The precipitate thus formed was filtered off and washed with
water.
benzene (100 ml)] was stirred for 1 h. Compound 5 was
obtained as a solid [2.04 g (67%) when methyl acetoacetate was
used as the active methylene compound and 1.64 g (54%) when
ethyl acetoacetate was used as the active methylene compound],
Method B. The active methylene compound 2 (0.03 mol) was
added dropwise to a mixture of sodium hydride (55–60%
sodium hydride in oil; 0.03 mol) in anhydrous benzene (90 ml)
and the thick, white slurry thus formed was stirred at room
temperature for 1 h. Compound 1b (1.4 g, 0.01 mol) was added
to the mixture and stirring continued for 1–2.5 h. Water and
diethyl ether were added to the reaction mixture, and the
aqueous layer was separated and acidified with 10% hydro-
chloric acid, in an ice–water bath. The precipitate thus formed
was filtered off and washed with water.
mp 167–170 ЊC (from CHCl ) (Found: C, 58.01; H, 4.07; N,
3
11.38. C H O N requires C, 58.53; H, 4.09; N, 11.38%);
1
2
10
4
2
δ (300 MHz; CDCl ; Me Si) 2.69 (6 H, s, COCH and N-
H
3
4
3
COCH ), 7.50 (1 H, pseudotriplet, 6-H), 8.98 (1 H, dd, J 7.5,
3
5,6
J5,7 1.9, 5-H), 9.26 (1 H, dd, J6,7 7.5, J5,7 1.9, 7-H) and 15.75
(1 H, br, OH); δ (75 MHz; CDCl ; Me Si) 198.81 (C-COCH ),
C
3
4
3
163.87 (C-4), 163.00 (C-2), 155.30 (N-COCH ), 149.18 (C-8a),
3
144.85 (C-7), 131.90 (C-5), 122.56 (C-4a), 116.37 (C-6), 115.04
1
-Acetyl-3-methoxycarbonyl-4-hydroxy-1,8-naphthyridin-2-
one 3. Following method A.—The reaction mixture [compound
b (1.4 g, 0.01 mol), dimethyl malonate 2 (Y = CO Me, R = Me)
(C-3), 31.87 (C-COCH ) and 23.91 (N-COCH ).
3
3
Methyl [(2-acetylamino-3-pyridyl)hydroxymethylidene]cyano-
acetate 7. Following method A.—The reaction mixture was
stirred at room temperature for 1 h to give the C-acylation
product 7 as a solid (1.57 g, 65%), mp 176–178 ЊC (from EtOH)
(Found: C, 55.18; H, 4.36; N, 15.87. C H O N requires C,
1
(
2
4 g, 0.03 mol) and potassium tert-butoxide (2.24 g, 0.02 mol) in
tert-butyl alcohol 100 ml)] was stirred for 30 min after which it
was acidified with 10% hydrochloric acid to give a coloured pre-
cipitate. This was filtered off and washed with water to afford
the product 3 (2.13 g, 82%), mp 175–176 ЊC (from CHCl ).
Following method B.—The reaction mixture [compound 1b
1
2
11
Ϫ1
4
3
55.17; H, 4.24; N, 16.09%); νmax(Nujol)/cm 2210s (CN), 1720
and 1700s (CO ester, keto form) and 1600s (C᎐C ring stretch-
ing); δ (60 MHz; CDCl ; Me Si) 2.80 (3 H, s, COCH ), 3.78
3
H
3
4
3
(
(
1.4 g, 0.01 mol), dimethyl malonate 2 (Y = CO Me, R = Me)
(3 H, s, CO CH ), 7.08 (1 H, dd, J 8, J5,6 5, 5-H), 8.25–8.48
(2 H, m, 4-H and 6-H), 9.30 (1 H, br, NH) and 12.76 (1 H,
br, OH).
2
2 3 4,5
4 g, 0.03 mol) and sodium hydride (0.03 mol) in anhydrous
benzene (100 ml)] was stirred for 1 h after which it was acidified
with 10% hydrochloric acid to give a coloured precipitate. This
was filtered off and washed with water to afford the product 3
Ethyl [(2-acetylamino-3-pyridyl)hydroxymethylidene]cyano-
acetate 8. Following method A.—The reaction mixture was
stirred at room temperature for 1 h to give the C-acylation
product 8 as a solid (1.80 g, 71%), mp 106–108 ЊC (from CHCl3)
(Found: C 56.67; H 4.82; N 15.91. C H O N requires C,
(
1.23 g, 48%), mp 173–175 ЊC (from CHCl ) (Found: C, 54.94;
3
H, 3.97; N, 10.67. C H O N requires C, 54.96; H, 3.84; N,
1
(
1
2
10
5
2
0.68%); δ (60 MHz; CDCl ; Me Si) 2.70 (3 H, s, COCH ), 4.00
H 3 4 3
13 13
4
Ϫ1
3
3 H, s, CO CH ), 7.50 (1 H, pseudotriplet, 6-H), 9.06 (1 H, dd,
56.72; H, 4.76; N, 15.27%); νmax(Nujol)/cm 3500m (OH),
2
3
J5,6 7, J5,7 1, 5-H), 9.33 (1 H, dd, J6,7 7, J5,7 1, 7-H) and 15.56 (1
2210w (CN), 1710w (CO ester, keto form), 1670s (CO ester,
H, br, OH).
enol form) and 1600s (C=C ring stretching); δ (60 MHz;
H
1
-Acetyl-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-2-one
. Following method A.—The reaction mixture [compound 1b
1.4 g, 0.01 mol), diethyl malonate 2 (Y = CO Et, R = Et) (4.8 g,
CDCl ; Me Si) 1.36 (3 H, t, J 7, CH CH ), 2.83 (3 H, s,
3
4
2
3
4
(
0
COCH ), 4.26 (2 H, q, J 7, CH CH ), 7.09 (1 H, dd, J 8, J5,6 5,
3 2 3 4,5
5-H), 8.28–8.53 (2 H, m 4-H and 6-H), 7.73 (1 H, br, NH) and
12.83 (1 H, br, OH).
2
.03 mol) and potassium tert-butoxide (2.24 g, 0.02 mol) in tert-
butyl alcohol (100 ml)] was stirred for 30 min after which it was
acidified with 10% hydrochloric acid to give a coloured precipi-
tate. This was filtered off and washed with water to afford the
1-Acetyl-3-cyano-4-hydroxy-1,8-naphthyridin-2-one 6. The
C-acylation compound [0.002 mol 7 (0.50 g) or 8 (0.55 g)]
dissolved in a small quantity of ethanol was added to a solution
of sodium ethoxide in ethanol [prepared from sodium (0.09 g,
4 mmol) in absolute ethanol (10 ml)] containing anhydrous
benzene (10 ml). The reaction mixture was refluxed for 3 h
and set aside overnight at room temperature. Water and diethyl
ether were then added to the reaction mixture after which
the aqueous layer was separated, acidified with 10% hydro-
chloric acid and extracted with ethyl acetate and diethyl
ether. The organic layers were combined, dried (Na SO ) and
product 4 (2.37 g, 87%) mp 155–157 ЊC (from CHCl ).
3
Following method B.—The reaction mixture [compound 1b
(
0
(
1
1.4 g, 0.01 mol), diethyl malonate 2 (Y = CO Et, R = Et) (4.8 g,
2
.03 mol) and sodium hydride (0.03 mol) in anhydrous benzene
100 ml)] was stirred for 1 h after which it was acidified with
0% hydrochloric acid to give a coloured precipitate. This was
filtered off and washed with water to afford the product 4 (1.35
g, 40%), mp 157–159 ЊC (from CHCl ) (Found: C 56.70; H 4.46;
3
2
4
N 10.25. C H O N requires C, 56.52; H, 4.38; N, 10.14%);
evaporated in vacuo. The resulting red solid was triturated with
diethyl ether, filtered off and washed with small amounts of
diethyl ether to give the title compound 6 [0.26 g (59%) from 7
1
3
12
5
2
δ (300 MHz; CDCl ; Me Si) 1.43 (3 H, t, J 7,CH CH ), 2.68 (3
H
3
4
2
3
H, s, COCH ), 4.46 (2 H, q, J 7, CH CH ), 7.48 (1 H, pseudotri-
3
2
3
Ϫ1
plet, 6-H), 9.00 (1 H, dd, J5,6 8.1, J5,7 1.6, 5-H), 9.28 (1 H, dd, J6,7
.5, J5,7 1.6, 7-H) and 15.89 (1 H, br, OH); δ (75 MHz; CDCl ;
and 0.25 g (60%) from 8], mp 213–214 ЊC; νmax(Nujol)/cm
6
2210w (CN), 1690m (CO stretching, amide I) and 1610 (C᎐C
C
3
᎐
2
Me Si) 164.51 (CO ester), 163.09 (C-4), 162.22 (C-2), 153.91
ring stretching); δ (60 MHz; CDCl –[ H ]DMSO; Me Si) 2.76
4
H
3
6
4
(
COCH ), 149.30 (C-8a), 144.68 (C-7), 132.05 (C-5), 122.49 (C-
(3 H, s, COCH ), 6.78 (1 H, br, OH), 7.73 (1 H, pseudotriplet,
3
3
4
a), 116.22 (C-6), 109.77 (C-3), 62.03 (CH CH ), 23.27
6-H), 9.00 (1 H, dd, J5,6 8, J5,7 1, 5-H) and 9.93 (1 H, dd, J6.7 8,
J5,7 1, 7-H).
2
3
(COCH ) and 14.21 (CH CH ).
3 2 3
1
,3-Diacetyl-4-hydroxy-1,8-naphthyridin-2-one 5. Following
method A.—The reaction mixture [compound 1b (1.4 g, 0.01
mol), methyl acetoacetate 2 (Y = COMe, R = Me) (2.3 g, 0.02
mol) or ethyl acetoacetate 2 (Y = COMe, R = Et) (2.6 g, 0.02
mol) and potassium tert-butoxide (2.24 g, 0.02 mol) in tert-
butyl alcohol (130 ml)] was stirred for 1 h. Compound 5 was
obtained as a solid [1.88 g (62%) when methyl acetoacetate was
used as the active methylene compound and 1.53 g (50%) when
ethyl acetoacetate was used as the active methylene compound]
References
1
2
M. H. Sherlock, W. C. T. Kaminski, J. F. Lee, S.-C. Wong,
W. Kreutner, R. W. Bryant and A. McPhail, J. Med. Chem., 1988,
3
1, 2108.
(a) T. Duelfer and D. Gala, J. Labelled Compd. Radiopharm., 1991,
29, 651; (b) W. Kreutner, J. Sherwood, S. Sehring, C. Rizzo, R. W.
Chapman, M. I. Siegel and R. W. Egan, J. Pharmacol. Exp.
Ther., 1988, 247, 997; (c) D. J. Blythin, H.-J. Shue, E. Carlon,
J. Spitler and W. Kreutner, Bioorg. Med. Chem. Lett., 1994, 4, 1327.
A. A. Santilli, A. C. Scotese, R. F. Bauer and S. C. Bell, J. Med.
Chem., 1987, 30, 2270.
mp 170–171 ЊC (from CHCl ).
3
Following method B.—The reaction mixture [compound 1b
3
4
(1.4 g, 0.01 mol), methyl acetoacetate 2 (Y = COMe, R = Me)
(3.5 g, 0.03 mol) or ethyl acetoacetate 2 (Y = COMe, R = Et)
(3.9 g, 0.03 mol) and sodium hydride (0.03 mol) in anhydrous
T. Kuroda, F. Suzuki, T. Tamura, K. Ohmori and H. Hosoe, J. Med.
Chem., 1992, 35, 1130.
J. Chem. Soc., Perkin Trans. 1, 1997
1489