A facile synthesis of 2-substituted thieno[3′,2′-5,6]-pyrido[4, 3-d]pyilmidin-4(3H)-ones

Article abstract of DOI:10.1002/jhet.5570430345

The thienopyridine derivative 2, obtained from reaction of acetoacetic ester with 1 in the presence of tin tetrachloride, was treated with triphenylphosphine in hexachloroethane and Et₃N to give iminophosphorane 3. Iminophosphorane 3 reacted wi

Full text of DOI:10.1002/jhet.5570430345

May-Jun 2006
803
A Facile Synthesis of 2-substituted Thieno[3',2'-5,6]-
pyrido[4,3-d]pyrimidin-4(3H)-ones
Jian-Chao Liu, Hong-Wu He*, Qing-Yun Ren and Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan, 430079, P. R. China
e-mail: he1208@public.wh.hb.cn
Received July 18, 2005
NH2
N
N
PPh3
CO2C2H5
CN
CO2C2H5
CH3COCH2CO2C2H5
SnCl4
PPh3/CH3CN
C2Cl6/Et3N
S
NH2
S
S
N
OR
Ph
N
N
C
NPh
N
N
N
CO2C2H5
/CH3CN
HOR
K2CO3
PhNCO
CH2Cl2
O
NaOC2H5
or
S
S
The thienopyridine derivative 2, obtained from reaction of acetoacetic ester with 1 in the presence of tin
tetrachloride, was treated with triphenylphosphine in hexachloroethane and Et3N to give
iminophosphorane 3. Iminophosphorane 3 reacted with phenyl isocyanate to give carbodiimide 4, which
was further treated with phenols or ethenol to produce 2-substituted 5,8,9-trimethyl-3-phenyl-thieno[3',2'-
5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5 in presence of catalytic amount of K2CO3 or EtONa. The
structures of compounds 5 were confirmed by 1H NMR, IR, MS, and elemental analysis.
J. Heterocyclic Chem., 43, 803 (2006).
Introduction.
with phenols did not cyclize to produce 2-aryloxyl-thieno-
[3',2'-5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5. However,
the reaction took place to give compound 5 in good yields
under the condition of heating in presence of catalytic
amount of K2CO3. Irrespective of the fact whether the
substitutes on the phenols were electron-withdrawing or
electron-releasing groups, the cyclization was carried out
smoothly. Thin layer chromatography was employed to
follow the progress of every above reaction. Most of the
compounds 5 were readily soluble in polar organic
solvents and melt within 223-300 °C. The results are
listed in Table 1.
It is noteworthy that the direct reaction of carbodiimide
4 with EtOH gave a complex mixture. However, when the
reaction was achieved in presence of catalytic amount of
EtONa, the reaction took place completely and 2-ethoxy-
thieno[3',2'-5,6]pyrido[4,3-d]pyrimidin-4(3H)-one 5r was
obtained in satisfactory yields.
The derivatives of heterocycles containing pyrido-
pyrimidine system are of great importances because of
their remarkable biological properties [1]. For example,
some pyridopyrimidine derivatives were used as a novel
class of adenosine kinase inhibitors [2,3]. Thus, a large
number of general methods for the preparation of fused
pyridines have been reported [4-7].
Recently we have been interested in the synthesis of
fused pyrimidinones via aza-Wittig reaction of ꢀ-ethoxy-
carbonyl iminophosphorane with aromatic isocyanate and
subsequent reaction with various nucleophiles under mild
conditions [8]. As a continuation of our research for new
bioactive heterocycles [9], here we wish to report an
efficient synthesis of 2-substituted thieno[3',2'-5,6]pyrido-
[4,3-d]pyrimidin-4(3H)-ones, a series of compounds
which have not been reported before.
Results and Discussion.
The structure of compounds 5 was confirmed by
their elemental analysis and spectral data. IR spectral
data of compound 5 are presented in Table 2. The
The 2,3-dimethyl-4-cyano-5-aminothiophene 1 [10] was
converted to thienopyridine derivative 2 via reaction with
acetoacetic ester and tin tetrachloride under heating
(Scheme 1). The iminophosphorane 3 was subsequently
obtained in a satisfactory yield when 2 was treated with
triphenylphosphine, hexachloroethane and Et3N.
Iminophosphorane 3 reacted with phenyl isocyanate to
give carbodiimide 4. The direct reaction of carbodiimide 4
1
elemental analysis and H NMR spectra are given in
Table 3. The EI-mass spectra are presented in Table 4.
For example, the IR spectra of compound 5a revealed
C=O absorption bands at 1699 cm-1 and 1688 cm-1 and
absorption bands at 3136 cm-1 due to Ar-H group. The
1H NMR spectral data of 5a show the signals of three

804
J.-C. Liu, H.-W. He, Q.-Y. Ren and M.-W. Ding
Vol 43
CH3 at 1.98 ppm, 2.39 ppm, 3.06 ppm as singlet with
the other signals appeared at 7.14~7.60 (m, 10H, Ar-
H). The MS spectrum of 5a shows an obvious
molecule ion peak at m/z 413 with 100% abundance.
The structure of 5a was also established on the basis
of elemental analysis data. The difference between
found value and calculated value of elemental analysis
of all compounds was under 0.5%.
Scheme 1
NH2
N
CN
CO2C2H5
CH3COCH2CO2C2H5
PPh3/CH3CN
C2Cl6/Et3N
SnCl4
S
NH2
S
1
2
N
N
C
NPh
CO2C2H5
N
PPh3
CO2C2H5
PhNCO
CH2Cl2
HOR
S
S
N
3
4
OR
C
OR
NHPh
Ph
N
N
N
N
CO2C2H5
/CH3CN
K2CO3
O
NaOC2H5
or
S
S
N
5
Table 1
Physical Constants of Compounds 5
Compd.
R
Formula
Color
m. p .(°C)
r. t. (h)
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
Ph-
2-MePh-
4-CH3Ph-
4-ClPh-
2,4-diClPh-
2-ClPh-
4-BrPh-
C24H19N3O2S
C25H21N3O2S
C25H21N3O2S
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
colorless crystals
268~269
258~260
243~244
267~268
240~241
260~261
276~277
250~252
290~292
254~255
266~267
271~273
257~259
>300
14
13
13
12
14
13
12
13
11
12
13
12
12
13
13
13
11
14
87
60
84
68
69
70
67
76
82
67
75
40
74
59
60
44
43
55
C24H18ClN3O2S
C24H17Cl2N3O2S
C24H18ClN3O2S
C24H18BrN3O2S
C24H17F2N3O2S
C24H18FN3O2S
C24H17FClN3O2S
C24H17FClN3O2S
C25H20ClN3O2S
C25H20ClN3O2S
C24H17F2N3O2S
C24H18N4O4S
2,4-diFPh-
3-FPh-
2-Cl-4-FPh-
3-Cl-4-FPh-
2-Cl-5-CH3Ph-
4-Cl-3-CH3Ph-
3,5-diFPh-
4-NO2Ph-
2-NO2Ph-
PentaClPh-
CH3CH2-
235~237
299~300
>300
C24H18N4O4S
C24H14Cl5N3O2S
C20H19N3O2S
223~225
Table 2
IR Spectral Data of Compounds 5
IR (KBr, ꢀ/ cm-1)
Compd.
5a
5b
5c
5d
5e
5f
3136(Ph-H), 2910(C-H), 1699,1688(C=O), 1617, 1561, 1511, 1490, 1401, 1373, 1266, 1205, 807, 731, 690
3136(Ph-H), 2925(C-H), 1733,1697(C=O), 1617, 1593, 1562, 1514, 1491, 1400, 1372, 1319, 1266, 1240, 1157, 750, 688
3125(Ph-H), 2917(C-H), 1699(C=O),1618,1561,1504,1402,1370,1266,1201,835,807,700
3135(Ph-H), 2924(C-H), 1700,1687(C=O), 1616, 1560, 1510, 1488, 1402, 1263, 1208, 1012, 844, 740, 690
3137(Ph-H), 2926(C-H), 1699(C=O), 1622, 1563, 1516, 1403, 1371, 1251, 1225, 1096, 1049, 834, 757, 690
3137(Ph-H), 2935(C-H), 1696(C=O), 1618, 1562, 1514, 1477, 1401, 1371, 1263, 1221, 1051, 806, 745

May-Jun 2006 A Facile Synthesis of 2-substituted Thieno[3',2'-5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones
805
Table 2 (continued)
Compd.
IR (KBr, ꢀ/ cm-1)
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
3098(Ph-H), 2927(C-H), 1701(C=O), 1614, 1560, 1512, 1485, 1402, 1371, 1322, 1263, 1207, 1066, 1009, 842, 740, 630
3124(Ph-H), 2921(C-H), 1700(C=O), 1621, 1561, 1506, 1402, 1372, 1265, 1195, 1143, 965, 830, 746, 703
3136(Ph-H), 2936(C-H), 1696(C=O), 1621, 1592, 1562, 1516, 1489, 1400, 1373, 1264, 1141, 944, 810, 706
3124(Ph-H), 2927(C-H), 1732, 1701(C=O), 1623, 1594, 1561, 1490, 1420, 1371, 1265, 1182, 1047, 830, 702
3117(Ph-H), 2924(C-H), 1699(C=O), 1620, 1560, 1493, 1400, 1319, 1247, 1194, 1054, 873, 773, 693
3136(Ph-H), 2926(C-H), 1699(C=O), 1621, 1562, 1518, 1399, 1367, 1268, 1236, 1171, 1050, 806, 703, 687
3136(Ph-H), 2926(C-H), 1700(C=O), 1622, 1562, 1519, 1476, 1401, 1371, 1323, 1265, 1243, 1163, 1047, 877, 752
3134(Ph-H), 2932(C-H), 1701,1686(C=O), 1618, 1560, 1510, 1491, 1466, 1400, 1375, 1264, 1156, 1120, 1091, 992
3116(Ph-H), 2928(C-H), 1700(C=O), 1621, 1562, 1520, 1490, 1419, 1403, 1342, 1322, 1261, 1214, 1160, 863, 734
3147(Ph-H), 2935(C-H), 1695(C=O), 1620, 1562, 1525, 1492, 1401, 1349, 1263, 1220, 1047, 806, 733, 692
3094(Ph-H), 2915(C-H), 1737,1721(C=O), 1656, 1592, 1573, 1495, 1423, 1396, 1376, 1270, 1200, 1009, 806, 705, 662
3152(Ph-H), 2927(C-H), 1689(C=O), 1604, 1589, 1560, 1515, 1493, 1419, 1340, 1310, 1263, 1174, 764, 694
Table 3
Elemental Analysis and 1H NMR Spectral Data of Compounds 5
Calcd. (Found)/%
H.
1H NMR (ꢁ / ppm, CDCl3 , TMS, 400 MHz )
Compd.
C.
N.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
69.73(69.47) 4.60(4.63)
70.24(69.95) 4.95(4.83)
70.24(70.50) 4.95(5.02)
64.36(64.09) 4.02(4.03)
59.75(59.90) 3.53(3.67)
64.36(64.69) 4.02(4.18)
58.54(58.35) 3.66(3.79)
64.14(63.86) 3.79(3.84)
66.82(66.64) 4.18(4.25)
61.87(61.85) 3.65(3.72)
61.87(62.16) 3.65(3.82)
65.00(64.79) 4.36(4.45)
65.00(64.86) 4.36(4.27)
64.13(64.22) 3.81(3.92)
62.87(62.65) 3.96(3.91)
62.87(63.03) 3.96(3.99)
49.21(48.97) 2.41(2.56)
65.75(66.01) 5.21(5.28)
10.17(10.33) 1.98 (s, 3H, CH3), 2.39(s, 3H, CH3), 3.06 (s, 3H, CH3), 7.14~7.60 (m, 10H, Ar-H)
9.83(10.02)
9.83(9.86)
9.39(9.50)
8.71(8.53)
9.39(9.41)
8.54(8.49)
9.35(9.48)
9.74(9.90)
9.02(9.11)
9.02(9.09)
9.10(9.04)
9.10(9.29)
9.35(9.32)
2.06 (s, 3H, CH3), 2.39(s, 3H, CH3), 2.41(s, 3H, CH3), 3.04 (s, 3H, CH3), 6.96~7.62 (m, 9H, Ar-H)
2.02(s, 3H, CH3), 2.38(s,3H, CH3), 2.40(s,3H,CH3), 3.05(s, 3H, CH3), 7.07~7.60 (m, 9H, Ar-H)
2.04 (s, 3H, CH3), 2.40(s, 3H, CH3), 3.03 (s, 3H, CH3), 7.10~7.62 (m, 9H, Ar-H)
1.96 (s, 3H, CH3), 2.41(s, 3H, CH3), 3.05 (s, 3H, CH3), 7.19~7.61 (m, 8H, Ar-H)
1.89 (s, 3H, CH3), 2.39(s, 3H, CH3), 3.07 (s, 3H, CH3), 7.23~7.61 (m, 9H, Ar-H)
2.04 (s, 3H, CH3), 2.41(s, 3H, CH3), 3.03 (s, 3H, CH3), 7.04~7.60 (m, 9H, Ar-H)
2.01 (s, 3H, CH3), 2.65(s, 3H, CH3), 3.06 (s, 3H, CH3), 7.26~7.61 (m, 8H, Ar-H)
2.05 (s, 3H, CH3), 2.41(s, 3H, CH3), 3.05 (s, 3H, CH3), 6.96~7.60 (m, 9H, Ar-H)
1.98 (s, 3H, CH3), 2.52(s, 3H, CH3), 3.06 (s, 3H, CH3), 7.26~7.56 (m, 8H, Ar-H)
2.10 (s, 3H, CH3), 2.43(s, 3H, CH3), 3.04 (s, 3H, CH3), 7.26~7.60 (m, 8H, Ar-H)
1.94 (s, 3H, CH3), 2.35(s, 3H, CH3), 2.40(s, 3H, CH3), 3.07 (s, 3H, CH3), 7.06~ 7.60 (m, 8H, Ar-H)
2.06 (s, 3H, CH3), 2.39(s, 3H, CH3), 2.41(s, 3H, CH3), 3.03 (s, 3H, CH3), 6.94~7.62 (m, 8H, Ar-H)
2.14 (s, 3H, CH3), 2.44(s, 3H, CH3), 3.07 (s, 3H, CH3), 6.78~7.61 (m, 8H, Ar-H)
12.22(12.37) 2.00 (s, 3H, CH3), 2.41(s, 3H, CH3), 3.06 (s, 3H, CH3), 7.26~8.34 (m, 9H, Ar-H)
12.22(12.03) 1.86 (s, 3H, CH3), 2.38(s, 3H, CH3), 3.06 (s, 3H, CH3), 7.26~8.24 (m, 9H, Ar-H)
7.17(7.30)
2.53 (s, 3H, CH3), 2.67(s, 3H, CH3), 3.01 (s, 3H, CH3), 7.26~7.59 (m, 5H, Ar-H)
11.51(11.40) 1.33(d, 3H, J=7.2Hz, CH3), 2.51(s, 3H, CH3), 2.71 (s,3H,CH3), 3.03(s, 3H, CH3), 4.55(m,2H,
J=7.2Hz ,CH2), 7.25~7.54(m, 5H, Ar-H)
Table 4
The EI-mass Spectra of Compounds 5
Compd.
MS (EI, m/z, % )
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
415 (M++2, 6), 414 (M++1, 21), 413 (M+, 100), 321 (11), 320 (66), 189 (12), 76 (24), 64 (10), 49 (9)
429 (M++2, 8), 428 (M++1, 27), 427 (M+, 100), 320 (10), 90 (19), 76 (31), 64 (12), 50 (7)
428 (M++1, 11), 427 (M+, 28), 320 (11), 252 (12), 169 (10), 166 (48), 98 (27), 95 (15), 82 (64), 67 (38), 66 (34), 55 (100), 40 (48), 38 (38)
449 (M++1, 20), 448 (M+, 32), 447 (100), 336 (25), 126 (17), 110 (19), 98 (48), 76 (58), 74 (19), 72 (10), 58 (13), 49 (13)
485 (M++3, 15), 484 (M++2, 20), 483 (M++1, 64), 482 (M+, 33), 481 (100), 160 (8), 134 (17), 132 (31), 76 (96), 50 (15), 44 (14), 41 (22)
449 (M++1, 38), 448 (M+, 29), 447 (100), 127 (6), 110 (20), 98 (31), 76 (69), 74 (18), 50 (14)
494 (M++2, 26), 493 (M++1, 90), 492 (M+, 31), 491 (100), 320 (9), 144 (9), 142 (10), 76 (35), 62 (10), 49 (7)
451 (M++2, 9), 450 (M++1, 25), 449 (M+, 100), 128 (10), 118 (12), 100 (19), 76 (73), 62 (13), 50 (16), 49 (9)
433 (M++2, 8), 432 (M++1, 27), 431 (M+, 100), 320 (8), 111 (13), 94 (53), 82 (43), 76 (85), 74 (25), 56 (12), 50 (25)
467 (M++2, 27), 466 (M++1, 23), 465 (M+, 74), 144 (10), 128 (12), 118 (32), 116 (30), 90 (28), 76 (100), 62 (11), 50 (30)
467 (M++2, 19), 465 (M+, 88), 337 (14), 319 (100), 190 (13), 188 (51), 127 (6), 76 (29), 50 (5)
464 (M++2, 11), 463 (M++1, 36), 462 (M+, 30), 461 (100), 426 (20), 124 (12), 112 (9), 76 (72), 62 (7), 50 (15)
464 (M++3, 24), 463 (M++2, 16), 461 (M+, 85), 432 (13), 319 (100), 307 (24), 305 (22), 189 (18), 172 (11), 112 (10), 76 (38)
451 (M++2, 6), 450 (M++1, 19), 449 (M+, 65), 320 (10), 112 (28), 100 (21), 76 (100), 50 (24)
460 (M++2, 8), 459 (M++1, 26), 458 (M+, 100), 427 (6), 320 (37), 76 (17), 56 (9), 54 (9), 38 (8)
458 (M+, 100), 441 (53), 412 (35), 411 (64), 337 (20), 336 (31), 333 (15), 319 (61), 92 (19), 76 (28), 66 (21)
585 (M+, 1), 340 (8), 339 (21), 337 (100), 292 (27), 245 (31), 218 (11), 190 (26), 189 (12), 171 (24), 119 (10)
365 (M+, 100), 337 (13), 336 (14), 76 (5), 63 (3)

806
J.-C. Liu, H.-W. He, Q.-Y. Ren and M.-W. Ding
Vol 43
EXPERIMENTAL
stirred for 11~14 h at 80 °C, the solution was concentrate and
the residue was recrystallized from CH3CN to give 2-aryloxyl-
5,8,9-trimethyl-3-phenylthieno[3',2'-5,6]pyrido[4,3-d]pyrimidin-
4(3H)-ones 5a~5q.
Melting points were determined with a WRS-1B Digital
melting point apparatus and are uncorrected. EI-MS spectra
were measured on a Finnigan Trace Mass Spactrometer. IR
Preparation of compound 5r.
spectra were recorded on
a Shimadzu IR-408 Infrared
1
To the solution of 4 prepared above in CH3CH2OH (15 mL)
were added several drops of CH3CH2ONa in CH3CH2OH. After
the mixture was stirred for 14 h at room temperature, the
solution was condensed and the residue was recrystallized from
CH3CH2OH to give 2-ethyloxyl-5,8,9-trimethyl-3-phenyl thieno-
[3',2'-5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5r.
Spectrometer. H NMR spectra were taken on a Varian XL-300
Spectrometer. Elemental Analysis were recorded on a Varian EL
III elemental analysis instrument. All of the solvents and
materials were reagent grade and purified as required.
Thienopyridine derivative 2 was prepared according to the
literature procedures [10] in 69%, Colorless crystals, mp
131~132 °C. 1H NMR (CDCl3, ꢀ): 6.65~6.73 (s, 2H, NH2), 4.40
(m, 2H, J=7.2Hz, CH2CO), 2.77 (s, 3H, CH3), 2.57 (s, 3H, CH3),
2.39 (s, 3H, CH3), 1.20 (s, 3H, J=7.2Hz, CH3).
Acknowledgement.
We gratefully acknowledge financial support of this work by
the National Key Project for Basic Research and the National
Natural Science Foundation of China (No. 2003CB114400 and
Project No. 20372023 )
Preparation of iminophosphorane 3.
A solution of thienopyridine derivative 2 (1.06 g, 4 mmol) in
CH3CN (15mL) was added to triphenylphosphine (1.31 g, 5 mmol)
and C2Cl6 (1.19 g, 5 mmol). The mixture was treated with
triethylamine (8.0 mL), then stirred for 18~24 h at 0 °C, the
solution was condensed and the residue was recrystallized from
CH3CH2OH to give iminophosphorane 3 in yield 93%, Colorless
crystals, mp 174~175 °C. 1H NMR (CDCl3, ꢀ): 7.42~7.63 (m, 18H,
3Ph-H), 3.16 (m, 2H, J = 7.2 Hz, CH2CO), 2.46 (s, 3H, CH3), 2.35
(s, 3H, CH3), 2.11 (s, 3H, CH3), 1.02 (s, 3H, J = 7.2 Hz, CH3).
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