A Convenient Approach to the Synthesis of Novel Substituted Cyclohexadienes by the Vinylogous Michael Addition of α,α-Dicyanoolefins

Abstract

A concise and efficient approach to substituted cyclohexadienes has been developed. The method involves vinylogous addition of α,α-dicyanoolefins to Michael adduct intermediates, formed from malononitrile and dialkyl acetylenedicarboxylates, in the presence of triethylamine in ethanol. The method has the advantages of good yields and simple operations, and of not requiring a metal catalyst or an inert atmosphere.

Key words

alkenes - nitriles - alkynes - Michael additions - cyclization - cyclohexadienes - addition

• References

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• 24 Dialkyl 5-Amino-4,6,6-tricyano-1-(2-methoxy-2-oxoethyl)cyclohexa-2,4-diene-1-carboxylates (3); General Procedure A mixture of malononitrile (1.0 mmol), dialkyl acetylenedicarboxylate 2 (1.0 mmol), and Et₃N (one drop) in EtOH (5 mL) was stirred at r.t. for 20 min. A solution of α,α-dicyanoolefin 1 (1.0 mmol) and Et₃N (1 mmol) in EtOH (3 mL) was then added. When the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by column chromatography [silica gel, hexane/EtOAc, (1:8)]. Methyl 5-Amino-4,6,6-tricyano-1-(2-methoxy-2-oxoethyl)-3-phenylcyclohexa-2,4-diene-1-carboxylate (3a) Green powder; yield: 0.27 g (72%); mp = 273–275 °C. IR (KBr): 3448, 3361 (NH₂), 2219 (CN), 1726 (CO₂Me), 1633 (C=C), 1570, 1504 (Ar), 1256 cm^–1 (C–O). ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 2.71 (AB system, ² J _HH = 15.6 Hz, 2 H, CH ₂CO₂Me), 3.30 (s, 3 H, OCH₃), 3.45 (s, 3 H, OCH₃), 6.52 (s, 1 H, CH), 7.18 (s, 2 H, NH₂), 7.47–7.49 (m, 2 H, 2 × CH _ortho of Ph), 7.53–7.54 (m, 1 H, CH _para of Ph), 7.47–7.70 (d, ³ J _HH = 6.2 Hz, 2 H, 2 × CH _meta of Ph). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 35.23 (CH₂), 46.08 [C(CN)₂], 50.31 (OCH₃), 53.14 (OCH₃), 58.00 (CCN), 72.11 (C–CO₂Me), 114.58 (CN), 114.72 (CN), 115.34 (CN), 118.30 (CH), 128.24 (CH _para of Ph), 128.43 (2 × CH _meta of Ph), 128.81 (2 × CH _ortho of Ph), 133.26 (C _ipso ), 154.15 (C–Ph), 169.52 (CH₂ CO₂Me), 172.41 (C–NH₂), 180.50 (CO₂Me). MS (EI, 70 eV): m/z = 376 [M⁺], 344, 310, 303, 291, 279, 263, 247, 219, 192, 163, 140, 128, 113, 100, 87, 77, 63, 51. Anal. Calcd for C₂₀H₁₆N₄O₄: C, 63.83; H, 4.28; N, 14.89. Found: C, 63.75; H, 4.21; N, 14.84. Methyl 5-Amino-4,6,6-tricyano-1-(2-methoxy-2-oxoethyl)-3-(4-tolyl)cyclohexa-2,4-diene-1-carboxylate (3b) Yellow powder; yield: 0.26 g (66%); mp = 295–298 °C. IR (KBr): 3443, 3323 (NH₂), 2220 (CN), 1732 (CO₂Me), 1635 (C=C), 1573, 1511 (Ar), 1258 cm^–1 (C–O). ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 2.38 (s, 3 H, CH₃), 2.68 (AB system, ² J _HH = 15.6 Hz, 2 H, CH ₂CO₂Me), 3.30 (s, 3 H, OCH₃), 3.44 (s, 3 H, OCH₃), 6.53, (s, 1 H, CH), 7.11 (s, 2 H, NH₂), 7.35 (d, ³ J _HH = 8.0 Hz, 2 H, 2 × CH of Ar), 7.61 (d, ³ J _HH = 8.4 Hz, 2 H, 2 × CH of Ar). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 21.00 (CH₃), 36.30 (CH₂), 43.56 [C(CN)₂], 48.70 (OCH₃), 50.29 (OCH₃), 58.83 (CCN), 72.00 (C–CO₂Me), 112.59 (2 × CN), 114.79 (CN), 120.14 (CH), 128.16 (2 × CH of Ar), 130.10 (2 × CH of Ar), 130.31 (C_ipso –CH₃), 133.10 (C _ipso ), 155.89 (C–Ph), 169.59 (CH₂ CO₂Me), 172.73 (C–NH₂), 180.78 (CO₂Me). MS (EI, 70 eV): m/z = 390 [M⁺], 360, 330, 291, 260, 232, 217, 205, 190, 178, 151, 140, 115, 102, 91. Anal. Calcd for C₂₁H₁₈N₄O₄: C, 64.61; H, 4.65; N, 14.35. Found: C, 64.55; H, 4.73; N, 14.40. Ethyl 5-Amino-4,6,6-tricyano-1-(2-ethoxy-2-oxoethyl)-3-phenylcyclohexa-2,4-diene-1-carboxylate (3c) Yellow powder; yield: 0.24 g (58%); mp = >300 °C. IR (KBr): 3456, 3372 (NH₂), 2359, 2224 (CN), 1734 (CO₂Et), 1639 (C=C), 1575, 1515 (Ar), 1265 cm^–1 (C–O). ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 1.02 (t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 1.03 (, t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 2.67 (2 H, AB system, ² J _HH = 16.0 Hz, CH ₂CO₂Et), 3.62–3.71 (m, 2 H, OCH ₂CH₃), 3.85–3.96 (m, 2 H, OCH ₂CH₃), 6.48 (s, 1 H, CH), 7.15 (s, 2 H, NH₂), 7.47–7.50 (m, 2 H, 2 × CH _meta of Ph), 7.53–7.55 (m, 1 H, CH _para of Ph), 7.70 (d, ³ J _HH = 6.4 Hz, 2 H, 2 × CH _ortho of Ph). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 10.35 (OCH₂ CH₃), 14.36 (OCH₂ CH₃), 36.83 (CH₂), 44.01 [C(CN)₂], 58.71 (CCN), 62.19 (OCH₂CH₃), 58.80 (OCH₂CH₃), 70.24 (C–CO₂Et), 112.60 (2 × CN), 114.8 (CN), 123.91 (CH), 128.17 (2 × CH _meta of Ph), 130.08 (2 × CH _ortho of Ph), 130.34 (CH _para of Ph), 133.28 (C _ipso ), 156.09 (C–Ph), 164.53 (CH₂ CO₂ Et), 169.54 (C–NH₂), 180.7 (CO₂Et). MS (EI, 70 eV): m/z = 404 [M⁺], 347, 319, 291, 256, 243, 217, 205, 194, 173, 159, 145, 129, 117, 103, 91, 71, 59. Anal. Calcd for C₂₂H₂₀N₄O₄: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.42; H, 4.90; N, 13.91. Ethyl 5-Amino-4,6,6-tricyano-1-(2-ethoxy-2-oxoethyl)-3-(4-tolyl)cyclohexa-2,4-diene-1-carboxylate (3d) Yellow powder; yield: 0.30 g (70%); mp = >300 °C. IR (KBr): 3462, 3364, (NH₂), 2213 (CN), 1729 (CO₂Et), 1630 (C=C), 1553, 1540 (Ar), 1227 and 1150 cm^–1 (C–O). ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 1.01 (t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 1.03 (t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 2.38 (s, 3 H, CH₃), 2.65 (AB system, ² J _HH = 15.6 Hz, 2 H, CH ₂COOCH₂CH₃), 3.61–3.70 (m, 2 H, OCH ₂CH₃), 3.81–3.98 (m, 2 H, OCH ₂CH₃), 6.42 (s, 1 H, CH), 7.10 (s, 2 H, NH₂), 7.35 (d, ³ J _HH = 8.00 Hz, 2 H, 2 × CH of Ar), 7.61 (d, ³ J _HH = 8.00 Hz, 2 H, 2 × CH of Ar). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 11.42 (OCH₂CH ₃), 14.36 (OCH₂CH ₃), 21.01 (CH₃), 36.75 (CH₂), 44.01 [C(CN)₂], 57.91 (CCN), 58.71 (OCH ₂CH₃), 61.77 (OCH ₂CH₃), 72.44 (C–CO₂Et), 112.60 (2 × CN), 114.80 (CN), 123.91 (CH), 128.17 (2 × CH of Ar), 130.08 (2 × CH of Ar), 130.90 (C_ipso–CH₃), 133.42 (C _ipso ), 155.78 (C–Ph), 164.57 (CH₂ CO₂Et), 171.90 (C–NH₂), 179.95 (CO₂Et). MS (EI, 70 eV): m/z = 418 [M⁺], 405, 345, 319, 305, 291, 259, 205, 173, 159, 144, 129, 103, 91, 71, 59. Anal. Calcd for C₂₃H₂₂N₄O₄: C, 66.02; H, 5.30; N, 13.39. Found: C, 65.98; H, 5.36; N, 13.31. Methyl 3-Amino-2,2,4-tricyano-1-(2-methoxy-2-oxoethyl)-1,2,9,10-tetrahydrophenanthrene-1-carboxylate (3e) Green powder; yield: 0.30 g (75%); mp = 293 °C (dec.). IR (KBr): 3445 (NH₂), 2939 (CH), 2359, 2226 (CN), 1721 (CO₂Me), 1655 (C=C), 1570, 1450 (Ar), 1196 (C–O) cm^–1. ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 2.15–2.18 (m, 2 H, CH₂), 2.24–2.27 (m, 2 H, CH₂), 2.71 (AB system, ² J _HH = 15.6 Hz, 2 H, CH ₂CO₂Me, 3.58 (s, 3 H, OCH₃), 3.90 (s, 3 H, OCH₃), 7.16 (s, 2 H, NH₂), 7.44 (t, ³ J _HH = 7.2 Hz, 1 H, CH of Ar), 7.55 (t, ³ J _HH = 7.2 Hz, 1 H, CH of Ar), 7.72 (d, ³ J _HH = 7.6 Hz, 1 H, CH of Ar), 7.89 (d, ³ J _HH = 7.6 Hz, 1 H, CH of Ar). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 23.79 (CH₂), 24.42 (CH₂), 40.57 (CH₂), 41.59 [C(CN)₂], 51.00 (OCH₃), 54.90 (OCH₃), 55.89 (CCN), 75.47 (C–CO₂Me), 113.24 (CN), 113.78 (CN), 114.09 (CN), 126.47 (CH of Ar), 126.58 (C=C–CH₂), 128.17 (CH of Ar), 129.75 (CH of Ar), 133.69 (CH of Ar), 133.77 (C _ipso ), 139.54 (C _ipso ), 139.73 (C=C–CH₂), 173.58 (CH₂ CO₂Me), 174.46 (C–NH₂), 181.55 (CO₂Me). MS (EI, 70 eV): m/z = 402 [M⁺], 386, 368, 321, 209, 193, 178, 166, 151, 139, 128, 115, 102, 83, 69, 57. Anal. Calcd for C₂₂H₁₈N₄O₄: C, 65.67; H, 4.51; N, 13.92. Found: C, 65.73; H, 4.44; N, 13.84. Ethyl 3-Amino-2,2,4-tricyano-1-(2-ethoxy-2-oxoethyl)-1,2,9,10-tetrahydrophenanthrene-1-carboxylate (3f) Yellow powder; yield: 0.27 g (63%); mp = >300 °C. IR (KBr): 3450, 3368 (NH₂,), 2925 (CH), 2220 (CN), 1732 (CO₂Et), 1636 (C=C), 1573, 1513 (Ar), 1263 (C–O) cm^–1. ¹H NMR (400.1 MHz, DMSO-d ₆): δ = 1.18 (t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 1.40 (t, ³ J _HH = 7.2 Hz, 3 H, OCH₂CH ₃), 2.10–2.18 (m, 2 H, CH₂), 2.20–2.28 (m, 2 H, CH₂), 2.67 (AB system, ² J _HH = 15.6 Hz, 2 H, CH ₂CO₂Et), 4.00–4.10 (m, 2 H, OCH ₂CH₃), 4.28–4.41 (m, 2 H, OCH ₂CH₃), 7.16 (s, 2 H, NH₂), 7.45 (t, ³ J _HH = 7.2 Hz, 1 H, CH⁶ of Ar), 7.54 (t, ³ J _HH = 7.2 Hz, 1 H, CH⁷ of Ar), 7.68 (d, ³ J _HH = 7.6 Hz, 1 H, CH⁸ of Ar), 7.59 (d, ³ J _HH = 7.6 Hz, 1 H, CH⁵ of Ar). ¹³C NMR (100.62 MHz, DMSO-d ₆): δ = 10.34 (OCH₂ CH₃), 14.38 (OCH₂ CH₃), 23.78 (CH₂), 24.41 (CH₂), 40.73 (CH₂), 41.59 [C(CN)₂], 55.77 (CCN), 58.79 (OCH₂CH₃), 62.17 (OCH₂CH₃), 75.46 (C–CO₂Et), 113.54 (CN), 113.78 (CN), 114.07 (CN), 126.47 (CH of Ar), 126.58 (C=C–CH2), 128.16 (CH of Ar), 129.74 (CH of Ar), 133.69 (CH of Ar), 133.77 (C _ipso ), 139.53 (C _ipso ), 139.76 (C=C–CH2), 173.47 (CH₂ CO₂Et), 177.16 (C–NH₂), 182.60 (CO₂Et). MS (EI, 70 eV): m/z = 386, 362, 321, 209, 193, 178, 166, 151, 139, 128, 115, 102, 89, 77, 63, 51. Anal. Calcd for C₂₄H₂₂N₄O₄: C, 66.97; H, 5.15; N, 13.02. Found: C, 66.91; H, 5.10; N, 13.09.
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