Synthesis of fused pyrimidine derivatives using NCNCC+C approach

D. S. Granat, A. V. Biitseva, O. O. Grygorenko, S. V. Ryabukhin


The methods of synthesis of various substituted fused pyrimidine derivatives using NCNCC+C approach have been systematized and summarized in the review. Approaches based on the reaction of carbonyl compounds with NCNCC binucleophiles, in particular, N-aryl(thio)ureas, derivatives of aniline and aromatic heterocyclic amines, N-arylamidines and N-imidoylphosphoranes have been considered. Although these methods have been known for a long time, recent efforts in this area are put towards development of mild reaction conditions, in particular with the use of chlorotrimethylsilane or microwave irradiation. Besides, palladium-catalyzed cyclizations have been discussed, they involve N-arylamidines or N-arylcarbodiimides as the NCNCC components, and carbon(II) oxide or isocyanides – as single-carbon synthetic equivalents. These methods have received much attention in recent years. Most of them are three-component reactions, which involve an additional nucleophilic reagent; therefore, these approaches have some advantages in the view of diversity of the products obtained. Other methods for NCNCC+C cyclization have been also considered, including reactions of ketimines derived from aminoheterocycles with isocyanates, reactions of N-arylcarbodiimides with molybdenum carbonyl, Cu- and Rh-catalyzed processes, etc. It has been shown that [5+1] cyclization discussed in the review can be used for preparation of fused pyrimidines, which can bear moieties of annelated isoquinolines, thiazoles, pyridines, pyrazines, triazoles, pyrazoles, etc., apart from the simple ring.


heterocycles; cyclization; pyrimidines; quinazolines


Scheele K. W. Opuscula, 1776, Vol. 2, pp.73.

Armarego W. L. F. The Chemistry of Heterocyclic Compounds. Fused Pyrimidines. – New York – London – Sydney: Interscience Publishers, 1967, Vol. 24/1, 564 p.

Dinakaran V. S., Bomma B., Srinivasan K. K., Dinakaran V. S. Der Pharma Chemica, 2012, Vol. 4, pp.255-265.

Selvam T. P., James C. R., Dniandev P. V., Valzita S. K. Research in Pharmacy, 2012, Vol. 2, pp.01-09.

Aly A. A., Ishak E. A., Ramadan M., Germoush M., El-Emary T., Al-Muaikel N. J. Heterocycl. Chem., 2013, Vol. 50, pp.451-472.

Bentya A. V., Vas’kevych R. I., Stanitets’ V. I., Vovk M. V. Zhurn. Org. Farm. Khim., 2013, No.1, pp.4-25.

Kashyap S. J., Sharma P. K., Garg V. K., Dudhe R., Kumar N. J. Adv. Sci. Res., 2011, Vol. 2, pp.18-24.

El Ashry E. S. H., Rashed N. Adv. Heterocycl. Chem., 1998, Vol. 71, pp.57-114.

Qingyun R., Xiaosong T., Hongwu H. Curr. Org. Synth., 2011, Vol. 8, pp.752-763.

Ding M. W., Yang G. F. Trends in Heterocycl. Chem., 2006, Vol. 11, pp.87-94.

Pictet A., Spengler T. Berichte der deutschen chemischen Gesellschaft, 1911, Vol. 44, pp.2030-2036.

Houlihan W. J., Cooke G., Denzer M., Nicoletti J. J. Heterocycl. Chem., 1982, Vol. 19, pp.1453-1456.

Cooke G. A., Houlihan W. J. Pat. 3963717 USA, 260/251, 1976.

Houlihan W. J., Cooke G., Bochoven R. V., Perrine J., Takesue E. I., Jukniewicz E. J. Med. Chem., 1982, Vol. 25, pp.1110-1113.

Upasani R., Cai S. X., Lan N. C., Wang Y., Field G., Fick D. B. Pat. 6465472 USA, 514/258, 2002.

Katayama S., Koshiba M., Yamamoto H., Yamamoto M. Pat. 4202974 USA, 544/25, 1980.

Yamamoto M., Katayama S., Koshiba M., Yamamoto H. Pat. 4048168 USA, 260/251, 1977.

Chaturvedula P. V., Pin S., Tholady G., Conway C. M., Macor J. E., Dubowchik G. M. Bioorg. Med. Chem. Lett., 2012, Vol. 22, pp.4719-4722.

Lorthiois E., Bernardelli P., Vergne F., Oliveira C., Mafroud A.-K., Proust E., Heuze L., Moreau F., Idrissi M., Tertre A., Bertin B., Coupe M., Wrigglesworth

R., Descours A., Soulard P., Berna P. Bioorg. Med. Chem. Lett., 2004, Vol. 14, pp.4623-4626.

Bernardelli P., Lorthiois E., Vergne F., Oliveira C., Mafroud A.-K., Proust E., Pham N., Ducrot P., Moreau F., Idrissi M., Tertre A., Bertin B., Coupe M., Chevalier E., Descours A., Berlioz-Seux F., Berna P., Li M. Bioorg. Med. Chem. Lett., 2004, Vol. 14 (18), pp.4627-4631.

Bernardelli P., Vergne F., Mendes C., Ducrot P. Pat. 1400244 EP, 239/80, 2004.

Rawson D. J., Swain N. A., Watson L. Pat. 2008142550 USA, 239/70, 2008.

Wagner E. C., Eisner A. J. Am. Chem. Soc., 1937, Vol. 59, pp.879-883.

Walther R., Bamberg R. J. Prakt. Chem., 1906, Vol. 73, pp.209-228.

Wagner Е. C. J. Org. Chem., 1937, Vol. 2, pp.157-164.

Potikha L. M., Gutsul R. M., Plaskon A. S., Kovtunenko V. A., Tolmachev A. A. Chem. Heterocycl. Comp., 2011, Vol. 47, pp.342-354.

Lipson V. V., Desenko S. M., Shirobokova M. G., Borodina V. V. Chem. Heterocycl. Comp., 2003, Vol. 39, pp.1213-1217.

Petrova A. A., Kasatochkina A. N., Emelina E. E., Nelyubina Y. V., Antipin M. Y. Russ. J. Org. Chem., 2009, Vol. 45, pp.1390-1401.

Sadek K. U., Mekheimer R. A., Mohamed T. M., Moustafa M. S., Elnagdi M. H. Beilstein J. Org. Chem., 2012, Vol. 8, pp.18-24.

Dandia A., Arya K., Khaturia S., Jain A. K. Monatsh. Chem., 2010, Vol. 141, pp.979-985.

Ryabukhin S. V., Shivanyuk A. N., Granat D. S., Plaskon A. S., Volovenko Yu. M., Tolmachev A. A. ACS Comb. Sci., 2012, Vol. 14, pp.465-470.

Gunzenhauser S., Balli H. Helv. Chim. Acta, 1988, Vol. 71, pp.33-46.

Rossi E., Celentano G., Stradi R., Strada A. Tetrahedron Lett., 1990, Vol. 31, pp.903-906.

Kumar V., Sharma A., Mahajan M. P. Synth. Commun., 2004, Vol. 34, pp.49-53.

Bedi P. M. S., Kumar V., Mahajan M. P. Bioorg. Med. Chem. Lett., 2004, Vol. 14, pp.5211-5213

Яковлев В. П. Антибиотики и химиотерапия, 1997, №1, cc.69-71.

Burger K., Penninger S., Greisel M., Daltrozzo E. J. Fluor. Chem., 1980, Vol. 15, pp.1-27.

Kumar V., Mohan C., Gupta M., Mahajan M. P. Tetrahedron, 2005, Vol. 61, pp.3533-3538.

Goel R. K., Kumar V., Mahajan M. P. Bioorg. Med. Chem. Lett., 2005, Vol. 15, pp.2145-2148.

Barnard C. F. J. Organometallics, 2008, Vol. 27, pp.5402-5422.

Zhang M., Buchwald S. L. J. Org. Chem., 1996, Vol. 61, pp.4498-4499.

Kamijo S., Yamamoto Y. J. Am. Chem. Soc., 2002, Vol. 124, pp.11940-11945.

Shibata T., Yamashita K., Katayama E., Takagi K. Tetrahedron, 2002, Vol. 58, pp.8661-8667.

Onitsuka K., Suzuki S., Takahashi S. Tetrahedron Lett., 2002, Vol. 43, pp.6197-6199.

Vlaar T., Ruijter E., Orru R. V. A. Adv. Synth. Cat., 2011, Vol. 353, pp.809-841.

Crociani B., Dibianca F., Bertani R., Castellani C. B. Inorg. Chim. Acta, 1985, Vol. 101, pp.161-169.

Bertani R., Berton A., Bianca F.D., Crociani B. J. Organometall. Chem., Vol. 303, pp.283-299.

Schuster O., Yang L., Raubenheimer H. G., Albrecht M. Chem. Rev., 2009, Vol. 109, pp.3445-3478.

Baelen G. V., Kuijer S., Rýček L., Sergeyev S., Janssen E., de Kanter F. J. J., Maes B. U. W., Ruijter E., Orru R. V. A. Chem. Eur. J., 2011, Vol. 17, pp.15039-15044.

Le T. N., Yang S. H., Khadka D. B., Van H. T. M., Cho S. H., Kwon Y., Lee E.-S., Lee K.-T., Cho W.-J. Bioorg. Med. Chem., 2011, Vol. 19, pp.4399-4404.

Wang Y., Wang H., Peng J., Zhu Q. Org. Lett., 2011, Vol. 13, pp.4604-4607.

Ma B., Wang Y., Peng J., Zhu Q. J. Org. Chem., 2011, Vol. 76, pp.6362-6366.

Yang S., Chao H., Shuying C., Ping L., Yanguang W. Tetrahedron Lett., 2012, Vol. 53, pp.5671-5673.

Zeng F., Alper H. Org. Lett., 2010, Vol. 12, pp.1188-1191.

Saluste C. G., Whitby R. J., Furber M. Angew. Chem., Int. Ed., 2000, Vol. 39, pp.4156-4158.

Komeyama K., Sasayama D., Kawabata T., Takehira K., Takaki K. Chem. Commun., 2005, pp.634-636.

Qiu G., He Y., Wu J. Chem. Commun., 2012, Vol. 48, pp.3836-3838.

Qiu G., Liu G., Pu S., Wu J. Chem. Commun., 2012, Vol. 48, pp.2903-2905.

Qiu G., Lub Y., Wu J. Org. Biomol. Chem., 2013, Vol. 11, pp.798-802.

Tietze L. F., Brasche G., Gericke K. Domino Reactions in Organic Synthesis. – Weinheim: Wiley-VCH, Verlag GmbH & Co, 2006. – 617 p.

Zeng F., Alper H. Org. Lett., 2010, Vol. 12, pp.3642-3644.

Morimoto T., Kakiuchi K. Angew. Chem., Int. Ed., 2004, Vol. 43, pp.5580-5588.

Kuninobu Y., Nishimura S., Takai K. Org. Biomol. Chem., 2006, Vol. 4, pp.203-205.

Abe N., Matsuda H., Sugihara Y., Kakehi A. J. Heterocycl. Chem., 1996, Vol. 33, pp.1323-1331.

Roberts B., Liptrot D., Luker T., Stocks M. J., Barber C., Webb N., Dods R., Martin B. Tetrahedron Lett., 2011, Vol. 52, pp.3793-3796.

Roberts B., Liptrot D., Alcaraz L., Luker T., Stocks M. Org. Lett., 2010, Vol. 12, pp.4280-4283.

Tilley J. W., Coffen D. L., Schaer B. H., Lind J. J. Org. Chem., 1987, Vol. 52, pp.2469-2474.

Connolly D. J., Cusack D., O‘Sullivan T. P., Guiry P. J. Tetrahedron, 2005, Vol. 61, pp.10153-10202.

Ohta Y., Tokimizu Y., Oishi S., Fujii N., Ohno H. Org. Lett., 2010, Vol. 12, pp.3963-3965.

Willwacher J., Rakshit S., Glorius F. Org. Biomol. Chem., 2011, Vol. 9, pp.4736-4770.

GOST Style Citations


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)