Three-Component Reactions of α- and β-Bromo Aldehydes with Amides and Dienophiles - An Easy Way to Versatile 1-Amido-2-Cyclohexenes

Abstract

The scope of the three-component reaction of aldehydes, amides, and dienophiles, the so-called AAD reaction, is extended to the formation of 2- and 3-bromo-substituted 1-amido-2-cyclohexene derivatives. The incorporation of the halogen substituent allows further elaboration of this interesting class of products.

Key words

halogenated aldehydes - amides - dienophiles - multicomponent reaction - Diels-Alder reaction

References and Notes

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8

The crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 635328 (6).

10

rac - N -(5-Bromo-2-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1 H -isoindol-4-yl)-4-methoxybenzamide (5)
4-Methoxybenzamide (152 mg, 1.00 mmol) was filled in a CEM pressure tube (10 mL), then toluene (2 mL), α-bromo-crotonaldehyde (2.00 mmol, 298 mg), and N-methyl-maleimide (1.50 mmol, 167 mg) were added. The reaction vessel was sealed and the mixture was subject to microwave irradiation (max. 50 W, 2450 MHz) under stirring at 150 °C for 20 min. After cooling, compound 5 precipitated from the reaction mixture. It was obtained as a colorless solid (84% yield) after washing with CH₂Cl₂. Further purification was not necessary. The assignment of the NMR signals was carried out according to the numbering given in Table [2] .
Mp 257 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.31 (d, ³ J _9,4 = 9.0 Hz, 1 H, H-9), 7.75 (m, 2 H, H-12), 7.05 (m, 2 H, H-13), 6.35 (ddd, ³ J _{6,7 eq} = 6.3 Hz, ³ J _{6,7 ax} = 4.0 Hz, ⁴ J _6,4 = 1.8 Hz, 1 H, H-6), 5.07 (m, 1 H, H-4), 3.82 (s, 3 H, H-15), 3.62 (dd, ³ J _3a,4 = 9.0 Hz, ³ J _3a,7a = 7.0 Hz, 1 H, H-3a), 3.32 (m, 1 H, H-7a), 2.82 (s, 3 H, H-8), 2.63 (ddd, ² J _{7 eq ,7 ax} = 16.7 Hz, ³ J _{7 eq ,6} = 6.3 Hz, ³ J _{7 eq ,7a} = 3.2 Hz, 1 H, H-7 _eq ), 2.46 (m, 1 H, H-7 _ax ) ppm. ¹³C{¹H} NMR (125 MHz, DMSO-d ₆): δ = 179.0 (CO), 177.8 (CO), 165.3 (CO), 161.9 (C-14), 129.7 (C-6), 128.9 (C-12), 126.0 (C-11), 122.7 (C-5), 113.8 (C-13), 55.4 (C-15), 47.7 (C-4), 43.6 (C-3a), 37.4 (C-7a), 25.1 (C-7), 24.6 (C-8) ppm. IR (mull): ν = 3403 (m), 1769 (m), 1695 (s), 1665 (s), 1617 (w), 1604 (m), 1575 (m), 1533 (m), 1498 (s), 1351 (w), 1323 (m), 1313 (m), 1284 (m), 1253 (m), 1223 (w), 1185 (m), 1135 (w), 1107 (m), 1044 (w), 1024 (m), 1009 (m), 954 (w), 929 (w), 882 (w), 850 (m), 818 (m), 782 (m), 767 (m), 723 (w), 699 (w), 654 (w), 611 (m), 595 (m), 580 (s) cm^-1. MS (EI): m/z (%) = 394 (1) [M]⁺, 392 (1) [M]⁺, 313 (100) [M - Br]⁺, 259 (46) [M - C₈H₇O₂]⁺, 257 (45) [M - C₈H₇O₂]⁺, 202 (77), 135 (99), 112 (12), 107 (21), 92 (24), 77 (43), no further peaks >10%. HRMS (EI): m/z calcd for C₁₇H₁₇ ⁷⁹BrN₂O₄: 392.0366; found: 392.0355 [M]⁺.