A Concise and Convenient Method for the Synthesis of Pure Substituted Thioureas K. Ramadas* and N. Janarthanan Centre for Agrochemical Research, SPIC Science Foundation, 110, Mount Road, Guindy, Madras 600 032, India Zinc dialkyldithiocarbamates offer excellent substrates for the pure thioureas required for antifungal and X-ray crystallographic studies. The synthetic methodology for variously substituted sym- metrical1 and unsymmetrical2 thioureas and guanidines3 has been well established in this laboratory and their biological activity is also well known.4 In pursuit of our interest in the study of the antifungal properties of thioureas, we required the products in a highly pure state.It may be noted that the end products were contaminated with sulfur which is un- desirable for antifungal studies since sulfur is well known to function as a fungicide. The removal of sulfur from the product poses problems in the isolation of the pure product. The approach presented herein makes use of dialkyldithio- carbamates, particularly the zinc salt, which as substrates provide a ready access to mixed thiocarbamides.The high- lights of the work include easy removal of the by-product zinc sulRde by Rltration, trapping of hydrogen sulRde by triethanolamine5 and excellent yield of the product in a pure form. The method involves the reaction of a zinc salt of dialkyldithiocarbamic acid with primary aliphatic or aromatic amine in the ratio of 1:2 in dimethylformamide at 65�}70 8C which led to the trisubstituted unsymmetrical thioureas (Scheme, Table A).In the above procedure (Scheme), if 4 equivalents of amine nucleophile were used instead of 2, both the dialkyl amine functionalities were displaced to yield 1,3- disubstituted symmetrical thioureas (Scheme, Table B). 1,3-Diaryl symmetrical thioureas containing deactivated arylamines, which are otherwise dicult to synthesise, were obtained in good yields. The reactions of zinc dialkyldithio- carbamate were extended to those with aliphatic diamines to provide cyclic thioureas (Scheme, Table C).Cava and co-workers18 studied the reactions of tetramethylthiuram disulRde (TMTD) with phenyllithium and showed the products to be a mixture of about equal amounts of the thioamide and the corresponding aryldithiocarbamate formed by competing nucleophilic attack at the thione carbon of the TMTD and the sulfur atom respectively. However, in our reactions the formation of the product is rationalised in terms of the formation of the intermediate isothiocyanate resulting from the nucleophilic attack on the thione carbon of zinc dialkyldithiocarbamate exclusively.To conclude then, this strategy involving the inexpensive zinc salts as ideal substrates for the synthesis of di€erently substituted thioureas works better than other methods available for this purpose.23 Techniques used: 1H NMR and elemental analysis References: 23 Schemes: 3 Tables A�}C: Reaction times, yield, mp and literature references for all thioureas J.Chem. Research (S), 1998, 228�}229 J. Chem. Research (M), 1998, 1101�}1108 Scheme Table A Synthesis of trisubstituted thioureas using zinc dialkyldithiocarbamates Product Reaction Yield Entry R R' time/h (%) 1 Me n-Butyl 2.0 76 2 Me Phenyl 2.0 86 3 Me o-Tolyl 2.0 88 4 Me m-NO2C6H4 2.5 86 5 Et Cyclohexyl 1.5 90 6 Et Phenyl 1.5 82 7 Et o-Tolyl 1.5 79 8 Et p-ClC6H4 2.5 75 Table B Synthesis of 1,3-disubstituted symmetrical thioureas using dialkyldithiocarbamates Product Reaction Yield Entry R R' time/h (%) 9 Me Phenyl 2.0 86 10 Me o-Tolyl 2.0 80 11 Me Cyclohexyl 2.0 88 12 Me n-Butyl 2.0 78 13 Me m-NO2C6H4 3.0 72 14 Me o-ClC6H4 2.5 76 15 Et Phenyl 2.0 84 16 Et o-Tolyl 2.0 82 17 Et m-NO2C6H4 3.0 71 Table C Synthesis of cyclic thioureas using zinc dialkyldithiocarbamates Product Reaction Yield Entry R X' time/min (%) 18 Me 2 30 76 19 Me 3 45 70 20 Et 2 45 80 21 Et 3 60 72 *To receive any correspondence (e-mail: ramadas@agro.smi.ernet.in). 228 J. CHEM. RESEARCH (S), 1998Received, 24th November 1997; Accepted, 14th January 1998 Paper E/7/08483H References cited in this synopsis 1 K. Ramadas, N. Janarthanan and S. Velmathi, Synth. Commun., 1997, 27, 2255. 2 K. Ramadas, N. Srinivasan and N. Janarthanan, Tetrahedron Lett., 1993, 34, 6447; K. Ramadas and N. Srinivasan, Synth. Commun., 1995, 25, 3381. 3 K. Ramadas and N. Srinivasan, Tetrahedron Lett., 1995, 36, 2841; K. Ramadas, N. Janarthanan and R. Pritha, Synth. Lett., 1997, 1053. 4 D. C. Schroeder, Chem. Rev., 1955, 55, 181. 5 K. Ramadas, Tetrahedron Lett., 1996, 37, 5161. (The success of the synthesis of thioureas depends upon the elimination of hydrogen sul®de from the reaction mixture. Triethanolamine forms a water soluble adduct with H2S which is liberated quanti- tatively by gentle warming of the acidi®ed solution to regenerate the tertiary amine.) 18 K.-Y. Jen and M. P. Cava, Tetrahedron Lett., 1982, 23, 2001. 23 G. Y. Sarkis and E. D. Faisal, J. Heterocycl. Chem., 1985, 22, 137; Houben, Methoden Org. Chem. (Houben-Weyl), 1983, VE4, 843; N. Yamazaki, T. Tomioki and F. Higashi, Synthesis, 1975, 384; A. R. Katritzky and M. F. Govdeer, J. Chem. Soc., Perkin Trans. 1, 1991, 2199 and all other methods cited therein. J. CHEM. RESEARCH (S),