H. Ban et al. / Tetrahedron Letters 44 (2003) 6021–6023
6023
2
. Sherlock, M. H.; Kaminski, J. J.; Tom, W. C.; Lee, J. F.;
Wong, S.; Kreutner, W.; Bryant, R. W.; McPhail, A. T.
J. Med. Chem. 1988, 31, 2108.
3
4
5
6
. Kuroda, T.; Suzuki, F.; Tamura, T.; Ohmori, K.; Hosoe,
H. J. Med. Chem. 1992, 35, 1130.
. Santilli, A. A.; Scotese, A. C.; Bauer, R. F.; Bell, S. C. J.
Med. Chem. 1987, 30, 2270.
. Muraoka, M.; Ioriya, K.; Ohashi, N. World Patent
WO9638445A1; Chem Abstr. 1996, 126, 89279.
. (a) Takayama, K.; Iwata, M.; Hisamichi, H.; Okamoto,
Y.; Aoki, M.; Niwa, A. Chem. Pharm. Bull. 2002, 50,
Scheme 3. Reagents and conditions: (a) 47% aq. HBr, reflux, 2
h; (b) butyl bromide (1.2 equiv.), NaH (1.2 equiv.), DMF, rt,
5
h.
1
050; (b) Takayama, K.; Iwata, M.; Okamoto, Y.; Aoki,
M. World Patent WO9606843A1; Chem Abstr. 1996, 125,
6620.
N-butylnaphthyridine (Scheme 3). Such N-alkylation
would provide a variety of N-substituted 4-aryl-1,8-
naphthyridin-2(1H)-ones.
8
7
. (a) El-Taweel, F. M. J. Prakt. Chem. 1990, 332, 762; (b)
Kubo, K.; Ito, N.; Isomura, Y.; Sozu, I.; Homma, H.;
Murakami, M. Yakugaku Zasshi 1979, 99, 788.
. Davis, H. L.; Gedir, R. G.; Hawes, E. M. Eur. J. Med.
Chem. Chim. Ther. 1985, 20, 381.
In summary, we have developed a convenient synthesis
of 4-aryl-1,8-naphthyridin-2(1H)-one derivatives start-
ing from 2-chloronicotinic acid employing the Suzuki
coupling reaction in the biaryl bond formation.
8
9
. Turner, J. A. J. Org. Chem. 1990, 55, 4744.
1
0. Lutz, R. E.; Codington, J. F.; Rowlett, R. J.; Deinet, A.
J.; Bailey, P. S. J. Am. Chem. Soc. 1946, 68, 1810.
1. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
2. Hersperger, R.; Bray-French, K.; Mazzoni, L.; M u¨ ller, T.
J. Med. Chem. 2000, 43, 675.
Cyclization procedure: 2-(Benzylamino)nicotinic acid
5
b (2.00 g, 8.76 mmol) was suspended in a mixture of
1
1
acetic anhydride (25 mL) and acetic acid (17 mL) under
a nitrogen atmosphere, and the mixture was stirred
under reflux for 2 h. After cooled, volatile materials
was evaporated, and the residue was purified by silica
gel chromatography to give 1-benzyl-2-oxo-1,2-dihy-
13. Kelly, T. R.; Bridger, G. J.; Zhao, C. J. Am. Chem. Soc.
1990, 112, 8024.
1
8
14. Brunel, S.; Montginoul, C.; Torreilles, E.; Giral, L. J.
Heterocyclic Chem. 1980, 17, 235.
dro-1,8-naphthyridin-4-yl acetate 6b (1.62 g, 63%).
1
5. (a) Ullman, U. Liebigs Ann. Chem. 1907, 355, 320; (b)
Nantka-Namirski, P. Acta. Pol. Pharm. 1967, 24, 113.
6. (a) Suzuki, F.; Kuroda, T.; Kawakita, T.; Manabe, H.;
Kitamura, S.; Ohmori, K.; Ichimura, M.; Kase, H.;
Ichikawa, S. J. Med. Chem. 1992, 35, 4866; (b) Kuroda,
T.; Suzuki, F. J. Heterocyclic Chem. 1991, 28, 2029.
7. Buckle, D. R.; Cantello, B. C. C.; Smith, H.; Spicer, B.
A. J. Med. Chem. 1975, 18, 726.
The Suzuki coupling: 1-Butyl-4-chloro-1,8-naph-
thyridin-2(1H)-one 8a (100 mg, 0.384 mmol), phenyl-
boronic acid (56.2 mg, 0.461 mmol), Cs CO (225 mg,
1
2
3
0
.691 mmol), and Pd(PPh ) (22.2 mg, 5 mol%) were
3 4
suspended in 1,4-dioxane (7 mL) under a nitrogen
atmosphere, and the mixture was stirred under reflux
for 4 h. The reaction mixture was cooled to room
temperature, and water was added. The organic materi-
als were extracted with ethyl acetate (20 mL), washed
1
1
−
1 1
8. Mp 133–134°C; IR (neat): w 1770, 1651 cm ; H NMR
DMSO-d , 300 MHz), l (ppm) 2.44 (3H, s), 5.60 (2H, s),
(
with brine (20 mL), and dried over MgSO . The solvent
6
4
6.70 (1H, s), 7.20–7.30 (5H, m), 7.37 (1H, dd, J=4.6, 7.9
was removed under vacuum, and the residue was
Hz), 7.26 (1H, dd, J=1.7, 7.9 Hz), 8.68 (1H, dd, J=1.7,
purified by silica gel chromatography to give 1-butyl-4-
19
4.6 Hz). Anal. calcd for C H N O : C, 69.38; H, 4.79;
phenyl-1,8-naphthyridin-2(1H)-one (96.4 mg, 90%).
17 14
2
3
N, 9.52. Found: C, 69.53; H, 4.65; N, 9.63.
6b
−1
19. Mp 96–97°C (lit. Mp 96–97°C); IR (neat): w 1647 cm ;
1
H NMR (DMSO-d , 300 MHz), l (ppm) 0.92 (3H, t,
References
6
J=7.4 Hz), 1.37 (2H, qt, J=7.4, 7.4 Hz), 1.64 (2H, tt,
J=7.4, 7.4 Hz), 4.42 (2H, t, J=7.4 Hz), 6.60 (1H, s), 7.28
1
. For review of the synthesis of 1,8-naphtyridin-2(1H)-
ones, see: (a) Paudler, W. W.; Kress, T. J. Adv. Hetero-
cyclic Chem. 1970, 11, 123; (b) Cheng, C.; Yan, S.-J. Org.
React. 1982, 28, 37; (c) Paudler, W. W.; Sheets, R. M.
Adv. Heterocyclic Chem. 1983, 33, 147.
(
1H, dd, J=4.6, 7.9 Hz), 7.48–7.55 (5H, m), 7.85 (1H, d,
J=7.9 Hz), 8.68 (1H, d, J=4.6 Hz). Anal. calcd for
C H N O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.74;
18
18
2
H, 6.49; N, 9.84.