Jpn. 1976, 49, 3177–3180; (f) Dalton, J. R.; Regen, S. L. J. Org.
Chem. 1979, 44, 4443–4444; (g) Akita, Y.; Shimazaki, M.; Ohta,
A. Synthesis 1981, 974–975; (h) Anderson, Y.; Lẩngström, B. J.
Chem. Soc. Perkin Trans. 1994, 1, 1395–1400; (i) Anderson, B.
A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepsiec,
J. P. J. Org. Chem. 1998, 63, 8224–8228; (j) Grossman, O.;
Gelman, D. Org. Lett. 2006, 8, 1189–1191; (k) Weissman, S. A.;
Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508–1510; (l)
Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46,
2585–2588; (m) Pitts, M. R.; McCormack, P.; Whittall, J.
Tetrahedron 2006, 62, 4705–4708; (n) Schareina, T.; Zapf, A.;
Beller, M. J. Organomet. Chem. 2004, 689, 4576–4583. (o)
Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.;
Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9(8), 1828–1836; (p)
Hajipoura, A. R.; Karami, K.; Pirisedigh, A. Appl. Organometal.
Chem. 2010, 24, 454–457.
9. Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779–
794.
10. Hu, W. X.; Pankayatselvan, R.; Guziec, F. S. Organic Preparation
and Procedure International 1994, 26, 685–687.
11. Göhring, W.; Schildknecht, J.; Federspiel, M. Chimia, 1996, 50,
538–543.
In summary,
a new and practical synthesis of 2-
cyanopyrimidines by the displacement of 2-chloropyrimidines
with potassium cyanide catalyzed by 3-quinuclidinol is described
12. Altman, E.; Hayakama, K.; Iwasaki, G. PCT Int. Appl. WO
03/020278 A1.
13. Drewes, S. E.; Freese, S. D.; Emslie, N. D.; Roos, G. H. P. Synth.
Commun.1988, 18, 1565–1572.
Acknowledgments
We thank Mr. Ruoqiu Wu for helpful discussions.
14. Typical procedure for Table 1, entries 2–8: A mixture of 2-
chloropyrimidines (10 mmol), potassium cyanide (13–15 mmol),
water (20 mmol), and DMSO (20 mL) was heated to 60 oC.
A
.
solution of 3-quinuclidinol (0.1–0.2 mmol) in DMSO (5 mL) was
added to the reaction mixture over 0.5 h. The reaction mixture
was stirred at 50–70 C for additional hours as specified in Table
References and notes
o
1. Upon completion, the mixture was cooled to room temperature
and water (50 mL) was added. The resulting mixture was
extracted with isopropyl acetate (3 x 40 mL) (product 7a
precipitated out after water addition and was collected by
filtration). The combined organic layers were washed with water
(2 x 30 mL), dried over MgSO4, filtered, and concentrated under
vacuum to give crude 2-cyanopyrimidines, which were purified by
column chromatography (SiO2) to afford pure products.
1. Grundmann, C. In Houben-Weyl: Methoden der organischen
Chemie, 4th ed., Falbe, J., Ed., Georg Thieme: Stuttgart, 1985;
Vol. E5, 1985, pp 1313–1527.
2. Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances: Syntheses, Patents, Applications, 4th
ed., Georg Thieme Verlag, Stuttgart, New York, 2001.
3. (a) Moon, J. B.; Coleman, R. S.; Hanzlik, R. P. J. Am. Chem. Soc.
1986, 108, 1350–1351; (b) Thompson, S. A.; Andrew, P. R.;
Hanzlik, R. P. J. Med. Chem. 1986, 29, 104–111; (c) Robichaud,
J.; Bayly, C.; Oballa, R.; Prasit, P.; Mellon, C.; Falgueyret, P.;
Percival, M. D.; Wesolowski, G.; Rodan, S. B. Bioorg. Med.
Chem. Lett. 2004, 14, 4291–4295; (d) Altmann, E.; Cowan-Jacob,
S. W.; Missbach, M. J. Med. Chem. 2004, 47, 5833–5836.
4. (a) Altmann, E.; Aichholz, R.; Betschart, C.; Buhl, T.; Green, J.;
Irie, O.; Teno, N.; Lattmann, R.; Tintelnot-Blomley, M.;
Missbach, M. J. Med. Chem., 2007, 50, 591–594; (b) Irie, O.;
2008, 18, 4642–4646.
o
1
Representative products, 1a: mp 204–205 C; H NMR (DMSO-
d6, 300 MHz) δ 8.90–8.82 (m, 1H), 8.10 (s, 1H), 7.81–7.74 (m,
2H), 6.95 (d, J = 9.0 Hz, 2H), 4.38 (d, J = 5.9 Hz, 2H), 3.37 (s,
1H), 3.27–3.18 (m, 6H), 2.46–2.31 (m, 4H), 2.19 (s, 3H), 0.90 (s,
9H); 13C NMR (DMSO-d6, 75 MHz) δ 167.6, 160.9, 154.5, 153.5,
143.0, 129.1, 122.1, 118.8, 116.7, 113.7, 54.7, 52.0, 47.1, 46.1,
37.5, 32.4, 27.6; MS (ESI) 422.3 (M + H+); Anal. Calcd for
C23H31N7O: C, 65.56; H, 7.36; N, 23.27. Found: C, 65.33; H,
7.56; N, 23.40. 4a: oil; 1H NMR (CDCl3, 300 MHz) δ 8.71 (s, 2H),
2.79 (q, J = 7.7 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 157.8, 143.2, 140.3, 116.2, 24.2, 14.7; MS
(ESI) 134.3 (M + H+); Anal. Calcd for C7H7N3: C, 63.09; H, 5.26;
N, 31.54. Found: C, 62.99; H, 5.46.; N, 31.37. 6a: mp 182–183
1
oC; H NMR (CDCl3, 400 MHz) δ 9.01 (s, 2H), 7.58 (d, J = 8.84
5. (a) Mowry, D. F. Chem. Rev. 1948, 42, 189–283; (b) Rosenmund,
K. W.; Struck, E. Chem. Ber. 1919, 52, 1749–1756.
6. (a) Suzuki, N.; Kaneko, Y.; Nomoto, T.; Izawa, Y. J. Chem. Soc.,
Chem. Commun. 1984, 22, 1523–1524; (b) Beletskaya, I. P.;
Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V. J. Organomet.
Chem. 2004, 689, 3810–3812.
Hz, 2H), 7.08 (d, J = 8.84 Hz, 2H), 3.89 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 161.5, 155.0, 142.7, 136.0, 128.5, 124.6,
115.9, 115.4, 55.6; MS (ESI) 211.9 (M + H+). Anal. Calcd for
C12H9N3O: C, 68.24; H, 4.29; N, 19.89. Found: C, 67.71; H,
4.13; N, 19.51. 7a: mp 143–144 oC; 1H NMR (CDCl3, 400 MHz) δ
8.78 (d, J = 5.31 Hz, 1H), 7.74 (d, J = 5.31 Hz, 1H), 7.67 (d, J
=1.01 Hz, 1H), 7.45 (d, J = 3.54 Hz, 1H) 6.65 (dd, J = 1.77 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 158.3, 156.3, 150.0, 146.6,
145.3, 116.4, 115.7, 115.2, 113.3; MS (ESI) 172.9 (M + H+). Anal.
Calcd for C9H5N3O: C, 63.16; H, 2.94; N, 24.55. Found: C,
63.02; H, 2.99.; N, 24.58.
7. Zheng, Q.; Huang, C.; Xie, G.; Xu, C.; Chen, Y. Synth. Commun.
1999, 29, 2349–2353.
8. (a) Cassar, L.; Foa, M.; Montanari, F.; Marinelli, G. P. J.
Organomet. Chem. 1979, 173, 335–339; (b) Sakakibara, Y.;
Okuda, F.; Shimoyabashi, A.; Kirino, K,; Sakai, M.; Uchino, N.;
Takagi, K. Bull. Chem. Soc. Jpn. 1988, 61, 1985–1990; (c)
Sakakibara, Y.; Ido, Y.; Sasaki, K.; Sakai, M.; Uchino, N. Bull.
Chem. Soc. Jpn. 1993, 66, 2776–2778; (d) Takagi, K.; Okamoto,
T.; Sakakibara, Y.; Ohno, A.; Oka, S.; Hayama, N. Bull. Chem.
Soc. Jpn. 1975, 48, 3298–3301; (e) Takagi, K.; Okamoto, T.;
Sakakibara, Y.; Ohno, A.; Oka, S.; Hayama, N. Bull. Chem. Soc.
15. For a review of nucleophilic chiral amines as catalysts in
synthesis, see: France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. Rev. 2003, 103, 2985–3012.
Click here to remove instruction text...