Rapid Assembly of Functionalised Spirocyclic Indolines by Palladium-Catalysed Dearomatising Diallylation of Indoles with Allyl Acetate

Herein, we report the application of allyl acetate to the palladium-catalysed dearomatising diallylation of indoles. The reaction can be carried out by using a readily available palladium catalyst at room temperature, and can be applied to a wide range of substituted indoles to provide access to the corresponding 3,3-diallylindolinines. These compounds are versatile synthetic intermediates that readily undergo Ugi reactions or proline-catalysed asymmetric Mannich reactions. Alternatively, acylation of the 3,3-diallylindolinines with an acid chloride or a chloroformate, followed by treatment with aluminium chloride, enables 2,3-diallylindoles to be prepared. By using ring-closing metathesis, functionalised spirocyclic indoline scaffolds can be accessed from the Ugi products, and a dihydrocarbazole can be prepared from the corresponding 2,3-diallylindole.


General methods
All chemicals were purchased from Sigma-Aldrich, Acros, Alfa Aesar, Santa Cruz Biotechnology and used without further purification. 1-allyl-1H-indole 5a, 3-allyl-1H-indole 4a, 1,3-diallyl-1H-indole 6a were synthesized according to literature procedures. 1 Anhydrous Tetrahydrofuran, Dichloromethane and Acetonitrile were purchased from Fisher Scientific. All other solvents used as received. PE refers to Petroleum Ether. Flash column chromatography was carried out using normal phase silica gel (33-70 μm) supplied by VWR. Thin layer chromatography was carried out using Merck TLC Silica gel 60 F 254 plates and products were visualized using combinations of UV light (254 nm) and potassium permanganate (KMnO 4 ) when required. 1 H NMR spectra were recorded at 400 or 600 MHz on a Bruker AMX400 and AMX600 spectrometer using the residual protic solvent CDCl 3 (δ = 7.26 ppm, s) as the internal standard.
Chemical shifts are quoted in ppm to the nearest 0.01 ppm using the following abbreviations: s (singlet), d, (doublet), t (triplet), q, (quartet), qn (quintet), sext (sextet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet) defined as all multi-peak signals where overlap or complex coupling of signals makes definitive descriptions of peaks difficult. The coupling constants J are measured in Hz. 13 C{ 1 H} NMR spectra were recorded at 100 or 150 MHz on a Bruker AMX400 and AMX600 at 25°C in CDCl 3 as described below. All chemical shifts were referenced with CDCl 3 solvent (δ = 77.0 ppm, t) as the internal standard. Chemical shifts are reported to the nearest 0.1 ppm. Coupling constants are defined as J and quoted in Hz. Mass spectra were performed in the Department of Chemistry, University College London.
Infrared spectra were obtained on a Perkin Elmer Spectrum 100 FT-IR Spectrometer operating in ATR mode. Melting points were measured with a Gallenkamp apparatus and are uncorrected. The enantiomeric excess were determined using a Varian ProStar and PrepStar HPLC, with a UV detector system at 254 nm with a CHIRALPAK-AD column (Daicel; Chemical Industries, LTD) 25 × 0.46 cm. Optical rotation [α] D 20 values are given in 10 −1 deg cm 2 g −1 , concentration (c) in g/100 mL and were measured on a Perkin-Elmer 343 polarimeter.

3,3-Diallyl-5-benzyloxy-3H-indole (3f)
The product was obtained by following the General procedure A. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 70/30) as eluent. The product was obtained as orange oil (

3,3-Diallyl-4-bromo-3H-indole (3h)
The product was obtained by following the General procedure A with slight modifications. The reaction was conducted at 50 °C for 24 hours. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 90/10) as eluent. The product was obtained as a purple oil (159 mg

3,3-Diallyl-5-bromo-3H-indole (3i)
The product was obtained by following the General procedure A with slight modifications. The reaction was conducted at 50 °C for 8 hours. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 80/20) as eluent. The product was obtained as a brown oil (123 mg, 58%); R f =

3,3-Diallyl-5-chloro-3H-indole (3j)
The product was obtained by following the General procedure A with slight modifications. The reaction was conducted at 50 °C for 3 hours, then stirred at room temperature for a further 18 hours. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 90/10) as eluent. The product was obtained as pale yellow oil (126 mg, 41%). R f = 0.21 (PE/EtOAc 4/1); 1

3,3-Diallyl-5-methoxy-2-methyl-3H-indole (3m)
The product was obtained by following the General procedure A. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 90/10) as eluent. The product was obtained as a yellow oil (

1-Allyl-5-nitro-1H-indole (7a)
The product was obtained by following the General procedure A with slight modifications. The reaction mixture was heated at 50 °C overnight. The crude residue was purified by column chromatography on

1-Allyl-2-methyl-5-nitro-1H-indole (7b)
The product was obtained by following the General procedure A with slight modifications. The reaction mixture was heated at 50 °C overnight. The crude residue was purified by column chromatography on SiO 2 using a mixture of PE/EtOAc (100/0 to 80/20) as eluent. The title compound was obtained as a orange oil (234 mg, 86%);

UGI reactions
General procedure B: The carboxylic acid (1eq.) and the isocyanide (1eq.) were added to a solution of 3,3-diallyl-3H-indole (1eq.) in MeOH (C ≈ 0.25 mol/L). The reaction mixture was left to stir between 2 -24 hours at room temperature before evaporation of the volatiles under vacuum. Pure compounds were obtained by washing the crude residue with PE, or by purification by column chromatography on SiO 2 .

3,3-Diallyl-1-benzoyl-N-(tert-butyl)indoline-2-carboxamide (8a)
The product was obtained by following the General procedure B. After evaporation of the volatiles The desired product was obtained as a pale yellow oil

3,3-Diallyl-N-(tert-butyl)-1-(1H-pyrazole-3-carbonyl)indoline-2-carboxamide (8g)
The product was obtained according to the General procedure B. After 4 hours at room temperature, volatiles were removed under vacuum and the crude residue was purified by several washing with PE and dried. The desired product was obtained as

Synthesis of substituted 3,3-diallyl-2-hydroxyindoline
General procedure C: The chloroformate or acid chloride (1 eq.) was added to a solution of the 3,3diallyl-3H-indole in CH 2 Cl 2 (C ≈ 0.07 mol/L) and left to stir for 30 minutes at room temperature before addition of NaHCO 3sat . After extraction of the reaction mixture with CH 2 Cl 2 , the combined organic layers were washed with water, dried over Na 2 SO 4 and filtered through cotton wool. Pure compounds were obtained by evaporation of the volatiles under reduced pressure or by purification by column chromatography on silica.

Methyl 3,3-diallyl-2-hydroxyindoline-1-carboxylate (10a)
The product was obtained by following the General procedure C. After evaporation of the volatiles the crude mixture was purified by column chromatography on SiO 2 using

General procedure D: Preparation of 2,3-diallylindole from 2-hydroxy-3,3-diallylindoline (13)
Aluminium chloride (1.1 eq.) was added to a solution 3,3-diallyl-2-hydroxyindoline (1.0 eq.) in CH 2 Cl 2 (C ≈ 1 mol/L) at room temperature. The mixture was stirred for 30 minutes before addition of NEt 3 (≈ 2eq.). After 5 minutes at room temperature water was added and the product was extracted with CH 2 Cl 2 (3 times). The combined organic layers were dried over Na 2 SO 4 . After evaporation, the crude material was purified by filtration through a small pad of SiO 2 to yield the rearranged product.

Preparation of 2,3-diallylindole starting from 3,3-diallylindolinine General procedure E: Using an acyl chloride
The acyl chloride (1 eq.) was added to a solution of 3,3-diallyl-3H-indole (1 eq.) in CH 2 Cl 2 (C ≈ 0.3 mol/L) at room temperature. After 30 minutes, the reaction was quenched by addition of water and the mixture was extracted with CH 2 Cl 2 (3 times). The combined organic layers were dried over Na 2 SO 4 and filtered. Evaporation of the volatiles give the 3,3-diallyl-2-hydroxyindoline which was directly dissolved in CH 2 Cl 2 (C ≈ 0.3 mol/L) and AlCl 3 (1.1 eq.) was added. After 30 minutes at room temperature the reaction was quenched with NaHCO 3sat before extraction with CH 2 Cl 2 (3 times). The combined organic phases were washed with water, dried over Na 2 SO 4 and filtered. After evaporation of the volatiles under vacuum, the crude residue was purified by a filtration on a small pad of SiO 2 using PE/Et 2 O (90/10) as eluent.

General procedure F: Using a chloroformate
The chloroformate (1 eq.) was added to a solution of 3,3-diallyl-3H-indole (1 eq.) in CH 2 Cl 2 (C ≈ 0.2 mol/L) at room temperature. After 30 minutes, the reaction was quenched by addition of NaHCO 3 sat and the mixture was extracted with CH 2 Cl 2 (3 times). The combined organic layers were washed with water and dried over Na 2 SO 4 before filtration. Evaporation of the volatiles gave 3,3-diallyl-2-hydroxy-indoline derivative which was directly dissolved in CH 2 Cl 2 (C ≈ 0.2 mol/L) and AlCl 3 (1.1 eq.) was added. After organic phases were washed with water, dried over Na 2 SO 4 and filtered. After evaporation of the volatiles under vacuum, the crude residue was purified by filtration through a small pad of SiO 2 using PE/Et 2 O (100/0 to 90/10) as eluent.

(L)-Proline catalysed asymmetric Mannich reaction
General procedure G: L-proline (30 mol%) was added at 0 °C to a solution of 3,3-diallyl-3H-indole (1 eq.) in a mixture of acetone:CHCl 3 (4.5:1, C ≈ 0.022 mol/L). The reaction mixture was allowed to warm up slowly to room temperature and stirred for 2 days. Evaporation of the solvent followed by purification by column chromatography on SiO 2 afforded the Mannich product.
General proce.ure H: L-proline (30 mol%) was added at 0 °C to a solution of 3,3-diallyl-3H-indole (1 eq.) in a mixture of acetone/DMSO (4:1, C ≈ 0.016 mol/L). The solution was allowed to warm up slowly to room temperature and stirred for 2 days. The reaction mixture was diluted with diethyl ether and washed with NaHCO 3sat . The product was extracted with Et 2 O (3 times) and combined organic layers were washed with water, brine and dried with MgSO 4. After filtration and removal of the solvents under reduce pressure the crude product was purified by column chromatography on SiO 2 .

1-(3,3-Diallylindolin-2-yl)propan-2-one (14a)
The product was obtained by following the General procedure G. After evaporation of the volatiles, the crude mixture was purified by column chromatography on SiO 2 using (CH 2 Cl 2 /Et 2 O 100/0 to 95/5) as eluent. The title compound was obtained as a

Ring closing metathesis reactions of UGI compounds
General procedure I: First generation Grubbs catalyst (15 mol %) to a degassed solution of the corresponding Ugi product (1eq.) in CH 2 Cl 2 (C ≈ 0.06 mol/L) at 45°C. The reaction mixture was heated at reflux overnight under argon before evaporation of the solvent under reduced pressure. The crude residue was purified by column chromatography on SiO 2 to yield the desired product.