Efficient Synthesis of 6-(1H-1,2,4-Triazol-1-yl)-thieno[2,3-d]pyrimidin- 4(3H)-ones via an Iminophosphorane

Article abstract of DOI:10.1080/00397910903219351

Ethyl 2-amino-4-methyl-5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2, obtained from Gewald reaction of 1-(1H-1,2,4-triazol-1-yl)acetone 1 with ethyl cyanoacetate and sulfur, was transferred into iminophosphorane 3. Further reaction of 3 with aromatic isocyanates gave carbodiimides 4, which were treated subsequently with a secondary amine to give 6-(1H-1,2,4-triazol-1-yl)-thieno[2, 3-d]pyrimidin-4(3H)-ones 6 in good yields in the presence of a catalytic amount of sodium ethoxide. Copyright

Full text of DOI:10.1080/00397910903219351

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Efficient Synthesis of 6-(1H-1,2,4-
Triazol-1-yl)-thieno[2,3-
d]pyrimidin-4(3H)-ones via an
Iminophosphorane
Yong Sun a b , Nian-Yu Huang a & Ming-Wu Ding a
a Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, Central China Normal University , Wuhan, China
b Department of Chemistry , Yunyang Teachers College , Danjiangkou
Hubei, China
Published online: 08 Jun 2010.
To cite this article: Yong Sun , Nian-Yu Huang & Ming-Wu Ding (2010) Efficient Synthesis of 6-
(1H-1,2,4-Triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:13, 1985-1991, DOI: 10.1080/00397910903219351
To link to this article: http://dx.doi.org/10.1080/00397910903219351
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Synthetic Communications1, 40: 1985–1991, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219351
EFFICIENT SYNTHESIS OF 6-(1H-1,2,4-TRIAZOL-1-
YL)-THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES VIA
AN IMINOPHOSPHORANE
Yong Sun,1,2 Nian-Yu Huang,1 and Ming-Wu Ding1
1Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, Central China Normal University, Wuhan, China
2Department of Chemistry, Yunyang Teachers College,
Danjiangkou Hubei, China
Ethyl 2-amino-4-methyl-5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2, obtained from
Gewald reaction of 1-(1H-1,2,4-triazol-1-yl)acetone 1 with ethyl cyanoacetate and sulfur,
was transferred into iminophosphorane 3. Further reaction of 3 with aromatic isocyanates
gave carbodiimides 4, which were treated subsequently with a secondary amine to give
6-(1H-1,2,4-triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones 6 in good yields in the
presence of a catalytic amount of sodium ethoxide.
Keywords: Aza-Wittig reaction; Gewald reaction; iminophosphorane; thieno[2,3-d]pyrimidin-4(3H)-one;
1,2,4-triazole
The derivatives of heterocycles containing the thienopyrimidine system are of great
importance because of their remarkable biological properties. They have shown
significant antifungal, antibacterial, antimalarial, and antiallergic activities.[1–6] The
chemistry of thienopyrimidinones has also received attention because their starting
materials, 2-amino-3-carboxythiophenes, can conveniently be synthesized by the
Gewald reaction.[7] On the other hand, many 1-substituted 1,2,4-triazole compounds
show good fungicidal and plant-growth-regulative activities.[8,9] The introduction of
1,2,4-triazole to the thienopyrimidine system is expected to influence the biological
activities significantly. However, there are few reports about the 1,2,4-triazole-
substituted thienopyrimidinone system, which is of considerable interest as potential
agricultural or pharmaceutical fungicides.
Recently, we have been interested in the syntheses of imidazolinones, quinazo-
linones, and thienopyrimidinones via the aza-Wittig reaction of a- or b-ethoxycarbo-
nyl iminophosphorane with aromatic isocyanate and subsequent reaction with
various nucleophiles under mild conditions, with the aim of evaluating their
fungicidal activities.[10–14] Herein we report an efficient synthesis of 6-(1H-1,2,4-
triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via an iminophosphorane 3.
Received July 18, 2008.
Address correspondence to Ming-Wu Ding, Key Laboratory of Pesticide and Chemical Biology of
Ministry of Education, Central China Normal University, Wuhan 430079, China. E-mail: mwding@
mail.ccnu.edu.cn
1985

1986
Y. SUN, N.-Y. HUANG, AND M.-W. DING
Scheme 1. Preparation of iminophosphorane 3.
The ethyl 2-amino-4-methyl-5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2
was obtained by the Gewald method from 1-(1H-1,2,4-triazol-1-yl)acetone 1, ethyl
cyanoacetate, and sulfur in the presence of triethylamine. Compound 2 was easily
converted to iminophosphorane 3 by treatment with triphenylphosphine, hexachlor-
oethane, and triethylamine in dry acetonitrile in good yield (Scheme 1).
The iminophosphorane 3 reacted with an equimolar quantity of the aromatic
isocyanates to give the carbodiimides 4, which were allowed to react with secondary
amines to provide guanidine intermediates 5. By treatment with sodium ethoxide in
ethanol at room temperature, the intermediates 5 underwent intramolecular hetero-
cyclization to give the expected 6-(1H-1,2,4-triazol-1-yl)-thieno[2,3-d]pyrimidin-4
(3H)-ones 6 in good yields (Scheme 2). The results are listed in Table 1.
Owing to the instability of carbodiimide 4, the preparation of carbodiimides 4
must be carried out at low temperature (0–5 ꢀC) for a long reaction time (12 h) under
dry conditions; otherwise, hydrolysis or polymeric reaction of carbodiimide 4 takes
place, which results in poor yields. In preparation of products 6, all of the reactions
between carbodiimide 4 and the secondary amine proceeded smoothly at room
temperature though the reactivity of the carbodiimides 4 varied with the substituent
on the benzene ring. This implied the high reactivity of the carbodiimide 4.
The structure of the synthesized compound 6 was confirmed by their spectral
1
data and elemental analyses. For example, the H NMR spectral data of 6a show
the signals of –NCH3 and CH3 at 2.70 and 2.41 ppm as singlets. The triazole ring’s
signals appeared at 8.33 ppm (3-CH) and 8.13 (5-CH) as singlets. The phenyl signals
appeared at 7.53–7.26 ppm. The mass spectrum (MS) of 6a shows a molecule ion
peak (Mþ) at m=z 352 with 100% abundance.
Scheme 2. Preparation of thieno[2,3-d]pyrimidin-4(3H)-ones 6.

SYNTHESIS OF THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
1987
Table 1. Preparation of thieno[2,3-d]yrimidine-4(3H)-ones 6
Compound
Ar
NR1R2
Conditions
Yield (%)a
6a
6b
6c
Ph
Ph
Ph
NMe2
N(n-Bu)2
N(i-Pr)2
rt=4 h
rt=4 h
rt=8 h
81
78
77
6d
Ph
rt=4 h
91
6e
6f
6g
6h
6i
Ph
N(Me)Ph
NEt2
rt=6 h
rt=4 h
rt=5 h
rt=7 h
rt=4 h
rt=5 h
rt=5 h
72
85
87
80
76
88
83
3-CH3-C6H4
3-CH3-C6H4
3-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
N(n-Pr)2
N(n-Bu)2
NMe2
6j
6k
NEt2
N(n-Pr)2
aIsolated yields based on iminophosphorane 3.
In conclusion, we have developed an efficient synthesis of 2-substituted 6-(1H-
1,2,4-triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via reaction of functionalized
carbodiimides with various secondary amines. Because of the easily accessible and
versatile starting material, this method has potential for the syntheses of many
biologically and pharmaceutically active 1,2,4-triazolyl-containing thienopyrimidi-
none derivatives.
EXPERIMENTAL
Melting points were uncorrected. MS were measured on Finnigan Trace MS
1
spectrometer. H NMR spectra were recorded in CDCl3 on a Varian Mercury 400
spectrometer, and resonances are given in parts per million (d) relative to tetramethyl-
silane (TMS). Elemental analyses were performed on a Vario EL III elementary
analysis instrument. 1-(1H-1,2,4-Triazol-1-yl)acetone 1 was obtained quantitatively
by the reaction of 1-chloroacetone with 1H-1,2,4-triazole (1.5 equiv.) and solid
potassium carbonate in acetone at 60 ꢀC for 20 h.
Preparation of Ethyl 2-Amino-4-methyl-5-(1H-1,2,4-triazol-1-
yl)thiophene-3-carboxylate 2
Triethyl amine (1.2 mL) was added to a stirred mixture of 1-(1H-1,2,4-triazol-1-
yl)acetone 1 (0.62 g, 5 mmol), sulfur (0.16 g, 5 mmol), and ethyl cyanoacetate (0.57 g,
5 mmol) in dimethylformamide (DMF; 10 mL). After the mixture was stirred at room
temperature for 12 h, it was poured into water (50 mL), and the formed solid was
filtered and recrystallized from ethanol=petroleum ether (1:1, v=v) to give 2 as light
1
yellow needles: 0.67 g (53%), mp 122–124 ꢀC; H NMR (CDCl3, 400 MHz): d 8.24
(s, 1H, triazolyl-3-H), 8.08 (s, 1H, triazolyl-5-H), 6.60 (br, 2H, NH2), 4.31 (q, 2H,
J ¼ 7.2 Hz, OCH2), 2.13 (s, 3H, CH3), 1.36 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %):
252 (Mþ, 100), 224 (11), 206 (81), 178 (51), 124 (17). Anal. calcd. for C10H12N4O2S:
C, 47.61; H, 4.79; N, 22.21. Found: C, 47.85; H, 4.71; N, 22.05.

1988
Y. SUN, N.-Y. HUANG, AND M.-W. DING
Preparation of Iminophosphorane 3
NEt3 (2.42 g, 24 mmol) was added dropwise to a mixture of 2-amino-4-methyl-
5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2 (2.02 g, 8 mmol), PPh3 (3.14 g,
12 mmol), and C2Cl6 (2.84 g, 12 mmol) in dry CH3CN (40 mL) at room temperature.
The color of the reaction mixture quickly turned yellow. After the mixture was
stirred for 4 h, the solvent was removed under reduced pressure and the residue
was recrystallized from EtOH to give iminophosphorane 3 as light yellow needles:
1
3.32 g (81%), mp 179–181 ꢀC; H NMR (CDCl3, 400 MHz): d 8.10–7.48 (m, 17H,
Ar-H), 4.35 (q, 2H, J ¼ 7.2 Hz, OCH2), 2.13 (s, 3H, CH3), 1.38 (t, J ¼ 7.2 Hz, 3H,
CH3). MS (m=z, %): 512 (Mþ, 100), 467 (6), 320 (9), 261 (86), 182 (54), 107 (24).
Anal. calcd. for C28H25N4O2SP: C, 65.61; H, 4.92; N, 10.93. Found: C, 65.87; H,
4.68; N, 10.97.
Preparation of Carbodiimides 4
Aromatic isocyanate (2 mmol) was added to a solution of iminophosphorane 3
(1.02 g, 2 mmol) in anhydrous CH2Cl2 (10 mL) under a nitrogen atmosphere at room
temperature. After the reaction mixture was left unstirred for 6–12 h at 0–5 ꢀC, the
iminophosphorane 3 had disappeared (monitored by thin-layer chromatography,
TLC). The solvent was removed under reduced pressure, and Et2O=petroleum ether
(1:2, 20 mL) was added to precipitate triphenylphosphine oxide. Removal of the
solvent gave carbodiimides 4, which were used directly without further purification.
Carbodiimide 4a was also isolated from the reaction mixture by column chromato-
graphy on silicon gel as a light yellow solid. Mp: 82–84 ꢀC, IR (KBr): 2253, 1701,
1
1656, 1530, 1438, 1190 cmꢁ1. H NMR (CDCl3, 600 MHz): d 8.23 (s, 1H, triazolyl-
3-H), 8.10 (s, 1H, triazolyl-5-H), 7.40–7.21 (m, 5H, Ar-H), 4.33 (q, 2H, J ¼ 7.2 Hz,
OCH2), 2.10 (s, 3H, CH3), 1.37 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 353 (Mþ,
100), 307 (62), 293 (34), 265 (74), 178 (67), 124 (47). Anal. calcd. for C17H15N5O2S:
C, 57.78; H, 4.28; N, 19.82. Found: C, 57.54; H, 4.01; N, 19.95.
General Preparation of 6-(1H-1,2,4-Triazol-1-
yl)-thieno[2,3-d]pyrimidin-4(3H)-ones 6
Aliphatic amine (2 mmol) was added to the solution of 4 in dichloromethane
(10 mL). After the reaction mixture was left unstirred for 5–6 h, the solvent was
removed and anhydrous EtOH (10 mL) with several drops of EtONa was added.
The mixture was stirred for 4–8 h at room temperature. The solution was condensed,
and the residue was recrystallized from EtOH to give the expected cyclic compouds
6a–k in good yields.
Compound 6a. Light yellow solid, mp 222–223 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.33 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.53–7.26 (m,
5H, Ar-H), 2.70 (s, 6H, 2CH3N), 2.41 (s, 3H, CH3). MS (m=z, %): 352 (Mþ,
100%), 337 (6), 308 (12), 287 (17), 145 (70), 130 (76). Anal. calcd. for C17H16N6OS:
C, 57.94; H, 4.58; N, 23.85. Found: C, 57.80; H, 4.36; N, 23.94.

SYNTHESIS OF THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
1989
Compound 6b. Light yellow solid, mp 123–125 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.32 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.51–7.26 (m,
5H, Ar-H), 3.03 (t, J ¼ 6.8 Hz, 4H, 2CH2N), 2.41 (s, 3H, CH3), 1.23–1.13 (m, 8H,
2CH2CH2), 0.84 (t, J ¼ 6.8 Hz, 6H, 2CH3). MS (m=z, %): 436 (Mþ, 100%), 407
(13), 394 (53), 378 (78), 353 (23), 308 (40). Anal. calcd. for C23H28N6OS: C, 63.28;
H, 6.46; N, 19.25. Found: C, 63.35; H, 6.61; N, 19.48.
Compound 6c. Light yellow solid, mp 174–176 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.32 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.49–7.27 (m,
5H, Ar-H), 3.60–3.53 (m, 2H, 2CHN), 2.40 (s, 3H, CH3), 1.09 (d, J ¼ 6.8 Hz, 12H,
4CH3). MS (m=z, %): 408 (Mþ, 38%), 365 (100), 350 (20), 307 (21), 118 (16), 100
(17). Anal. calcd. for C21H24N6OS: C, 61.74; H, 5.92; N, 20.57. Found: C, 61.52;
H, 5.85; N, 20.76.
Compound 6d. Light yellow solid, mp 125–127 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.35 (s, 1H, triazolyl-3-H), 8.14 (s, 1H, triazolyl-5-H), 7.55–7.27 (m,
5H, Ar-H), 3.44 (t, J ¼ 4.4 Hz, 4H, 2CH2O), 3.16 (t, J ¼ 4.4 Hz, 4H, 2CH2N), 2.44
(s, 3H, CH3). MS (m=z, %): 394 (Mþ, 100%), 363 (7), 349 (19), 337 (19), 308 (8),
205 (18). Anal. calcd. for C19H18N6O2S: C, 57.85; H, 4.60; N, 21.31. Found: C,
57.94; H, 4.74; N, 21.17.
Compound 6e. Light yellow solid, mp 222–224 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.36 (s, 1H, triazolyl-3-H), 8.15 (s, 1H, triazolyl-5-H), 7.12–6.60 (m,
10H, Ar-H), 3.30 (s, 3H, CH3N), 2.44 (s, 3H, CH3). MS (m=z, %): 414 (Mþ,
100%), 308 (32), 253 (25), 167 (35), 104 (25), 91 (24). Anal. calcd. for C22H18N6OS:
C, 63.75; H, 4.38; N, 20.28. Found: C, 63.51; H, 4.58; N, 20.33.
Compound 6f. Light yellow solid, mp 115–117 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.34 (s, 1H, triazolyl-3-H), 8.14 (s, 1H, triazolyl-5-H), 7.41–7.10 (m,
4H, Ar-H), 3.15 (q, J ¼ 7.2 Hz, 4H, 2CH2N), 2.41 (s, 6H, 2CH3), 0.85 (t, J ¼ 7.2 Hz,
6H, 2CH3). MS (m=z, %): 394 (Mþ, 100%), 365 (45), 322 (16), 275 (24), 206 (26), 119
(63). Anal. calcd. for C20H22N6OS: C, 60.89; H, 5.62; N, 21.30. Found: C, 60.74;
H, 5.45; N, 21.58.
Compound 6g. Light yellow solid, mp 150–152 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.33 (s, 1H, triazolyl-3-H), 8.14 (s, 1H, triazolyl-5-H), 7.40–7.09 (m,
4H, Ar-H), 3.02 (t, J ¼ 7.2 Hz, 4H, 2CH2N), 2.41 (s, 6H, 2CH3), 1.31–1.24 (m,
4H, 2CH2), 0.74 (t, J ¼ 7.2 Hz, 6H, 2CH3). MS (m=z, %): 422 (Mþ, 100%), 393
(36), 322 (19), 289 (15), 132 (25). Anal. calcd. for C22H26N6OS: C, 62.53; H, 6.20;
N, 19.89. Found: C, 62.47; H, 6.41; N, 19.74.
Compound 6h. Light yellow solid, mp 94–96 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.33 (s, 1H, triazolyl-3-H), 8.14 (s, 1H, triazolyl-5-H), 7.39–7.08 (m,
4H, Ar-H), 3.05 (t, J ¼ 7.2 Hz, 4H, 2CH2N), 2.41 (s, 6H, 2CH3), 1.23–1.11 (m,
8H, 2CH2CH2), 0.84 (t, J ¼ 7.2 Hz, 6H, 2CH3). MS (m=z, %): 450 (Mþ, 84%), 393
(35), 322 (48), 294 (32), 105 (100). Anal. calcd. for C24H30N6OS: C, 63.97; H,
6.71; N, 18.65. Found: C, 63.71; H, 6.94; N, 18.78.
Compound 6i. Light yellow solid, mp 210–212 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.34 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.50–7.27 (m,

1990
Y. SUN, N.-Y. HUANG, AND M.-W. DING
4H, Ar-H), 2.72 (s, 6H, 2CH3), 2.40 (s, 3H, CH3). MS (m=z, %): 386 (Mþ, 100%), 352
(26), 308 (34), 286 (47), 130 (85). Anal. calcd. for C17H15ClN6OS: C, 52.78; H, 3.91;
N, 21.72. Found: C, 52.72; H, 3.84; N, 21.87.
Compound 6j. Light yellow solid, mp 156–158 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.33 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.50–7.26 (m,
4H, Ar-H), 3.13 (q, J ¼ 7.2 Hz, 4H, 2CH2N), 2.40 (s, 3H, CH3), 0.90 (t, J ¼ 6.8 Hz,
6H, 2CH3). MS (m=z, %): 414 (Mþ, 100%), 365 (63), 322 (63), 206 (35), 119 (76).
Anal. calcd. for C19H19ClN6OS: C, 55.00; H, 4.62; N, 20.25. Found: C, 55.16; H,
4.37; N, 20.28.
Compound 6k. Light yellow solid, mp 150–152 ꢀC. 1H NMR (CDCl3,
400 MHz): d 8.33 (s, 1H, triazolyl-3-H), 8.13 (s, 1H, triazolyl-5-H), 7.50–7.25 (m,
4H, Ar-H), 3.01 (t, J ¼ 7.6 Hz, 4H, 2CH2N), 2.40 (s, 3H, CH3), 1.38–1.29 (m, 4H,
2CH2), 0.77 (t, J ¼ 7.6 Hz, 6H, 2CH3). MS (m=z, %): 442 (Mþ, 74%), 408 (24), 365
(100), 307 (47), 118 (74). Anal. calcd. for C21H23ClN6OS: C, 56.94; H, 5.23; N,
18.97. Found: C, 56.86; H, 5.25; N, 18.75.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the National
Natural Science Foundation of China (Project Nos. 20672041 and 20772041), the
Key Project of Chinese Ministry of Education (No. 107082), and the Science
Foundation of Hubei Education Commission of China (Project No. Q20086001).
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