Nov-Dec 2004
Synthesis of Classical and Nonclassical
945
2-Amino-4-oxo-6-benzylthieno[2,3-d]pyrimidines
COOCH CH ), 6.43 (1H, s, 4-H), 6.46-6.53 (2H, d, 5', 6'-H),
2-Amino-4-oxo-6-(2'-methoxybenzyl)thieno[2,3-d]pyrimidine
(5).
2
3
7.03, 7.05 (1H, d, 3'-H), 7.05 (2H, s, NH , exch).
2
Compound 5 (1.7 g, 59%) was obtained from 21 (2.9 g, 10
2-Amino-5-(4'-ethoxycarbonyl-benzyl)thiophene-3-carboxylic
mmol) and chloroformamidine hydrochloride (1.7 g, 15 mmol).
Acid Ethyl ester (25).
1
R = 0.83, (chloroform:methanol = 7:1); mp 291-293 °C; H nmr
f
This compound was obtained as a red oil (2.2 g, 33%); R =
0.65 (hexanes:ethyl acetate = 3:1); H nmr (DMSO-d ): δ 1.19-
1.23 (3H, t, COOCH CH ), 1.30 (3H, t, COOCH CH ), 4.00
f
(DMSO-d ): δ 3.79 (3H, s, C H -OCH ), 3.95 (2H, s, C H -
6
6
4
3
6 4
1
6
CH ), 6.44 (2H, s, 2-NH , exch), 6.74 (1H, s, 5-H), 6.88-7.20
2
2
2
3
2
3
(4H, m, C H ); 10.81 (1H, s, 3-NH, exch).
6
4
(2H, s, C H -CH ), 4.12-4.16 (2H, q, COOCH CH ), 4.28-4.30
6
4
2
2
3
Anal. Calcd. for C
H N O S·0.2H O: C, 57.80; H, 4.64; N,
14 13 3 2 2
(2H, q, COOCH CH ), 6.60 (1H, s, 4-H), 7.15 (2H, s, NH ,
2
3
2
14.44; S, 11.02. Found: C, 57.75; H, 4.58; N, 14.44; S, 11.07.
exch), 7.36-7.95 (4H, m, C H ).
6
4
2-Amino-4-oxo-6-(2',4'-dimethylbenzyl)thieno[2,3-d]pyrimidine
(6).
General Procedure for the Synthesis of Compounds 2-8 and 26.
A solution of hydrogen chloride in diethyl ether (100 ml, 0.1
mol) was cooled in an ice-bath. To this vigorously stirred solution
was added a solution of cyanamide (1.8 g, 0.05 mol) in diethyl
ether (34.5 ml) over a 15 minute period. The reaction mixture was
then allowed to stir for 15 minutes. A white, solid precipitate of
chloroformamidine hydrochloride that formed was collected by
filtration and washed with diethyl ether. An intimate mixture of
appropriate thiophenes and chloroformamidine hydrochloride
(1:1.5) in dimethylsulfone (4 g) was heated at 120-130° C for 30
minutes. The mixture was cooled to room temperature, 10 ml of
water was added and ammonium hydroxide was used to neutralize
the suspension. The greenish brown solid obtained was collected
by filtration, washed with water and dried. The crude product was
dissolved in DMF and silica gel was added followed by evapora-
tion of the DMF to afford a dry silica gel plug. The plug was then
loaded onto a silica gel column and eluted with 3% methanol in
chloroform. The fractions containing the desired product (tlc)
were pooled and the solvent evaporated to afford the product.
Compound 6 (1.4 g, 61%) was obtained from 22 (2.3 g, 8
mmol) and chloroformamidine hydrochloride (1.38 g, 12 mmol).
1
R = 0.7, (chloroform:methanol = 7:1); mp 297-300 °C; H nmr
f
(DMSO-d ): δ 2.19 (3H, s, C H -CH ), 2.24 (3H, s, C H -CH ),
6
6
3
3
6
3
3
3.97 (2H, s, C H -CH ), 6.49 (2H, s, 2-NH , exch), 6.67 (1H, s,
6
3
2
2
5-H), 6.94-7.09 (3H, dd, C H ); 10.84 (1H, s, 3-NH, exch).
6
3
Anal. Calcd. for C
H N OS · 0.2H O: C, 62.35; H, 5.37; N,
15 15 3 2
14.54; S, 11.10. Found: C, 62.26; H, 5.34; N, 14.60; S, 11.16.
2-Amino-4-oxo-6-(2',4'-dichlorobenzyl)thieno[2,3-d]pyrimidine
(7).
Compound 7 (1.1 g, 56%) was obtained from 23 (2.0 g, 6
mmol) and chloroformamidine hydrochloride (1.0 g, 9 mmol). R
= 0.7, (chloroform:methanol = 7:1); mp 298-301 °C; H nmr
f
1
(DMSO-d ): δ 4.14 (2H, s, C H -CH ), 6.52 (2H, s, 2-NH ,
6
6
3
2
2
exch), 6.80 (1H, s, 5-H), 7.43-7.63 (3H, m, C H ); 10.87 (1H, s,
6
3
3-NH, exch).
Anal. Calcd. for C H N OSCl : C, 47.60; H, 2.83; N, 12.81;
13
9
3
2
S, 9.78; Cl, 21.62. Found: C, 47.41; H, 2.99; N, 12.78; S, 9.63;
Cl, 21.31.
2-Amino-4-oxo-6-benzylthieno[2,3-d]pyrimidine (2).
Compound 2 (0.54 g, 34%) was obtained from 18 (1.6 g, 6 mmol)
2-Amino-4-oxo-6-(2',4'-dimethoxybenzyl)thieno[2,3-d]pyrimi-
dine (8).
and chloroformamidine hydrochloride (1.0 g, 9 mmol). R = 0.63,
f
1
(chloroform: methanol = 7:1); mp 306-309 °C; H nmr (DMSO-d ):
6
δ 4.03 (2H, s, C H -CH ), 6.48 (2H, s, 2-NH , exch), 6.83 (1H, s, 5-
6
5
2
2
Compound 8 (1.2 g, 63%) was obtained from 24 (1.9 g, 6
H), 7.22-7.34 (5H, m, C H ); 10.83 (1H, s, 3-NH, exch).
6
5
mmol) and chloroformamidine hydrochloride (1.0 g, 9 mmol). R
= 0.72, (chloroform:methanol = 7:1); mp 262-265° C; H nmr
f
Anal. Calcd. for C H N OS: C, 60.68; H, 4.31; N, 16.33; S,
1
13 11
3
12.46. Found: C, 60.75; H, 4.38; N, 16.41; S, 12.56.
(DMSO-d ): δ 3.74 (3H, s, C H -OCH ), 3.78 (3H, s, C H -
6
6
3
3
6 3
OCH ), 3.88 (2H, s, C H -CH ), 6.43 (2H, s, 2-NH , exch), 6.48
3
6
3
2
2
2-Amino-4-oxo-6-(2'-methylbenzyl)thieno[2,3-d]pyrimidine (3).
Compound 3 (1.6 g, 65%) was obtained from 19 (2.57 g, 9
(1H, s, 5-H), 6.56-7.10 (3H, m, C H ); 10.79 (1H, s, 3-NH,
6
3
exch).
Anal. Calcd. for C
mmol) and chloroformamidine hydrochloride (1.7 g, 14 mmol).
H
N O S: C, 56.77; H, 4.76; N, 13.24; S,
3 3
15 15
1
R = 0.60, (chloroform:methanol = 7:1); mp 295-297 °C; H nmr
f
10.10. Found: C, 56.62; H, 4.87; N, 13.26; S, 10.16.
(DMSO-d ): δ 2.25 (3H, s, C H -CH ), 4.03 (2H, s, C H -CH ),
6
6
4
3
6
4
2
4-(2-Amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-
ylmethyl)benzoic Acid Ethyl Ester (26).
6.47 (2H, s, 2-NH , exch), 6.69 (1H, s, 5-H), 7.165 (4H, m,
2
C H ); 10.82 (1H, s, 3-NH, exch).
6
4
Anal. Calcd. for C
H N OS · 0.6H O: C, 59.60; H, 5.07; N,
14 13 3 2
Compound 26 (1.0 g, 51%) was obtained from 25 (2.0 g, 6
14.89; S, 11.36. Found: C, 59.35; H, 4.74; N, 14.68; S, 11.13.
2-Amino-4-oxo-6-(2'-chlorobenzyl)thieno[2,3-d]pyrimidine (4).
Compound 4 (0.85 g, 24%) was obtained from 20 (3.6 g, 12
mmol) and chloroformamidine hydrochloride (1.0 g, 9 mmol). R
= 0.6, (chloroform:methanol = 7:1); mp 193-198 °C; H nmr
f
1
(DMSO-d ): δ 1.15-1.17 (3H, t, COOCH CH ), 4.12 (2H, s,
6
2
3
C H -CH ), 4.25-4.32 (2H, q, COOCH CH ), 6.51 (2H, s, 2-
6
4
2
2
3
mmol) and chloroformamidine hydrochloride (2.1 g, 18 mmol).
NH , exch), 6.88 (1H, s, 5-H), 7.24-7.91 (4H, dd, C H ); 10.54
2
6 4
1
R = 0.73, (chloroform:methanol = 7:1); mp 290-294 °C; H nmr
f
(1H, s, 3-NH, exch).
(DMSO-d ): δ 4.15 (2H, s, C H -CH ), 6.50 (2H, s, 2-NH ,
6
6
4
2
2
4-(2-Amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-
ylmethyl)benzoic Acid (27).
exch), 6.78 (1H, s, 5-H), 7.31-7.44 (4H, dd, C H ); 10.85 (1H, s,
6
4
3-NH, exch).
Anal. Calcd. for C
S, 10.99; Cl, 12.15. Found: C, 53.26; H, 3.54; N, 14.26; S, 10.87;
Cl, 12.43.
H N OSCl: C, 53.52; H, 3.45; N, 14.40;
13 10 3
To a solution of 26 in ethanol (10 ml) was added aqueous 1 N
NaOH (1ml) and the reaction mixture stirred at room temperature
for 18 hours and carefully acidified to pH 4 with drop wise