Transition metal catalyzed C(sp2)-C and C(sp2)-N bond forming reactions

The thesis describes the development of transition metal catalysed C-H functionalization of C(sp2)-H bonds of arenes and their application in organic synthesis. In the first chapter, recent advancements in the transition metal catalysed sp2 C-H functionalization of aromatic compounds by the installation of directing groups like amide, carbamate and ketimines are described concisely. In the second chapter, a general protocol for iridium catalyzed direct C-H amidation of cyclic N-sulfonyl ketimines using sulfonyl, acyl and aryl azides as nitrogen source is discussed. Benefiting from the robustness and high efficiency of this transformation, a variety of functional groups were well tolerated during this mild process. With the use of sultams as directing group, monoamidation products can be produced efficiently in excellent ortho-selective manner, providing a simple method for the synthesis of biologically relevant aminosultam compounds. In the third chapter, we reported a synthetic protocol for the trifluoroethylation of N-alkyl benzamides with mesityl(2,2,2-trifluoroeth-yl)iodonium salt. The very mild reaction condition employed allows a compatibility of a vast variety of synthetic useful functional groups. Further, we isolated the dimeric palladacycle complex with arene amide and carried out some mechanistic studies. In chapter four, we described a new synthetic route to meta-arylated phenol and its derivatives. We achieved this transformation by employing cheap copper catalyst under mild conditions using phenol carbamates and diaryliodonium salts as coupling partners. The reported method is compatible with a broad range of phenols as well as diaryliodonium salts. The meta-arylated carbamate products obtained from this reaction can be further functionalized to get multisubstituted biaryl systems.​Doctor of Philosophy (SPMS

Copper-catalyzed meta-selective arylation of phenol derivatives: an easy access to m-aryl phenols

Achieving selective meta-functionalization of phenols is a significant challenge. Accessing such compounds generally needs elevated temperature or incorporation of complex templates. Here, we report a general approach to achieve meta-arylated phenols with a simple and common directing group. This coppercatalyzed protocol proceeds with complete meta-selectivity and tolerates a variety of functional groups in both coupling partners. Computational studies have revealed that the reaction proceeded via a Heck-like pathway.Ministry of Education (MOE)Nanyang Technological UniversityWe gratefully acknowledge the financial support from Northwestern Polytechnical University (NPU), China, Tier 1 grant M4012045.110 (RG12/18-S) from the Ministry of Education of Singapore and Distinguished University Professor grant, Nanyang Technological University, Singapore

Macrolactam synthesis via ring-closing alkene-alkene cross-coupling reactions

Reported herein is a practical method for macrolactam synthesis via a Rh(III)-catalyzed ring closing alkene-alkene cross-coupling reaction. The reaction proceeded via a Rh-catalyzed alkenyl sp2 C-H activation process, which allows access to macrocyclic molecules of different ring sizes. Macrolactams containing a conjugated diene framework could be easily prepared in high chemoselectivities and Z,E stereoselectivities.Ministry of Education (MOE)Nanyang Technological UniversityThe authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21702108), the Natural Science Foundation of Jiangsu Province, China (No. BK20160977), the Six Talent Peaks Project in Jiangsu Province (No. YY-033), Tier 1 grant M4012045.110 (No. RG12/18-S) from the Ministry of Education of Singapore and Distinguished University Professor grant, Nanyang Technological University, Singapore

Iridium(III)-catalyzed selective and mild C-H amidation of cyclic N-sulfonyl ketimines with organic azides

A general protocol for iridium catalyzed direct C−H amidation of cyclic N‐sulfonyl ketimines using sulfonyl, acyl and aryl azides as nitrogen source is reported herein. The reaction takes place at room temperature with acyl and aryl azides, while an elevated temperature needed with sulfonyl azides to furnish aminated sultams in excellent yields with complete chemo and regioselectivity, thus providing a robust and environmentally benign process to the synthesis of aminosultams.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)Accepted versio

Palladium-Catalyzed Direct C–H Trifluoroethylation of Aromatic Amides

A simple and direct C–H trifluoroethylation of aromatic amides has been developed. The protocol is applicable to a variety of aromatic amides, including ones derived from amino acids. The developed method can be used for further modifications of peptides. Preliminary mechanistic studies have been done by isolating the reaction intermediate

Palladium-Catalyzed Direct C–H Trifluoroethylation of Aromatic Amides

A simple and direct C–H trifluoroethylation of aromatic amides has been developed. The protocol is applicable to a variety of aromatic amides, including ones derived from amino acids. The developed method can be used for further modifications of peptides. Preliminary mechanistic studies have been done by isolating the reaction intermediate

Recent advances in alkenyl sp² C-H and C-F bond functionalizations: scope, mechanism, and applications

Alkenes and their derivatives are featured widely in a variety of natural products, pharmaceuticals, and advanced materials. Significant efforts have been made toward the development of new and practical methods to access this important class of compounds by selectively activating the alkenyl C(sp2)-H bonds in recent years. In this comprehensive review, we describe the state-of-the-art strategies for the direct functionalization of alkenyl sp2 C-H and C-F bonds until June 2022. Moreover, metal-free, photoredox, and electrochemical strategies are also covered. For clarity, this review has been divided into two parts; the first part focuses on currently available alkenyl sp2 C-H functionalization methods using different alkene derivatives as the starting materials, and the second part describes the alkenyl sp2 C-F bond functionalization using easily accessible gem-difluoroalkenes as the starting material. This review includes the scope, limitations, mechanistic studies, stereoselective control (using directing groups as well as metal-migration strategies), and their applications to complex molecule synthesis where appropriate. Overall, this comprehensive review aims to document the considerable advancements, current status, and emerging work by critically summarizing the contributions of researchers working in this fascinating area and is expected to stimulate novel, innovative, and broadly applicable strategies for alkenyl sp2 C-H and C-F bond functionalizations in the coming years.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Nanyang Technological UniversityWe gratefully acknowledge the financial support from Distinguished University Professor grant (Nanyang Technological University), AcRF Tier1 grants from the Ministry of Education of Singapore (RG11/20 and RT14/20), and the Agency for Science, Technology and Research (A*STAR) under its MTC Individual Research Grants( M21K2c0114). We also gratefully acknowledge the financial support from the National Natural Science Foundation of China (no.22101095)

Intramolecular alkene-alkene coupling via Rh(III)-catalyzed alkenyl sp² C-H functionalization: divergent pathways to indene or α-naphthol derivatives

Highly selective synthesis of either indene or 1-naphthol derivatives through intramolecular alkene-alkene cross-coupling is reported. The reaction works with different alkene pairs that couple to give the corresponding products in good to satisfactory yields. The indene products of our reaction also allow further derivatization. The reaction pathway is dependent on alkene functionalities.Ministry of Education (MOE)Nanyang Technological UniversityThe authors gratefully acknowledge the financial support of Tier 1 grant M4012045.110 (RG12/18-S) from the Ministry of Education of Singapore and Distinguished University Professor grant, Nanyang Technological University, Singapore. H.H. acknowledges a Presidential Fellowship and a University Development Fund (UDF01001996) from the Chinese University of Hong Kong, Shenzhen

Incorporating a guanidine-modified cytosine base into triplex-forming PNAs for the recognition of a C-G pyrimidine–purine inversion site of an RNA duplex

RNA duplex regions are often involved in tertiary interactions and protein binding and thus there is great potential in developing ligands that sequence-specifically bind to RNA duplexes. We have developed a convenient synthesis method for a modified peptide nucleic acid (PNA) monomer with a guanidine-modified 5-methyl cytosine base. We demonstrated by gel electrophoresis, fluorescence and thermal melting experiments that short PNAs incorporating the modified residue show high binding affinity and sequence specificity in the recognition of an RNA duplex containing an internal inverted Watson-Crick C-G base pair. Remarkably, the relatively short PNAs show no appreciable binding to DNA duplexes or single-stranded RNAs. The attached guanidine group stabilizes the base triple through hydrogen bonding with the G base in a C-G pair. Selective binding towards an RNA duplex over a single-stranded RNA can be rationalized by the fact that alkylation of the amine of a 5-methyl C base blocks the Watson–Crick edge. PNAs incorporating multiple guanidine-modified cytosine residues are able to enter HeLa cells without any transfection agent.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)Published versio

Targeting RNA Editing of Antizyme Inhibitor 1: a Potential Oligonucleotide-Based Antisense Therapy for Cancer.

10.1016/j.ymthe.2021.05.008Mol The