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Synlett 2017; 28(20): 2839-2844
DOI: 10.1055/s-0036-1588530
letter
© Georg Thieme Verlag Stuttgart · New York

Rhodium-Catalyzed Regioselective C7-Functionalization of Indole Derivatives with Acrylates by Using an N-Imino Directing Group

Lanting Xu
a   Shanghai Research Institute of Fragrance and Flavor Industry, 480 Nanning Road, Shanghai 200232, P. R. of China
,
Lushi Tan*
b   Merck Research Laboratories, P.O. Box 2000, RY800-D280, Rahway, NJ 07065-0900, USA   Email: lushi_tan@merck.com
,
Dawei Ma*
c   State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China   Email: madw@sioc.ac.cn
› Author AffiliationsWe are grateful to the Shanghai Sailing Program (17YF1418900) and Merck for their financial support.
Further Information

Publication History

Received: 07 June 2017

Accepted after revision: 06 July 2017

Publication Date:
17 August 2017 (online)

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Dedicated to Professor Victor Snieckus on the occasion of his 80th birthday

Abstract

An efficient rhodium-catalyzed method for C–H olefination at the C7 position of indoles has been developed. The N-imino directing group was shown to be crucial for high regioselectivity and reactivity of the metal catalyst. The utility of this protocol was further demonstrated through a concise, four-step synthesis of pyroquilon from indole.

Key words

indoles - C7 regioselectivity - C–H activation - rhodium - olefination

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1588530.
  • Supporting Information
 

  • References and Notes

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  • 18 The structure of 10ha was confirmed by X-ray crystal analysis; details are given in the Supporting Information.
  • 19 General Experimental Procedure for the Synthesis of N-Imino Indole Substrates 8ha–hv, 14a and 14b: A sealed tube (50.0 mL) was charged with N-aminoindoles (10.0 mmol) and 2,6-dimethylbenzaldehyde (1.34 g, 10.0 mmol). The tube was evacuated and backfilled with argon before DCE (3.0 mL) was added. The reaction mixture was stirred at 120–130 °C for 4 h. After the reaction mixture was cooled to room temperature, the solvent was distilled off under ambient pressure by simple distillation. Purification of the residual oil by flash chromatography gave the desired products. (E)-1-(2,6-Dimethylphenyl)-N-(1H-indol-1-yl)methanimine (8ha): Yield: 2.3 g (92%); light-yellow solid; R f = 0.72 (5% EtOAc/petroleum ether). 1H NMR (500 MHz, CDCl3): δ = 8.81 (s, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.76 (d, J = 3.6 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.25–7.20 (m, 2 H), 7.17 (d, J = 7.5 Hz, 2 H), 6.74 (d, J = 3.4 Hz, 1 H), 2.64 (s, 6 H); 13C NMR (125 MHz, CDCl3): δ = 144.42, 138.11, 136.58, 130.93, 129.26, 129.17, 126.88, 123.44, 121.15, 121.02, 116.08, 110.81, 104.13, 21.84; HRMS (ESI): m/z [M + H]+ calcd for C17H17N2: 249.1386; found: 249.1383. (E)-1-(2,6-Dimethylphenyl)-N-(5-methoxy-1H-indol-1-yl)methanimine (8hh): Yield: 2.4 g (88%); brown solid; Rf = 0.46 (5% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.72 (d, J = 3.6 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.23–7.19 (m, 1 H), 7.15 (d, J = 7.6 Hz, 2 H), 7.09 (d, J = 2.4 Hz, 1 H), 6.99 (dd, J = 8.9, 2.4 Hz, 1 H), 6.64 (d, J = 3.5 Hz, 1 H), 3.88 (s, 3 H), 2.61 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 155.23, 144.11, 138.07, 131.82, 130.96, 129.21, 129.17, 127.21, 116.40, 113.51, 111.55, 103.71, 102.81, 56.01, 21.84; HRMS (ESI): m/z [M + H]+ calcd for C18H19ON2: 279.1492; found: 279.1488.
  • 20 General Experimental Procedure for the Synthesis of C7-Alkenylated Indole Derivatives 10ha–ht, 15a and 15b: A sealed tube (10.0 mL) was charged with indole substrates 8 (0.25 mmol), [RhCp*Cl2]2 (1.5 mg, 1 mol%), Cu(OAc)2·H2O (104 mg, 0.53 mmol), and AgSbF6 (3.1 mg, 4 mol%). The tube was evacuated and backfilled with argon before acrylate (1.0 mmol) and dichloromethane (1.0 mL) were added. The reaction mixture was stirred at 120–140 °C for 48–72 h. After cooling to room temperature, the mixture was diluted with dichloromethane, filtered through a plug of diatomite, concentrated under vacuum and the residue was purified by chromatography on silica with a gradient eluent of petroleum ether and ethyl acetate to give the corresponding products. Methyl (E)-3-(1-{[(E)-2,6-Dimethylbenzylidene]amino}-1H-indol-7-yl)acrylate (10ha): Yield: 70 mg (85%); white solid; Rf = 0.25 (10% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 9.01 (d, J = 16.0 Hz, 1 H), 8.72 (s, 1 H), 7.68 (d, J = 3.7 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.16–7.05 (m, 4 H), 6.65 (d, J = 3.6 Hz, 1 H), 6.36 (d, J = 16.0 Hz, 1 H), 3.66 (s, 3 H), 2.52 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 167.56, 146.83, 143.25, 138.45, 133.06, 130.60, 129.68, 129.07, 128.61, 123.37, 122.76, 121.04, 121.03, 117.95, 117.67, 104.47, 51.52, 21.44; HRMS (ESI): m/z [M + H]+ calcd for C21H21O2N2: 333.1598; found: 333.1601. Methyl (E)-3-(1-{[(E)-2,6-Dimethylbenzylidene]amino}-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-1H-indol-7-yl)acrylate (10hp): Yield: 88 mg (70%); white solid; Rf = 0.17 (25% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 9.06 (d, J = 16.0 Hz, 1 H), 8.75 (s, 1 H), 7.86–7.84 (m, 2 H), 7.77–7.71 (m, 4 H), 7.56 (d, J = 7.5 Hz, 1 H), 7.24–7.14 (m, 4 H), 6.42 (d, J = 16.0 Hz, 1 H), 4.10 (t, J = 7.4 Hz, 2 H), 3.75 (s, 3 H), 3.24 (t, J = 7.3 Hz, 2 H), 2.61 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 168.51, 167.55, 146.04, 143.22, 138.40, 134.17, 133.42, 132.23, 130.74, 129.52, 129.02, 128.23, 123.42, 122.99, 121.21, 121.03, 120.83, 117.98, 115.68, 114.45, 51.53, 37.96, 24.52, 21.46; HRMS (ESI): m/z [M + H]+ calcd for C31H28O4N3: 506.2074; found: 506.2068.
  • 21 General Experimental Procedure for the Synthesis of 11a–d: A suspension of indole derivatives 10h (0.1 mmol) and activated Zn powder (5.0 mmol) in a 1:1 mixture of THF and saturated NH4Cl solution (2.0 mL) was stirred at room temperature to 50 °C until consumption of the starting material as monitored by TLC. The mixture was diluted with EtOAc and filtered through a plug of diatomite. The filtrate was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Residue was purified by chromatography on silica with a gradient eluent of petroleum ether and ethyl acetate to give the corresponding products. Methyl (E)-3-(1H-Indol-7-yl)acrylate (11a): Yield: 17 mg (85%); white solid; Rf = 0.38 (25% EtOAc/petroleum ether). 1H NMR (500 MHz, CDCl3): δ = 8.64 (br s, 1 H), 8.07 (d, J = 16.0 Hz, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.28 (t, J = 2.9 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H), 6.62 (dd, J = 3.2, 2.0 Hz, 1 H), 6.54 (d, J = 16.0 Hz, 1 H), 3.85 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ = 167.85, 141.47, 134.45, 129.06, 124.95, 123.59, 122.47, 120.30, 118.32, 117.71, 103.55, 51.95; HRMS (ESI): m/z [M + H]+ calcd for C12H12O2N: 202.0863; found: 202.0862.
  • 22 General Experimental Procedure for the Synthesis of 12a–d: C7-alkenylation of indole derivatives 10h (0.1 mmol) was dissolved in EtOH (3.0 mL). To the solution, an excess amount of Raney Ni slurry was added and the resulting mixture was stirred under H2 atmosphere (1 atm) at 50 °C until consumption of the starting material as monitored by TLC. The mixture was filtered through a plug of diatomite and extracted with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Residue was purified by chromatography on silica with a gradient eluent of petroleum ether and ethyl acetate to give the corresponding products. Methyl 3-(1H-Indol-7-yl)propanoate (12a): Yield: 16 mg (78%); white solid; Rf = 0.20 (25% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 8.86 (br s, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.24 (t, J = 2.8 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.00 (d, J = 6.9 Hz, 1 H), 6.56 (dd, J = 3.1, 2 Hz, 1 H), 3.68 (s, 3 H), 3.22 (t, J = 7.0 Hz, 2 H), 2.79 (t, J = 7.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 175.09, 135.01, 128.17, 124.42, 123.71, 121.77, 120.06, 119.25, 102.93, 52.07, 34.77, 26.43; HRMS (ESI): m/z [M + H]+ calcd for C12H14O2N: 204.1019; found: 204.1017.
  • 23 Procedure for the Synthesis of Pyroquilon: In a test tube C7-alkenylated indole derivative 10ha (0.1 mmol) was dissolved in EtOH (3 mL), and then an excess amount of Raney Ni slurry was added. The test tube was placed in a stainless steel autoclave, and autoclave was sealed under N2 before purging with hydrogen for three times. The autoclave was charged with hydrogen (40 kg/cm2), and the reaction mixture was stirred at 70 °C for 6 h. After cooling to room temperature, the remaining hydrogen was released. The mixture was filtered through a plug of diatomite and extracted with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Residue was purified by chromatography on silica with a gradient eluent of petroleum ether and ethyl acetate to give pyroquilon. 1,2,5,6-Tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (13): Yield: 16 mg (95%); white solid; Rf = 0.14 (25% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 7.3 Hz, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 6.94 (t, J = 7.4 Hz, 1 H), 4.10 (t, J = 8.4 Hz, 2 H), 3.21 (t, J = 8.4 Hz, 2 H), 2.99 (t, J = 7.6 Hz, 2 H), 2.70 (t, J = 7.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 167.82, 141.47, 129.07, 125.46, 123.42, 123.39, 120.35, 45.29, 31.80, 27.91, 24.53; HRMS (ESI): m/z [M + H]+ calcd for C11H12ON: 174.0913; found: 174.0913.
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