A. A.-M. Abdel-Aziz / Tetrahedron Letters 48 (2007) 2861–2865
2865
Usifer, D. J. Org. Chem. 1985, 50, 1125–1126; (f)
Houghton, P. G.; David, F. P.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 1985, 1471–1479; (g) Kobayashi, T.;
Nitta, M. Chem. Lett. 1986, 9, 1549–1552; (h) Katritzky,
A. R.; Aurrecoechea, J. M. Synthesis 1987, 4, 342–345; (i)
Kobayashi, T.; Kawate, H.; Kakiuchi, H.; Kato, H. Bull.
Chem. Soc. Jpn. 1990, 63, 1937–1942; (j) Kiselyov, A. S.
Tetrahedron Lett. 1995, 36, 9297–9300; (k) Promod, S.;
Dipak, P.; Jagir, S. S. Tetrahedron Lett. 2003, 44, 8725–
8727, and references cited therein.
H, 6.39; N, 9.01. Calcd for C22H20N2: C, 84.58; H, 6.45;
N, 8.97. Spectroscopic data for 2-(1-adamantyl)-3-cyano-
4,6-diphenylpyridine (11). Yield 69%; white crystals, mp
198–199 ꢁC (MeCN). IR (KBr): m 2983 (aromatic CH),
2216 (CN), 1608, 1587 (C@N, C@C) cmÀ1 1H NMR
;
(500 MHz, DMSO-d6, d ppm): 1.47 (s, 6H, adamantane-
H), 1.51 (d, 3H, J = 12.0 Hz, adamantane-H), 1.67 (d, 3H,
J = 12.1 Hz, adamantane-H), 2.06 (s, 3H, adamantane-
H), 7.19–7.50 (m, 10H, Ph-H), 7.69 (s, 1H, Pyr-H).
Analysis found: C, 85.98; H, 6.70; N, 7.14. Calcd for
C28H26N2: C, 86.12; H, 6.71; N, 7.17.
8. (a) Fatma, E. G.; Abdel-Aziz, A. A.-M.; Omar, A. Bioorg.
Med. Chem. 2004, 12, 1845–1852; (b) Abdel-Aziz, A. A.-
M.; El-Subbagh, H. I.; Kunieda, T. Bioorg. Med. Chem.
2005, 13, 4929–4935.
9. (a) Penney, J. M.; Miller, J. A. Tetrahedron Lett. 2004, 45,
4989–4992; (b) Miller, J. A.; Dankwardt, J. W.; Penney, J.
M. Synthesis 2003, 1643–1648.
16. Spectroscopic data for 2-tert-butyl-4,6-diphenylnicotinic
acid (22). Yield 88%; white crystals, mp 183–184 ꢁC
(methanol). IR (KBr): m 3321 (carboxyl OH), 2960
(aromatic CH), 1721 (carboxyl C@O), 1606, 1571 (C@N,
C@C) cmÀ1; 1H NMR (500 MHz, DMSO-d6, d ppm): 1.11
(s, 9H, t-Bu), 7.30–7.66 (m, 10H, Ph-H), 8.11 (s, 1H, Pyr-
H), 12.15 (s, 1H, OH). Analysis found: C, 79.68; H, 6.46;
N, 4.15. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23.
Spectroscopic data for 2-(1-adamantyl)-4,6-diphenylnico-
tinamide (23). Yield 86%; white crystals, mp 211–212 ꢁC
(ethanol). IR (KBr): m 3431, 3254, 3145 (NH2), 2991
(aromatic CH), 1685 (C@O), 1610, 1584 (C@N, C@C)
10. Typical procedure is as follows:
a solution of 4
(0.47 mmol) in THF (2.2 mL) and BF3ÆEt2O (134 mg,
0.94 mmol) was added to a suspension of LiC1 (175 mg,
4.13 mmol; dried at 150 ꢁC for 1 h under reduced
pressure), CuCN (185 mg, 2.07 mmol) and organo metal
reagent (1.88 mmol) in THF (9.9 mL) which had been
stirred at À78 ꢁC under nitrogen for 30 min. The mixture
was then stirred at 20 ꢁC for an additional 3 h. The
reaction was quenched by the addition of saturated NH4Cl
aq (1.4 mL) and EtOAc (100 mL) was added. The whole
was washed with (i) satd NH4Cl aq (20 mL · 3), (ii) brine
(45 mL · 3), dried (Na2SO4) and evaporated in vacuo
followed by chromatography on silica gel (hexane–EtOAc
(9:1 to 6:4)) to afford compounds 5–14 (Table 1).
11. Shono, T.; Terauchi, J.; Ohkr, Y.; Matsumura, Y.
Tetrahedron Lett. 1990, 31, 6385–6386.
cmÀ1 1H NMR (500 MHz, DMSO-d6, d ppm): 1.51 (s,
;
6H, adamantane-H), 1.64 (d, 3H, J = 12.0 Hz, adaman-
tane-H), 1.72 (d, 3H, J = 12.1 Hz, adamantane-H), 2.12 (s,
3H, adamantane-H), 6.10 (s, 2H, NH2), 7.26–7.43 (m,
10H, Ph-H), 7.98 (s, 1H, Pyr-H). Analysis found: C, 82.24;
H, 6.78; N, 6.66. Calcd for C28H28N2O: C, 82.32; H, 6.91;
N, 6.86.
17. Initial structures for complexes M-1, M-2, M-3 and M-4
were constructed using the HyperChem program version
5.1.19 The MM+20 (calculations in vacuo, bond dipole
option for electrostatics, Polak-Ribiere algorithm, RMS
12. Normant, J. F.; Alexakis, A.; Ghnbi, A.; Mangeney, P.
Tetrahedron 1989, 45, 507–516.
˚
gradient of 0.01 kcal/A mol) conformational searching in
13. For comparison, 2-methoxy-3-cyano-4,6-diphenylpyridine
was treated with n-BuMgBr and PhCH2MgBr (4.0 equiv)
and BF3ÆEt2O (1.5 equiv) in THF at À78 ꢁC to 20 ꢁC
(10 h) to give the 2-substituted products in 55% and 38%
yields, respectively.
14. (a) Kuramochi, T.; Kakefuda, A.; Sato, I.; Tsukamoto, I.;
Taguchi, T.; Sakamoto, S. Bioorg. Med. Chem. 2005, 13,
717–724; (b) Girgis, A. S.; Kalmouch, A.; Ellithey, M.
Bioorg. Med. Chem. 2006, 14, 8488–8494; (c) Girgis, A. S.;
Hosni, H. M.; Barsoum, F. F. Bioorg. Med. Chem. 2006,
14, 4466–4476.
torsional space was performed. Energy minima were
determined by a semi-empirical method PM321 and
AM122 (as implemented in HyperChem 5.1). The PM3
semi-empirical calculations were performed in the pres-
ence of one molecule of THF which gave good results
compared with AM1 semi-empirical calculations.
18. A study of the detailed substitution reactions and mech-
anism with 2-methoxy-4,6-diphenylpyridine 24 on experi-
mental and theoretical levels will be the subject of a
separate paper.
19. HyperChem version 5.1; Hypercube.
15. Spectroscopic data for 2-tert-butyl-3-cyano-4,6-diphenyl-
pyridine (10). Yield 77%; pale yellow crystals, mp 175–
176 ꢁC (ethanol). IR (KBr): m 2971 (aromatic CH), 2219
20. (a) Profeta, S.; Allinger, N. L. J. Am. Chem. Soc. 1985,
107, 1907–1918; (b) Allinger, N. L. J. Am. Chem. Soc.
1977, 99, 8127–8134.
21. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220.
22. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J.
J. P. J. Am. Chem. Soc. 1985, 107, 3902–3909.
(CN), 1608, 1587 (C@N, C@C) cmÀ1
;
1H NMR (500
MHz, DMSO-d6, d ppm): 1.05 (s, 9H, t-Bu), 7.12–7.45 (m,
10H, Ph-H), 7.71 (s, 1H, Pyr-H). Analysis found: C, 84.50;