LETTER
Diastereoselective Synthesis of Azabicyclo[2.2.2]octanes
2611
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In summary, we have developed an efficient and diastereo-
selective approach to the synthesis of azabicyclo-
[2.2.2]octanes by using malononitrile and dibenzalace-
tone. The ready accessibility of the starting materials and
the generality of this process make the reaction highly
valuable in view of the potential interest in these struc-
tures in synthetic and medicinal chemistry. The features
of this strategy include a convenient one-pot operation,
mild conditions, and the absence of byproducts.
References and Notes
(12) A mixture of malononitrile (1 mmol) and NaOH (2 mmol)
was stirred at 50 °C for 30 min, after this time
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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-d6): δ =
1.56–1.61 (m, 1 H, CH2), 1.85 (dd, 2JHH = 12.6 Hz, 3JHH = 6.3
Hz, 1 H, CH), 1.96 (dd, 2JHH = 12.6 Hz, 3JHH = 6.3 Hz, 1 H,
CH2), 3.11 (dd, 2JHH = 11.6 Hz, 3JHH = 6.1 Hz, 1 H, CH2),
3.25 (dd, 2JHH = 10.3 Hz, 3JHH = 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,
3JHH = 6.4 Hz, 2 H, 2 × CHortho 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-d6): 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 (CHpara of Ph), 127.52 (CHpara
of Ph), 128.04 (2 CHortho of Ph), 128.10 (2 × CHortho of Ph),
128.65 (2 × CHmeta of Ph), 130.10 (2 × CHmeta of Ph), 138.07
(Cipso), 142.15 (Cipso), 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): MW = 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, Dc =
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-d6): 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-d6): 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 ×
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2609–2612