Experimental and Computational insight into Transition Metal Catalyzed Cascade Reactions

Abstract

Great efforts have been devoted in the past many years to synthesizing clinically important novel heterocyclic compounds using transition metal-mediated reactions. Further, transition metal-catalyzed cascade or tandem reactions for the synthesis of crucial heterocyclic scaffolds have attracted a lot of attention in the last few years. These reactions can form multiple bonds in one pot without changing the reaction conditions and overall reduce the reaction steps and requirement of intermediate purifications. The reduction of reaction steps leads to saving reagents, energy and eliminates waste generation which makes the cascade reactions eco-friendly as well as highly economical. In this context, several transition metal catalysts like Rh, Pd, Cu, Ru, Ir, Fe, etc. have been employed to perform these kinds of reactions. In this view, carbenes or their precursors like diazo, hydrazones, etc. played an important role in making them more advantageous. On the other hand, computational chemistry is playing an important role and growing its roots in various fields of chemistry day by day. Particularly, in organic synthesis, DFT studies are widely used for mechanistic investigation and treated as an important tool for novel synthesis route detection. In the first chapter of this thesis, we are highlighting some appreciable efforts made in recent years towards the synthesis of highly important novel heterocyclic moieties by using palladium catalyzed cascade reactions including carbene transfer, isocyanide insertion, C-H activation, and cyclization as the vital steps. Also, mechanistic investigation via various experimental and computational studies, further transformation and applications, etc. are covered in these reports. In the second chapter, we have described a divergent and selective synthesis of (E)-3-alkylidene oxindole, which is a highly valuable framework due to its presence in the biologically important molecules, via palladium-catalyzed multicomponent reaction of 3-diazo oxindole, isocyanide, and aniline has been developed. Further, the feasibility of the reaction was demonstrated by employing differently substituted 3-diazo oxindoles, isocyanides, and anilines as starting material and obtaining the corresponding products in 31-83% isolated yields. Besides, a plausible mechanism has been presented and further investigated using DFT calculations which suggest the formation of the Pd-carbene complex and ketenimine intermediate as the key step during the catalytic cycle. In the third chapter of this thesis, we have reported a Pd-catalyzed multicomponent cascade reaction of 3-diazo oxindole and isocyanides to synthesize N-fused polycyclic indoles consisting of in-situ generated amide-assisted regioselective [3+1+1] annulation reaction provided yields up to 76% yield. Further, a good range of substrate libraries was also synthesized to check the feasibility of the protocol. The reaction includes carbene insertion methodology for amide formation which subsequently assists the reaction for further double isocyanide insertion. Additionally, a mechanism is proposed and investigated using the DFT study that strongly favors the role of amide in assisting the annulation reaction, which was further confirmed using control experiments. In the fourth chapter, we have synthesized (Z)-N-(tert-butyl)-2-oxo-3-(2-phenylhydrazono) indoline-1-carboxamide derivatives by using palladium-catalyzed isocyanide insertion methodology towards less reactive secondary N-H bond present in isatin phenyl hydrazone where phenyl hydrazone group act as a strong donating group enhancing the electron density at nitrogen atom to increase its nucleophilicity. These N-Carboxamide scaffolds can be used as valuable precursors for the synthesis of various biologically active moieties. A broad range of substrates have been synthesized in moderate to good yields by using different electron-withdrawing, electron-donating, and halogen substituents at isatin as well as hydrazone ring. Also, different isocyanides were incorporated to check the feasibility of the reaction. In the fifth chapter, we have developed a Pd-catalyzed one-pot cascade consisting of C-C/C-O/N-N bond formation to access clinically important fused 1,2,3-triazole using N-aryl-α-(tosyl hydrazone)acetamides with isocyanide. Besides, various substitutions on the N-aryl part of acetamides along with different isocyanides show good compatibility in this protocol. Next, two plausible mechanistic routes were proposed, however, one of the routes was more favorable and involved the formation of the benzoxazine ring first followed by the realization of a triazole ring. Additionally, the more favorable mechanistic route was investigated using DFT studies which suggests Pd(II)-isocyanide complex and α-diazoimino intermediate formation were key steps in the catalytic cycle.