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Synthesis of Substituted 5-(1,2,4-Oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thiones

Juliya V. Kharchenko, Oleksandr S. Detistov, and Valeriy D. Orlov J. Comb. Chem., 2009, 11 (2), 216-219* DOI: 10.1021/cc800111h Publication Date (Web): 09 January 2009 Downloaded from http://pubs.acs.org on March 13, 2009

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Journal of Combinatorial Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036

216

J. Comb. Chem. 2009, 11, 216-219

Synthesis of Substituted 5-(1,2,4-Oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1//)-thiones

Juliya V. Kharchenko, Oleksandr S. Detistov,[1] and Valeriy D. Orlov

Chemical Department, V.N. Karazin Kharkiv National University, 4 Svoboda Sq.,

Kharkiv 61077, Ukraine

Received July 2, 2008

We have developed a liquid-phase route for combinatorial synthesis of novel substituted 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1^)-thiones. Biginelli-type three-component condensation of 1-(3-aryl-1,2,4-oxadiazol-5-yl)acetones, thiourea, and benzaldehydes is shown to result in new 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1^)-thione heterocyclic system. If salicylaldehydes are used in this reaction, a mixture of 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1#)-thiones and 11-(1,2,4-oxadiazol-5-yl)-2,3,5,6-tetrahydro-4H-2,6-methano-1,3,5-benzoxadiazocine-4-thiones is formed.

Introduction

Multicomponent reactions (MCRs) are in general of increasing importance in organic and medicinal chemistry.1 Now, when the drug discovery strongly requires speed, diversity, and efficiency, MCR strategies offer significant advantages over conventional linear-type syntheses.2 The Biginelli protocol is particularly attractive because the resulting dihydropyrimidine (DHPM) scaffold displays a wide range of biological activities, which has led to the development of a number of leading compounds based on that structural core.3 Recent publications on Biginelli-type reactions describe the use of different catalysts,4,5 micro-wave,6 and ultrasound7 irradiations. On the other hand, substances containing a disubstituted 1,2,4-oxadiazoles frag­ment are frequently used in drug discovery as an important bioisostere for esters and amides to improve pharmacokinetic properties of drug candidates.8 Oxadiazoles have been being the subject of investigation in a number of different therapeutic areas, usually as a replacement for ester or amide functional groups. 1,2,4-Oxadiazoles have been proposed as muscarinic receptor agonist,9,10 benzodiazepine receptor agonist,11 histamine H3 receptor antagonist,12 and antiviral compounds.13 This paper presents a new library of 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1#)-thiones; it in­cludes 70 substances obtained by the three-component condensation of the Biginelli type.

Results and Discussion

Below we describe a new liquid-phase parallel synthesis of the library of compounds 1 (Figure 1).

Our approach is based on the condensation of 1-(3-aryl-1,2,4-oxadiazol-5-yl)acetones 2, thiourea 3 and aromatic aldehydes 4, which is carried out under the classic Biginelli reaction conditions.

We started with chemsets 2A-G obtained by the reaction of arylamidoximes 5A—G with 2,2,6-trimethyl-4#-1,3-dioxin-4-one 6 (Scheme 1). Chemsets 5A-G were obtained using the reported method.14

The synthesis of building blocks 2A—G was carried out in dioxane with triethylamine as the catalyst. Yields of target products are satisfactory (32—64%) (Figure 2, Table 1).

In 1H NMR spectra of compounds 2A— G, the signals of methyl and methylene groups are observed at 2.20—2.30 and 4.40—4.55 ppm correspondingly. All other proton signals are observed at their usual positions.

Biginelli-type three-component condensation of building blocks 2A— G, thiourea 3, and benzaldehydes 4a-j (Figure 3) leads to the formation of dihydropyrimidines 1A—G,a—j

Figure 1. 5-(1,2,4-Oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1fl)-thiones, 1.

Table 1. Yields of Building Blocks 2A—G

substance

yield, %

2A

32

2B

41

2C

39

2D

47

2E

51

2F

64

2G

56

Scheme 1. Synthesis of 1-(3-Aryl-1,2,4-oxadiazol-5-yl)acetones, 2A—G

5A-G 6 2A-G

Yields: 32-64%

© 2009 American Chemical Society ^eb 01/09/2009

Figure 2. Selected 1-(3-aryl-1,2,4-oxadiazol-5-yl)acetones 2A—G for library design.

Figure 3. Selected benzaldehydes 4a—j for library design.

Figure 4. Examples of 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thiones synthesized, 1.

(Scheme 2, Figure 4). The yields of products are different depending on the structure of initial reagents. Thus, if electron-releasing groups are in para-positions of R1 and R2 substitutes in scaffold 1, the yields of the target products are high. If, alternatively, R1 and R2 substitutes have no electron-releasing groups or if positions of these groups are different, yields of products decrease to good and seldom to satisfactory.

Dihydropyrimidines 1 were characterized by 1H NMR, 13C NMR, DEPT, and LC/MS analysis. The 1H, 13CNMR,and DEPT spectra confirm the suggested structures. According to the LC/MS data, all the synthesized compounds were more than 90% pure. Results of the element analysis are in accordance with theoretical considerations. This complex of experimental data proofs the purity of obtained substances. In 1H NMR spectra the proton H4 in 3,4-dihydropyrimidine-2(1H)-thione structures 1 is clearly observed as singlet in the range of д 5.35—5.55 ppm. The protons NH are observed as singlets in two ranges of д 10.60—10.80 and 9.60—9.90 ppm. All other proton signals are observed in their usual resonance areas.

Figure 5. Salicylaldehyde inputs 4k, l.

We also studied the three-componentcondensation of chemset 2A— G, thiourea 3, and salicylaldehydes 4k, l (Figure 5). As a rule, thin-layer chromatography (TLC) showed the formation of mixtures of dihydropyrimidines 1 and methanobenzoxadiazocines 7 under the reaction condi­tions (Scheme 3).

Sporadically pure dihydropyrimidines 1 and methanoben-zoxadiazocines 7 were formed. Thus, in the case of salicylal-dehyde 4k and building block 2A, pure compound 1Ak was formed; in the case of salicylaldehyde 4l and building blocks 2B, D, pure compounds 7Bl, 7Dl were formed (Figure 6).

The formation of methanobenzoxadiazocine heterocyclic system was proved for compound 7Bl by 1HNMR,13C

NMR, and DEPT analysis. In 1H NMR spectra of this

substance, the signals of 4 protons of methanobenzoxadia-

218   Journal of Combinatorial Chemistry, 2009 Vol. 11, No. 2

Kharchenko et al.

ІАк 7B1 7D1

Figure 6. Examples of pure 4-(2-hydroxyphenyl)-5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thiones, 1Ak, and 11-(1,2,4-oxadiazol-5-yl)-2,3,5,6-tetrahydro-4H-2,6-methano-1,3,5-benzoxadiazocine-4-thiones synthesized, 7Bl, 7Dl.

Scheme 2. Synthesis of 5-(1,2,4-Oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thiones, 1A—G,a—j

2A-G

1A-G,a-j

Yields: 35-74%

4f 4g 4h 4i 4j

Scheme 3. Three-Component Condensation of Chemsets 2A—G, Thiourea 3, and Salicylaldehydes 4k, l

2A-G

zocine moiety were observed: two protons NH in the ranges of д 9.30—9.40 and 9.55—9.65 ppm, the proton H6 in the range 5.40—5.45 ppm, and the proton H11 in the range 4.30—4.35 ppm. The signal of proton H11 is characteristic for methanobenzoxadiazocine heterocyclic system: it is absent in 1H NMR spectra of dihydropyrimidine with 2-hydroxyphenyl substitute 1Ak, whereas proton OH is observed as singlet in the range of д 9.25—9.30 ppm. 1H NMR spectra of all other substances of this series show complex signals of both proton H11 of methanobenzoxa-diazocine heterocyclic system and proton OH of substitutes at dihydropyrimidines core. The 1H, 13C NMR, and DEPT spectra of substances 7Bl and 1Ak confirm the offered structures.

Conclusions

An efficient synthetic route has been developed for the combinatorial synthesis of novel 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thione library in solution. It is based on the Biginelli-type three-component condensation of 1-(3-aryl-1,2,4-oxadiazol-5-yl)acetones, thiourea, and aromatic aldehydes. Substances with low levels of impurities were obtained using a simple crystallization from the reaction mixtures. Product yields varied depending on the reactant structures, but in most cases, the desired products were obtained with high and good yields. The three-component condensation of1-(3-aryl-1,2,4-oxadiazol-5-yl)acetones, thio-urea and salicylaldehydes was also studied. As a rule, the mixture of 5-(1,2,4-oxadiazol-5-yl)-3,4-dihydropyrimidine-2(1H)-thiones and 11-(1,2,4-oxadiazol-5-yl)-2,3,5,6-tetrahy-dro-4H-2,6-methano-1,3,5-benzoxadiazocine-4-thiones was formed under reaction conditions.

Supporting Information Available. Experimental pro­cedures, spectroscopic data, references for known com­pounds, 1HNMR,13CNMR,and13C NMR DEPT spectra,

and LC/MS data of synthesized compounds. This material is available free of charge via the Internet at http:// pubs.acs.org.

References and Notes

(1) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131.

(2) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med.

Chem. 1999, 6, 255-270.

(3) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043-1052.

(4) Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.

Lett. Org. Chem. 2007, 4, 39-42.

(5) Gopalakrishnan, M.; Sureshkumar, P.; Thanusu, J.; Kanaga-rajan, V.; Ezhilarasi, M. R. Lett. Org. Chem. 2008, 5, 142­147.

(6) Arfan, A.; Paquin, L.; Bazureau, J. Russ. J. Org. Chem 2007, 43, 1058-1064.

(7) Wang, J.-S.; Li, J.-T.; Lin, Z.-P. Lett. Org. Chem 2006, 3,

523-525.

(8) Young, J. R.; DeVita, R. J. Tetrahedron Lett. 1998, 39, 3931­3934.

(9) Messer, J. W. S.; Abuh, Y. F.; Liu, Y.; Periyasamy, S.; Ngur, D. O.; Edgar, M. A. N.; El-Assadi, A. A.; Sbeih, S.; Dunbar, P. G.; Roknich, S.; Rho, T.; Fang, Z.; Ojo, B.; Zhang, H.; Huzl, J. J.; Nagy, P. I. J. Med. Chem. 1997, 40, 1230-1246.

(10) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley, M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.; Wadsworth,

H. J.; Wyman, P. J. Med. Chem. 1991, 34, 2726-2735.

 (11) Watjen, F.; Baker, R.; Engelstoft, M.; Herbert, R.; MacLeod,

A.; Knight, A.; Merchant, K.; Moseley, J.; Saunders, J.; Swain,

C. J.; Wong, E.; Springer, J. P. J. Med. Chem. 1989, 32, 2282­2291.

(12) Clitherow, J. W.; Beswick, P.; Irving, W. J.; Scopes, D. I. C.; Barnes, J. C.; Clapham, J.; Brown, J. D.; Evans, D. J.; Hayes,

A. G. Bioorg. Med. Chem. Lett. 1996, 6, 833-838.

(13) Diana, G. D.; Volkots, D. L.; Hitz, T. J.; Bailey, T. R.; Long,

M. A.; Vescio, N.; Aldous, S.; Pevear, D. C.; Dutko, F. J.

J. Med. Chem. 1994, 37, 2421-2436.

(14) Bergmann, E. D.; Bendas, H.; D Avilla, U. J. Org. Chem. 1953, 18, 64-69.

CC800111H


[1] To whom correspondence should be addressed. E-mail: DeAS@ INBOX.ru.

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