A Novel Isocyanide-Based Multicomponent Reaction: An Easy Access to Substituted Propionamides and Succinimides

Abstract

A new approach to the design of multicomponent reactions is introduced. As a result the novel reaction of gem-diactivated olefins with 4-nitrophenol and isocyanides leading to substituted propionamides or succinimides was discovered.

multicomponent reactions - isocyanides - nucleophilic additives - reaction design - combinatorial chemistry

References and Notes

1 Multicomponent Reactions   Zhu J. Bienayme H. WILEY-VCH Verlag; Weinheim: 2005. 

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11

General Procedure: Pyridine (8 µL, 0.1 mmol) was added to isocyanide (0.5 mmol), gem-dicyano (0.5 mmol), olefin (0.5 mmol), and 4-nitrophenol (0.5 mmol) in MeCN-H₂O (3:1, 0.5 mL). The resulting mixture was stirred at r.t. for 5-8 h. After the reaction was complete, the solution was concentrated to dryness and the crude product was purified by crystallization or flash chromatography.

12

3b: ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 8.32 (d, J = 8.8 Hz, 2 H, C₆H₄NO₂), 7.78 (d, J = 8.8 Hz, 2 H, C₆H₄NO₂), 7.69 (s, 1 H, NH), 7.26-6.85 (m, 4 H, C₆H₄OMe), 4.45 (s, 1 H, CH), 3.76 (s, 3 H, OMe), 1.13 (s, 9 H, t-Bu). ¹³C NMR (100 MHz, DMSO-d ₆ ): δ = 165.82, 158.99, 148.25, 137.20, 133.19, 129.72, 128.55, 124.40, 121.50, 115.03, 114.42, 113.98, 113.96, 58.11, 55.00, 50.76, 45.62, 27.83. MS (70 eV): m/z (%) = 406 (17, [M]⁺), 379 (12, [M - HCN]⁺), 353 (24), 322 (37), 296 (100), 57 (55, [C₄H₉]⁺).

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General Procedure: Et₃N (65 µL), isocyanide (0.5 mmol), gem-dicyano olefin (0.5 mmol), and 4-nitrophenol (0.5 mmol) were mixed together in MeCN-H₂O (3:1, 0.5 mL). The resulting solution was stirred at r.t. for 6-9 h. When the reaction was complete, solutions were concentrated to dryness, and the crude product was purified by crystallization or flash chromatography.

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5e: ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 9.55 (s, 1 H, NH), 8.36 (d, J = 8.9 Hz, 2 H, C₆H₄NO₂), 7.75 (d, J = 8.9 Hz, 2 H, C₆H₄NO₂), 3.04 (d, J = 4.0 Hz, 1 H, CH), 2.41-2.37 (m, 1 H, CHMe₂), 1.62 (s, 9 H, t-Bu), 1.09 (d, J = 6.8 Hz, 3 H, Me), 1.02 (d, J = 6.8 Hz, 3 H, Me). ¹³C NMR (100 MHz, DMSO-d ₆ ): δ = 173.36, 161.27, 147.65, 143.02, 127.65, 124.54, 116.64, 59.10, 56.29, 53.51, 30.42, 27.83, 20.89, 17.54. MS (70 eV): m/z (%) = 342 (2, [M]⁺), 327 (2, [M - CH₃]⁺), 287 (100), 243 (6), 216 (9), 57 (49, [C₄H₉]⁺).