Synthesis of 2-R-5-amino-4-(1H-tetrazol-5-yl)-1,3-oxazoles from 2-R-5-amino-1,3-oxazole-4-carbonitriles

Abstract: This short communication reports about new 5-amino-4-(1H-tetrazol-5-yl)-1,3-oxazoles which were synthesized by [3+2] cycloaddition of 2-R-5-amino-1,3-oxazole-4-carbonitriles and trimethylsilyl azide with dibutyltin oxide present. The reaction conditions provided high yields of the products, and were tolerant to some active functional fragments in the oxazole substituents (amino, amido, and hydroxy group). In the case of 2-((4-cyano-2-phenyloxazol-5-yl)amino)-N-methylacetamide the by-product (N-((1-(2-(methylamino)-2-oxoethyl)-1H-tetrazol-5-yl)(1H-tetrazol-5-yl)methyl)-benzamide) was formed together with the expected tetrazolyloxazole.

How to cite this paper

 Shablykin, O., Herasymov, E., Shablykina, O & Kozytsky, A. (2025). Synthesis of 2-R-5-amino-4-(1H-tetrazol-5-yl)-1,3-oxazoles from 2-R-5-amino-1,3-oxazole-4-carbonitriles.Current Chemistry Letters, 14(1), 233-238.

Refrences

1 Zou Y., Liu L., Liu J., and Liu G. (2020) Bioisosteres in drug discovery: focus on tetrazole. Future Med. Chem., 12 (2) 91-93.

2 Bredael K., Geurs S., Clarisse D., De Bosscher K., and D’hooghe M. (2022) Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties. J. Chem., 2022 Article ID 2164558.

3 Dhiman N., Kaur K., and Jaitak V. (2020) Tetrazoles as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Bioorg. Med. Chem., 28 (15) 115599.

4 Malik M. A., Wani M. Y., Al-Thabaiti S. A., and Shiekh R. A. (2014) Tetrazoles as carboxylic acid isosteres: chemistry and biology. J. Incl. Phenom. Macro., 78 (1-4) 15-37.

5 Vishwakarma R., Gadipelly C., and Mannepalli L. K. (2022) Advances in Tetrazole Synthesis – An Overview. ChemistrySelect, 7 (29) e202200706.

6 Takahashi H., Watanabe H., Fujii K., Shibasaki M., Kawashima M., Kamiya M., and Ohata K. (2016) Urea derivative or pharmacologically acceptable salt thereof. WO Patent 2016189877.

7 Lachance N., Li C. S., Leclerc J.-P., and Ramtohul Y. K. (2009) Novel heteroaromatic compounds as inhibitors of stearoyl-coenzyme A delta-9 desaturase. WO Patent 200973973.

8 Apostol T.-V., Chifiriuc M. C., Nitulescu G. M., Olaru O. T., Barbuceanu S.-F., Socea L.-I., Pahontu E. M., Karmezan C. M., and Marutescu L. G. (2022) In Silico and In Vitro Assessment of Antimicrobial and Antibiofilm Activity of Some 1,3-Oxazole-Based Compounds and Their Isosteric Analogues. Appl. Sci., 12 (11) 5571.

9 Shablykin O. V., Brovarets V. S., and Drach B. S. (2007) New transformations of 5-Hydrazino-2-phenyl-1,3-oxazole-4-carbonitrile. Russ. J. Gen. Chem., 77 (5) 936-939.

10 Spencer J., Patel H., Amin J., Callear S. K., Coles S. J., Deadman J. J., Furman C., Mansouri R., Chavatte P., and Millet R. (2012) Microwave-mediated synthesis and manipulation of a 2-substituted-5-aminooxazole-4-carbonitrile library. Tetrahedron Lett., 53 (13) 1656-1659.

11 Merzhyievskyi D. O., Shablykin O. V., Shablykina O. V., Kozytskiy A. V., Rusanov E. B., Moskvina V. S., and Brovarets V. S. (2021) Functionalized 5-Amino-4-cyanoxazoles, their Hetero- and Macrocyclic Derivatives: Preparation and Synthetic Applications. Eur. J. Org. Chem., 2021 (47) 6511-6523.

12 Shablykin O. V., Brovarets V. S., and Shablykina O. V. (2024) Recyclization of 5-Amino- oxazoles as a Route to new Functionalized Heterocycles (Developments of V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine). Chem. Rec., 24 (2) e202300264.

13 Zhao G., Sun X., Bienayme H., and Zhu J. (2001) Activation of a terminal carboxylic acid by an internal oxazole: A novel synthesis of macrocyclodepsipeptide. J. Am. Chem. Soc., 123 (27) 6700-6701.

14 Shablykin O. V., Merzhyievskyi D. O., Brovarets V. S., and Shishkina S. V. (2023) New oxazole to oxazole recyclization. Chem. Heterocycl. Comp., 59 (6-7) 521-524.

15 Clerin D., and Fleury J.-P. (1973) Hétérocyclization des -acylaminoamides. II. – Sur l’hétérocyclization des amides -acylaminés tertiaires. Bull. Soc. Chim. Fr., (11) 3134-3142.

16 Dresler E., Woliński P., Wróblewska A., Jasiński R. (2023) On the Question of Zwitterionic Intermediates in the [3+2] Cycloaddition Reactions between Aryl Azides and Ethyl Propiolate. Molecules, 28 (24) 8152.

17 Kozachenko A. P, Shablykin O. V., and Brovarets V. S. (2012) Synthesis of 4-alkyl-2-aryl-1,3-oxazole[5,4-d]pyrimidine-7(4H)-thiones and 6-alkyl-2-aryl-1,3-oxazole[5,4-d]pyrimidin-7(6H)-ones from 2-aroylamino-3,3-dichloroacrylonitriles. Russ. J. Gen. Chem., 82 (4) 739-743.