Synthesis of some new pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones and pyrido[3′,2′: 4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives

Article abstract of DOI:10.1002/jccs.200100172

2,3-Disubstituted-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4( 3H) -ones 8a-8c, 9a-9c were obtained by treatment of pyrido[3′,2′:4,5]thieno[3,2-d][1,3]oxazin-4(3H)-one derivative 3, 3-diacetylamino-thieno[2,3-b]pyridine derivative 5 and 3-ethoxymethyleneaminothieno[2,3-b]pyridine derivative 7a with appropriate amines, respectively. Condensation of compounds 8b, 9b with appropriate α-chlorocarbonyl compounds gave the corresponding 3-substituted carbonylmethylene-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 13a-d. 3-N-Substituted-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 15a,b, 16a,b and 18a,b were also obtained by cyclization of carbohydrazide 14 with different reagents under a variety of conditions. On the other hand, cyclization of 3-amino-4-imino-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 21a,b with appropriate orthoesters afforded the corresponding 3,5-dialkyl-pyrido[3′,2′:4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c] pyrimidines 22a-f.

Full text of DOI:10.1002/jccs.200100172

JournaloftheChineseChemicalSociety, 2001, 48, 1163-1174
1163
Syn the sis of Some New Pyrido[3,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
and Pyrido[3 ,2 : 4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
Derivatives
Yuh-Wen Ho (
)
DepartmentofTextileEngineering,NanyaInstituteofTechnology,Chung-Li,Taiwan32034, R.O.C.
2,3-Disubstituted-pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 8a-8c, 9a-9c were ob tained by
treat ment of pyrido[3 ,2 :4,5]thieno[3,2-d][1,3]oxazin-4(3H)-onederivative3, 3-diacetylamino- thieno[2,3-
b]pyridinederivative5 and 3-ethoxymethyleneaminothieno[2,3-b]pyridinederivative7awithappropriate
amines,respectively.Condensationofcompounds 8b, 9b withappropriate -chlorocarbonyl com pounds
gavethecorresponding3-substitutedcarbonylmethylene-pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-one
derivatives13a-d. 3-N-Substituted-pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 15a,b, 16a,b and
18a,bwere also ob tained by cyclization of carbohydrazide 14 withdifferentreagentsunderavarietyofcondi-
tions. On the other hand, cyclization of 3-amino-4-imino-pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-
ones21a,bwithappropriateorthoestersaffordedthecorresponding3,5-dialkyl-pyrido[3 ,2 :4,5]thieno[2,3-
e]-1,2,4-triazolo[1,5-c]pyrimidines22a-f.
INTRODUCTION
Pyridothienopyrimidines have been the sub ject of many
Sev eral pub li ca tions have dealt with the syn the sis of
fused 1,2,4-triazole heterocyclic sys tems.16-18 Shishoo et al.19
and Giuliana Biagi et al.20 haverecentlydescribedthesynthe-
sis of 5-phenyl-1,2,4-triazolo[4,3-c]thieno[3,2-e]pyrimidine
from 4-hydrazinothieno[2,3-b]pyridine with triethyl ortho-
for mate or for mic acid and 7-phenyl-1,2,3- triazolo[4,5-e]-
1,2,4-triazolo[3,4-c]pyrimidinesfrom7-hydrazino-1,2,3-
triazolo[4,5-d]py rimi dines with triethyl orthobenzoate. The
6-cyano-7-(4-methoxyphenyl)-2-phenyl-5-oxo-1,2,4-triazolo-
[1,5-a]pyrimidine21 also has been pre pared from 2-benzalhy-
drazine-5-cyano-6-(4-methoxyphenyl)-3,4-dihydropyrimidin-
4-one with fer ric chlo ride. In pre ced ing pa pers22,23 we have
de scribed the syn the sis of some new pyrazole de riv a tives
from ethyl 3-amino 2-thieno[2,3-b]pyridine carboxylate 1
and 3-amino-2-cyano-thieno[2,3-b]pyridine 19.Incontinua-
tion of our stud ies, we re port here the syn the sis of some new
pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones and
pyrido[3 ,2 :4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]py rimi-
dines by mak ing use of com pounds1 and 19 as the start ing
materials.
chemicalandbiologicalstudiesonaccountoftheirinterest-
ingpharmacologicalproperties.1 A num ber of syn the ses for
sub sti tuted de riv a tives of this triheterocyclic ring sys tem,
featuringavarietyofpharmacologicaleffects,havebeende-
veloped.Suchderivativeshaveanalgesic,2 antipyretic,3 anti-
anaphilactic4 and anti-inflammatory5 activities. Also, some
areclinicallyeffectiveantiallergic6 or po ten tially antineo-
plas tic agents 7 andafewpossesssignificanthypocholester-
olemic8 activity.Likewise,the1,2,4-triazolederivativesalso
possessavarietyofpharmacologicalactivities.9-12 In view of
these it was con sid ered of in ter est to syn the size some new
pyridothienopyrimidines and 1,2,4-triazole de riv a tives. The
pyridothienopyrimidine triheterocyclic ring can be syn the-
sizedfromanappropriatepyridothienoderivativessystem
upon treat ment with a one-carbon re agent such as for mic
acid. Other one-carbon re agents13 that can be used for this
pur pose in clude amides, urea, cya nates, isothiocyanates,
chlorocarbonates, car bon disulfide and thiophosgenes. Re-
cently, the 8-cyano-7-ethoxy-9-phenyl-3-aryl-2-(oxo or thi-
oxo)-2 ,3-dihydropyrido[3 ,2 :4,5]thieno[3,2-d]pyrimi-
dines14 has been pre pared from 2-[(N-arylimino)methyl]-5-
cyano-6-ethoxy-4-phenyl-3-[(triphenylphophoranyldene)-
amino]thieno[2,3-b]pyridineswithcarbondioxideand2-thi-
oxo-1,2,3,4,5,6,7,8-octahydrobenzo[4,5]thieno[2,3-d]py-
rimidines15 from 3-benzoyl-2-isothiocyanato-4,5,6,7- tetra-
hydrobenzo[b]thiophene.
RESULTS AND DISCUSSION
All rel e vant re ac tions are de picted in Schemes I-III.
Saponifiction of the ethyl 3-amino-2-thieno[2,3-b]pyridine
carboxylate 1 withpotassiumhydroxideinaqueousalcohol
yielded the 3-aminothieno[2,3-b]pyridine-2-carboxylic acid
2, in 96% yield. Treat ment of com pound2 with ace tic an hy-

1164 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
Scheme I
CH3
N
CH3
O
CH3
N
S
.
NH2OH HCl
O
3
(CH3CO)2O
CH3
Pyridine
reflux
Pyridine
NH2
CH3
reflux
N
CH3
OH
COOH
CH3
CH3
N
S
NHCOCH3
COOH
N
2
CH3
N
S
O
4
CH3
N
S
6b
.
KOH/C2H5OH
NH2OH HCl
Pyridine
reflux
reflux
CH3OH
/KOH
reflux
CH3
CH3
CH3
NH2
COOC2H5
(CH3CO)2O
N(COCH3)2
COOC2H5
10 % H SO
2
NHCOCH3
COOC2H5
4
CH COOH
3
reflux
CH3
reflux
N
S
1
CH3
N
S
CH3
N
S
5
6a
NH NH-
2
CH C(OC H )
5 3
CH(OC2H5)3
/(CH3CO)2O
reflux
3
2
ethanol
/(CH CO) O
3
2
reflux
reflux
CH3
CH3
CH3
CH3
N
CH3
N=COC2H5
N=CHOC2H5
COOC2H5
N
COOC2H5
CH3
CH3
N
S
NH-
N
S
CH3
N
S
O
7b
7a
8d
R-NH2
C2H5OH
reflux
CH3
N
R-NH2
N
R
R-NH2
C2H5OH
3
C2H5OH
reflux
5
N
CH3
S
R1
reflux
O
R= NH2, H, CH3
8a~c, 9a~c
8a 8b 8c 9a 9b 9c
R
H
CH3 CH3 CH3
H
H
R1
NH2
H
CH3
NH2
H
CH3
1
dride in pyridine produced the 2,7,9-trimethylpyrido-
[3 ,2 :4,5]thieno[3,2-d][1,3]oxazin-4(3H)-one 3. Refluxing
oxazinone com pound3 withhydroxylaminehydrochloridein
pyridine yielded the 3-hydroxy-2,7,9-trimethylpyrido [3 ,2 :
4,5]thieno[3,2-d]pyrimidin-4(3H)-one 4 (Scheme I). The
structureofcompound4 wasestablishedbyexaminingspec-
traldataandelementalanalysis.Compound 1, when re acted
with the ace tic an hy dride at re flux in gla cial ace tic acid for 6
h, in tro duced two acetyl groups to give ethyl 3- diacetyl-
aminothieno[2,3-b]pyridine-2-carboxylate 5. The IR spec tra
of com pound5in di cated the ab sence of the amino group, and
containsthecharacteristicabsorptionbandat1729cm-1 due
to the car bonyl group (C=O). The H NMR spec tra (CDCl3)
of com pound 5 showed a sharp sin glet at 2.29 (6H, s) which
is as signed to the N(COCH3)2 pro tons and a trip let at 1.35
(3H, t) and a quar tet at 4.33 (2H, q) as signed to the ethyl
group (CH2CH3).
Furthermore,reactionofcompound5 with hydroxyl-
amine hy dro chlo ride at refluxing in pyridine for 4 h yielded a
white solid (87%, mp 193 C).Spectroscopicanalysesofthe
re ac tion prod uct re vealed that ethyl 3-acetylamino- thieno-
[2,3-b]pyridine-2-carboxylate 6a had been ob tained in stead
oftheexpectedcompound4(Scheme I). The IR spec tra of the
re ac tion prod uct showed a strong ab sorp tion band at 3295

Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1165
Scheme II
NaNO2/
CH3I/K2CO3
CH3COOH
40~50oC
8c
8a
8b
Acetone
reflux
NH4OH
6a
reflux
CH3
.
NH2CHO
reflux
24h
NH2OH HCl
N
1
7a
9b
pyridine
reflux
N
CH3
N
S
OH
O
9d
CH3
N
CH3
N
O
CHO
CH3COOH
NO2
(CH3CO)2O
CH3COOH
R
N
O
R
8a,9a
N
N
CH3
S
NHCOCH3
N
S
CH3
N=CH
NO2
O
CH3COOH
11a,b
reflux
10a,b
CH3
N
O
R
R
N
CH3
10a, 11a
10b, 11b
N
S
CH3
N=
H
12
CH3
N
O
R
ClCH2COR1/K2CO3
8b,9b
N
Acetone
reflux
CH2COR1
CH3
N
S
13a~d
13a 13b 13c 13d
CH3
R
R1 CH3
CH3
H
H
OC2H5
OC2H5 CH3
cm-1 fortheNHgroupandcontainsthecharacteristicabsorp-
tion band at 1729 cm-1 due to the car bonyl group (C=O). The
1H NMR spectra (CDCl3) of the re ac tion prod uct, which
showed a sin glet at 2.24 (3H, s) as signed to the COCH3 pro-
tons, a broad sin glet at 8.59 (1H, br) as signed to the NH pro-
ton, was also confirmed by the mass spec trum m/z 292
(M+100). The same prod uct6a was also ob tained through the
reactionofthecompound5with10%sulfuricacid.3-Acetyl-
amino-thieno[2,3-b]pyridine-2-carboxylic acid 6b was also
ob tained by treat ment of com pound5 withmethanol/potas-
sium hy drox ide. Next, con den sa tion of com pound 1 with
triethylorthoformateatrefluxinginaceticanhydridefor24h
to give ethyl 3-ethoxymethyleneamino-thieno[2,3-b]pyri-
dine-2-carboxylate 7a (Scheme I). With treat ment of com-
pound 1withtriethylorthoacetateundersimilarreactioncon-
ditions,themajorproductwascompound5, in stead of the ex-
pected com pound7b,asevidencedbyanalyticalandspectral
data.
On the other hand, treat ment of oxazinone com pound 3
withtheappropriateprimaryaliphaticamines, suchashydra-
zine hydrate, ammonia and methylamine gave the cor re-
sponding3-substituted-2,7,9-trimethylpyrido[3 ,2 :4,5] thi-
eno[3,2-d]pyrimidin-4(3H)-ones 8a-c. Alternatively,when
com pound 5was treated sim i larly with ap pro pri ate pri mary

1166 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
Scheme III
CH3
CH3
N
N
N
O
N
CH3
NH2
N
N
S
N
X
CH2-
CH3
S
O
HC(OC H ) /
CH3COOH
2
5 3
9a
15a,b
X
reflux
H- N
X
Room
temperature
15a CH2
15b
HCHO
CH3
O
NH2
CONHNH2
CHO
C2H5OH/
CH3COOH
CH3
N
S
reflux
RC(OC
H
) /C2H5OH
2
5
3
14
reflux
8a,9a
CH3
NH2
CONHN=CH
CH3
N
S
CH3
17
N
N
R
N=COC2H5
CH3
N
S
RC(OC
H ) /
5 3
2
reflux
O
(CH3CO)2O
CH3
16a,b
N
O
R
N
R
CH3
H
N=CH
CH3
N
S
16a, 18a
16b, 18b
18a,b
CH3
R
CH3
CH3
NH2
N=COC2H5
.
N
R
RC(OC2H5)3
NH2NH2 H20
(CH3CO)2O
C2H5OH
reflux
CN
CH3
N
S
N
reflux
CN
CH3
N
S
CH3
N
S
NH2
19
20a,b
NH
21a,b
C2H5OH
reflux
NH2C2H5
C2H5OH
reflux
H
20a, 21a, 23a, R=
20b, 21b, 23b, R=
R1C(OC2H5)3
CH3
CH3
N
R
CH3
N
R
N
CH3
N
S
23a,b
C2H5
N
NH
CH3
N
S
N
N
22a~f
R1
22a 22b 22c 22d 22e 22f
H
H
R
H
CH3
CH3
CH3
CH3
R1
H
C2H5
H
CH3
C2H5
aliphatic amines, in each case a sin gle prod uct was ob tained,
iden ti cal in all as pects with com pounds 8a-c,respectively.
Thus this route con sti tutes a fac ile and con ve nient syn the sis
of pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones.
(Scheme I). The struc tures of com pounds 8a-c were con-
firmed on the ba sis of an a lyt i cal data and spec tra ev i dence.
The IR spec tra of com pounds 8a-c showedstrongabsorption
at 3.50-3.29 (3H, s) as signed for the 2-CH3 of the pyri-
midinone ring. Also, the chem i cal shift of 2-CH3 has a lower
field shift than that of 7, 9-CH3 of com pounds 8a-c. Sim i-
larly, treatment of com pound 7a with primary aliphatic
amines in eth a nol led to cyclization and af forded the cor re-
spond ing 3-substituted-7,9-dimethyl-pyrido[3 ,2 :4,5]- thi-
eno[3,2-d]pyrimidin-4(3H)-ones 9a-c,respectively(Scheme
1
1
bands at 1680-1662 cm-1 for the car bonyl group. The H
I). The H NMR spec tra, which showed the pres ence of the
NMR spec tra (CDCl3) of com pounds 8a-c re vealed a sin glet
ex pected pro tons, re veal a sig nal in agree ment with the pro-

Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1167
posed struc ture. The com pounds9a-c showed a sharp one
pro ton sin glet in1H NMR spec tra at 8.93 (1H, s), 8.58 (1H,
s) and 8.64 (1H, s), which were readily as signed to the hy dro-
genattachedatC 2 ofthepyrimidinonering, respectively. The
phys i cal con stants and spec tral data of com pounds 8a-c and
9a-c are re corded in Ta bles 1, 2. Our at tempts to cyclize 6a
with am mo nia to the com pound8bwereunsuccessful.Com-
pound 8b was also ob tained by the diazotiation of com pound
8a with so dium ni trite in gla cial ace tic acid at 45-50 C with
yields of 98%. Methylation of com pound 8bby heat ing with
excessmethyliodideandpotassiumcarbonateindryacetone
gave the com pound8c (86%yield)(SchemeII). However, re-
ac tion of com pound 5 with phenylhydrazine at refluxing in
ethanol, aproductofmolecularformulaC14H16N2O3S (mp
193-192 C) was ob tained. Spec tro scopic anal y ses of the
C14H16N2O3S re vealed that com pound6a had been ob tained
insteadoftheexpectedcompound8d(Scheme I). At tempts to
cyclize com pound7awith hydroxylamine hy dro chlo ride at
refluxing in pyridine to give com pound9d wasunsuccessful
and the start ing ma te rial was re cov ered. More over, cycliza-
tion of com pound1 with formamide af forded the com pound
9b (Scheme II).
In ad di tion, the re ac tion of com pounds8a and 9a with
p-nitrobenzaldehyde at refluxing in gla cial ace tic acid gave
the 2-substituted-3-(4-nitrobenzylideneamino)pyrido[3 ,2 :
4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 10a,b,respectively.
The 3-acetylamino-pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4(3H)-one 11a,bwereobtainedwhenthereactionofthecom-
pounds 8a and 9awithaceticanhydrideinboilingglacialace-
ticacid. Undersimilarreactionconditions, reactionofcom-
pounds 8a and 9awith cyclohexanone did not pro duce the de-
sired com pound 12, but led only to the re cov ery of start ing
ma te ri als (Scheme II). Fur ther more, con den sa tion of com-
pounds 8b and 9bwithappropriate -chlorocarbonyl com-
pounds and po tas sium car bon ate in dry ac e tone gave the cor-
responding 3-substituted carbonylmethylenepyrido[3 ,2 :
4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 13a-d,respectively
(SchemeIII). Evidenceforthestructureofcompounds13a-d
in cluded the IR spec trum, which re vealed no NH stretch, was
ob served. The 1H NMR spec tra (CF3COOD) of com pounds
13a-d re vealed a sin glet at 5.40-4.92 (2H, s) as signed for
the N-CH2CO- pro tons of the pyrimidinone ring. The phys i-
cal con stants and spec tral data of com pounds 13a-d are re-
corded in Ta bles 1, 2.
Table 1. Physical and Analytical Data of Compounds 8a-c, 9a-c, 13a-d and 16a,b
Compound
R
R1
Yield
%
Mp
C
Molecular
Formula
Element Analysis (%)
Calcd/Found
C
H
N
8a
CH3
CH3
CH3
H
NH2
H
53
83
48
90
98
95
77
90
85
83
72
73
320
> 350
205
C12H12N4OS
C12H11N3OS
C13H13N3OS
C11H10N4OS
C11H9N3OS
C12H11N3OS
C15H15N3O2S
C16H17N3O3S
C14H13N3O2S
C15H15N3O3S
C15H16N4O2S
C14H14N4O2S
55.38
55.46
58.77
58.49
60.23
60.32
53.65
53.77
57.14
57.22
58.77
58.51
59.78
59.98
57.99
58.08
58.52
58.41
56.77
56.87
56.96
56.88
55.62
55.46
4.61
4.55
4.49
4.58
5.02
5.11
4.06
4.16
3.89
3.78
4.49
4.51
5.02
5.26
5.17
5.32
4.56
4.56
4.76
4.74
5.06
5.32
4.63
4.79
21.53
21.33
17.14
17.32
16.21
16.20
22.76
22.99
18.18
18.06
17.14
17.26
13.94
13.81
12.68
12.75
14.62
14.65
13.24
13.33
17.72
17.62
18.54
18.55
8b
8c
CH3
NH2
H
9a
274
9b
H
> 350
243
9c
H
CH3
CH3
OC2H5
CH3
OC2H5
-
13a
13b
13c
13d
16a
16b
CH3
CH3
H
276
216
250
H
240
CH3
H
195
-
222

1168 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
Table 2. Spectral Data of Compounds 8a-c, 9a-c, 13a-d and 16a,b
Compound
MS
(M )
IR
1H NMR
(CF3COOD)
(ppm)
+
(KBr)
(cm-1)
8a
8b
8c
260
245
259
246
231
245
301
3279, 3205 (NH2), 1669 (C=O)
3440 (NH), 1677 (C=O)
1675 (C=O)
3.16 (3H, s, 9-CH3), 3.36 (3H, s, 7-CH3),
3.70 (3H, s, 2-CH3), 8.10 (1H, s, 8-H).
2.93 (3H, s, 9-CH3), 3.12 (3H, s, 7-CH3),
3.47 (3H, s, 2-CH3), 7.85 (1H, s, 8-H).
2.93 (3H, s, 9-CH3), 2.96 (3H, s, 7-CH3), 3.29
(3H, s, 2-CH3), 3.88 (3H, s, N-CH3), 7.70 (1H, s, 8-H).
3.42 (3H, s, 9-CH3), 3.73 (3H, s, 7-CH3),
8.17 (1H, s, 8-H), 8.93 (1H, s, 2-H).
2.88 (3H, s, 9-CH3), 3.21 (3H, s, 7-CH3),
7.63 (1H, s, 8-H), 8.58 (1H, s, 2-H).
2.93 (3H, s, 9-CH3), 3.32 (3H, s, 7-CH3), 3.84
(3H, s, N-CH3), 7.67 (1H, s, 8-H), 8.64 (1H, s, 2-H).
2.54 (3H, s, COCH3), 2.72 (3H, s, 9-CH3),
2.95 (3H, s, 7-CH3), 3.30 (3H, s, 2-CH3),
5.40 (3H, s, N-CH2), 7.69 (1H, s, 8-H).
9a
9b
9c
3295, 3189 (NH2), 1680 (C=O)
3136 (NH), 1662 (C=O)
1666 (C=O)
13a
1722, 1675 (C=O)
13b
331
1758, 1726 (C=O)
1.28 (3H, t, J = 2.5 Hz, CH3), 2.58 (3H, s, 9-CH3),
2.62 (3H, s, 7-CH3), 2.88 (3H, s, 2-CH3), 4.25
(2H, q, J = 2.4 Hz, CH2), 4.92 (3H, s, N-CH2),
7.02 (1H, s, 8-H)a.
13c
13d
16a
287
317
316
1729 (C=O)
1754 (C=O)
1690 (C=O)
2.36 (3H, s, COCH3), 2.84 (3H, s, 9-CH3),
3.15 (3H, s, 7-CH3), 5.08 (3H, s, N-CH2),
7.56 (1H, s, 8-H), 8.26 (1H, s, 2-H).
1.29 (3H, t, J = 2.4 Hz, CH3), 2.92 (3H, s, 9-CH3),
3.22 (3H, s, 7-CH3), 4.31 (2H, q, J = 2.4 Hz, CH2),
4.96 (3H, s, N-CH2), 7.60 (1H, s, 8-H), 8.39 (1H, s, 2-H).
1.37 (3H, t, J = 2.4 Hz, CH3), 2.23 (3H, s, N=C-CH3),
2.56 (3H, s, 9-CH3), 2.58 (3H, s, 7-CH3), 4.33
(2H, q, J = 2.4 Hz, OCH2), 6.93 (1H, s, 8-H),
8.59 (1H, s, 2-H)a.
16b
302
1686 (C=O)
1.36 (3H, t, J = 2.4 Hz, CH3), 2.99 (3H, s, 9-CH3),
3.31 (3H, s, 7-CH3), 4.38 (2H, q, J = 2.4 Hz, OCH2),
7.77 (1H, s, 8-H), 8.17 (1H, s, N=CH), 8.53 (1H, s, 2-H).
a 1H NMR in CDCl3
The 3-amino-2-thieno[2,3-b]pyridine carbohydrazide
14 could be cyclized un der dif fer ent con di tions to form dif-
fer ent polycyclic com pounds. Thus, when carbohydrazide14
was treated with form al de hyde and sec ond ary amines (pip-
eridine and morpholine) yielded the Mannich-type base
3-substituted aminomethyl-pyrido[3 ,2 :4,5]thieno[3,2-d]-
pyrimidin-4(3H)-ones 15a,b(Scheme III). The IR spec tra of
15a,b showed ab sence of the NH2 and NH ab sorp tion bands,
in di cat ing the for ma tion of a cy clic struc ture. The 1H NMR
spectra(CDCl3) of com pounds 15a,b re vealed a sharp two
protonssingletat 4.79 (2H, s) and 5.38 (2H, s), which were
readily as signed to the N-CH2N of the pyrimidinone ring and
re vealed a sig nal at 8.09 (1H, s) and 7.82 (1H, s), which
were readily as signed to 2-H of the pyrimidinone ring, re-
spec tively. The spec tra also re vealed a multiplet at 4.34-
4.30, 2.25-2.07 (10H, m) as signed to the piperidyl pro tons of
com pound15a, and a multiplet at 3.70-3.64, 2.88-2.47 (8H,
m) assigned to the morpholyl protons of com pound 15b.
More over, the com pound 9a was also ob tained when car-
bohydrazide 14 was re act ing with triethyl orthoformate at
refluxing in gla cial ace tic acid. Nev er the less, when carbohy-
drazide 14 was treated with orthoesters in ab so lute eth a nol
the 3-(sub sti tuted ethoxymethylene)amino-pyrido[3 ,2 : 4,5]-
thieno[3,2-d]pyrimidin-4(3H)-ones 16a,bwere smoothly ob-
tained, rather than the ex pected com pounds8a, 9a (Scheme
1
III). The H NMR spec tra (CDCl3) of com pounds 16a,b re-
vealed a trip let at 1.37-1.36 (3H, t) and a quar tet at
4.38-4.33 (2H, q) as signed to the ethyl group (CH2CH3), and
a sin glet at 8.59 and 8.53 as signed to the 2-H of pyrimidin-
one ring, re spec tively. Carbohydrazide 14 was found to con-

Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1169
dense readily with benzaldehyde to yield the 2-carboxy benz-
ylidenehydrazide-thieno[2,3-b]pyridine 17, which can be
cyclized with ap pro pri ate orthoesters in ace tic an hy dride to
lead to formation of the 2-substituted-3-N-benzylidene-
pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 18a,b
in good yields (Scheme III). The 1H NMR spec tra of com-
pounds 18a,brevealedthedisappearanceofNH2 and the NH
group of com pound17 and a multiplet at 7.88-7.38 (5H, m)
assignedtothephenylprotons, asingletat 9.05 and 8.37 as-
signedtotheN=CHproton, respectively.
tives 21a,bwithappropriateorthoesters,respectively(Scheme
III). The IR spec tra of com pounds 22a-f in di cated the ab-
sence of the NH2 and NH groups. The struc tures of com-
pounds 22a-fwereestablishedbyspectraldateandelemental
anal y sis. Phys i cal and spec tral data of the 20a,b, 21a,b and
22a-f are re corded in Ta bles 3 and 4.
Finally, treat ment of com pound 20a,b with ethylamine
undersimilarreactionconditionsproducedthecorrespond-
ing 3-ethyl-4-imino-pyrido[3 ,2 :4,5]thieno[3,2-d]pyr imi-
din-4(3H)-ones 23a,b,respectively.
On the other hand, in ter ac tion of 3-amino-2-cyano-
thieno[2,3-b]pyridine 19 with orthoesters af forded the cor re-
sponding3-alkylethoxymethyleneamino-thieno[2,3-b]pyr-
In con clu sion, ethyl 3-amino-2-thieno[2,3-b]pyridine
carboxylate 1 has been shown to be a use ful build ing block
for the syn the sis of some new pyrido[3 ,2 :4,5]thieno[3,2-
d]pyrimidin-4(3H)-onederivatives.Thepyrido[3 ,2 :4,5] thi-
eno[2,3-e]-1,2,4-triazolo[1,5-c]pyrimidinederivativeswere
also pre pared from 3-amino-2-cyano-thieno[2,3-b]pyridine
19.
1
idinederivatives 20a,b (Scheme III). The H NMR spec tra
(CDCl3) of com pound20a,b showed a trip let at 1.42-1.37
(3H, t) and a quar tet at 4.42-4.33 (2H, q) as signed to the
ethyl group (CH2CH3), re spec tively. Hydrazinolysis of the
com pounds20a,b in eth a nol yielded the cor re spond ing 3-
amino-4-imino-pyrimido[4 ,5 :4,5]thieno[2,3-b]pyridines
21a,b. The 3,5-disubstituted pyrido[3 ,2 :4,5]thieno[2,3-e]-
1,2,4-triazolo[1,5-c]pyrimidines22a-fwere ob tained by con-
den sa tion and intramolecular cyclization of imino de riv a-
EXPERIMENTAL SECTION
All melt ing points were de ter mined in a cap il lary tube
Table 3. Physical and Analytical Data of Compounds 18a,b, 20a,b, 21a,b and 22a-f
Compound
R
R1
Yield
%
Mp
C
Molecular
Formula
Element Analysis (%)
Calcd/Found
C
H
N
18a
18b
20a
20b
21a
21b
22a
22b
22c
22d
22e
22f
CH3
H
-
-
-
-
-
-
69
87
84
83
77
78
82
74
72
77
89
85
283
247
130
78
C19H16N4OS
C18H14N4OS
C13H13N3OS
C14H15N3OS
C11H11N5S
C12H13N5S
C12H9N5S
65.51
65.66
64.65
64.62
60.23
60.11
61.54
61.44
53.88
53.73
55.06
55.79
56.47
56.44
57.99
57.87
59.36
59.66
59.77
59.52
59.36
59.58
60.60
60.74
4.97
4.71
4.22
4.09
5.02
5.09
5.49
5.38
4.49
4356
5.02
5.00
3.53
3.58
4.09
4.16
4.59
4.63
4.21
4.35
4.59
4.54
5.05
5.01
16.09
16.33
16.75
16.62
16.22
16.25
16.22
16.13
28.57
28.38
27.03
27.17
27.45
27.59
26.02
26.24
24.73
24.73
26.81
26.91
24.73
24.71
23.56
23.61
H
CH3
H
242
196
281
223
225
285
314
172
CH3
H
H
H
CH3
C2H5
H
C13H11N5S
C14H13N5S
C13H11N5S
C14H13N5S
C15H15N5S
H
CH3
CH3
CH3
CH3
C2H5

1170 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
Table 4. Spectral Data of Compounds 18a,b, 20a,b, 21a,b and 22a-f
Compound
MS
(M+)
IR
1H NMR
(CF3COOD)
(ppm)
(KBr)
(cm-1)
18a
18b
20a
20b
348
334
259
273
1673 (C=O)
2.62 (3H, s, 9-CH3), 2.66 (3H, s, 7-CH3), 2.89
(3H, s, 2-CH3), 7.00 (1H, s, 8-H), 7.88-7.44
(5H, m, phenyl-H), 9.05 (1H, s, N=CH).a
1670 (C=O)
2205 (CN)
2206 (CN)
2.57 (3H, s, 9-CH3), 2.85 (3H, s, 7-CH3),
7.00 (1H, s, 8-H), 7.80-7.38 (5H, m, phenyl-H),
8.37 (1H, s, N=CH), 9.59 (1H, s, 2-H).a
1.42 (3H, t, J = 2.4 Hz, CH3), 2.59 (3H, s, 4-CH3),
2.62 (3H, s, 6-CH3), 4.42 (2H, q, J = 2.4 Hz, OCH2),
6.95 (1H, s, N=CH), 7.23 (1H, s, 5-H)a.
1.37 (3H, t, J = 2.4 Hz, CH3), 1.98 (1H, s, N=C-CH3),
2.52 (3H, s, 4-CH3), 2.59 (3H, s, 6-CH3), 4.33
(2H, q, J = 2.4 Hz, OCH2), 6.94 (1H, s, 5-H)a.
3.15 (3H, s, 9-CH3), 3.44 (3H, s, 7-CH3),
21a
21b
22a
22b
22c
245
259
255
269
283
3275, 3249
(NH2, NH)
3315, 3293
(NH2, NH)
-
7.94 (1H, s, 8-H), 9.08 (1H, s, 2-H)a.
3.12 (3H, s, 9-CH3), 3.38 (3H, s, 7-CH3),
3.66 (3H, s, 2-CH3), 8.09 (1H, s, 8-H).
2.91 (3H, s, 7-CH3), 3.29 (3H, s, 9-CH3), 7.76
(1H, s, 8-H), 9.00 (1H, s, 3-H), 9.75 (1H, s, 5-H).
3.11 (3H, s, 7-CH3), 3.24 (3H, s, 9-CH3), 3.57
(3H, s, 3-CH3), 8.06 (1H, s, 8-H), 9.98 (1H, s, 5-H).
1.37 (3H, t, J = 2.4 Hz, CH3), 2.58 (3H, s, 7-CH3),
2.70 (3H, s, 9-CH3), 4.32 (2H, q, J = 2.4 Hz, CH2),
6.92 (1H, s, 8-H), 8.85 (1H, s, 5-H).
-
-
22d
22e
22f
261
283
297
-
-
-
3.09 (3H, s, 7-CH3), 3.38 (3H, s, 9-CH3), 3.46
(3H, s, 5-CH3), 7.93 (1H, s, 8-H), 9.78 (1H, s, 3-H).
2.88 (3H, s, 7-CH3), 3.22 (6H, s, 9-CH3 and 3-CH3),
3.24 (3H, s, 5-CH3), 7.70 (1H, s, 8-H).
1.37 (3H, t, J = 2.4 Hz, CH3), 2.50 (3H, s, 7-CH3),
2.60 (3H, s, 9-CH3), 2.82 (3H, s, 5-CH3), 4.37
(2H, q, J = 2.4 Hz, CH2), 6.90 (1H, s, 8-H).
a 1H NMR in CDCl3
and are un cor rected. The IR spec tra were re corded on po tas-
siumbromidepelletsonaJASCOFTIR-3spectrometer. The
1H NMR spectra were ob tained on a Bruker AM-300WB
FT-NMRspectrometerandchemicalshiftsareexpressedin
ppmusingTMSasaninternalstandard.Electronimpactmass
spectra were obtained at 70 eV by us ing a Finingan Mat
TSQ-46C spec trom e ter. Microanalyses for C, H, and N were
performedonaPerkin-Elmer240elementalanalyzer.
pres sure, the res i due was dis solved in wa ter, acid i fied with
1M hy dro chlo ric acid and the pre cip i tated prod uct was col-
lected by fil tra tion to give 1.70 g pale yel low nee dles (96%
yield), mp 149 C; IR: 3518, 3382 cm-1 (NH2, OH), 1634
(C=O) cm-1; MS: 222 (M+).
Anal. Calcd. for C10H10N2O2S: C, 54.04; H, 4.53; N,
12.60. Found: C, 53.86; H, 4.50; N, 12.66%.
2,7,9-Trimethylpyrido[3 ,2 :4,5]thieno[3,2-d][1,3]oxazin-
4(3H)-one (3)
3-Amino-2-carboxylic acid-4,6-dimethylthieno[2,3-b]-
pyridine (2)
Ethyl 3-amino-2-thieno[2,3-b]pyridine carboxylate 1
(2.0 g, 8 mmol) was dis solved in eth a nol (15 mL), aque ous
2M so dium hy drox ide (12 mL) was added and stirred at re-
flux for 4 h. Af ter evap o ra tion of the sol vent un der re duced
Asolutionofcompound2 (2.22 g, 0.01 mol) in pyridine
(7 mL) and ace tic an hy dride (7 mL) was refluxed for 5 h. The
re ac tion mix ture was cooled and the re sult ing crys tals col-
lected, washed with wa ter and recrystallized from ace tic acid
to give 2.1 g nee dle crys tals (85% yield), mp 208 C; IR:

Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1171
1
1758 (C=O) cm-1; H NMR (CDCl3): 2.52 (3H, s, 9-CH3),
3-Acetylamino-2-carboxylic acid-4,6-dimethylthieno-
[2,3-b]pyridine (6b)
2.62 (3H, s, 7-CH3), 2.83 (3H, s, 2-CH3), 7.05 (1H, s, 8-H);
MS: 246 (M+).
Asolutionofcompound5 (0.34 g, 1mmol) in dis solved
meth a nol (10 mL), po tas sium hy drox ide (0.52 g) was added
andstirredatrefluxtemperaturefor4h.Afterevaporationof
thesolventunderreducedpressuretheresiduewasdissolved
inwater,acidifiedwith1Mhydrochloricacidandtheprecipi-
tatedproductwascollectedbyfiltrationtogive0.25gofpale
yel low nee dles (94% yield), mp 262 C; IR: 3433, 3275
cm-1 (OH, NH), 1691 (C=O) cm-1; 1H NMR (CF3COOD):
2.72 (3H, s, COCH3), 3.18 (3H, s, 4-CH3), 3.21 (3H, s,
6-CH3), 7.87 (1H, s, 5-H), MS: 264 (M+).
Anal. Calcd. for C12H10N2O2S: C, 58.52; H, 4.09; N,
11.37. Found: C, 58.43; H, 4.08; N, 11.19%.
3-Hydroxy-2,7,9-trimethylpyrido[3 ,2 :4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one (4)
A so lu tion of com pound 3 (0.52 g, 2.1 mmol) in pyr-
idine (5 mL) and hydroxylamine hy dro chlo ride (0.19 g, 2.73
mmol) was refluxed for 4 h. The re ac tion mix ture was cooled
and the re sult ing crys tals col lected, washed with wa ter and
recrystallized from ace tic acid/wa ter to give 0.32 g of nee dle
crys tals (50% yield), mp 318 C; IR: 3602 (OH), 1644
(C=O) cm-1; 1H NMR (CF3COOD): 3.16 (3H, s, 9-CH3),
3.23 (3H, s, 7-CH3), 3.58 (3H, s, 2-CH3), 7.96 (1H, s, 8-H);
MS: 261 (M+).
Anal. Calcd. for C10H10N2O2S: C, 54.53; H, 4.58; N,
10.60. Found: C, 54.56; H, 4.43; N, 10.62%.
Ethyl 3-ethoxymethyleneamino-4,6-dimethylthieno[2,3-b]-
pyridine-2-carboxylate (7a)
Anal. Calcd. for C12H11N3O2S: C, 55.16; H, 4.24; N,
16.08. Found: C, 55.15; H, 4.18; N, 15.99%.
Asolutionofcompound1 (1.50 g, 6 mmol) and triethyl
orthoformate(8mL)wasrefluxedinaceticanhydride(5mL)
for24h. Thereactionmixturewascooled. Theresultingsolid
prod uct was col lected by fil tra tion and recrystallized from
eth a nol to give 1.25 g of col or less nee dles (68% yield), mp
109 C; IR: 1705 (C=O) cm-1; 1H NMR (CDCl3): 1.33
(3H, t, J = 2.4 Hz, CH3), 1.42 (3H, t, J = 2.4 Hz, CH3), 2.57
(3H, s, 4-CH3), 2.60 (3H, s, 6-CH3), 4.29 (2H, q, J = 2.4 Hz,
OCH2), 4.44 (2H, q, J = 2.4 Hz, OCH2), 6.88 (1H, s, 5-H),
7.73 (1H, s, N=CH); MS: 306 (M+).
Ethyl 3-diacetylamino-4,6-dimethylthieno[2,3-b]pyridine-
2-carboxylate (5)
Asolutionofcompound1 (1.0 g, 4 mmol), ace tic an hy-
dride (10 mL) and an hy drous so dium ac e tate (0.8 g) was
refluxed in gla cial ace tic acid (6 mL) for 6 h. The re ac tion
mix ture was cooled. The re sult ing solid prod uct was col-
lected by fil tra tion and recrystallized from eth a nol to give
1.33 g of pale yel low nee dles (85% yield), mp 168 C; IR:
1729 (C=O) cm-1; 1H NMR (CDCl3): 1.35 (3H, t,J = 2.4 Hz,
CH3), 2.29 (6H, s, N(CH3CO)2), 2.42 (3H, s, 4-CH3), 2.62
(3H, s, 6-CH3), 4.33 (2H, q, J = 2.4 Hz, OCH2), 7.00 (1H, s,
5-H); MS: 334 (M+).
Anal. Calcd. for C15H18N2O3S: C, 58.80; H, 5.92; N,
9.14. Found: C, 58.34; H, 5.71; N, 9.41%.
General procedure of 3-Substituted-2,7,9-trimethyl-
pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones (8a-c)
Toasolutionofcompounds3 and5 (0.01 mol) in eth a-
nol (20 mL), amines (hydrazine hy drate, am mo nia and meth-
yl amine) (15 mL) was added. The re ac tion mix ture was re-
fluxed for 3 h. Af ter cool ing, the pre cip i tate was fil tered and
recrystallized from ace tic acid. Phys i cal and spec tral data of
the 8a-c are re corded in Ta bles 1 and 2.
Anal. Calcd. for C16H18N2O4S: C, 57.47; H, 5.43; N,
8.38. Found: C, 57.41; H, 5.39; N, 8.49%.
Ethyl 3-acetylamino-4,6-dimethylthieno[2,3-b]pyridine-2-
carboxylate (6a)
A so lu tion of com pound5 (0.67 g, 2 mmol) in 10%
H2SO4 (10 mL) was stirred at a tem per a ture of 80-90 C for 1
h. Thereactionmixturewascooledandpouredintoice-water.
Ad di tion of 10% NaOH pre cip i tated a solid prod uct which
was recrystallized from eth a nol to give 0.51 g of col or less
nee dles (87% yield), mp 192 C; IR: 3295 (NH), 1729
2,7,9-Trimethylpyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (8b)
From com pound8a andsodiumnitrite/aceticacid
Asuspensionofcompound8a (0.26 g, 1 mmol) in 50%
aque ous ace tic acid (30 mL) was warmed to 45-50 C and
then treated with so dium ni trite (0.5 g, 7.2 mmol) in por tions.
The re ac tion mix ture was heated (45-50 C) un til the evo lu-
tion of ni tro gen di ox ide ceased; the re sult ing so lu tion was
cooled and di luted with wa ter. The solid prod uct was col-
lected by fil tra tion to give 0.24 g (98% yield).
1
(C=O) cm-1; H NMR (CDCl3): 1.37 (3H, t, J = 2.4 Hz,
CH3), 2.24 (3H, s, COCH3), 2.56 (3H, s, 4-CH3), 2.58 (3H, s,
6-CH3), 4.33 (2H, q, J = 2.4 Hz, OCH2), 6.93 (1H, s, 5-H),
8.59 (1H, br, NH); MS: 292 (M+).
Anal. Calcd. for C14H16N2O3S: C, 57.52; H, 5.52; N,
9.58. Found: C, 57.23; H, 5.20; N, 9.21%.

1172 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
2,3,7,9-Tetramethylpyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (8c)
17.80. Found: C, 58.26; H, 3.79; N, 17.85%.
From com pound8b and methyl io dide
7,9-Dimethyl-3-(4-nitrobenzylideneamino)-pyrido[3 ,2 :4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (10b)
Toasolutioncontainingcompound8b (0.5 g, 2 mmol),
wasaddedmethyliodide(0.5g, 3.5mmol)andanhydrouspo-
tas sium car bon ate (0.28 g, 2 mmol) in dry ac e tone (20 mL).
The mix ture was refluxed for 6 h and poured into ice-water.
The pre cip i tated prod uct was col lected by fil tra tion to give
0.46 g (86% yield).
This com pound was syn the sized from com pound9a
(0.49 g, 2 mmol) andp-nitrobenzaldehyde (0.3 g, 2 mmol) in
amannersimilartothatdescribedforthepreparationof10a.
It was recrystallized from chlo ro form to give 0.69 g of yel low
nee dles (91% yield), mp 292 C; IR: 1690 (C=O) cm-1; 1H
NMR (CF3COOD): 2.95 (3H, s, 9-CH3), 3.28 (3H, s, 7-
CH3), 7.68 (1H, s, 8-H), 8.14 (2H, d, J = 3.0 Hz, 2, 6-H of
phenyl), 8.37 (2H, d, J = 3.0 Hz, 3, 5-H of phenyl), 8.75 (1H,
s, N=CH), 9.44 (1H, s, 2-H); MS: 379 (M+).
General Procedure of 3-Substituted-7,9-dimethylpyrido-
[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones (9a-c)
Thesecompoundsweresynthesizedfromcompound7a
(3.06 g, 0.01 mol) and amines (hydrazine hy drate, am mo nia
and methylamine) (15 mL) in a man ner sim i lar to that de-
scribed for the prep a ra tion of8a-c. It was recrystallized from
ace tic acid. Phys i cal and spec tral data of the 9a-c are re-
corded in Ta bles 1 and 2.
Anal. Calcd. for C18H13N5O3S: C, 56.99; H, 3.45; N,
18.46. Found: C, 57.07; H, 3.16; N, 18.23%.
2,7,9-Trimethyl-3-acetylamino-pyrido[3 ,2 :4,5]thieno[3,2-
d]pyrimidin-4(3H)-one (11a)
Amixtureofcompounds8a (0.52 g, 2 mmol) and ace tic
an hy dride (5 mL) was refluxed in gla cial ace tic acid (10 mL)
for 24 h. The re ac tion mix ture was cooled and poured into
ice-water. Theresultingsolidproductwascollectedbyfiltra-
tion and recrystallized to give 0.52 g (86% yield), mp 156 C;
IR: 3449 (NH), 1692 (C=O) cm-1; 1H NMR (CF3COOD):
2.58 (3H, s, COCH3), 2.90 (3H, s, 9-CH3), 3.11 (3H, s, 7-
CH3), 3.45 (3H, s, 2-CH3), 7.85 (1H, s, 8-H); MS: 302 (M+).
Anal. Calcd. for C14H14N4O2S: C, 55.62; H, 4.67; N,
18.53. Found: C, 55.46; H, 4.79; N, 18.55%.
3-Amino-7,9-dimethylpyrido[3 ,2 :4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one (9a)
From com pound14 and triethyl orthoformate
A mix ture of carbohydrazide 14 (0.24 g, 1 mmol) and
triethylorthoformate(8mL)wasrefluxedinaceticanhydride
(2 mL) for 24 h. The re ac tion mix ture was cooled. The re sult-
ing solid prod uct was col lected by fil tra tion and washed with
wa ter to give 0.21 g (86% yield).
7,9-Dimethylpyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (9b)
From com pound1 and formamide
7,9-Dimethyl-3-acetylamino-pyrido[3 ,2 :4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one (11b)
A so lu tion of com pound 1 (3 g, 1.2 mmol) and form-
amide (30 mL) was refluxed for 24 h. The re ac tion mix ture
was cooled and the crude prod uct was col lected and washed
with wa ter to give 2.26 g (82% yield).
This com pound, syn the sized from com pound 9a (0.49
g, 2 mmol) and ace tic an hy dride (5 mL), was refluxed in gla-
cial ace tic acid (10 mL) in a man ner sim i lar to that de scribed
for the prep a ra tion of11a. It was recrystallized from chlo ro-
form to give 0.53 g (92% yield), mp 227 C; IR: 3193 (NH),
1
2,7,9-Trimethyl-3-(4-nitrobenzylideneamino)-pyrido-
[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-one (10a)
Toasolutionofcompounds8a (0.52 g, 2 mmol) in gla-
cial ace tic acid (10 mL),p-nitrobenzaldehyde (0.3 g, 2 mmol)
was added. The re ac tion mix ture was refluxed for 3 h. Af ter
cool ing, the pre cip i tate was fil tered and recrystallized from
chlo ro form to give 0.67 g of yel low nee dles (85% yield), mp
284 C; IR: 1690 (C=O) cm-1; 1H NMR (DMSO-d6): 2.57
(3H, s, 9-CH3), 2.65 (3H, s, 7-CH3), 2.88 (3H, s, 2-CH3), 7.65
(1H, s, 8-H), 8.09 (2H, d, J = 3.0 Hz, 2, 6-H of phenyl), 8.27
(2H, d, J = 2.9 Hz, 3, 5-H of phenyl), 9.31 (1H, s, N=CH);
MS: 393 (M+).
1755 (C=O) cm-1; H NMR (CF3COOD): 2.33 (3H, s,
COCH3), 3.10 (3H, s, 9-CH3), 3.42 (3H, s, 7-CH3), 7.86 (1H,
s, 8-H), 8.60 (1H, s, 2-H); MS: 288 (M+).
Anal. Calcd. for C13H12N4O3S: C, 54.16; H, 4.20; N,
19.43. Found: C, 54.14; H, 4.18; N, 19.49%.
3-Substituted Carbonylmethylenepyrido[3 ,2 :4,5]thieno-
[3,2-d]pyrimidin-4(3H)-ones (13a-d)
Toasolutioncontainingcompounds 8b, 9b (2 mmol),
was added methyl io dide (0.5 g, 3.5 mmol) and an hy drous po-
tas sium car bon ate (0.28 g, 2 mmol) in dry ac e tone (20 mL).
The mix ture was refluxed for 6 h and poured into ice-water.
The pre cip i tated prod uct was col lected and recrystallized.
Anal. Calcd. for C19H15N5O3S: C, 58.01; H, 3.84; N,

Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1173
Physicalandspectraldataofthe13a-darerecordedinTables
yield), mp 251 C; IR: 3475-3277 (NH2, NH), 1631 (C=O)
cm-1; 1H NMR (DMSO-d6): 2.49 (3H, s, 4-CH3), 2.74 (3H,
s, 6-CH3), 7.01 (1H, s, 5-H), 7.38 (2H, br, NH2), 7.50-7.40
(5H, m, phenyl-H), 7.81 (1H, s, N=CH), 11.41 (1H, br, NH);
MS: 324 (M+).
1 and 2.
7,9-Dimethyl-3-piperidinomethylamino-pyrido[3 ,2 :4,5]-
thieno[3,2-d]pyrimidin-4(3H)-one (15a)
To a mix ture of carbohydrazide14 (0.47 g, 2 mmol) and
piperidine (0.68 g, 8 mmol) was added form al de hyde (10 mL
of a 40% aque ous so lu tion). The re ac tion mix ture was left at
room tem per a ture for 4 h and the re sult ing pre cip i tate fil-
tered, washed with pe tro leum ether and recrystallized from
ace tic acid/DMF to give 0.33 g (51% yield), mp 127 C; IR:
1659 (C=O) cm-1; 1H NMR (CF3COOD): 4.34-4.30, 2.25-
2.07 (10H, m, Piperidyl-H), 3.07 (3H, s, 9-CH3), 3.15 (3H, s,
7-CH3), 5.38 (2H, s, N-CH2), 7.72 (1H, s, 8-H), 8.09 (1H, s,
2-H); MS: 328 (M+).
Anal. Calcd. for C17H16N4OS: C, 62.94; H, 4.97; N,
17.27. Found: C, 62.73; H, 4.67; N, 17.00%.
2-Substituted-3-N-benzylidene-7,9-trimethylpyrido-
[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-one (18a,b)
A mixture of compound 17 (1.0 g, 3.0 mmol) and
orthoesters (10 mL) in ace tic an hy dride (10 mL) was refluxed
with stir ring for 3 h. The re ac tion mix ture was cooled. The re-
sult ing solid prod uct was col lected by fil tra tion and re crys-
tallizedfromchloroform.Thephysicalconstantsandspectral
data of com pounds18a,b are re corded in Ta bles 3, 4.
Anal. Calcd. for C17H20N4O2S: C, 62.17; H, 6.14; N,
17.06. Found: C, 62.11; H, 6.08; N, 17.21%
2-Cyano-3-alkylethoxymethyleneamino-4,6-dimethylthieno-
[2,3-b]pyridine (20a,b)
7,9-Dimethyl-3-morpholinomethylamino-pyrido[3 ,2 :4,5]-
thieno[3,2-d]pyrimi-din-4(3H)-one (15b)
Thesecompoundsweresynthesizedfromcompound19
(1.22 g, 6 mmol) and orthoesters (8 mL) in a man ner sim i lar
to that de scribed for the prep a ra tion of7a. It was recrys tal-
lizedfromchloroformorchloroform/ethanol.Thephysical
constantsandspectraldataofcompounds20a,bare re corded
in Ta bles 3, 4.
This com pound was syn the sized from carbohydrazide
14 (0.47 g, 2 mmol) and morpholine (0.70 g, 8 mmol) by add-
ing form al de hyde (10 mL of a 40% aque ous so lu tion) in a
mannersimilartothatdescribedforthepreparationof15a. It
was recrystallized from ace tic acid/DMF to give 0.48 g (72%
yield), mp 173 C; IR: 1664 (C=O) cm-1; 1H NMR (CDCl3):
3.70-3.64, 2.88-2.47 (8H, m, morpholyl-H), 2.57 (3H, s, 9-
CH3), 2.60 (3H, s, 7-CH3), 4.79 (2H, s, N-CH2), 6.95 (1H, s,
8- H), 7.82 (1H, s, 2-H); MS: 330 (M+).
2-Substituted-3-amino-4-imino-7,9-dimethylpyrido-
[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-one (21a,b)
These com pounds were syn the sized from com pounds
20a,b (6 mmol) in eth a nol (20 mL) and hydrazine hy drate (10
mL)inamannersimilartothatdescribedforthepreparation
of 7a. It was recrystallized from chlo ro form/eth a nol. The
physicalconstantsandspectraldataofcompounds21a,b are
recordedinTables3, 4.
Anal. Calcd. for C16H18N4O2S: C, 58.18; H, 5.45; N,
16.96. Found: C, 58.07; H, 5.36; N, 17.03%.
3-Alkylethoxymethyleneamino-7,9-dimethylpyrido-
[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-one (16a,b)
A solution of com pound 14 (0.5 g, 2.1 mmol) and
orthoesters (5 mL) was refluxed in eth a nol (5 mL) for 4 h.
Thereactionmixturewascooled.Theresultingsolidproduct
was col lected by fil tra tion and recrystallized from eth a nol.
Thephysicalconstantsandspectraldataofcompounds16a,b
are re corded in Ta bles 1, 2.
General Procedureof3,5-disubstituted-7,9-dimethylpyrido-
[3 ,2 :4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
(22a-f)
To a so lu tion of imino com pounds21a,b (5 mmol) in
eth a nol (20 mL), ap pro pri ate orthoesters (20 mmol) were
added. The re ac tion mix ture was refluxed for 24 h. Af ter
cool ing, the pre cip i tate was fil tered and recrystallized from
chloroform/ethanol. Physicalandspectraldataofthe 22a-f
are re corded in Ta bles 3 and 4.
3-Amino-2-carboxybenzenzylidenehydrazide-4,6-
dimethylthieno[2,3-b]pyridine (17)
Toasolutionofcompound14 (0.5 g, 2.1 mmol), benz-
aldehyde (0.3 g, 2.1 mmol) in ab so lute eth a nol (8 mL), a few
drops of gla cial ace tic acid was added. The mix ture was
heated un der re flux for 4 h. Af ter cool ing, the re sult ing solid
prod uct was col lected by fil tra tion and recrystallized from
chlo ro form/eth a nol to give 0.59 g of yel low nee dles (86%
3-Ethyl-4-imino-7,9-dimethylpyrido[3 ,2 :4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one (23a)
This com pound was syn the sized from com pound 20a
(0.01mol)andethylamine(15mL)inamannersimilartothat

1174 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Ho
de scribed for the prep a ra tion of8a-c. It was recrystallized
from ace tic acid/eth a nol to give 2.45 g (95% yield), mp 195
C; IR: 3305 (NH) cm -1 ; 1H NMR (CDCl3): 1.47 (3H, t,J =
2.4 Hz, CH3), 2.80 (3H, s, 9-CH3), 3.04 (3H, s, 7-CH3), 3.86
(2H, q,J = 2.4 Hz, CH2), 7.04 (1H, s, 8-H), 8.27 (1H, s, 2-H);
MS: 258 (M+).
3. (a) Bousquet, E.; Romero, G.; Guerrera, F.; Caruso, A.;
Roxas, M. A. Farmaco Ed. Sci., 1985, 40, 869. (b)
Bousquet, E.; Guerrera, F.; Siracusa, N. A.; Caruso, A.;
Roxas, M. A. Farmaco Ed. Sci. 1984, 39, 110.
4. Vieweg, H.; Leistner, S.; Wagner, G.; Boehm, N.;
Krasset, U.; Grupe, R.; Lohmann, D.; Loban, G. East
Ger man Pat ent DD 1988, 257830; Chem. Abstr. 1989,
110, 95262p.
Anal. Calcd. for C13H14N4S: C, 60.46; H, 5.42; N,
21.70. Found: C, 60.33; H, 5.10; N, 21.54%.
5. (a) Chaykovsky, M.; Lin, M.; Rosowsky, A.; Mod est, E. J.
J. Med. Chem. 1973, 10, 188. (b) Eslager, E. F.; Ja cob, P.
W.; Leslic, M. J. J. Heterocyclic Chem. 1972, 9, 775.
6. Madding, G. D.;Thompson, M. D. J. Heterocyclic Chem.
1987, 24, 581.
7. Cheng, C. C. In ProgressinMedicinalChemistry; Vol.
25; Ellis, G. P.; West, G. B., Eds; Elsevier Sci ence Pub-
lisherB.V.1000AEAmsterdam,TheNetherlands,1989;
p 35.
8. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S. In dian Pat ent
1983, 151, 456; Chem. Abstr. 1984, 100, 209858.
9. Al bert, A. Adv. Heterocycl. Chem. 1986, 39, 117.
10. Ried, W.; Laoutidis, J. Liebigs Ann. Chem. 1988, 1107.
11. Kartizky, A. R.; Rees, C. W. ComprehensiveHeterocycl.
Chem. 1984, 5, 904.
3-Ethyl-4-imino-2,7,9-dimethylpyrido[3 ,2 :4,5]thieno[3,2-
d]pyrimidin-4(3H)-one (23b)
This com pound was syn the sized from com pound20b
(0.01 mol) and ethylamine (15 mL) in a man ner sim i lar to that
de scribed for the prep a ra tion of8a-c. It was recrystallized
from chlorofrom to give 2.50 g (92% yield), mp 116 C; IR:
3309 (NH) cm-1; 1H NMR (CDCl3): 1.47 (3H, t, J = 2.5 Hz,
CH3), 2.67 (3H, s, 9-CH3), 2.99 (3H, s, 7-CH3), 3.04 (2H, q, J
= 2.5 Hz, CH2), 7.13 (1H, s, 8-H), 9,28 (1H, s, NH); MS: 272
(M+).
Anal. Calcd. for C14H16N4S: C, 61.76; H, 5.88; N,
20.58. Found: C, 61.33; H, 5.90; N, 20.54%.
ACKNOWLEDGEMENT
12. Love, B.; Musser, J. H.; Brown, R. E.; Jones, H.; Kahen,
R.; Huang, F. C.; Khandwala, A.; Goldman, P. S.;
Leibowitz, M. J. Med. Chem. 1985, 28, 363.
13. Ellis, G. P. In Syn the sis of Fu sed Heterocycles. Hetero-
cyclic Com pounds; Vol. 47; Tay lor, Ed.; John Wiley and
Sons: New York, NY, 1991; pp 210-218.
We are grate ful to the Na tional Sci ence Coun cil of the
Re pub lic of China (NSC 89-2113-M-253-001) for their fi-
nancialsupport.
14. Peinador, C.; Moreira, Maria, J.; Quintela, Jose M. Tet ra-
hedron. 1994, 50, 6705.
Received May 24, 2001.
15. Vega, S.; Alonso, J.; Diaz, J. A.; Junquera, F. J.
Heterocyclic Chem. 1990, 27, 269.
Key Words
16. Moustafa, M. A. A.; Ismaiel, A. M.; Eisa, H. M.;
El-Eman, A. A. J. Chin. Chem. Soc. 1991, 38, 199.
17. Singh, G. B.; Bani, S. J.IndianChem.Soc. 1991, 48, 420.
18. Pfeif fer, Walf-Diethard.; Hetzheim, A. S.; Pazderza, P.;
Bodtke, A.; Mucke, J. J. Heterocyclic Chem. 1999, 36,
1327.
Pyrido[3 ,2 :4,5]thieno[3,2-d]pyrimidin-4(3H)-ones;
Pyrido[3 ,2 :4,5]thieno[2,3-e]-1,2,4-triazolo[1,5-c]-
pyrimidines; Ethyl 3-amino-thieno[2,3-b]pyridine
carboxylate; 3-Amino-2-cyano-thieno[2,3-b]-
pyridine.
19. Shishoo, C. J.; Devani, M. B.; Ullas, G. V.; Ananthan, S.;
Bhadti, V. S. J. Heterocyclic Chem. 1985, 22, 825.
20. Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni, V. J.
Heterocyclic Chem. 1999, 36, 1195.
21. Rashed, N.; Mousaad, A.; Saleh, A. J. Chin. Chem. Soc.
1993, 40, 393.
REFERENCES
1. Brown, D. J.; Katritzky; Rees ComprehensiveHetero-
cyclicChemistry; Vol. 3; Boulton, A. J.; McKillop, A.,
Eds.; 1984; p 57.
22. Ho, Y. W.; Wang, I. J. DyesandPigments . 1995, 29, 295.
23. Ho, Y. W. J. Chin. Chem. Soc. 1999, 46, 955.
2. Dave, C. G.; Shah, P. R.; Dave, K. C. J. In dian Chem.
Soc. 1989, 66, 48.