The thesis titled “Novel Strategies for the Synthesis of Organo-Sulfur Compounds Under Metal-free Reaction conditions” is presented into three main sections. Section A– deals with the synthesis of thiourea and thioamide. Section B– describes the sulfenylation of electron-rich arenes, ketones and β- diketones Section C– deals with the sulfur/fluorine assisted deacylation of α-sulfenylated β- diketones. Section A: This section is divided in to two chapters, Chapter 1 and Chapter 2. Chapter 1 of this section describes the non-isothiocyanate route to obtain trisubstituted thioureas of arylamines by using in situ generated dithiocarbamates of secondary amines. Trisubstituted thioureas of aryl amines are important precursors for the synthesis of heterocyles like 2-aminobenzothiazoles derivatives,1 amidines,2 and guanidines.3 Therefore, this strategy provides an excellent opportunity to access thioureas containing primary aryl amines without employing isothiocyanates. From the current method, the broad substrate scope was achieved with excellent yield of the corresponding products. Further, under the optimized reaction conditions a variety of functional groups like ketones, carboxylic acids, amides and sulfonamides were found to be well tolerated. A few representative examples are shown in Scheme 1.4 (a) Jordan, A. D.; Luo, C.; and Reitz, A. B. J. Org. Chem. 2003, 68, 8693. (b) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792 and references therein. (c) Jamir, L.; Khatun, N.; Patel, B. K. RSC Adv., 2011, 1, 447. 1 Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946. 2 (a) Wilson, L. J.; Klopfenstein, S. R.; Li, M. Tetrahedron Lett. 1999, 40, 3999. (b) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V. Tetrahedron 1998, 54, 15063. 3 Varun, B. V.; Prabhu, K. R. RSC Adv.2013, 3, 3079. Synopsis Chapter 2 describes the rapid, high yielding and easily isolable method for the synthesis of thioamide by nucleophilic addition of electron-rich arenes to isothiocyanates. Thioamides are essential structural motifs which are found in a variety of biologically active molecules.5 They are also crucial building blocks for synthesizing sulfur conntaining heterocycles.6 The current method employs triflic acid (TfOH) to activate the nitrogen of isothiocyanate, where as, in the earlier methods AlCl3 was used.7 Also, the reaction was found to be highly regioselective and the broad substrate scope of the reaction was demonstrated (Scheme 2).85 (a) Cremlyn, R. J. An Introduction to Organosulfur Chemistry,John Wiley and Sons, Chichester, 1996. (b) Gottesman, M. M.; Fojo, T.; Bates, S. E. Nat. Rev. Cancer 2002, 2, 48; (c) Angehrn, P.; Goetschi, E.; Gmuender, H.; Hebeisen, P.; Hennig, M.; Kuhn, B.; Luebbers, T.; Reindl, P.; Ricklin, F.; Schmitt-Hoffmann, A. J. Med. Chem.2011, 54, 2207 6 (a)Shibuya, I.; Honda, K.; Gama, Y.; Shimizu, M. Heterocycles 2000, 53, 929. (b) Takido, T.; Itabashi, K.; Synthesis 1985, 430. (c) Shibuya, I.; Gama, Y.; Shimizu, M. Heterocycles 2001, 55, 381. (d) Wang, H.; Wang, L.; Shang, J.; Li, X.; Wang, H.; Gui, J.; Lei, A. Chem. Commun., 2012, 48, 76. (e) Alla, S. K.; Sadhu, P.; Punniyamurthy, T. J. Org. Chem., 2014, 79, 7502. (f) Chaudhari, P. S.; Pathare, S. P.; Akamanchi, K. G. J. Org. Chem., 2012, 77, 3716. (g) Mendoza-Espinosa, D.; Ung, G.; Donnadieu, B.; Bertrand, G. Chem. Commun.,2011, 47, 10614. (h) Potts, K. T.; Houghton, E.; Singh, U. P. J. Org. Chem., 1974, 39, 3627. 7 a) Jagodzinski, T.; Jagodzinska, E.; Jabłonski, Z. Tetrahedron 1986, (b) Jagodzinski, T. Synthesis 1988, 717. 8 Varun, B. V.; Sood, A.; Prabhu, K. R. RSC Adv.2014, 4, 60798. Scheme 2: Synthesis of thioamide Section B This section is divided in to two chapters, Chapter 1 and Chapter 2. Chapter 1 of this section describes a facile transition metal-free oxidative CDC (Cross Dehydrogenative Coupling) reaction leading to a regioselective thiolation of electron-rich arenes and hetero-arenes. This strategy provides a rare opportunity of using thione in a CDC reaction to form C–S bonds to obtain arylthiobenzoxazoles, hetero-arylthiobenzoxazoles and arylthiobenzthiazoles, which are pharmaceutically valuable compounds.9 This highly regioselective CDC reaction is unique as it requires the reversing the reactivity of sulfur to form the C–S bonds. Despite the propensity of thiols to undergo oxidation, this method provides an elegant and new avenue for synthesizing thioethers of benzazoles (Scheme 3).10 a) Greco, M. N.; Hageman, W. E.; Powell, E. T.; Tighe, J. J.; Persico, F. J. J. Med. Chem. 1992, 35, 3180. b) Zhang, J.-T.; Qi, J.; Feng, H.; Dong, Z. WO2010048603, 2010. c) Greco, M. N.; Hageman, W. E.; Powell, E. T.; Tighe, J. J.; Persico, F. J. J. Med. Chem. 1992, 35, 3180. d) Barchuk, W. T.; Dunford, P. J.; Edwards, J. P.; Fourie, A. M.; Karlsson, L.; Quan, J. M. US 2008194630. e) Koci, J.; Klimesova, V.; Waisser, K.; Kaustova, J.; Dahse, H.-M.; Moellmann, U.;Bioorg. Med. Chem. Lett. 2002, 12, 3275. 10 Varun, B. V.; Prabhu, K. R. J. Org. Chem.2014, 79, 9655. xii Synopsis Scheme 3: C-H-Functionalization of electron-rich arenes Chapter 2 is discussed in two parts, Part A and Part B. Part A: deals with the C–H functionalization of β-diketones via CDC reactions. A variety β-diketones were sulfenylated at α-position with a variety of benzazole-2-thione derivatives. Sulfenylation of β-diketones is challenging as β-diketones undergo deacylation after sulfenylation in the reaction medium.11 The highlight of this work is that the resultant products do not undergo deacylation. Under the optimal reaction conditions a variety of functional group like ketones, acids and esters were well tolerated. Also, the resultant sulfenylated β-diketones were further manipulated to α,α-disubstituted β-diketones and pyrazoles (Scheme 4).12 11 (a) Ogura, K.; Sanada, K.; Takahashi, K.; Iida, H. Tetrahedron Lett.1982, 23, 4035. (b) Zou, L.-H.; Priebbenow, D. L.; Wang, L.; Mottweiler, J.; Bolm, C. Adv. Synth. & Catal. 2013, 355, 2558. 12 Varun, B. V.; Gadde, K.; Prabhu, K. R. Org. Lett. 2015, 17, 2944. Scheme 4: C-H Functionalization of β-diketones via CDC reaction Chapter 2, Part B: deals with the C–H functionalization of ketones via CDC, which is the continuation of the above discussed work (Chapter 2, Part B). The products obtained from this method can be further modified and can be used for the synthesis of α,β-unsaturated carbonyl compounds under Trost or Julia olefination reaction conditions.13 A variety of actophenone derivatives, propiophenone derivatives and simple alkyl ketones were sulfenylated at the α-position with various benzazole-2-thiones (Scheme 5).14 Scheme 5: C-H Functionalization of ketones via CDC reaction (a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1975, 98, 4887. (b) Baudin, J. B.; Hareau, G.; Julia, S. A. Tetrahedron Lett. 1991, 32, 1175. (c) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26. 14 Manuscript under preparation. Section C This section describes the ‘sulfur/fluorine assisted deacylation of β-diketones.’ Achieving a controlled mono fluorination at α- position of a ketone group is a difficult task. Therefore, an alternate approach is to have a sulfide group at α-position to a ketone (electron withdrawing moiety) and thereby providing additional stability to the generated reactive intermediate at α-position. Till date, this transformation has been achieved only by electrochemical methods.15 In continuation of our earlier work of α-sulfenyl β-diketones for exploring the synthetic utility of α-sulfenyl β-diketones (like benzylation and allylation), we performed the fluorination reaction. In this reaction, the fluorinated product (a diketone) underwent a de-acylation process to furnish the corresponding α-fluorinated ketone and we further optimized the reaction conditions and explored the substrate scope for this reaction. Under the optimized reaction conditions a variety of fluorinated products were isolated in excellent yield (Scheme 6) Scheme 6: Sulfur/Fluorine assisted deacylation of β-diketones 15Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J. Org. Chem. 1990, 55, 6074 16 Manuscript under preparation.