19th Iranian Chemistry Congress , 2017-02-21

Title : ( Synthesis and regioselective determination of new derivatives of pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine )

Authors: yasaman etemadi , Ali Shiri , Hossein Eshghi ,

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Introduction Fused heterocycles containing thiazolopyrimidine and pyrimidopyrimidine have been greatly investigated in several medicinal activities.[1] General synthetic methods for the synthesis of thiazolopyrimidines involve the reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates[2] or the reaction of ethyl-4-(3-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with bromomalononitrile in the presence of strong base.[3] The synthesis of pyrimidopyrimidine as the other significant heterocyclic moiety has been reported via a one-pot three component heterocyclization of 5-aminopyrimidine with formamide.[4] Also, reaction of 9-cyanopurines with O-benzylhydroxylamine resulted in the formation of pyrimidopyrimidines.[5,6] Recently, a method for the synthesis of aromatic 4-acylhydrazido-8-arylamino pyrimidopyrimidine derivatives has been published.[7] Methods and Experimental In the mixture of 2-chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine 3 and Et3N in dry ethanol, the appropriate alkyl halide was added and the solution was heated under reflux. After the completion of the reaction, monitored by TLC, the solvent was evaporated under reduced pressure, water was added and the solution was filtered off.Results and discussion Compound 1 reacted with 4,5-dihydrothiazol-2-amine 2 as a binucleophile in CHCl3 to give 2-chloro-4-methyl-7,8-dihydro-5H-pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine 3. The formation of compound 3 proceed through a combined nucleophilic substitution and an addition-elimination reaction involving the nitrogen atoms in 4,5-dihydrothiazol-2-amine followed by elimination of two molecules of HCl. Since there are two different nitrogen atoms on reactant 2 which are candidates to act as nucleophile, two regioisomers are supposed to produce as well. To shed light and dispel this ambiguity, condensed Fukui indices were computed. The results revealed more electrophilicity on C-5′ in 1 and more nucleophilicity on N-3 in 2. Therefore, condensed Fukui calculations suggest that compound 3 is formed in the way that endocyclic nitrogen of compound 2 was first reacted with exocyclic carbon of compound 1 to obtain C(sp3)-N bond in the depicted structure of compound 3. Further investigation was carried out via nucleophilic substitution of the 2-Cl substituent with various secondary amines to produce substituted derivatives 4a-f of the new heterocyclic ring in good to excellent yields. All the physical, chemical and spectral data were in agreement with the newly proposed structures.ConclusionThe objective of the present study was to synthesize and assign the regiochemistry of heterocyclization of new pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine derivatives. Further structural confirmations were also made using two-dimensional COSY and NOESY techniques. The newly synthesized compounds were conducted to exhibit essentially equipotent antibacterial activity against some pathogenic bacteria. Results are suggesting pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine derivatives emerge as valuable compounds with great potential to be used as antibacterial.References 1. S. Fatima, A. Sharma, R. Saxena, R. Tripathi, S. K. Shukla, S. K. Pandey, R. Tripathi and R. P. Tripathi, Eur. J. Med. Chem., 2012, 55, 195–204.2. J. Liu, R. J. Patch, C. Schubert, M. R., J. Org. Chem., 2005, 70, 10194-10197. 3. H. Nagarajaiah, I. A. M. Khazi and N. S. Begum, J. Chem. Sci., 2015, 127, 467-479. 4. F. F. Wong, Y.-Y. Huang and C.-H. Chang, J. Org. Chem., 2012, 77, 8492-8500. 5. A. Ribeiro, M. A. Carvalho and M. F. Proença, Eur. J. Org. Chem., 2009, 4867-4872. 6. A. H. Bacelar, M. A. Carvalho and M. F. Proença, Eur. J. Med. Chem., 2010, 45, 3234-3239. 7. A. Rocha, A. H. Bacelar, J. Fernandes, M. F. Proenca and M. A. Carvalho, Synlett, 2014, 25, 343-348.


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author = {Etemadi, Yasaman and Shiri, Ali and Eshghi, Hossein},
title = {Synthesis and regioselective determination of new derivatives of pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine},
booktitle = {19th Iranian Chemistry Congress},
year = {2017},
location = {شیراز, IRAN},
keywords = {pyrimido[4;5-d]thiazolo[3;2-a]pyrimidine},


%0 Conference Proceedings
%T Synthesis and regioselective determination of new derivatives of pyrimido[4,5-d]thiazolo[3,2-a]pyrimidine
%A Etemadi, Yasaman
%A Shiri, Ali
%A Eshghi, Hossein
%J 19th Iranian Chemistry Congress
%D 2017