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Synlett 2014; 25(18): 2609-2612
DOI: 10.1055/s-0034-1379204
letter
© Georg Thieme Verlag Stuttgart · New York

Highly Efficient Diastereoselective Synthesis of Azabicyclo[2.2.2]octanes

Abdolali Alizadeh*
a   Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: aalizadeh@modares.ac.ir   Email: abdol_alizad@yahoo.com
,
Vahideh Sadeghi
a   Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: aalizadeh@modares.ac.ir   Email: abdol_alizad@yahoo.com
,
Fahimeh Bayat
a   Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: aalizadeh@modares.ac.ir   Email: abdol_alizad@yahoo.com
,
Long-Guan Zhu
b   Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
› Author Affiliations
Further Information

Publication History

Received: 10 August 2014

Accepted after revision: 01 September 2014

Publication Date:
07 October 2014 (online)

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Abstract

A one-pot, diastereoselective synthesis of diverse azabicyclo[2.2.2]octanes from readily available starting materials is reported. The key strategy relies on creation of 2-aminoprop-1-ene-1,1,3-tricarbonitrile through dimerization of malononitrile which undergoes nucleophilic attack on dibenzalacetone at three sites leading to bicyclo[2.2.2]octanes.

Key words

malononitrile - dibenzalacetone - azabicyclo[2.2.2]octanes - one-pot reaction
 

  • References and Notes

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  • 12 A mixture of malononitrile (1 mmol) and NaOH (2 mmol) was stirred at 50 °C for 30 min, after this time dibenzalacetone (1, 1 mmol) and piperidine (one drop) was added and stirred for another 2 h. Upon completion, as monitored by TLC, the mixture was filtered, and the precipitate was washed with EtOH (4 mL) to afford the pure product 2a–f. 2-{4-Cyano-1-hydroxy-5,8-diphenyl-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2a) White powder; yield 0.33 g (89%); mp 195 °C. IR (KBr): 3379 (NH), 3031 (OH), 2245, 2186 and 2151 (CN), 1542 and 1447 (Ar) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.56–1.61 (m, 1 H, CH2), 1.85 (dd, 2 J HH = 12.6 Hz, 3 J HH = 6.3 Hz, 1 H, CH), 1.96 (dd, 2 J HH = 12.6 Hz, 3 J HH = 6.3 Hz, 1 H, CH2), 3.11 (dd, 2 J HH = 11.6 Hz, 3 J HH = 6.1 Hz, 1 H, CH2), 3.25 (dd, 2 J HH = 10.3 Hz, 3 J HH = 5.9 Hz, 1 H, CH2), 3.30–3.35 (m, 1 H, CH), 4.33 (s, 1 H, OH), 5.64 (s, 1 H, NH), 7.03 (d, 3 J HH = 6.4 Hz, 2 H, 2 × CH ortho of Ph), 7.17–7.25 (m, 3 H, 3 × CH of Ph), 7.31–7.48 (m, 5 H, 5 × CH of Ph). 13C NMR (75 MHz, DMSO-d 6): δ = 35.78 and 41.46 (2 × CH2), 42.38 [C(CN)2], 45.09 (2 × CH), 46.42 (C4), 84.87 (C1), 118.03 (CN), 123.6 (2 × CN), 126.9 (CH para of Ph), 127.52 (CH para of Ph), 128.04 (2 CH ortho of Ph), 128.10 (2 × CH ortho of Ph), 128.65 (2 × CH meta of Ph), 130.10 (2 × CH meta of Ph), 138.07 (C ipso ), 142.15 (C ipso ), 159.95 (C3). MS (EI, 70 eV): m/z = 307, 220, 185, 147, 128, 104, 91, 77, 51. Anal. Calcd for C23H18N4O: C, 75.39; H, 4.95; N, 15.29. Found: C, 75.36; H, 4.97; N, 15.30. Crystal Data for 2a C46H38N8O5Na2 (CCDC 1016275): M W = 828.82, a = 15.9057(10) Å, b = 15.8824(11) Å, c = 16.6277(11) Å, α = 90.00° β = 90.00°, γ = 90.00°, V = 4200.5(5) Å3, Z = 4, D c = 1.311mg m–3, F(000) = 1728, radiation, Mo Kα (λ = 0.71073 Å), 2.84 ≤ 2θ ≤ 25.04, intensity data were collected at 295(2) K with a Bruker APEX area-detector diffractometer, and employing ω/2θ scanning technique, in the range of –17 ≤ h ≤ 18, –17 ≤ k ≤ 18, –16 ≤ l ≤ 19; the structure was solved by a direct method, all nonhydrogen atoms were positioned and anisotropic thermal parameters refined from 3225 observed reflections with R (into) = 0.0811 by a full-matrix least-squares technique converged to R = 0.0706 and wR2 = 0.1985 [I > 2σ(I)]. 2-{5,8-Bis-(4-chlorophenyl)-4-cyano-1-hydroxy-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2b) White powder; yield 0.37 g (85%); mp 255 °C. IR (KBr): 3422 (NH), 3046 (OH), 2193 and 2152 (CN), 1533 and 1491 (Ar) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.56–1.58 (m, 1 H, CH2), 1.89–1.91 (m, 2 H, CH and CH2), 3.18–3.21 (m, 3 H, CH and CH2), 3.36 (s, 1 H, OH), 5.74 (s, 1 H, NH), 6.69–7.12 (m, 2 H, 2 × CH of Ar), 7.17–7.33 (m, 2 H, 2 × CH of Ar), 7.37–7.96 (m, 4 H, 4 × CH of Ar). 13C NMR (75 MHz, DMSO-d 6): δ = 35.93 and 38.31 (2 × CH2), 40.88 [C(CN)2], 45.60 (2 × CH), 45.84 (C4), 84.80 (C1), 117.96 (CN), 123.4 (2 × CN), 128.10 (4 × CH of Ar), 130.63 (2 × CH of Ar), 132.05 (2 × CH of Ar), 131.78 and 132.31 (2 × C ipso Cl), 137.14 and 140.88 (2 × C ipso ), 159.39 (C3). MS (EI, 70 eV): m/z = 304, 267, 239, 204, 179, 165, 137, 125, 101. Anal. Calcd for C23H16Cl2N4O: C, 63.46; H, 3.70; N, 12.87. Found: C, 63.44; H, 3.71; N, 12.89. 2-{5,8-Di-(3-bromophenyl)-4-cyano-1-hydroxy-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2c) White powder; yield 0.37 g (70%); mp 181 °C. IR (KBr): 3414 (NH), 3023 (OH), 2187 and 2152 (CN), 1523 and 1454 (Ar) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.58–1.60 (m, 1 H, CH2), 1.82–1.91 (m, 1 H, CH2), 1.91 (dd, 3 J HH = 6.6 Hz, 1 H, CH2), 2.42 (s, 1 H, OH), 3.00–3.05 (m, 1 H, CH2), 3.18–3.20 (m, 1 H, CH2), 3.34 (s, 1 H, CH), 5.64 (s, 1 H, NH), 6.89 (t, 3 J HH = 6.6 Hz, 1 H, CH of Ar), 6.91 (s, 1 H, CH of Ar), 7.03 (d, 3 J HH = 6.6 Hz, 2 H, 2 × CH of Ar), 7.19 (t, 3 J HH = 6.9 Hz, 1 H, CH of Ar), 7.21 (s, 1 H, CH of Ar), 7.32 (d, 3 J HH = 6.6 Hz, 2 H, 2 × CH of Ar). 13C NMR (75 MHz, DMSO-d 6): δ = 35.69 and 41.08 (2 × CH2), 42.5 [C(CN)2], 46.00 (2 × CH), 46.12 (C4), 84.86 (C1), 118.18 (CN), 123.70 (2 × CN), 128.57 (2 × CHof Ar), 128.65 (4 × CH of Ar), 129.98 (2 × CH of Ar), 135.14 (C ipso Br), 135.82 (C ipso Br), 136.57 (C ipso ), 139.30 (C ipso ), 159.84 (C3). MS (EI, 70 eV): m/z = 262, 247, 233, 219, 204, 170, 145, 115. Anal. Calcd for C23H16Br2N4O: C, 52.70; H, 3.08; N, 10.69. Found: C, 52.71; H, 3.11; N, 10.70. 2-{4-Cyano-1-hydroxy-5,8-di-(3-nitrophenyl)-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2d) White powder; yield 0.40 g (87%); mp 230 °C. IR (KBr): 3471 (NH), 3375 (OH), 2184 and 2152 (CN), 1533 and 1460 (Ar), 1533 and 1352 (NO2) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.68–1.70 (m, 1 H, CH2), 1.97–1.99 (m, 2 H, CH and CH2), 3.34–3.35 (m, 3 H, CH and CH2), 5.87 (s, 1 H, OH), 7.46 (d, 3 J HH = 11.9 Hz, 1 H, CH of Ar), 7.66–8.26 (m, 7 H, 7 × CH of Ar), 8.62 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-d 6): δ = 21.9 and 36.19 (2 × CH2), 43.2 [C(CN)2], 45.54 (2 × CHAr), 46.12 (C4), 84.71 (C1), 118.30 (CN), 121.50 (2 × CN), 122.96 (2 × CH of Ar), 123 (CH of Ar), 125.26 (CH of Ar), 129.63 (2 × CH of Ar), 135.73 (CH of Ar), 136.50 (CH of Ar), 140.12 (C ipso ), 143.69 (C ipso ), 147.52 (2 × CH ipso NO2), 158.90 (C3). MS (EI, 70 eV): m/z = 176, 146, 128, 115, 102, 89. Anal. Calcd for C23H16N6O5: C, 60.53; H, 3.53; N, 18.41. Found: C, 60.56; H, 3.54; N, 18.40. 2-{4-Cyano-1-hydroxy-5,8-di-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2e) White powder; yield 0.32 g (76%); mp 230 °C. IR (KBr): 3487 (OH and NH), 2189 and 2152 (CN), 1542 and 1455 (Ar) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.53–1.55 (m, 1 H, CH2), 1.78–1.80 (m, 1 H, CH), 1.87–1.92 (m, 1 H, CH2), 2.41 (t, 3 J HH = 11.6 Hz, 1 H, CH), 3.04 (dd, 3 J HH = 6.4 Hz, 1 H, CH2), 3.15 (dd, 3 J HH = 5.8 Hz, 1 H, CH2), 3.71 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 5.60 (s, 1 H, OH), 6.78 (d, 3 J HH = 8.6 Hz, 2 H, 2 × CH of Ar), 6.93 (d, 3 J HH = 8.4 Hz, 2 H, 2 × CH of Ar), 6.95 (d, 3 J HH = 8.3 Hz, 2 H, 2 × CH of Ar), 7.35 (d, 3 J HH = 8.5 Hz, 2 H, 2 × CH of Ar), 8.30 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-d 6): δ = 35.67 (2 × CH2), 42.7 [C(CN)2], 45.51 (2 × CH), 46.45 (C4), 55.01 (2 × OMe), 79.16 (C1), 113.39 (4 × CH of Ar), 118.33 (CN), 123.72 (2 × CN), 129.70 (2 × CH of Ar), 130.05 (C ipso ), 131.15 (2 × CH of Ar), 134.31 (C ipso ), 158.08 (C ipso OMe), 158.51 (C ipso OMe), 159.74 (C3). MS (EI, 70 eV): m/z = 294, 186, 161, 145, 134, 121, 89. Anal. Calcd for C25H22N4O3: C, 70.41; H, 5.20; N, 13.14. Found: C, 70.41; H, 5.21; N, 13.13. 2-{4-Cyano-5,8-di-(3,4-dimethoxyphenyl)-1-hydroxy-2-azabicyclo[2.2.2]oct-3-yliden}malononitrile (2f) White powder; yield 0.43 g (88%); mp 230 °C. IR (KBr): 3421 (NH), 3250 (OH), 2189 and 2155 (CN), 1521 and 1446 (Ar) cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.54–1.56 (m, 1 H, CH2), 1.78–1.80 (m, 1 H, CH), 1.87–1.91 (m, 1 H, CH2), 2.40 (t, 3 J HH = 11.0 Hz, 1 H, CH), 3.04–3.06 (m, 1 H, CH2), 3.18–3.20 (m, 1 H, CH2), 3.31 (s, 1 H, OH), 3.69 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.78 (s, 6 H, 2 × OMe), 5.63 (s, 1 H, NH), 6.47 (d, 3 J HH = 7.6 Hz, 1 H, CH of Ar), 6.73 (d, 3 J HH = 7.6 Hz, 1 H, CH of Ar), 6.75 (s, 1 H, CH of Ar), 6.97 (d, 3 J HH = 7.6 Hz, 2 H, 2 × CH of Ar), 6.99 (s, 1 H, CH of Ar). 13C NMR (75 MHz, DMSO-d 6): δ = 35.85 and 41.25 (2 × CH2), 42.71 [C(CN)2], 45.87 (C4), 46.34 (2 × CH),55.06 (OMe), 55.24 (OMe), 55.38 (OMe), 55.56 (OMe), 84.83 (C1), 110.68, 111.24, 111.47 and 114.78 (4 × CH of Ar), 118.39 (CN), 121.24 and 121.54 (2 × CH of Ar), 123.74 (2 × CN), 130.46 (C ipso ), 134.81 (C ipso ), 147.73, 147.94, 148.10 and 148.44 (4 × C ipso OMe), 159.91 (C3). MS (EI, 70 eV): m/z = 358, 239, 191, 165, 151, 123, 107, 91. Anal. Calcd for C27H26N4O5: C, 66.66; H, 5.39; N, 11.52. Found: C, 66.64; H, 5.41; N, 11.53.