FULL PAPER DOI: 10.1002/ejoc.201301710 One-Pot Synthesis of 2-Imino-4-(trifluoromethyl)thiazolidin-4-ol Derivatives in a Three-Component Reaction: Application to Structurally Diverse Scaffolds of Biological Interest Through Subsequent Reactions Tulshiram Dalmal, [a] K. Appalanaidu, [a] Umesh B. Kosurkar, [a] N. Jagadeesh Babu, [b] and Ravindra M. Kumbhare* [a] Keywords: Medicinal chemistry / Multicomponent reactions / Cyclization / Nitrogen heterocycles / Sulfur heterocycles / Fluorine A highly efficient method for the synthesis of 2-imino-4-(tri- fluoromethyl)thiazolidin-4-ol derivatives has been achieved by the one-pot, three-component reactions of primary amines, aryl isothiocyanates, and 3-bromo-1,1,1-trifluoro- Introduction There has been increasing interest in the introduction of fluorine or a fluorinated group into organic compounds, since this influences the pharmacodynamic and pharmaco- kinetic properties of a drug. [1] The introduction of a tri- fluoromethyl group into cyclic compounds, especially at strategic positions of drug molecules, has become an impor- tant aspect of pharmaceutical research, owing to the unique physical and biological properties of fluorine. [2,3] Therefore, the development of fluorinated potential drugs is a key is- sue and a challenge for medicinal chemistry and related dis- ciplines. [4] 2-Imino-1,3-thiazolidines and 2-imino-1,3-thiaz- olines have emerged as important classes of heterocyclic compounds, due to their diverse applications in medicinal chemistry. [5,6] These heterocycles show a wide range of bio- logical properties, including anti-inflammatory, anodyne, anti-Alzheimer, antimicrobial, antihistaminic, antihyperten- sive, anticonvulsant activities, and also as myeloperoxidase inhibitors etc. [7,8] For example, 4,5-dialkyl-substituted thi- azolidines I (Figure 1) are reported to be nitric oxide syn- thase inhibitors. [9] A member of another class of thiazolid- ines, 3-methylthiazolidine II (Figure 1; R 1 = H, R 2 = Me), is a potent inhibitor of indole–ethylamine N-methyltrans- ferase. [10] β-(Hydroxyethyl)thiazolidines III (Figure 1) are reported to be effective antihypertensive agents. [11] 2-(Tetra- [a] Fluoroorganic Division, Indian Institute of Chemical Technology, CSIR, Hyderabad, India E-mail: kumbhare@iict.res.in, rakumbhare@yahoo.com http://www.iictindia.org/ [b] Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, CSIR, Hyderabad, India Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201301710. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 2468–2479 2468 propanone. The reactions go via symmetrical and unsymmet- rical thiourea intermediates. Subsequent reactions of the products allow the synthesis of various scaffolds, including isoxazoles, triazoles, and propargylamine derivatives. hydronaphthalen-1-yl)iminothiazolidine IV (Figure 1) acts as an antidepressant. [12] 3-Substituted 2-(cyanoimino)- thiazolidines V (Figure 1) can be used in agriculture, due to their neonicotinoid insecticidal activity, and thiacloprid (V : R = H) is a commercially available insecticide released by Bayer in 2001. [13] Figure 1. Biologically active 2-imino-1,3-thiazolidine motifs. Furthermore, thiazoline derivatives have applications in agriculture as pesticides, acaricides, insecticides, and plant- growth regulators. [14] Consequently, in recent decades, there has been continuous interest in developing new synthetic strategies for the synthesis of such attractive target mo- lecules. A detailed literature survey revealed the various methods available for the synthesis of functionalized 2-iminothiazol- idines and related compounds. These include acid-mediated intramolecular cyclization of N-(2-hydroxyethyl)thiourea, ring transformation of 2-(thiocyanomethyl)aziridines, treat- ment of aziridines with thiocyanuric acid, reaction of 2-vin- ylaziridine with phenyl isothiocyanate, condensation of α- halo ketones with thioureas, etc. [15,16] However, methods for the synthesis of 2-imino-1,3-thiazolidin-4-ol derivatives are