Gold-Catalyzed Conjugate Addition Type Reaction of Indoles with α,β-Enones

Abstract

3-Unsubstituted indoles undergo regioselective alkylation at the 3-position of the indole nucleus through gold-catalyzed conjugated addition type reaction with α,β-enones. 3-Substituted indoles undergo C-2 alkylation. Sequential C-3/C-2 gold catalyzed alkylation of the indole with dibenzylidene acetone gives a poly­cyclic indole b-annulated with a seven-membered cycle.

gold catalysis - indoles - α,β-enones - conjugated addition

References

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16

General Procedure for the Synthesis of Indoles 3. To a 1:1 mol ratio solution of indole 1 and α,β-enone 2 in EtOH was added NaAuCl₄·2H₂O (5 mol%). The resulting mixture was allotted to react under stirring at r.t. or at 30 °C and the reaction was monitored by TLC or GC-MS. After completion, the solvent was removed by evaporation. To the residue, acetone (few mL) was added to precipitate the catalyst, which was separated by filtration. The filtrate was concentrated and the crude products were purified by chromatography on silica gel (230-400 mesh) eluting with n-hexane/EtOAc mixtures.

17

Selected data for 3b: IR (neat): 3420, 1725 cm^-1. ¹H NMR: δ = 8.25 (bs, 1 H), 7.64-7.60 (m, 1 H), 7.24-7.03 (m, 3 H), 6.80 (d, J = 2.3 Hz, 1 H), 3.47-3.40 (m, 1 H), 2.84-2.76 (m, 2 H), 1.95 (s, 3 H), 1.73-1.63 (m, 2 H), 1.25-1.15 (m, 4 H), 0.77 (t, J = 3.9 Hz, 3 H). ¹³C NMR: δ = 209.51, 136.39, 126.34, 121.55, 121.26, 119.02, 118.86, 118.38, 111.31, 50.07, 35.49, 32.73, 30.24, 29.63, 22.51, 13.89. MS: m/e (relative intensity) = 244 (100) [M + 1]⁺, 243 (35) [M⁺], 186 (63). 3c: IR (KBr): 3430, 1715 cm^-1. ¹H NMR (diastereomeric mixture, 2:1 ratio): δ = 7.80 (bs, 2 H), 7.39-7.03 (m, 18 H), 6.73 (bs, 2 H), 4.82 (t, J = 7.4 Hz, 2 H), 3.24 (dd, J = 16.3 and 7.4 Hz, 2 H), 3.09 (dd, J = 16.3 and 7.4 Hz, 2 H);(diastereoisomer) δ = 7.78 (bs, 2 H), 7.32-7.00 (m, 18 H), 6.69 (bs, 2 H), 4.82 (t, J = 7.4 Hz, 2 H), 3.19 (dd, J = 16.3 and 7.5 Hz, 2 H), 3.09 (dd, J = 16.3 and 7.5 Hz, 2 H). ¹³C NMR (diastereomeric mixture, 2:1 ratio): δ = 207.79, 143.97 136.65, 128.37, 127.66, 126.59, 126.19, 122.11, 121.62, 119.54, 119.45, 118.85, 111.09, 49.77, 38.12; (diastereoisomer) δ = 207.70, 144.15, 136.62, 128.43, 127.77, 126.64, 126.26, 122.11, 121.49, 119.50, 119.40, 118.78, 111.05, 49.90, 38.18. ESI-MS: m/e (relative intensity) = 469 (100) [M + 1⁺]. 3e: IR (KBr): 3360, 1720 cm^-1. ¹H NMR: δ = 8.28 (bs, 1 H), 7.44 (s, 1 H), 7.17 (s, 1 H), 7.04 (s, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.79 (t, J = 7.2 Hz, 2 H), 2.13 (s, 3 H). ¹³C NMR: δ = 208.03, 135.59, 132.11, 129.09, 123.61, 121.49, 116.21, 117.06, 43.73, 29.99, 19.07. MS: m/e (relative intensity) = 259 (10) [M⁺], 257 (63) [M⁺], 256 (63) [M + 1]⁺, 255 (100) [M⁺], 214 (34), 213 (49), 212 (19), 200(83), 199 (100), 198 (39). 3f: IR (KBr): 3400, 1710 cm^-1. ¹H NMR: δ = 8.20 (bs, 1 H), 7.57-7.14 (m, 9 H), 3.19-3.11 (m, 2 H), 2.79-2.71 (m, 2 H), 2.05 (s, 3 H). ¹³C NMR: δ = 208.93, 135.86, 134.44, 132.97, 128.86, 128.66, 127.89, 127.68, 122.27, 119.59, 118.82, 111.55, 110.97, 44.45, 29.90, 18.70. MS: m/e (relative intensity) = 264 (63) [M + 1]⁺, 207 (100). 3g: IR (KBr): 3360, 1710 cm^-1. ¹H NMR: δ = 8.15 (s, 1 H), 7.62-7.10 (m, 14 H), 5.09 (t, J = 7.4 Hz, 1 H), 3.46 (dd, J = 16.4 and 7.4 Hz, 1 H), 3.37 (dd, J = 16.4 and 7.4 Hz, 1 H), 1.97 (s, 3 H). ¹³C NMR: δ = 207.51, 144.45, 136.28, 135.73, 132.98, 128.81, 128.76, 128.43, 128.14, 127.70, 127.48, 126.05, 122.08, 120.61, 119.76, 114.03, 111.21, 49.31, 37.09, 30.31. MS: m/e (relative intensity) = 339 (23) [M⁺], 283 (100). 3h: IR (KBr): 3300, 1690 cm^-1. ¹H NMR: δ = 8.14 (s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.50-7.46 (m, 4 H), 7.44-7.40 (m, 2 H), 7.24 (t, J = 7.9 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 3.46-3.40 (tt, J = 12.9 and 4.1 Hz, 1 H), 3.14 (t, J = 13.6 Hz, 2 H), 2.62-2.45 (m, 2 H), 2.21-1.66 (m, 4 H). ¹³C NMR: δ = 211.33, 136.29, 134.52, 132.97, 128.88, 128.75, 128.16, 126.94, 122.13, 120.10, 119.55, 115.11, 111.38, 48.11, 41.39, 37.14, 31.70, 25.87. MS: m/e (relative intensity) = 289 (100) [M⁺], 246 (49), 232 (74), 218 (58). 3i: IR (neat): 3360, 1715 cm^-1. ¹H NMR: δ = 8.25 (bs, 1 H), 7.57-7.10 (m, 7 H), 3.26-3.18 (m, 2 H), 2.83-275 (m, 2 H), 2.12 (s, 3 H). ¹³C NMR: δ = 207.45, 139.58, 132.00, 131.34, 130.88, 130.01, 128.72, 128.52, 127.89, 127.73, 126.25, 122.49, 120.59, 37.33, 32.91, 29.80. MS: m/e (relative intensity) = 269 (63) [M⁺], 213 (100). 3j: IR (KBr): 3400, 1710 cm^-1. ¹H NMR: δ = 8.13 (bs, 1 H), 7.52-7.06 (m, 9 H), 6.04 (bs, 1 H), 3.15-3.07 (m, 2 H), 2.80-2.72 (m, 2 H), 2.50-1.95 (m, 7 H), 2.13 (s, 3 H). ¹³C NMR: δ = 209.09, 146.37, 135.97, 135.13, 129.82, 128.65, 128.44, 127.15, 126.82, 126.19, 121.83, 119.30, 118.38, 110.63, 110.51, 44.79, 39.42, 33.67, 30.02, 29.83, 28.74, 19.10. MS: m/e (relative intensity) = 343 (100) [M⁺], 286 (86). 3k: IR (neat): 3440, 1730 cm^-1. ¹H NMR: δ = 7.92 (bs, 1 H), 7.46-7.01 (m, 14 H), 6.02 (bs, 1 H), 5.08-5.05 (m, 1 H), 3.43-3.36 (m, 2 H), 2.62-2.46 (m, 1 H), 2.16-2.08 (m, 4 H), 2.06 (s, 3 H), 2.04-1.96 (m, 2 H). MS: m/e (relative intensity) = 419 (38) [M⁺], 362 (100). 3l: IR (neat): 3380, 1680 cm^-1. ¹H NMR: δ = 7.92 (d, J = 7.9 Hz, 1 H), 7.54-7.04 (m, 14 H), 5.17 (t, J = 7.3 Hz, 1 H), 4.01 (dd, J = 16.7 and 6.9 Hz, 1 H), 3.93 (dd, J = 16.7 and 6.9 Hz, 1 H), 2.87-2.75 (m, 2 H), 1.62-1.58 (m, 2 H), 1.39-1.36 (m, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). ¹³C NMR: δ = 199.08, 144.26, 137.09, 136.34, 135.54, 132.84, 128.41, 128.18, 128.01, 127.47, 125.78, 120.70, 119.36, 119.08, 113.27, 110.50, 43.84, 36.59, 31.83, 26.02, 22.52, 13.82. EI-MS: m/e (relative intensity) = 381 (30) [M⁺], 263 (100).

18 Sundberg RJ. In Indoles   Academic Press; London: 1996. 

19

Temperatures are reported as bath temperature.

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22

Sequential Procedure for the Preparation of 5a. To a solution of the indole 1a (0.072 g, 0.612 mmol) and the trans,trans-dibenzylidene acetone 2c (0.287 g, 1.22 mmol) in EtOH (3 mL) was added NaAuCl₄·2H₂O (0.012 g, 0.0306 mmol). The resulting mixture was allotted to react under stirring at 30 °C. After 2 h, the temperature was raised at 60 °C and the heating was continued for 3 h after which the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography eluting with n-hexane/EtOAc 90/10 v/v mixture to afford 4a (0.17 g, 80% yield). IR (KBr): 3440, 1720 cm^-1. ¹H NMR (diastereomeric mixture, 2.1:1 ratio): major isomer: δ = 7.56 (bs, NH, 1 H), 7.50-6.90 (m, C_sp2-H, 14 H), 4.82 (t, J = 4.5 Hz, 10-CH, 1 H), 4.54 (dd, J = 2.3 and 12.1 Hz, 6-CH, 1 H), 3.40 (d, J = 4.5 Hz, 9-CH, 2 H), 3.21 (dd, J = 12.1 and 15.5 Hz, 7-CH _a , 1 H) 2.73 (dd, J = 2.3 and 15.5 Hz, 7-CH _b , 1 H); minor isomer: δ = 7.68 (bs, NH, 1 H), 7.50-6.90 (m, C_sp2-H, 14 H), 4.86 (dd, X part of ABX system, 6-CH, 1 H), 4.78 (dd, J = 4.5 and 7.9 Hz, 10-CH, 1 H), 3.47 (dd, J = 8.3 and 14.0 Hz, 9-CH _a , 1 H), 3.08 (dd, J = 4.5 and 14.4 Hz, 9-CH _b , 1 H), 3.18-3.09 (m, AB part of ABX system 7-CH, 2 H). ¹³C NMR: (diastereomeric mixture, 2.1:1 ratio): major isomer: δ = 209.97 (8-CO), 143.43 (1-C_Pha), 141.78 (1-C_Phb), 136.57 (5a-C), 134.88 (4a-C), 129.26, 128.62 (10b-C), 128.60, 128.05, 127.71, 127.42, 126.45 (Pha and Phb), 122.13 (3-C), 119.71 (2-C), 118.63 (1-C), 113.65 (10a-C), 110.53 (4-C), 50.37 (7-C), 49.08 (9-C), 41.13 (6-C), 36.42 (10-C); minor isomer: δ = 209.43 (8-CO), 143.66 (1-C_Pha), 140.01 (1-C_Phb), 136.04 (5a-C), 134.76 (4a-C), 129.19, 128.47 (10b-C), 128.18, 128.05, 127.45, 126.49 (Pha and Phb), 121.97 (3-C), 119.65 (2-C), 118.65 (1-C), 112.86 (10a-C), 110.53 (4-C), 50.06 (4-C), 49.93 (7-C), 41.02 (6-C), 38.63 (10-C). MS: m/e (relative intensity) = 351 (100) [M⁺], 219 (47).

23

Selected data for 5b: IR (neat): 3400, 1710 cm^-1. ¹H NMR: δ = 8.19 (bs, 1 H), 7.52-7.47 (m, 1 H), 7.28-7.24 (m, 1 H), 7.17-7.05 (m, 2 H), 3.30-3.25 (m, 1 H), 2.52-2.28 (m, 4 H), 2.21 (s, 3 H), 2.13-1.73 (m, 4 H). ¹³C NMR: δ = 210.85, 136.03, 135.11, 129.01, 121.28, 119.08, 118.25, 110.43, 106.25, 47.09, 41.07, 36.34, 30.77, 25.33, 8.37. MS: m/e (relative intensity) = 227 (100) [M⁺]. 5c: IR (neat): 3390, 1710 cm^-1. ¹H NMR: δ = 8.39 (bs, 1 H), 7.57-7.09 (m, 8 H), 3.85 (s, 3 H), 3.55-3.35 (m, 1 H), 2.63-2.58 (m, 2 H), 2.41-2.16 (m, 2 H), 2.05-1.98 (m, 4 H). ¹³C NMR: δ = 210.28, 158.21, 136.53, 135.20, 130.77, 128.03, 127.01, 121.98, 119.98, 119.20, 114.13, 113.86, 110.64, 55.29, 47.76, 41.10, 36.26, 31.72, 25.23. MS: m/e (relative intensity) = 319 (100) [M⁺].

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