bert U. W.; Orru, Romano V. A.
      Angewandte Chemie, International Edition (2020), 59 (2), 540-558CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. This minireview focus on emerging base metal catalyzed reactions and highlight their potential in synthetic org. chem. Although mechanistic studies are still scarce, distinct proposed catalytic cycles were discussed and the literature is categorized according to (1) the(hetero)atom bound to and (2) the type of bonding with the transition metal in which the (formal) insertion occurs.
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    11. 11
      Roose, T. R.; Verdoorn, D. S.; Mampuys, P.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Transition metal-catalysed carbene-and nitrene transfer to carbon monoxide and isocyanides. Chem. Soc. Rev. 2022, 51, 5842– 5877,  DOI: 10.1039/D1CS00305D
      11
      Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides
      Roose, T. R.; Verdoorn, D. S.; Mampuys, P.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A.
      Chemical Society Reviews (2022), 51 (14), 5842-5877CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Transition metal-catalyzed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compds. allowing in situ transformation towards numerous functional groups and org. compds., including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the org. chem. toolbox. This review discusses all known transition metal-catalyzed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations.
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    12. 12
      Roose, T. R.; Preschel, H. D.; Mayo Tejedor, H.; Roozee, J. C.; Hamlin, T. A.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Iron-Catalysed Carbene Transfer to Isocyanides as a Platform for Heterocycle Synthesis. Chem.─Eur. J. 2023, 29, e202203074  DOI: 10.1002/chem.202203074
      12
      Iron-Catalysed Carbene Transfer to Isocyanides as a Platform for Heterocycle Synthesis
      Roose, Thomas R.; Preschel, H. Daniel; Mayo Tejedor, Helena; Roozee, Jasper C.; Hamlin, Trevor A.; Maes, Bert U. W.; Ruijter, Eelco; Orru, Romano V. A.
      Chemistry - A European Journal (2023), 29 (9), e202203074CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An iron-catalyzed carbene transfer reaction of diazo compds. to isocyanides has been developed. The resulting ketenimines are trapped in situ with various bisnucleophiles to access a range of densely functionalized heterocycles (pyrimidinones, dihydropyrazolones, 1H-tetrazoles) in a one-pot process. The electron-rich Hieber anion ([Fe(CO)3NO]-) facilitates efficient catalytic carbene transfer from acceptor-type α-diazo carbonyl compds. to isocyanides, providing a cost-efficient and benign alternative to similar noble metal-catalyzed processes. Based on DFT calcns. a plausible reaction mechanism for activation of the α-diazo carbonyl carbene precursor and ketenimine formation is provided.
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    13. 13
      (a) Klein, J. E. M. N. The Hieber Anion [Fe(CO)3 (NO)]−. Synlett 2011, 2757– 2758,  DOI: 10.1055/s-0031-1289559
      13a
      The hieber anion [Fe(CO)3(NO)]-
      Klein, Johannes E. M. N.
      Synlett (2011), (18), 2757-2758CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
      There is no expanded citation for this reference.
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      (b) Klein, J. E. M. N.; Miehlich, B.; Holzwarth, M. S.; Bauer, M.; Milek, M.; Khusniyarov, M. M.; Knizia, G.; Werner, H. J.; Plietker, B. The Electronic Ground State of [Fe(CO)3 (NO)]−: A Spectroscopic and Theoretical Study. Angew. Chem., Int. Ed. 2014, 53, 1790– 1794,  DOI: 10.1002/anie.201309767
      13b
      The Electronic Ground State of [Fe(CO)3(NO)]-: A Spectroscopic and Theoretical Study
      Klein, Johannes E. M. N.; Miehlich, Burkhard; Holzwarth, Michael S.; Bauer, Matthias; Milek, Magdalena; Khusniyarov, Marat M.; Knizia, Gerald; Werner, Hans-Joachim; Plietker, Bernd
      Angewandte Chemie, International Edition (2014), 53 (7), 1790-1794CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      During the past 10 years iron-catalyzed reactions have become established in the field of org. synthesis. For example, the complex anion [Fe(CO)3(NO)]-, which was originally described by Hogsed and Hieber, shows catalytic activity in various org. reactions. This anion is commonly regarded as being isoelectronic with [Fe(CO)4]2-, which, however, shows poor catalytic activity. The spectroscopic and quantum chem. investigations presented herein reveal that the complex ferrate [Fe(CO)3(NO)]- cannot be regarded as a Fe-II species, but rather is predominantly a Fe0 species, in which the metal is covalently bonded to NO- by two π-bonds. A metal-N σ-bond is not obsd.
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      (c) Lin, C.-H.; Plietker, B. The Evolution of Fe-catalyzed Nucleophilic Activation of Acceptor-substituted Vinyl-and Arylcyclopropanes. Isr. J. Chem. 2016, 56, 409– 416,  DOI: 10.1002/ijch.201500085
      13c
      The Evolution of Fe-catalyzed Nucleophilic Activation of Acceptor-substituted Vinyl- and Arylcyclopropanes
      Lin, Che-Hung; Plietker, Bernd
      Israel Journal of Chemistry (2016), 56 (6-7), 409-416CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Acceptor-substituted vinyl- (VCP) and arylcyclopropanes (ACP) are reactive substrates for nucleophilic activation using Bu4N[Fe(CO)3(NO)] (TBA[Fe]). In this account, the application of this catalytic strategy in traceless allylic substitution, [3+2]-cycloaddn., and Cloke-Wilson rearrangement will be presented. Addnl. information, derived from detailed spectroscopic and theor. investigations, is discussed. These results not only lead to a deeper understanding of the reactivity of the catalyst in VCP and ACP activation, but also set the stage for a new type of catalyst activation using photochem. irradn. at 415 nm.
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    14. 14

      Application of the Hieber anion in carbene transfer reactions:

      (a) Holzwarth, M. S.; Alt, I.; Plietker, B. Catalytic Activation of Diazo Compounds Using Electron-Rich, Defined Iron Complexes for Carbene-Transfer Reactions. Angew. Chem., Int. Ed. 2012, 51, 5351– 5354,  DOI: 10.1002/anie.201201409
      14a
      Catalytic Activation of Diazo Compounds Using Electron-Rich, Defined Iron Complexes for Carbene-Transfer Reactions
      Holzwarth, Michael S.; Alt, Isabel; Plietker, Bernd
      Angewandte Chemie, International Edition (2012), 51 (22), 5351-5354, S5351/1-S5351/87CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The electron-rich Fe complex Bu4N[Fe(CO)3(NO)] efficiently catalyzes different carbene-transfer reactions. Various diazo compds. can be used. The high stability of the employed Fe complexes is demonstrated by the generation of the diazo reagent in situ and a sequential Fe-catalyzed allylic sulfenylation/Doyle-Kirmse reaction.
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      (b) Röske, A.; Alt, I.; Plietker, B. Scope and Limitations of TBA[Fe]-Catalyzed Carbene Transfer to X?H-bonds - Indication of a MechanisticDichotomy. ChemCatChem. 2019, 11, 5260– 5263,  DOI: 10.1002/cctc.201900459
      There is no corresponding record for this reference.
      (c) Picher, M. I.; Plietker, B. Fe-Catalyzed Selective Cyclopropanation of Enynes under Photochemical or Thermal Conditions. Org. Lett. 2020, 22, 340– 344,  DOI: 10.1021/acs.orglett.9b04521
      14c
      Fe-Catalyzed Selective Cyclopropanation of Enynes under Photochemical or Thermal Conditions
      Picher, Marie-Idrissa; Plietker, Bernd
      Organic Letters (2020), 22 (1), 340-344CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The nucleophilic Fe-complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the cyclopropanation of enynes to substituted propargyl cyclopropanes using diazoesters as carbene surrogates. The catalyst can be activated either thermally in the presence of catalytic amts. of 4-nitroanisole or under photochem. conditions. Cyclopropanation occurs selectively at the enyne moiety; alternative olefinic moieties remain intact.
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    15. 15
      Liddon, J. T. R.; Clarke, A. K.; Taylor, R. J. K.; Unsworth, W. P. Preparation and reactions of indoleninyl halides: scaffolds for the synthesis of spirocyclic indole derivatives. Org. Lett. 2016, 18, 6328– 6331,  DOI: 10.1021/acs.orglett.6b03221
      15
      Preparation and Reactions of Indoleninyl Halides: Scaffolds for the Synthesis of Spirocyclic Indole Derivatives
      Liddon, John T. R.; Clarke, Aimee K.; Taylor, Richard J. K.; Unsworth, William P.
      Organic Letters (2016), 18 (24), 6328-6331CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The dearomatization of 2-haloindole precursors allows access to indoleninyl halides, a hitherto underexploited functional handle with broad synthetic utility. Indoleninyl iodides react via three distinct modes: hydrolysis, nucleophilic substitution, and cross-coupling. This allows a broad array of functionalized spirocyclic indole derivs. to be generated from a common starting material. They are also useful precursors to functionalized quinolines following migratory rearrangement and subsequent derivatization reactions.
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    16. 16
      Liddon, J. T. R.; Rossi-Ashton, J. A.; Taylor, R. J. K.; Unsworth, W. P. Dearomatizing spiroannulation reagents: direct access to spirocycles from indoles and dihalides. Org. Lett. 2018, 20, 3349– 3353,  DOI: 10.1021/acs.orglett.8b01248
      16
      Dearomatizing Spiroannulation Reagents: Direct Access to Spirocycles from Indoles and Dihalides
      Liddon, John T. R.; Rossi-Ashton, James A.; Taylor, Richard J. K.; Unsworth, William P.
      Organic Letters (2018), 20 (11), 3349-3353CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Unfunctionalized indoles can be directly converted into 3,3'-spirocyclic indolenines and indolines upon reaction with electrophilic dihalides in the presence of t-BuOK/BEt3. This double C-C bond forming reaction, which simultaneously generates a quaternary spirocyclic center, typically proceeds in high yield and has good functional group tolerance. In contrast to existing dearomatizing spirocyclization approaches, there is no need to prep. a prefunctionalized arom. precursor, enabling faster access to valuable spirocyclic products from simple, com. available aroms. in one step.
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    17. 17
      Dufour, M.; Gramain, J. C.; Sinibaldi, M. E.; Troin, Y.; Husson, H. P. Total synthesis of indole alkaloids. A new strategy for (±)-19-oxoaspidospermidine and (±)-19-oxoaspidofractinine. J. Org. Chem. 1990, 55, 5483– 5490,  DOI: 10.1021/jo00307a019
      17
      Total synthesis of indole alkaloids. A new strategy for (±)-19-oxoaspidospermidine and (±)-19-oxoaspidofractinine
      Dufour, M.; Gramain, J. C.; Husson, H. P.; Sinibaldi, M. E.; Troin, Y.
      Journal of Organic Chemistry (1990), 55 (20), 5483-90CODEN: JOCEAH; ISSN:0022-3263.
      19-Oxoaspidospermidine (I, R = H) and 19-oxoaspidofractinine (II) were prepd. from the tetracyclic amido alc. III via cyclization of tetracycle IV to I (R = Ac).
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    18. 18
      Martin, G.; Angyal, P.; Egyed, O.; Varga, S.; Soós, T. Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification. Org. Lett. 2020, 22, 4675– 4679,  DOI: 10.1021/acs.orglett.0c01472
      18
      Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification
      Martin, Gabor; Angyal, Peter; Egyed, Orsolya; Varga, Szilard; Soos, Tibor
      Organic Letters (2020), 22 (12), 4675-4679CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff-Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (-)-aspidospermidine, (-)-limaspermidine, and (+)-17-demethoxy-N-acetylcylindrocarine and the formal total synthesis of (-)-1-acetylaspidoalbidine.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02160.

    • Experimental procedures, characterization data, and 1H and 13C NMR spectra for new compounds (PDF)

    • FAIR data, including the primary NMR FID files, for compounds 1g, 1h, 1i, 1k–1n, 1p, 1x, 1y, 20, 23a, 23ab, 23b, 23ab, 23bb, 23be, 23c–23g, 23i, 23j–23o, 25a, 25b, 25q, 25r–25v, 25w_D1, 25w_D2, 25x_D1, 25x_D2, 25y, and 26 (ZIP)


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