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Facile Synthesis of 2-Phenylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives as a New Ring System
Facile Synthesis of 2-Phenylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives as a New Ring System
Journal of the Korean Chemical Society. 2010. Dec, 54(6): 841-843
Copyright © 2010, The Korean Chemical Society
  • Received : July 19, 2010
  • Accepted : August 27, 2010
  • Published : December 20, 2010
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양헌 송
yhsong@mokwon.ac.kr

Abstract
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INTRODUCTION
Much attention has been recently paid to the synthesis of some thieno[1,2,4]triazolopyrimidines and thieno[1,2,4]tria-zolopyrimidinones because of their biological activities. 1 - 4 With this in mind and in continuation of our recent work on the synthesis of 2-phenylthieno[3,2- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives 7 5 we describe here a facile synthesis of 2-phenylthieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives 5 that have not been reported hitherto as a new ring system. Previous observations revealed that the thieno[3,2- e ][1,2,4]triazolo[4,3- c ]pyrimidines 6 can isomerizes in the presence of base to the thermodynamically more stable thieno[3,2- e ][1,2,4]triazolo[1,5- c ]pyrimidines 7 by Dimroth-type rearrangement. We, therefore, decided to apply this methodology also to the synthesis of 5 from 4 .
The compounds 4 were prepared through a series of reaction starting with 3-aminothiophene-2-carbonitrile ( 1 ) according to the modified procedure we have previously reported( 1 ). 1 The required starting material 1 was obtained by adopting the new synthetic method. 6 Reaction of 1 with triethyl orthoformate and the successive hydrazine hydrate gave 4-hydrazinothieno[3,2- d ]pyrimidine ( 2 ). The hydrazone derivatives 3 were synthesized by condensation of hydrazine compound 2 with the corresponding benzaldehydes in refluxing ethanol in the presence of catalytic amount of piperidine. The oxidative cyclization of the resultant hydrazone derivatives 3 to 4 was achieved using aluminasupported calcium hypochlorite (Ca(OCl) 2 /Al 2 O 3 = 1:1, grounded mixture) as a new oxidant. For instance, a maximum yield of 73% for 4a in 1 h was achieved with 1:3 molar ratio of hydrazone to calcium hypochlorite. The use of alumina-supported calcium hypochlorite as a heterogeneous oxidant in this reaction has advantage of enhanced reaction rate and yield, simple work-up, low cost, and eco-friendly reagent when compared to other oxidants such as bromine, 7 lead tetraacetate, 8 iodobenzene diacetate 1 , 9 or copper dichloride. 10
When each of 4 was treated with sodium acetate in refluxing ethanol, it underwent a Dimroth-type rearrangement to give compounds 5 through a sequence of ring opening and ring closure reaction. For instance, the reaction of 4a (1 mmol) with sodium acetate (2 mmol) in refluxing ethanol for 5 h afforded only one product, 5a in 68% yield. The structures of all new compounds 5 were identified by elemental analyses and spectral data. The results are summarized in 1 . It was noticed that the two isomeric 4 and 5 showed no appreciable differences in the fragmentation pattern of MS spectra, however, the 1 H NMR spectra of 5 revealed that the most prominent pyrimidine proton showed signal little more downfield than the one of their isomeric 4 . These results were in agreement with those reported in earlier report. 5 The conversion of 4 into 5 is also analogous to rearrangement of thieno[2,3- e ][1,2,4]triazolo[4,3- c ]pyrimidin-5(6 H )-ones in base to the isomeric thieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidin-5(6 H )-ones. 4
In conclusion, we report a facile synthesis of 2-phenylthieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives 5 via rearrangement of 3-phenylthieno[2,3- e ][1,2,4]triazolo [4,3- c ]pyrimidines 4 .
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Reagents and conditions; (A) (i) HC(OEt)3, reflux (ii) hydrazine hydrate/ethanol, reflux; (B) benzaldehydes, piperidine/ethanol, reflux; (C) Ca(OCl)2-Al2O3/methylene chloride, rt; (D) NaOAc/ethanol, reflux
Preparation of compounds5from4
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aIsolated yields.
EXPERIMENTAL
All products were characterized by IR, 1 H NMR, MS and elemental analysis. Melting points were measured by using the capillary tubes on Büchi apparatus and are uncorrected. Each compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F 254 and purified by column chromatography using Merck silica gel (70 - 230 mesh). IR spectra were recorded on the FT-IR Brucker Tensor 27. The 1 H NMR spectra were recorded on Bruker DRX-300 FT-NMR spectrometer (300 MHz) with Me 4 Si as internal standard and chemical shifts are given in ppm (δ). Electron ionization mass spectra were recorded on a HP 59580 B spectrometer. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.
- General procedure for the preparation of 2-phenylthieno [2,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives (5)
To a solution of each 3-phenylthieno[2,3- e ][1,2,4]triazolo [4,3- c ]pyrimidine 4 (1 mmol) in ethanol (30 mL) was added sodium acetate (0.164 g, 2 mmol) and the mixture was refluxed for 5 h and cooled. The precipitated solid was filtered, washed with water, dried and finally crystallized from ethanol to give the respective 2-phenylthieno[2,3- e ][1,2,4]triazolo[1,5- c ]pyrimidine 5 .
- 2-Phenylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5a)
Yield 68%; mp 105 - 107 ℃; IR (KBr): 3045, 1620 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.32 (s, 1H, H-4), 8.36-8.33 (m, 2H, H-2’ and H-6’), 7.88 (d, 1H, J = 5.9 Hz, H-7), 7.65 (d, 1H, J = 5.9 Hz, H-6), 7.55-7.52 (m, 3H, H-3’, H-4’ and H-5’); MS: ( m/z ) 252 (M + , 100), 149 (15), 134 (20), 118 (16). Anal. Calcd. for C 13 H 8 N 4 S: C, 61.89; H, 3.20; N, 22.21. Found: C, 61.69; H, 3.39; N, 22.48.
- 2-(4-Chlorophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5b)
Yield 70%; mp 250 - 252 ℃; IR (KBr): 3052, 1620 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.30 (s, 1H, H-4), 8.29 (d, 2H, H-2’ and H-6’), 7.88 (d, J = 5.9 Hz, 1H, H-7), 7.65 (d, J = 5.9 Hz, 1H, H-6), 7.51 (d, 2H, H-3’ and H-5’); MS: ( m/z ) 287 (M + , 100), 149 (30), 134 (22). Anal. Calcd. for C 13 H 7 ClN 4 S: C, 54.45; H, 2.46; N, 19.54. Found: C, 54.29; H, 2.31; N, 19.71.
- 2-p-Tolylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5c)
Yield 55%; mp 203 - 205 ℃; IR (KBr): 3050, 2973, 1620, 1370 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.30 (s, 1H, H-4), 8.23 (d, 2H, H-2’ and H-6’), 7.86 (d, J = 5.9 Hz, 1H, H-7), 7.63 (d, J = 5.9 Hz, 1H, H-6), 7.34 (d, 2H, H-3’ and H-5’), 2.44 (s, 3H, Me); MS: ( m/z ) 266 (M + , 99), 149 (35), 134 (20). Anal. Calcd. for C 14 H 10 N 4 S: C, 63.14; H, 3.78; N, 21.04. Found: C, 63.30; H, 3.59; N, 21.22.
- 2-(4-Methoxyphenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5d)
Yield 62%; mp 201 - 203 ℃; IR (KBr): 3044, 2980, 1622, 1375 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.27(s, 1H, H-4), 8.26 (d, 2H, H-2’and H-6’), 7.85 (d, J = 5.9 Hz, 1H, H-7), 7.62 (d, J = 5.9 Hz, 1H, H-6), 7.03 (d, 2H, H-3’ and H-5’), 3.89 (s, 3H, OMe); MS: ( m/z ) 282 (M + , 100), 149 (15), 134(22). Anal. Calcd. for C 14 H 10 N 4 OS: C, 59.56; H, 3.57; N, 19.85. Found:C, 59.44; H, 3.66; N, 19.93.
- 2-(4-Bromophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5e)
Yield 68%; mp 207 - 208 ℃; IR (KBr): 3033, 1625 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.30 (s, 1H, H-4), 8.22 (d, 2H, H-2’ and H-6’), 7.88 (d, J = 5.9 Hz, 1H, H-7), 7.69 (d, J = 5.9 Hz, 1H, H-6), 7.65 (d, 2H, H-3’ and H-5’); MS: ( m/z ) 331 (M + , 98), 149 (12), 134 (10). Anal. Calcd. for C 13 H 7 BrN 4 S: C, 47.14; H, 2.13; N, 16.92. Found: C, 46.99; H, 2.34; N, 17.14.
- 2-(3-Chlorophenyl)thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5f)
Yield 63%; mp 140 - 142 ℃; IR (KBr): 3035, 1629 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.30 (s, 1H, H-4), 8.55 (s, 1H, H-2’), 8.04 (m, 1H, H-6’), 7.72 (d, J = 5.9 Hz, 1H, H-7), 7.53 (d, J = 5.9 Hz, 1H, H-6), 7.46-7.39 (m, 2H, H-4’ and H-5’); MS: ( m/z ) 287 (M + , 100), 149 (16), 134 (20). Anal. Calcd. for C 13 H 7 ClN 4 S: C, 54.45; H, 2.46; N, 19.54. Found: C, 54.66; H, 2.30; N, 19.69.
- 2-m-Tolylthieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (5g)
Yield 60%; mp 164 - 166 ℃; IR (KBr): 3036, 1625, 1375 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.30 (s, 1H, H-4), 8.18-8.14 (m, 2H, H-2’ and H-6’), 7.87 (d, J = 5.9 Hz, 1H, H-7), 7.64 (d, J = 5.9 Hz, 1H, H-6), 7.42 (t, 1H, H-5’), 7.33 (d, 1H, H-4’), 2.48 (s, 3H, Me); MS: ( m/z ) 266 (M + , 100), 149 (10). Anal. Calcd. for C 14 H 10 N 4 S: C, 63.14; H, 3.78; N, 21.04. Found: C, 63.29; H, 3.65; N, 21.11.
- 2-(3-Bromophenyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5h)
Yield 65%; mp 134 - 136 ℃; IR (KBr): 3034, 1622 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.29 (s, 1H, H-4), 8.58 (s, 1H, H-2’), 8.05 (d, 1H, H-6’), 7.74 (d, J = 5.9 Hz, 1H, H-7), 7.59 (d, J = 5.9 Hz, 1H, H-6), 7.54 (d, 1H, H-4’), 7.36 (t, 1H, H-5’); MS: ( m/z ) 331 (M + , 100), 149 (11), 134 (20). Anal. Calcd. for C 13 H 7 BrN 4 S: C, 47.14; H, 2.13; N, 16.92. Found: C, 47.28; H, 2.26; N, 17.11.
- 2-(2-Methoxyphenyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5i)
Yield 50%; mp 127 - 129 ℃; IR (KBr): 3030, 2975, 1620, 1375 cm -1 ; 1 H NMR (CDCl 3 ): δ 9.28 (s, 1H, H-4), 8.14-8.10 (m, 2H, H-4’ and H-6’), 7.88 (d, J = 5.9 Hz, 1H, H-7), 7.55 (d, J = 5.9 Hz, 1H, H-6), 7.33 (t, 1H, H-5’), 7.24 (d, 1H, H-3’), 2.47 (s, 3H, OMe); MS: ( m/z ) 282 (M + , 100), 149 (14), 134 (18). Anal. Calcd. for C 14 H 10 N 4 OS: C, 59.56; H, 3.57; N, 19.85. Found: C, 59.69; H, 3.42; N, 19.62.
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