During the past decades, synthetic organic chemistry discovered that directing group assisted C–H activation is a key tool for the expedient and siteselective construction of C–C bonds. Among the v...

Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds.

The conservation of our element resources is a fundamental challenge of mankind. The development of alcohol refunctionalization reactions is a possible fossil carbon conservation strategy since alcohols can be obtained from indigestible and abundantly available biomass. The conservation of our rare noble metals, frequently used in key technologies such as catalysis, might be feasible by replacing them with highly abundant metals. The alkylation of amines by alcohols and related C–C coupling reactions are early examples of alcohol refunctionalization reactions. These reactions follow mostly the borrowing hydrogen or hydrogen autotransfer catalysis concept, and many 3d-metal catalysts have been disclosed in recent years. In this review, we summarize the progress made in developing Cu, Ni, Co, Fe, and Mn catalysts for C–N and C–C bond formation reactions with alcohols and amines using the borrowing hydrogen or hydrogen autotransfer concept. We expect that the findings in this field will inspire others to dev...

3d-Metal Catalyzed N- and C-Alkylation Reactions via Borrowing Hydrogen or Hydrogen Autotransfer

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C–H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

Modern advances in heterocyclic chemistry in drug discovery

The different types of acceptorless alcohol dehydrogenation (AAD) reactions are discussed, followed by the catalysts and mechanisms involved. Special emphasis is put on the common appearance in AAD of pincer ligands, of noninnocent ligands, and of outer sphere mechanisms. Early work emphasized precious metals, mainly Ru and Ir, but interest in nonprecious metal AAD catalysis is growing. Alcohol–amine combinations are discussed to the extent that net oxidation occurs by loss of H2. These reactions are of potential synthetic interest because they can lead to N heterocycles such as pyrroles and pyridines. AAD also has green chemistry credentials in that an oxidation occurs without the need for an oxidizing agent and hence without the waste formation that would result from its use.

Homogeneous Transition Metal Catalysis of Acceptorless Dehydrogenative Alcohol Oxidation: Applications in Hydrogen Storage and to Heterocycle Synthesis

This study represents the first example an environmentally benign, sustainable, and practical synthesis of substituted quinolines and pyrimidines using combinations of 2-aminobenzyl alcohols and alcohols as well as benzamidine and two different alcohols, respectively. These reactions proceed with high atom efficiency via a sequence of dehydrogenation and condensation steps that give rise to selective C–C and C–N bond formations, thereby releasing 2 equiv of hydrogen and water. A hydride Mn(I) PNP pincer complex recently developed in our laboratory catalyzes this process in a very efficient way. A total of 15 different quinolines and 14 different pyrimidines were synthesized in isolated yields of up to 91 and 90%, respectively.

Sustainable Synthesis of Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer Complexes.

The ability of hydrogen-transfer transition-metal catalysts, which enable increasingly rapid access to important structural scaffolds from simple starting materials, has led to a plethora of research efforts on the construction of heterocyclic scaffolds. Transition-metal-catalyzed hydrogen-transfer annulations are environmentally benign and highly atom-economical as they release of water and hydrogen as by-product and utilize renewable feedstock alcohols as starting materials. Recent advances in this field with respect to the annulations of alcohols with various nucleophilic partners, thus leading to the formation of heterocyclic scaffolds, are highlighted herein.

Transition-metal-catalyzed hydrogen-transfer annulations: access to heterocyclic scaffolds.

Iron-catalyzed dehydrogenation reactions and their applications in sustainable energy and catalysis

A transition-metal-catalyzed borrowing hydrogen/hydrogen auto-transfer strategy allows the utilization of feedstock alcohols as an alkylating partner, which avoids the formation of stoichiometric salt waste and enables a direct and benign approach for the construction of C-N and C-C bonds. In this study, a nickel-catalyzed α-alkylation of unactivated amides and ester (tert-butyl acetate) is carried out by using primary alcohols under mild conditions. This C-C bond-forming reaction is catalyzed by a new, molecularly defined nickel(II) NNN-pincer complex (0.1-1 mol %) and proceeds through hydrogen auto-transfer, thereby releasing water as the sole byproduct. In addition, N-alkylation of cyclic amides under Ni-catalytic conditions is demonstrated.

Avanashiappan Nandakumar

Papers

Transition-metal-catalyzed hydrogen-transfer annulations: access to heterocyclic scaffolds.

Iron-catalyzed dehydrogenation reactions and their applications in sustainable energy and catalysis

Ni‐Catalyzed α‐Alkylation of Unactivated Amides and Esters with Alcohols by Hydrogen Auto‐Transfer Strategy

Manganese-Catalyzed Direct Conversion of Ester to Amide with Liberation of H2

Pd(II)-Catalyzed gamma-C(sp3)–H alkynylation of amides: selective functionalization of R chains of amides R1C(O)NHR