Stereoselective Michael Halogenation Initiated Ring Closure (MHIRC) Synthesis of Spirocyclopropanes from Benzylidenemalononitriles and 3-Arylisoxazol-5(4H)-ones

Abstract

The new chemical cascade reaction was found: the direct formation of substituted 4-oxo-2,7-diaryl-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitriles from benzylidenemalononitriles and 3-aryl-2-isoxazol-5(4H)-ones. The action of bromine on the equimolar mixture of benzylidenemalononitrile and 3-aryl-2-isoxazol-5(4H)-one in the basic alcohol solution results in stereoselective formation of spirobicycle containing the 2-isoxazolin-5-one and the cyclopropane fragments in 53–92% yields. Thus, the new simple and efficient ‘one-pot’ approach to substituted (2R*,3R*)-4-oxo-2,7-diaryl-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitriles was found directly from simple and reasonable starting compounds as benzylidenemalonitriles and 3-aryl-2-isoxazol-5(4H)-ones.

Key words

MHIRC reaction - cyclopropane formation - 3-aryl-2-isoxazolin-5(4H)-ones - benzylidenemalononitriles - 5-oxa-6-azaspiro[2.4]hept-6-enes

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• 12 4-Oxo-2,7-diaryl-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitriles 3a-j; General Procedure To a 15 mL EtOH suspension of benzylidenemalononitrile 1 (4 mmol) and 3-aryl-2-isoxazol-5(4H)-one 2 (4 mmol) in a 50 mL beaker, sodium ethylate (4.8 mmol) in alcohol (5 mL) was poured. Then bromine (4 mmol) was added without cooling. The mixture was magnetically stirred at room temperature for 2 h. Then reaction mixture was cooled to –10 °C for 2 h, filtered out, and dried under reduced pressure to give pure 3. (2R*,3R*)-4-Oxo-2,7-diphenyl-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitrile (3a) White solid; yield 0.90 g (72%); mp 188–190 °C. IR (KBr): 3052, 2324, 2248, 1804, 1448, 1132, 872, 764, 700, 612 cm^–1. ¹H NMR (300.1 MHz, DMSO-d ₆): δ = 5.00 (s, 1 H, CH), 7.40–7.47 (m, 3 H, Ph), 7.50–7.66 (m, 5 H, Ph), 7.69–7.75 (m, 2 H, Ph). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 22.4, 40.6, 44.2, 109.1, 110.7, 125.8, 126.5, 128.4 (2 C), 128.8 (2 C), 129.0 (2 C), 129.1 (2 C), 130.0, 131.6, 163.1, 168.4. MS (EI, 70 eV): m/z (%) = 313 (3) [M⁺], 268 (11), 191 (10), 179 (54), 166 (60), 139 (44), 129 (75), 103 (18), 77 (100), 51 (87). Anal. Calcd for C₁₉H₁₁N₃O₂: C, 72.84; H, 3.54; N, 13.41. Found: C, 72.78; H, 3.64; N, 13.46. (2R*,3R*)-2-(4-Nitrophenyl)-4-oxo-7-phenyl-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitrile (3d) White solid; yield 1.07 g (75%); mp 175–177 °C. IR (KBr): 2924, 2340, 2252, 1804, 1520, 1352, 1136, 872, 764, 692 cm^–1. ¹H NMR (300.1 MHz, DMSO-d ₆): δ = 5.19 (s, 1 H, CH), 7.50–7.66 (m, 3 H, Ph), 7.68–7.74 (m, 2 H, Ph), 8.23 (d, J = 8.6 Hz, 2 H, Ar), 8.37 (d, J = 8.6 Hz, 2 H, Ar). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 22.6, 39.5, 40.0, 108.9, 110.3, 123.2 (2 С), 125.8, 128.8 (2 С), 129.0 (2 С), 131.7, 131.9 (2 С), 134.1, 147.8, 162.9, 168.8. MS (EI, 70 eV): m/z (%) = 358 (1) [M⁺], 267 (4), 207 (31), 179 (91), 165 (16), 129 (84), 103 (82), 77 (100), 51 (83). Anal. Calcd for C₁₉H₁₀N₄O₄: C, 72.84; H, 3.54; N, 13.41. Found: C, 63.77; H, 2.75; 15.70. (2R*,3R*)-7-(4-Chlorophenyl)-2-(4-nitrophenyl)-4-oxo-5-oxa-6-azaspiro[2.4]hept-6-ene-1,1-dicarbonitrile (3i) White solid; yield 1.44 g (92%); mp 189–191 °C. IR (KBr): 3048, 2336, 2250, 1796, 1576, 1524, 1356, 1088, 852, 740 cm^–1. ¹H NMR (300.1 MHz, DMSO-d ₆): δ = 5.31 (s, 1 H, CH), 7.65 (d, J = 8.4 Hz, 2 H, Ar), 7.76 (d, J = 8.4 Hz, 2 H, Ar), 7.98 (d, J = 8.3 Hz, 2 H, Ar), 8.30 (d, J = 8.3 Hz, 2 H, Ar). ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 22.6, 23.4, 39.9, 108.8, 110.8, 123.2 (2 C), 124.7, 129.0 (2 C), 130.6 (2 C), 131.0, 131.5 (2 C), 162.2, 168.7. MS (EI, 70 eV): m/z (%) = 392 (1) [M⁺], 302 (2), 267 (2), 213 (43), 163 (27), 137 (44), 99 (28), 75 (54), 44 (76), 30 (100). Anal. Calcd for C₁₉H₉ClN₄O₄: C, 58.10; H, 2.31; Cl, 9.03; N, 14.27. Found: C, 58.08; H, 2.36; Cl, 9.06; N, 14.22.
• 13 Crystal Data for 3f C₁₉H₉FN₄O₄ (M = 376.30 g·mol^–1): monoclinic, space group P21/n (no. 14), a = 15.47733(19) Å, b = 9.22402(10) Å, c = 12.46236(14) Å, β = 89.9765(10)°, V = 1779.17(4) ų, Z = 4, T = 298 K, μ(Cu Kα₁) = 0.926 mm^–1, D _calc = 1.405 g·cm^–3. At average Δd of 0.01 Å (K₁ = 44) the refinement converged to Rp/R_P′/ R_WP/ R_WP′/R_Bragg values of 3.384/7.663/4.545/8.187/1.514% with R_exp/R_exp′ of 0.856/1.543%, GOF = 5.307. CCDC 1454070 contains the supplementary crystallographic data for compound 3f. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.