Design and Development of Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions” is divided into two sections. Section-A, contains two chapters, describes the catalytic ability of iodine for cross coupling reactions. Section-B, divided into three chapters, presents the azidation of organic scaffolds under oxidative conditions. Section A Chapter 1 presents a C-H functionalization of tetrahydroisoquinolines using iodine as a catalyst under aerobic conditions.1 This methodology employs Cross Dehydrogenative Coupling (CDC) strategy as a key step, which is highly atom economical as it doesn’t require pre-functionalized starting materials.2 Owing to the importance of tetrahydroisoquinoline moiety which is present in the umpteen natural products, considerable attention has been put up to functionalize tetrahydroisoquinoline scaffold.3 Iodine a non-metal which is non-toxic was found to catalyze the C-H functionalization of tetrahydroisoquinolines with a variety of nucleophiles such as coumarin, alkyl phosphite, phenols, indoles, acetone and dialkyl malonoates were coupled to it. Significant mechanistic study has been carried out to find the possible intermediate and support the mechanistic proposal. A few representative examples are highlighted in Scheme 1.1 Synopsis Scheme 1: A CDC coupling of tetrahydroisoquinoline with variety of nucleophiles Chapter 2 describes the Cross Hetero Dehydrogenative Coupling (CHDC) reactions of amines, alcohols and sulfoximines with various phosphites.4 Phosphoramidates and phosphate esters are structural scaffolds that are present in a variety of biologically active molecules.5 The conventional methods for synthesizing phosphoramidates/phosphate esters largely involve treating alcohol/amine with appropriate phosphorus halides which generates stoichiometric amount of halogen waste.6 Due to the usage of stoichiometric reagents and difficulties associated with the reported methods, there is a need for developing a protocol which is catalytic and mild. Therefore, we developed a method which employs catalytic amount of iodine and aq. H2O2 as a sole oxidant under milder conditions. Using this methodology, variety of phosphoramidates, phosphorous triesters and sulfoximine derived Synopsis Scheme 2: Phosphorylation of amines, alcohols and sulfoximines phosphoramidates have been synthesized with great efficiency and environmentally benign conditions. A few representative examples are highlighted in Scheme 2.4 Section B Chapter 1 of Section B demonstrates a mild way of synthesizing quaternary azides from α-substituted active methylene compounds which will serve as surrogates for several unnatural amino acid derivatives.7 Azidation has emerged as one of the efficient methods to introduce nitrogen atom in to the organic molecules.8 Azides are versatile functional groups which can be converted to amine, amide, and nitro compounds by simple modification. Moreover, azides are potential handle for “click” chemistry and provide late stage modifications in drug candidates, biomolecules and polymers, etc.9 Azidation of 1,3-dicarbonyl compounds is challenging, as both azides and 1,3-dicarbonyl compounds are nucleophilic in nature. In this section of the thesis, azidation of 1,3-dicarbonyl compounds has been carried out using tetrabutyl ammonium iodide (TBAI) as a catalyst, aq. TBHP as an oxidant and TMSN3 as a azide source. This method uses water as a solvent under mild reaction conditions to generate Synopsis quaternary azides in good to excellent yields. This operationally simple, practical, mild and green method provides an opportunity for synthesizing a variety of azidated β-keto esters, amides and ketones in good yields, Scheme 3.7 The application of this methodology has been demonstrated by synthesising a few triazole and pyrazolone derivatives. Scheme 3: Azidation of 1,3-dicarbonyl compounds Chapter 2 of Section B comprises the azidation and peroxidation of β-napthol derivatives using dearomatization strategy. Azidation and peroxidation are efficient ways to introduce nitrogen and oxygen into organic molecules, which serve as surrogates for amines and alcohol functional groups. In the present study, the azidative or peroxidative dearomatization of naphthol derivatives have been described. The azidation of β-napthol derivatives has been achieved by using CuBr (5 mol %) as a catalyst, TMSN3 as an azide source and aq. TBHP as an oxidant. Whereas, the peroxidation β-napthol derivatives has been accomplished using CuBr (5 mol %) in the presence of aq. TBHP at ambient reaction conditions.10 The products obtained are naphthalenone derivatives, which serve as valuable Synopsis synthetic intermediates and has potential handle for further functionalization.11 Several α-amino or α-peroxy naphthalenones are synthesized using this method in good yields. The usefulness of the methodology has been illustrated by synthesizing a few chiral azides and peroxides in good yields and with moderate enantioselectivity Scheme 4.10 Scheme 4: Dearomatizative azidation and peroxidation of 2-naphthols Chapter 3 reveals the azidation of indole at C-2 position by employing CuBr (10 mol %) as a catalyst and aq. TBHP as an oxidant in acetonitrile under reflux conditions (Scheme 5).12 The C-H functionalization of indole at C-2 position is one of pivotal methods, since it paves a way for synthesizing a variety of indolo-alkaloids.13 Azide is a versatile functionality which can be converted to several other nitrogen containing functional groups such as Synopsis Scheme 5: Azidation of indoles amine, amide, triazole, etc.9 A variety of functional groups were tolerated under the reaction conditions, and furnished the azidated product in good to excellent yields. Through radical inhibition study, we presume that the reaction may be proceeding through radical mechanism. In Scheme 5, a few representative examples are depicted.

The thesis entitled “Design and Development of Metal-Free Cross Dehydrogenative Coupling Reactions for the construction of C-S, C-O and C-C bonds” is divided into three Chapters. Chapter 1 is presented in five parts, which reveals the cross dehydrogenative coupling (CDC) strategies for the C–S bond forming reactions through C–H functionalization strategy using heterocyclic thiols and thiones. Chapter 2 presents tetrabutyl ammonium iodide (TBAI) catalyzed chemoselective α-aminoxylation of ketones with N-hydroxyimidates using TBHP as oxidant under cross dehydrogenative coupling (CDC) strategy. Chapter 3 describes a transition metal-free Minisci reaction for the acylation of isoquinolines, quinolines, and quinoxaline. Chapter 1 Iodine Promoted C-S Bond Forming Reactions using Dimethyl Sulfoxide as an Oxidant Chapter 1 reveals the utility of cross dehydrogenative coupling (CDC) reactions for the formation of C–S bonds by employing C–H functionalization strategies.1 The direct functionalization of C–H bonds to form C–C and C–X (N, O, S and P) bonds using metal-free reaction conditions is an interesting research topic in recent years.2 Use of dimethyl sulfoxide as an oxidant is emerging as one of the research topics of great interest and utility.3 Heterocyclic thiols and thiones are important precursors for synthesizing a variety of pharmaceuticals and biologically active compounds.4 Therefore it is useful to develop CDC reactions using heterocyclic thiols and thiones as precursors. In this chapter, we describe CDC reactions of heterocyclic thiols and thiones for the sulfenylation of ketones, aldehydes, α, β unsaturated methyl ketone derivatives, pyrazolones, enaminones and imidazoheterocycles using DMSO as an oxidant Chapter 1: Part 1 Iodine Promoted Regioselective α-Sulfenylation of Carbonyl Compounds using Dimethyl Sulfoxide as an Oxidant: In this chapter, a rare regioselective C–H sulfenylation of carbonyl compounds with heterocyclic thiones and thiols have been described using iodine and dimethyl sulfoxide as reagents. Thus, dimethyl sulfoxide (as an oxidant) and stoichiometric amount of iodine have been used for the sulfenylation of ketones using heterocyclic thiones. Whereas the sulfenylation of ketones with heterocyclic thiols required catalytic amount of iodine. This protocol offers a rare regioselective sulfenylation of (i) methyl ketones in the presence of more reactive α-CH2 or α-CH groups, and (ii) aldehydes under CDC method. A few representative examples are highlighted in Scheme 1.5 The application of this methodology has been demonstrated by synthesizing a few precursors for Julia-Kocienski olefination intermediates. Scheme 1. Iodine promoted rare regioselective α-sulfenylation of ketones and aldehydes Siddaraj , Y.; Prabhu, K. R. Org. Lett. 2016, 18, 6090 Chapter 1: Part 2 Regioselective Sulfenylation of α’-CH3 or α’-CH2 Groups of α, β Unsaturated Ketones using Dimethyl Sulfoxide as an Oxidant: In this chapter, an interesting regioselective sulfenylation of α’-CH3 or α’-CH2 groups of α, β unsaturated ketones using dimethyl sulfoxide as an oxidant and catalytic amount of aq. HI (20 mol %) as an additive has been described. This eco-friendly method uses readily available, inexpensive I2 or HI and DMSO. This methodology exhibits a high regioselectivity without forming Michael addition product in the presence of strong acid such as aq. HI or iodine, which is difficult to achieve under cross dehydrogenative coupling (CDC) conditions. Current methodology exhibits a broad substrate scope. A few examples are shown in Scheme 2.6 Scheme 2. HI and DMSO promoted α’-sulfenylation of α, β unsaturated ketones Siddaraju, Y.; Prabhu, K. R. (Manuscript submitted) Chapter 1: Part 3 Iodine Catalyzed Sulfenylation of Pyrazolones using Dimethyl Sulfoxide as an Oxidant: In this chapter, a sustainable and efficient strategy for the sulfenylation of pyrazolones has been described using metal-free conditions by employing DMSO as an oxidant and iodine as a catalyst. A variety of heterocyclic thiols, heterocyclic thiones and disulfides undergo C–H functionalization reaction with pyrazolone derivatives furnishing the corresponding sulfenylated products in short time. Most of the products are isolated in pure form without column purification. A few examples are presented in Scheme 3.7 Scheme 3. Iodine promoted sulfenylation of pyrazolones Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2017, 15, 5191 Chapter 1: Part 4 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: Sulfenylation of Enaminones using Dimethyl Sulfoxide as an Oxidant: In this chapter, synthesis of poly functionalized aminothioalkenes has been described using substoichiometric amount of iodine and DMSO as an oxidant. This metal-free methodology enables a facile sulfenylation of enaminones with heterocyclic thiols and thiones. This methodology is one of the simple approaches for the sulfenylation of enaminones under cross dehydrogenative coupling method. A few examples are highlighted in Scheme 4.8 Scheme 4. Cross-dehydrogenative coupling approach for sulfenylation of enaminones Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2017, 82, 3084 Chapter 1: Part 5 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: A Regioselective Sulfenylation of Imidazoheterocycles using DMSO as an Oxidant: In this chapter, a simple synthetic approach for the regioselective sulfenylation of imidazoheterocycles using iodine as a catalyst and DMSO as an oxidant under cross dehydrogenative coupling (CDC) reaction conditions has been demonstrated. This protocol provides an efficient, mild and inexpensive method for coupling heterocyclic thiols and heterocyclic thiones with imidazoheterocycles. This is the first report on sulfenylation of imidazoheterocycles with heterocyclic thiols and heterocyclic thiones under metal-free conditions. A few examples are shown in Scheme 5.9 Scheme 5. Cross-dehydrogenative coupling approach for sulfenylation of imidazoheterocycles Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2016, 81, 7838 Chapter 2 Chemoselective α-Aminoxylation of Aryl Ketones: Cross Dehydrogenative Coupling Reactions Catalyzed by Tetrabutyl Ammonium Iodide: In this chapter, chemoselective α-aminoxylation of ketones with N-hydroxyimidates catalyzed by tetrabutyl ammonium iodide (TBAI) has been presented. The coupling reaction of a variety of ketones with N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) using TBHP as oxidant has been investigated. This α-aminoxylation of ketones is chemoselective as aryl methyl ketones, aliphatic ketones as well as benzylic position are inactive under the reaction condition. A few examples are highlighted in Scheme 6.10 The application of this method has been demonstrated by transforming a few coupled products into synthetically useful vinyl phosphates. Scheme 6. Chemoselective α-aminoxylation of ketones with N-hydroxyimidates Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2015, 13, 11651 Chapter 3 A Transition Metal-Free Minisci Reaction: Acylation of Isoquinolines, Quinolines, and Quinoxaline: In this chapter, transition metal-free acylation of isoquinoline, quinoline and quinoxaline derivatives with aldehydes has been described by employing TBAB (tetrabutyl ammonium bromide, 30 mol %) and K2S2O8 as an oxidant under cross dehydrogenative coupling (CDC) reaction. This intermolecular acylation of electron-deficient heteroarenes provides an easy access and a novel acylation method of heterocyclic compounds. The application of this CDC strategy has been illustrated by synthesizing isoquinoline-derived natural products. A few representative examples are shown in Scheme 7.11 Scheme 7. CDC reactions of heteroarenes with aldehydes Siddaraju, Y.; Lamani, M.; Prabhu, K. R. J. Org. Chem. 2014, 79, 3856

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