T. Cailly et al. / Tetrahedron Letters 46 (2005) 135–137
137
Table 4. Ortholithiation and trapping of 2- or 3-cyanopyridine in a two
step sequence at À80ꢁC, using 2equiv of LiTMP and I2 or C2Cl6 as
electrophiles
2. (a) Chen, C.; Wilcoxen, K. M.; Huang, C. Q.; Xie, Y. F.;
McCarthy, J. R.; Webb, T. R.; Zhu, Y. F.; Saunders, J.;
Liu, X. J.; Chen, T. K.; Bozigian, H.; Grigoriadis, D. E. J.
Med. Chem. 2004, 47, 4787–4798; (b) Roppe, J.; Smith, N.
D.; Huang, D.; Tehrani, L.; Wang, B.; Anderson, J.;
Brodkin, J.; Chung, J.; Jiang, X.; King, C.; Munoz, B.;
Varney, M. A.; Prasit, P.; Cosford, N. D. P. J. Med.
Chem. 2004, 47, 4645–4648.
Cyano group
position
Electrophiles
Products
Yieldsa
(%)
Product
number
CN
I
2
I2
52
19
7a
7b
N
3. (a) Watanabe, M.; Shinoda, E.; Shimizu, Y.; Furukawa, S.
Tetrahedron 1987, 43, 5281–5286; (b) Guillier, F.; Nivo-
´
liers, F.; Godard, A.; Marsais, F.; Queguiner, G.; Sidd-
CN
iqui, M. A.; Snieckus, V. J. Org. Chem. 1995, 60, 292–296;
(c) Ferraris, D.; Ko, Y. S.; Pahutski, T.; Ficco, R. P.;
Serdyiuk, L.; Alemu, C.; Bradford, C.; Chiou, T.; Hoover,
R.; Huang, S.; Lautar, S.; Liang, S.; Lin, Q.; Lu, M. X. C.;
Mooney, M.; Morgan, L.; Qian, Y.; Tran, S.; Williams, L.
R.; Wu, Q. Y.; Zhang, J.; Zou, Y.; Kalish, V. J. Med.
Chem. 2003, 46, 3138–3151.
I
N
I
CN
I
3
I2
56
17
75
37
7
8a
8b
´
4. Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059–
4090.
5. Meyers, A. I.; Gabel, R. A. J. Org. Chem. 1982, 47, 2633–
2637.
6. (a) Epsztajn, J.; Zbnigniew, B.; Brzezinski, J. Z.; Jozwiak,
A. Tetrahedron Lett. 1980, 21, 4739–4742; (b) Epsztajn, J.;
Bienik, A.; Brzezinski, J. Z.; Jozwiak, A. Tetrahedron Lett.
1983, 24, 4735–4738; (c) Epsztajn, J.; Brzezinski, J. Z.;
Jozwiak, A. J. Chem. Res. (s) 1986, 18–19; (d) Epsztajn,
J.; Bienik, A.; Plokta, M. W. J. Chem. Res. (s) 1986, 20–
21.
N
CN
I
I
N
CN
Cl
2
3
C2Cl6
C2Cl6
9
N
CN
Cl
´
7. (a) Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron
Lett. 1999, 40, 5483–5486; (b) Lazaar, J.; Rebstock, A. S.;
´
10a
10b
´
Mongin, F.; Godard, A.; Trecourt, F.; Marsais, F.;
Queguiner, G. Tetrahedron 2002, 58, 6723–6728.
N
´
8. (a) Krizan, T. D.; Martin, J. C. J. Org. Chem. 1982, 47,
2681–2682; (b) Krizan, T. D.; Martin, J. C. J. Am. Chem.
Soc. 1983, 105, 6155–6157.
9. Petnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002,
67, 9276–9287.
CN
Cl
N
a Isolated yields.
´
10. Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Org.
Lett. 2001, 3, 1435–1437.
11. Typical procedure: To a stirred solution under N2 of
2,2,6,6-tetramethylpiperidine (20.2mmol, 3.4mL) in THF
(40mL) was added at À30ꢁC 2.5M n-butyllithium
(19.2mmol, 7.7mL). The solution was allowed to reach
0ꢁC, kept under stirring during 15min and cooled to
À80ꢁC. 4-Cyanopyridine (9.6mmol, 1g) in THF (20mL)
was slowly added to the mixture over 15min. After 30min
of stirring at À80ꢁC, a solution of hexachloroethane
(20.2mmol, 4.78g) in THF (10mL) was slowly added over
15min and the resulting mixture stirred for 30min. The
solution was then allowed to warm slowly to room
temperature. The mixture was quenched with 40mL of a
saturated NH4Cl solution. The solution was extracted
with EtOAc (3 · 100mL), the combined organic layers
were washed with brine (2 · 100mL), dried with MgSO4,
filtered and evaporated under reduced pressure. The
product was purified by silica gel chromatography using
EtOAc/cyclohexane (1:4) as eluent to afford 3-chloroiso-
nicotinonitrile 4 (0.99g, Yield: 75%) as pale orange
needles. 3-Chloroisonicotinonitrile 4: 1H NMR
(400MHz, CDCl3) 7.56 (d, 3J = 4.8Hz, 1H), 8.68 (d,
3J = 4.8Hz, 1H), 8.82 (s, 1H); 13C NMR (100MHz,
CDCl3) 113.7, 120.9, 126.3, 133.1, 148.1, 150.4; IR
(KBr) 3016, 2953, 2475, 2238 (CN), 1573, 1471, 1401,
1384, 1280, 1162, 1036, 840, 795, 708, 576cmÀ1; mp 80ꢁC.
Anal. Calcd for C6H3ClN2 (%): C, 52.01; H, 2.18; N,
20.22; found C, 52.39; H, 2.37; N, 20.32.
was used as an ortho-directing group for the lithiation in
the pyridine series and allowed a facile access to new or
difficult to synthesize pyridine compounds.
Acknowledgements
´
We thank Servier laboratories, the ÔConseil Regional de
Basse-NormandieÕ for financial support and Mr. Yves
Dat for mass spectroscopy.
References and notes
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Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron Lett.
1992, 33, 7355–7356.
´
12. Mallet, M.; Queguiner, G. Tetrahedron 1985, 16, 3433–
3440.