1316
H. D. H. Showalter
Vol 43
4-Bromo-1-chloro-1,6-naphthyridine (12a).
Anal. Calcd. for C8H10N2O · HCl: C, 51.48; H, 5.94; N,
15.01; Cl¯, 19.00. Found: C, 51.28; H, 6.05; N, 15.13; Cl¯,
19.40.
A
suspension of 450 mg (2 mmol) of 8-bromo-1,6-
naphthyridine-5(6H)-one (11) and 2 mL (21.5 mmol) of
phosphorus oxychloride was heated at 100 ºC for 28 h. The
solution was concentrated to an oil that was diluted with
dichloromethane. The resultant solution was added cautiously to
cold saturated aqueous potassium bicarbonate. The phases were
separated and aqueous layer was further extracted with
dichloromethane. The combined organic extracts were washed
with water, dried, and concentrated to a solid that was triturated
in ethyl acetate. The precipitate was collected and recrystallized
from ethyl acetate to provide 150 mg (31%) of 12a in two crops;
mp 127-128 ºC; H nmr (deuteriochloroform): ꢀ 9.26 (d, J =
4.2 Hz, 1H), 8.77 (s, 1H), 8.67 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.73
(dd, J = 8.5 Hz, 4.2 Hz, 1H).
Anal. Calcd. for C8H4BrClN2: C, 39.46; H, 1.66; N, 11.50;
Br, 32.82; Cl, 14.56. Found: C, 39.33; H, 1.30; N, 11.45; Br,
32.75; Cl, 14.59.
The above reaction was repeated on a 2.75 g (12.2 mmol)
scale of 11 to provide 2.91 g (98%) of crude 12a showing one
spot by TLC; Rf 0.6 (1:1 ethyl acetate:hexanes). This material
was used directly for the synthesis of 12b below.
5,6-Dihydro-1-methyl-5-oxo-1,6-naphthyridinium iodide (14).
A suspension of 10.84 g (74.2 mmol) of 1,6-naphthyridin-
5(6H)-one (10a), 25.9 mL of iodomethane, and 593 mL of
anhydrous N,N-dimethylformamide was stirred at 25 ºC for 40 h,
and then poured slowly into 185 mL of stirring acetone. The
solids were collected, washed with acetone, and dried to leave
1
19.35 g (91%) of 14 as a yellow solid, mp 249-252 ºC; H nmr
(dimethyl sulfoxide-d6): ꢀ 12.62 (br s, 1H, D2O exchangeable),
9.32 (d, J = 6.0 Hz, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.06 (d, J =
7.7 Hz, 1H), 8.04-7.96 (m, 1H), 6.98 (d, J = 7.7 Hz, 1H), 4.34
(s, 3H).
Anal. Calcd. for C9H9N2OI: C, 37.52; H, 3.15; N, 9.72; I¯,
44.05. Found: C, 37.43; H, 3.04; N, 9.75; I¯, 44.29.
The filtrate was concentrated to leave a residue that was
triturated in hot 2-propanol and then recrystallized from
methanol to give 1.18 g (5%) of a second crop, mp 242-247 ºC.
1
1,2,3,4-Tetrahydro-1-methyl-1,6-naphthyridin-5(6H)-one (15).
An ice-cold solution of 11.2 g (38.9 mmol) of 5,6-dihydro-1-
methyl-5-oxo-1,6-naphthyridinium iodide (14) in 18.5 mL of
88% formic acid was treated dropwise over a 10 min period with
9.4 mL (93 mmol) of borane-pyridine complex. The bath was
removed and the solution was stirred for 3 d. The formed
suspension was concentrated to a residue that was pumped in
vacuo/50 ºC to leave a semisolid that was dissolved in methanol.
The solution was treated with a large excess of Amberlite IRA-
400 (OH¯), and the mixture was stirred at 25 ºC for 3 h. The
resin was filtered off, and the solution was concentrated to a solid
residue that was triturated in hot 2-propanol. After storage at 5
ºC, the solids were collected, washed with 2-propanol, and dried
4-Bromo-1-methoxy-1,6-naphthyridine (12b).
A stirred suspension of 2.91 g (12 mmol) of crude 4-bromo-1-
chloro-1,6-naphthyridine (12a) in 50 mL of dry, ice-cold methanol
was treated portion-wise with ca. 0.85 g (36 mmol) of sodium
metal. The temperature was maintained at 5 ºC for 30 min, and
then at 25 ºC overnight. The mixture was concentrated,
diluted with water, and extracted with dichloromethane (3x).
The combined extracts were washed with brine, dried, and filtered
over a small pad of silica gel, washing the pad with ethyl acetate
to strip off the product. Concentration of the filtrate left a solid
that was crystallized from 2-propanol to give 2.46 g (86%) of 12b
in three crops; mp 97-99 ºC; 1H nmr (deuteriochloroform): ꢀ 9.16
(dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.56 (dd, J = 8.3 Hz, 1.6 Hz, 1H),
8.45 (s, 1H), 7.55 (dd, J = 8.3 Hz, 4.4 Hz, 1H), 4.14 (s, 3H).
Anal. Calcd. for C9H7BrN2O: C, 45.22; H, 2.95; N, 11.72;
Br, 33.42. Found: C, 45.20; H, 2.85; N, 11.70; Br, 33.28.
1
to leave 5.19 g (80%) of 15, mp 260-261 ºC; H nmr (dimethyl
sulfoxide-d6): ꢀ 11.65 (br s, 1H, D2O exchangeable), 7.00 (d, J =
7.4 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 3.16 (t, J = 5.5 Hz, 2H),
2.88 (s, 3H), 2.31 (t, J = 6.3 Hz, 2H), 1.85-1.72 (m, 2H); 1H nmr
(dimethyl sulfoxide-d6/1 drop trifluoroacetic acid): ꢀ 7.64 (d, J =
7.4 Hz, 1H), 6.51 (d, J = 7.4 Hz, 1H), 3.44 (t, J = 5.6 Hz, 2H),
3.10 (s, 3H), 2.56 (t, J = 6.2 Hz, 2H), 1.92-1.80 (m, 2H).
Anal. Calcd. for C9H12N2O · 0.1 H2O: C, 65.12; H, 7.41; N,
16.87. Found: C, 65.10; H, 7.19; N, 16.70.
The filtrate was concentrated to a solid that provided 0.53 g
(8%) of additional 15, mp 260-261 ºC, after two crystallizations.
1,2,3,4-Tetrahydro-1,6-naphthyridine-5(6H)-one (13).
A suspension of 400 mg (2.7 mmol) of 1,6-naphthyridin-5(6H)-
one (10a), 40 mg of 20% palladium/carbon, and 10 mL of 50%
aqueous methanol was stirred under 1 atmosphere of hydrogen at
25 ºC for 3 h. The mixture was filtered through Celite, and the
filtrate was concentrated to leave a foam that was boiled in 2-
propanol and then cooled. The solids were collected, washed with
2-propanol, and dried to leave 120 mg (29%) of 13, mp >250 ºC
(dec); Rf 0.2 (9:1 ethyl acetate:methanol). Processing of the
Acknowledgment.
Special thanks are extended to Barbara Miller for her
assistance in the construction of this manuscript.
1
mother liquor yielded 165 mg (40%) of a second crop; H nmr
REFERENCES AND NOTES
(dimethyl sulfoxide-d6): ꢀ 6.90 (d, J = 7 Hz, 1H), 6.47 (br s, 1H,
D2O exchangeable), 5.56 (d, J = 7 Hz, 1H), 3.12 (t, J = 5 Hz, 2H),
2.31 (t, J = 6 Hz, 2H), 1.78-1.60 (m, 2H).
Anal. Calcd. for C8H10N2O · 0.1 H2O: C, 63.22; H, 6.76; N,
18.43. Found: C, 62.98; H, 6.71; N, 18.44.
Treatment of 270 mg of the free base of 13 with 2-propanolic
hydrogen chloride gave 210 mg (63%) of the hydrochloride salt,
mp 178-180 ºC; 1H nmr (dimethyl sulfoxide-d6): ꢀ 12.50-11.90
(br m, 1.75H, D2O exchangeable), 8.66 (br s, 0.75H, D2O
exchangeable), 7.49 (d, J = 7 Hz, 1H), 6.43 (d, J = 7 Hz, 1H),
3.24 (t, J = 5 Hz, 2H), 2.54 (t, J = 6 Hz, 2H), 1.82-1.66 (m, 2H).
[*] Corresponding author; Email: showalh@umich.edu; Tel:
734.764.5504; Fax: 734.647.8430.
[#] Current address: College of Pharmacy, University of
Michigan, Ann Arbor, MI 48109-1065.
[1] R. W. Pero, A. Olsson, H. Lindgren, and T. Leanderson In:
PARP as a Therapeutic Target, J. Zhang, Ed.; CRC Press LLC: Boca
Raton, 2002; pp 205-221.
[2a] S. Peukert, U. Schwahn, S. Guessregen, H. Schreuder and A.
Hofmeister, Synthesis 1550 (2005); [b] R. J. Griffin, L. C. Pemberton,
D. Rhodes, C. Bleasdale, K. Bowman, A. H. Calvert, N. J. Curtin, B. W.