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Document Type : Review Article


1 Faculty of Chemistry, Urmia University, Urmia, Iran

2 Department of Chemistry, Flinders University, Adelaide, Australia



This review provides an overview of the recent literature on application of arylglyoxals the synthesis of pyrrolo[2,3-d]pyrimidines via multicomponent reactions in the period of 2008–2018. 1,2-Dicarbonyl compounds are attractive precursors for synthesis of various heterocyclic compounds, and arylglyoxals are frequently applied in synthesis of various organic compounds, and in particular of pyrrolo[2,3-d]pyrimidines derivatives, which are important due to their biological and pharmaceutical activities.

Graphical Abstract

The Application of Arylglyoxals in the Synthesis of Pyrrolo[2,3-d]pyrimidines via Multicomponent Reactions


Main Subjects

[1] Parsons, P.J., Penkett, C.S., & Shell, A. (1996). Tandem Reactions in Organic Synthesis:  Novel Strategies for Natural Product Elaboration and the Development of New Synthetic Methodology. Journal of Chemical Review, 96, 195-206.
[2] Domling, A., Wang, W., & Wang, K. (2012). Chemistry and Biology of Multicomponent Reactions. Chemical Reviews, 112, 3083-3135.
[3] Rotstein, B.H., Zaretsky, S., Rai V., & Yudin, A.K. (2014). Small Heterocycles in Multicomponent Reactions. Chemical Reviews, 114, 8323-8359.
[4] Domling A. (2006). Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chemical Reviews, 106, 17-89.
[5] Chanda, A., Fokin, V.V. (2009). Organic Synthesis “On Water”. Chemical Reviews, 109, 725-748.
[6] Mahmudov, K.T., Kopylovich, M.N., Maharramov, A.M., Kurbanova, M.M., Gurbanov, A.V., Pombeiro, A.J.L. (2014). Barbituric acids as a useful tool for the construction of coordination and supramolecular compounds. Coordination Chemical Reviews, 265, 1-37.
[7] Estevez, V., Villacampa, M., Menendez, C.J. (2010). Multicomponent reactions for the synthesis of pyrroles. Chemical Society Reviews, 39, 4402-4421.
[8] Ma, L.Y., Zheng, Y.C., Wang, S.Q., Wang, B., Wang, Z.R., Pang, L.P., Zhang, M., Wang, J. W., Ding, L., Li, J., Wang C., Hu, B., Liu, Y., Zhang, X. D., Wang, J. J., Wang, Z. J., Zhao, W., Liu, H. M. (2015). Design, Synthesis, and Structure–Activity Relationship of Novel LSD1 Inhibitors Based on Pyrimidine–Thiourea Hybrids As Potent, Orally Active Antitumor Agents. Journal of Medicinal Chemistry, 58, 1705-1716.
[9] Allias, C., Grassot, J., Rodriguez, J., Constantieux, T. (2014). Metal-Free Multicomponent Syntheses of Pyridines. Chemical Reviews, 114, 10829-10868.
[10] Jiang, S., Gao, J., Han, L. (2016). One-pot catalyst-free synthesis of 3-heterocyclic coumarins. Research on Chemical Intermediates, 2, 1017-1028.
[11] Fu, Z., Qian, K., Li, S., Shen, T. (2016). MgCl2 catalyzed one-pot synthesis of 2-hydroxy-3-((5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)naphthalene-1,4-dione  derivatives in EG. Tetrahedron Letter, 57, 1104-1108.
[12] Pałasz, A., Cież, D. (2015). In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications. European Journal of Medicinal Chemistry, 97, 582-611.
[13] Tolstoluzhsky, N., Nikolaienko, P., Gorobets, N., Van der Eycken, E. V., Kolos, N. (2013). Efficient Synthesis of Uracil-Derived Hexa- and Tetrahydropyrido[2,3-d]pyrimidines. European Journal of Organic Chemistry, 2013, 5364-5369.
[14] Dhorajiya, B.D., Dholakiya, B.Z., Mohareb, R.M. (2014). Hybrid probes of aromatic amine and barbituric acid: highly promising leads for anti-bacterial, anti-fungal and anti-cancer activities. Medicinal Chemistry Research, 23, 3941-3952.
[15] Yagi, K., Akimoto, K., Mimori, N., Miyake, T., Kudo, M., Arai, K., Ishii, S. (2000) Pest Management Science, 56, 65-73.
[16] El-Gazzar, A.R.B.A., Hafez, H.N. (2009). Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents. Bioorganic & Medicinal Chemistry Letters, 19, 3392-3397.
[17] Siddiqui, Z. N. (2015). Chitosan catalyzed an efficient, one pot synthesis of pyridine derivatives. Tetrahedron Letter, 56, 1919-1924.
[18] Abu-Hashem, A.A., Gouda, M.A., Badria, F.A. (2010). Synthesis of some new pyrimido[2′,1′:2,3]thiazolo[4,5-b]quinoxaline derivatives as anti-inflammatory and analgesic agents. European Journal of Medicinal Chemistry, 45, 1976-1981.
[19] Kliethermes, C. L., Metten, P., Belknap, J. K., Buck, K. J., Crabbe, J.C. (2004). Selection for pentobarbital withdrawal severity: correlated differences in withdrawal from other sedative drugs. Brain Research, 1009, 17-25.
[20] Rewcastle G.W., Bridges A.J., Fry, D.W., Rubin, J.R., Denny, W.A. (1997). Tyrosine Kinase Inhibitors. 12. Synthesis and Structure−Activity Relationships for 6-Substituted 4-(Phenylamino)pyrimido[5,4-d]pyrimidines Designed as Inhibitors of the Epidermal Growth Factor Receptor. Journal of Medicinal Chemistry, 40, 1820-1826.
[21] Heravi, M.M., Oskooie, H.A., Karimi, N., & Hamidi, H. (2011). KAl (SO4) 2• 12H2O catalyzed efficient synthesis of 3, 4, 6-trisubstituted 2-pyridone in water. Chinese Chemical Letters, 22(9), 1059-1062.
[22] Shiri, M., Heravi, M.M., Hamidi, H., Zolfigol, M.A., Tanbakouchian, Z., Nejatinezhad-Arani, A., Shintre, S.A., & Koorbanally, N. A. (2016). Transition metal-free synthesis of quinolino [2′,3′:3,4] pyrazolo [5,1-b] quinazolin-8 (6H)-ones via cascade dehydrogenation and intramolecular N-arylation. Journal of the Iranian Chemical Society, 13(12), 2239-2246.
[23] Heravi, M.M., Hamidi, H., Karimi, N., & Amouchi, A. (2018). Caro's Acid-Silica Gel Catalyzed Regioselective Ring Opening of Epoxides with Indoles and Imidazoles under Solvent-Free Conditions. Advanced Journal of Chemistry-Section A, 1(1), 1-6.
[24] Jin, Y.Z., Yasuda, N., Furuno, H., Inanaga, J. (2003). Organic synthesis in solid media. Silica gel as an effective and reusable medium for the selective allylation of aldehydes with tetraallyltin. Tetrahedron Letter, 44, 8765-8768.
[25] Zhang, Q., Xu, C.-M., Chen, J.X., Xu, X.L., Ding, J.C., Wu, H.Y. (2009). Palladium‐catalyzed arylation of arylglyoxals with arylboronic acids. Applied Organometallic Chemistry, 23, 524-526.
[26] Itoh, T., Nagata, K., Miyazaki, M., Ishikawa, H., Kurihara, A., Ohsawa, A. (2004). A selective reductive amination of aldehydes by the use of Hantzsch dihydropyridines as reductant. Tetrahedron, 60, 6649-6655.
[27] Jang, H.-Y., Huddleston, R. R., Krische, M. J. (2003). A New Catalytic CC Bond‐Forming Hydrogenation: Reductive Coupling of Dienes and Glyoxals under Catalytic Hydrogenation Conditions. Angewandte Chemie International Edition, 42, 4074-4077.
[28] Wu, J., Sun, L., Dai, W.M. (2006). Microwave-assisted tandem Wittig–intramolecular Diels–Alder cycloaddition. Product distribution and stereochemical assignment. Tetrahedron, 62, 8360-8372.
[29] Schmitt, E., Schiffers, I., Bolm, C. (2009). Organocatalytic conversion of arylglyoxals into optically active mandelic acid derivatives. Tetrahedron Letter, 50, 3185-3188.
[30] Kobayashi, S., Araki, M., Yasuda, M. (1995). One-pot synthesis of β-amino esters from aldehydes using lanthanide triflate as a catalyst. Tetrahedron Letter, 36, 5773-57576.
[31] Blay, G., Hernández-Olmos, V., Pedro, J.R. (2011). The Construction of Quaternary Stereocenters by the Henry Reaction: Circumventing the Usual Reactivity of Substituted Glyoxals. Chemistry European Journal, 17, 3768-3773.
[32] Desai, J.T., Desai, C.K., Desai, K.R. (2008). A convenient, rapid and eco-friendly synthesis of isoxazoline heterocyclic moiety containing bridge at 2°-amine as potential pharmacological agent. Journal of the Iranian Chemical Society, 5, 67-73.
[33] Tangmouo, J.G., Meli, A.L., Komguem, J., Kuete, V., Ngounou, F.N., Lontsi, D., Beng, V.P., Choudhary, M.I., Sondengam, B.L. Crassiflorone, Crassiflorone, (2006)  Tetrahedron Letter, 47, 3067-3069.
[34] Satti, N.K., Suri, K.A., Sun, O.P., Kapil, A. (1993). Synthesis and antileishemanial activity of some pyrido[1,2-a]pyrimidines and phennathrolines.  Indian Journal of Chemistry -Section B., 32B, 978-980.
[35] Bystryakova, I., Burova, I., Chelysheva, G., Zhilinkova, S., Smirnova, N., Safonova, T. (1991). Synthesis of arylmethylureas and effects of their structure on anticonvulsant activity. Khimiko-Farmatsevticheskii Zhurnal, 25, 31-35.
[36] Emmadi, Atmakur, K., Bingi, C., Godumagadda, N.R., Kumar, C.G., Nanubolu, J.B. (2014). Regioselective synthesis of 3-benzyl substituted pyrimidino chromen-2-ones and evaluation of anti-microbial and anti-biofilm activities. Bioorganic & Medicinal Chemistry Letters, 24, 485-489.
[37] Ryota, M., Keisuke, A., Seijiro, M. (2013). Asymmetric Indoline Synthesis via Intramolecular Aza-Michael Addition Mediated by Bifunctional Organocatalysts. Organic Letters, 15, 3658-3661.
[38] Kliethermes, C.L., Metten, P., Belknap, J.K., Buck, K.J., Crabbe, J.C. (2004). Selection for pentobarbital withdrawal severity: correlated differences in withdrawal from other sedative drugs. Brain Research, 1009, 17-25.
[39] Isobe, Y., Tobe, M., Inoue, Y., Isobe, M., Tsuchiya, M., Hayashi, H. (2003). Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Bioorganic & Medicinal Chemistry, 11, 4933- 4940.
[40] Berghot, M.A., Kandeel, E.M., Abdel-Rahman, A.H., Abdel-Motaal, M. (2014). Medicinal chemistry synthesis, antioxidant and cytotoxic activities of novel naphthoquinone. Medicinal Chemistry, 4(3), 381-388.
[41] Abu-Hashem, A.A., Gouda, M.A., Badria, F.A. (2010). Synthesis of some new pyrimido[2′,1′:2,3]thiazolo[4,5-b]quinoxaline derivatives as anti-inflammatory and analgesic agents. European Journal of Medicinal Chemistry, 45, 1976- 1981.
[42] A.  Cutignano, G.  Bifulco, I., Bruno, A., Casapullo, L.,   Gomez-Paloma, R. Riccio, (2000). Dragmacidin F: A New Antiviral Bromoindole Alkaloid from the Mediterranean Sponge Halicortex sp. Tetrahedron, 56, 3743-3748.
[43] Sandberg, F. (1951). Anaesthetic Properties of Some New N‐substituted and N,N'‐disubstituted Derivatives of 5,5‐Diallyl‐Barbituric Acid.  Acta Physiologica Scandinavica, 24, 7-26.
[44] Yagi, K., Akimoto, K., Mimori, N., Miyake, T., Kudo, M., Arai, K., Ishii, S. (2000). Synthesis and insecticidal/acaricidal activity of novel 3‐(2,4,6‐trisubstituted phenyl)uracil derivatives. Pest Management Science, 56, 65-73.
[45] Elrazaz, E.Z., Serya, R. A.T., Ismail, N.S.M., Abou El Ella, D. A., Abouzid, K. A.M. (2015). Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents. Future Journal of Pharmaceutical Sciences, 1, 33-41.
[46] Rosowsky, A., Mota, C.E., Queener, S.F. (1995). Synthesis and antifolate activity of 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine analogues of trimetrexate and piritrexim. Journal of Heterocyclic Chemistry, 32, 335-340. 
[47] Limbach, P. A., Crain, P.F., McCloskey, J. A. (1994). Summary: the modified nucleosides of RNA. Nucleic Acids Research, 22, 2183-2196.
[48] Wojciechowski, F., Leumann, C.J. (2011). Alternative DNA base-pairs: from efforts to expand the genetic code to potential material applications. Chemical Society Reviews, 40, 5669-5679.
[49] Ranasinghe, R.T., Brown, T. (2005). Fluorescence based strategies for genetic analysis. Chemical Communications, 5487-5502.
[50] Greco, N.J., Sinkeldam, R.W., Tor, Y. (2009). An Emissive C Analog Distinguishes between G, 8-oxoG, and T. Organic Letters, 11, 1115-1118.
[51] Tanaka, K., Imai, K., Sanno, Y., Nakamori, R., Ando, Y., Sugawa, T. (1964). Studies on Nucleic Acid Antagonists. VI. Synthesis of 1, 4, 6-Triazain-denes(5H-Pyrrolo[3,2-d]pyrimidines). Chemical and Pharmaceutical Bulletin, 12, 1024-1030.
[52] Imai, K. (1964). Studies on Nucleic Acid Antagonists. VII. Synthesis and Characterization of 1, 4, 6-Triazaindenes (5H-Pyrrolo[3,2-d]pyrimidines). Chemical and Pharmaceutical Bulletin, 12, 1030-1042.
[53] De Coen, L.M., Heugebaert, T.S.A., García, D., Stevens, C.V. (2016). Synthetic Entries to and Biological Activity of Pyrrolopyrimidines. Chemical Reviews, 116, 80-139.
[54] Pathania, Sh., Rawal, R. K. (2018). Pyrrolopyrimidines: An update on recent advancements in their medicinal attributes. European Journal of Medicinal Chemistry, 157, 503-526.
[55] Takahashi, K. (1968). The Reaction of Phenylglyoxal with Arginine Residues in Proteins. Journal of Biological Chemistry, 243, 6171-6179.
[56] Tiffany, B.D., Wright, J.B., Moffett, R.B., Heinzelman, R. V., Strube, R. E., Aspergren, B. D., Lincoln, E. H., White, J. L. (1957). Antiviral Compounds. I. Aliphatic Glyoxals, α-Hydroxyaldehydes and Related Compounds. Journal of the American Chemical Society, 79, 1682-1687.       
[57] Moffett, R.B., Tiffany, B.D., Aspergren, B.D., Heinzelman, R. V. (1957). Antiviral Compounds. II. Aromatic Glyoxals. Journal of the American Chemical Society, 79, 1687-1690.
[58] von Pechmann, H. (1887). For cleavage of isonitroso compounds. Chemische Berichte , 20, 2904-2906.
[59] Riley, H.L., Morley, J.F., Friend, N.A.C. (1932). Selenium dioxide, a new oxidising agent. Part I. Its reaction with aldehydes and ketones. Journal of the Chemical Society, 1875-1883.
[60] Riley, H.A., Gray, A.R. (1935). Phenylglyoxal. Organic Syntheses, 15, 67, (1943) Organic Syntheses Collect. Vol., 2, 509.
[61] Bousset, R. (1939) Bull. Soc. Chim. France, 6, 986-996.
[62] Saldabol, N.O., Popelis, J., Slavinska, V. (2002). 5-Methyl-2-furylglyoxal, 5-Methyl-4-nitro-2-furylglyoxal, and Their Derivatives. Nitration of 2-(5-Methyl-2-furyl)quinoxaline. Chemistry Heterocyclic Compound, 38, 783-788.
[63] Sharma, V.K., Chandalia, S.B. (1986). Liquid phase oxidation of acetophenone to phenylglyoxal by selenium dioxide alone or with aqueous nitric acid. Journal of Chemical Technology & Biotechnology, 36, 456-460.
[64] Tiecco, M., Testaferri, L., Tingoli, M., Bartoli, D. (1990). Selenium-catalyzed conversion of methyl ketones into .alpha.-keto acetals. Journal of Organic Chemistry, 55, 4523-4528.
[65] Floyd, M.B., Du, M. T., Fabio, P. F., Jacob, L.A., Johnson, B.D. (1985). The oxidation of acetophenones to arylglyoxals with aqueoushydrobromic acid in dimethyl sulfoxide. Journal of Organic Chemistry, 50, 5022-5027.
[66] Kornblum, N., Powers, J.W., Anderson, G.J., Jones, W.J., Larson, H. O., Levand, O., Weaver, W. M. (1957). A new and selective method of oxidation. Journal of the American Chemical Society, 79, 6562-6562.
[67] Kato, T., Goto, Y., Yamamoto, Y. (1964). A New Synthetic Method of α-Ketoaldehyde: Reaction of α-Picoline N-Oxide with α-Halo Ketone.  Yakugaku Zasshi, 84, 287-289.
[68] Gunn, V.E., Anselme, J.P. (1977). The facile oxidation of phenacyl bromides with N,N-dialkylhydroxylamines. Journal of Organic Chemistry, 42, 754-755.
[69] Kornblum, N., Frazier, H. W. (1966) Journal of the American Chemical Society, 88, 865-866.
[70] Ihmels, H., Maggini, M., Prato, M., Scorrano, G. (1991). Oxidation of diazo compounds by dimethyl dioxirane: an extremely mild and efficient method for the preparation of labile α-oso-aldehydes. Tetrahedron Letter, 32, 6215-6218.
[71] Ballistreri, F., Failla, S., Tomaselli, G. A., Curci, R. (1986). A new facile synthesis of α-dicarbonyl compounds by oxidation of alkynes with Mo(VI) peroxocomplex promoted by mercuric acetate. Tetrahedron Letter, 27, 5139-5142.
[72] Wolfe, S., Pilgrim, W.R., Garrard, T.F., Chamberlain, P. (1971). N-Bromosuccinimide-Induced Dimethyl Sulfoxide Oxidation of Acetylenes. Canadian Journal of Chemistry, 49, 1099-1105.
[73] Santoro, S., Battistelli, B., Gjoka, B., Si, C.-W. S., Testaferri, L.,Tiecco, M., Santi, C. (2010). Oxidation of Alkynes in Aqueous Media Catalyzed by Diphenyl Diselenide. Synlett, 1402-1406.
[74] Mikol, G. J., Russell, G. A. (1968). Phenylglyoxal. Organic Syntheses 48, 109, (1973) Organic Syntheses Collect. Vol., 5, 937.
[75] Jagdale, A.R., Chouthaiwale, P.V., Sudalai, A. (2009). Cu(OTf)2-catalyzed -halogenation of ketones with 1,3-dichloro-5,5′-dimethylhydantoin and N-bromosuccinimide. Indian Journal of Chemistry, 48B, 1424-1430.
[76] Quiroga, J., Acosta, P. A., Cruz, S., Abonía, R., Insuasty, B., Nogueras, M., Cobo, J. (2010). Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal. Tetrahedron Letter, 51, 5443-5447.
[77] Raafat M. Shaker, R.M., Sadek, K.U., Hafez, E.A., Abd Elrady, M. Z. (2011). 5-Aminouracil as a Building Block in Heterocyclic Synthesis: Part IV. One-pot Synthesis of 1H-Pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione Derivatives Using Controlled Microwave Heating. Naturforsch., 66b, 843- 849.
[78] Rad-Moghadam, K., Azimi, S.C. (2012). Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a three-component sequential tandem reaction. Tetrahedron, 68, 9706-9712.
[79] Rad-Moghadam, K., Azimi, S.C. (2016). A  clean  and  highly  efficient  synthesis  of  oxindole  substituted pyrrolo[2,3-d]pyrimidines under ultrasound irradiation. Iran Chemical Communications, 5, 156-166.
[80] Dommaraju, Y., Borthakur, S., Rajesh, N., Prajapati, D. (2013). An Efficient Catalyst-free Chemoselective Multicomponent Reaction for the Synthesis of Pyrimidine Functionalized Pyrrolo-annelated Derivatives. RSC Advance, 00, 1-3.
[81] Naidu, P.S., Bhuyan, P.J. (2014). A novel one-pot three-component reaction for the synthesis of 5-arylamino-pyrrolo[2,3-d]pyrimidines under microwave irradiation. RSC Advance, 4, 9942-9945.
[82] Shaik Karamthulla, S., Asim Jana, A., Choudhury, L.H. (2017). Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine-2,4-Diones Via One-Pot Three-Component Reactions. ACS Combinatorial Science, 19, 108-112.
[83] Yadav, V.B., Rai, P., Sagir, H., Akhilesh Kumar, A., Siddiqui, I.R. (2018). A greener route for the synthesis of Pyrrolo[2,3-d]pyrimidine derivatives catalyzed by β-cyclodextrin. New Journal of Chemistry, 42, 628-633.
[84] Panday, A.K., Choudhury, L.H., Jagannath Pal, J., Subramanian, R., Verm, R. (2017). Multicomponent Reactions of Arylglyoxal, 4-Hydroxycoumarin, and Cyclic 1,3-C,N-Binucleophiles: Binucleophile Directed Synthesis of Fused Five and Six Membered N-Heterocycles. European Journal of Organic Chemistry, 2017, 2789-2800.
[85] Javahershenas, R., Khalafy, J. (2018). A new synthesis of pyrrolo[3,2-d]pyrimidine derivatives by a one-pot, three-component reaction in the presence of L-proline as an organocatalyst. Heterocyclic Communications, 24, 37-41.
[86] Saroha, M., Khanna, G., Khurana, J. M. (2017). Synthesis of Novel 5-Substituted 6-Phenylpyrrolo[2,3-d]pyrimidine Derivatives via One-pot Three-Component Reactions Under Catalyst-Free Condition. ChemistrySelect, 2, 7263-7266.
[87] Javahershenas, R., Khalafy, J. (2018). One-pot three-component Synthesis of pyrrolo[2,3-d]pyrimidine Derivatives. Journal of the Mexican Chemical Society, 62(1).
[88] Bayat, M., Nasri, Sh. J. (2018). Synthesis and dynamic 1H NMR study of pyrazolo substituted pyrrolo[2,3-d]pyrimidines via a regioselective heterocyclization. Journal of Molecular Structure, 1154, 366-372.
[89] Ahmadi Sabegh, M., Khalafy, J., Etivand, N.  (2018). One-pot, Three-component Synthesis of a Series of New Bis-pyrrolo[2,3-d]pyrimidines in the Presence of TPAB under Reflux Conditions. Journal of Heterocyclic Chemistry, 55(11), 2610-2618.