Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

Recent advances in the selective semi-hydrogenation of alkyne to (E)-olefins.

Considering the potential importance and upsurge in demand, the selective semi-hydrogenation of alkynes to (E)-olefins has attracted significant interest. This article highlights the recent advances in newer technologies and important methodologies directed to (E)-olefins from alkynes developed from 2015 to 2023. Notable features summarised include the catalyst or ligand design and control of product selectivity based on precious and nonprecious metal catalysts for semi-hydrogenation to (E)-olefins. Mechanistic studies for various catalytic transformations, including synthetic application to bioactive compounds, are summarised.

Recent advances on non-precious metal-catalyzed C-H functionalization of N-heteroarenes.

N-Heteroarenes are widely used for numerous medicinal applications, lifesaving drugs and show utmost importance as intermediates in chemical synthesis. This feature article highlights the recent advances, from 2015 to August 2021, on sp2 and sp3 C-H bond functionalization reactions of various N-heteroarenes catalyzed by non-precious transition metals (Mn, Co, Fe, Ni, etc.). The salient features of the report are: (i) the development of newer catalysis for Csp2-H activation of N-heteroarenes and categorized into alkylation, alkenylation, borylation, cyanation, and annulation reactions, (ii) recent advances on Csp3-H bond functionalization of N-heteroarenes considering newer approaches for alkylation as well as alkenylation processes, and (iii) synthetic applications and practical utility of the catalytic protocols utilized for late-stage drug development; (iv) scope for the development of newer catalytic protocols along with mechanistic studies and detail mechanistic findings of various important processes.

Recent advances in the synthesis of N-heteroarenes via catalytic dehydrogenation of N-heterocycles.

Bio-active molecules having N-heteroarene core are widely used for numerous medicinal applications and as lifesaving drugs. In this direction, dehydrogenation of partially saturated aromatic N-heterocycles shows utmost importance for the synthesis of heterocycles. This feature article highlights the recent advances, from 2009 to April 2021, on the dehydrogenation of N-heteroaromatics. Notable features considering the development of newer catalysis for dehydrogenations are: (i) approaches based on precious metal catalysis, (ii) newer strategies and catalyst development technology using non-precious metal-catalysts for N-heterocycles having one or more heteroatoms, (iii) Synthesis of five or six-membered N-heterocycles using photocatalysis, electrocatalytic, and organo-catalytic approaches using different homogeneous and heterogeneous conditions' (iv) metal free (base and acid-promoted) dehydrogenation along with I2, N-hydroxyphthalimide (NHPI) and bio catalyzed miscellaneous examples have also been discussed, (v) mechanistic studies for various dehydrogenation reactions and (vi) synthetic applications of various bio-active molecules including post-drug derivatization are discussed.

Recent advances in transition metal-catalyzed (1,n) annulation using (de)-hydrogenative coupling with alcohols.

(1,n) annulation reactions using (de)-hydrogenative coupling with alcohols or diols represent a straightforward technique for the synthesis of cyclic moieties. Utilization of such renewable resources for chemical transformations in a one-pot manner is the main focus, which avoids generation of stoichiometric waste. Application of such (1,n) annulation approaches drives the catalysis research in a more sustainable way and generates dihydrogen and water as by-products. This feature article highlights the recent (from 2015 to March 2021) progress in the synthesis of stereo-selective cycloalkanes and cycloalkenes, saturated and unsaturated N-heterocycles (cyclic amine, imide, lactam, tetrahydro ß-carboline, quinazoline, quinazolinone, 1,3,5-triazines etc.) and other N-heterocycles with the formation of multiple bonds in a one pot operation. Mechanistic studies, new catalytic approaches, and synthetic applications including drug synthesis and post-drug derivatization, scope, and limitations are discussed.

Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen.

Herein, an efficient and selective nickel-catalyzed dehydrogenation of five- and six-membered N-heterocycles is presented. The transformation occurs in the presence of alkyl, alkoxy, chloro, free hydroxyl and primary amine, internal and terminal olefin, trifluoromethyl, and ester functional groups. Synthesis of an important ligand and the antimalarial drug quinine is demonstrated. Mechanistic studies revealed that the cyclic imine serves as the key intermediate for this stepwise transformation.

Nickel-catalyzed hydrogen-borrowing strategy: chemo-selective alkylation of nitriles with alcohols.

The first nickel-catalyzed hydrogen-borrowing alkylation of a series of aryl acetonitriles with a variety of aryl, heteroaryl, allylic and alkyl alcohols releasing water as the by-product (>33 examples, up to 90% yield) is reported.

Iron-catalysed alkylation of 2-methyl and 4-methyl azaarenes with alcohols via C-H bond activation.

The first Fe-catalysed alkylation of 2-methyl and 4-methyl-azaarenes with a series of alkyl and hetero-aryl alcohols is reported (>39 examples and up to 95% yield). Multi-functionalisation of pyrazines and synthesis of anti-malarial drug (±) Angustureine significantly broaden the scope of this methodology. Preliminary mechanistic investigation, deuterium labeling and kinetic experiments including trapping of the enamine intermediate 1a' are of special importance.

Nickel-Catalyzed Double Dehydrogenative Coupling of Secondary Alcohols and ß-Amino Alcohols To Access Substituted Pyrroles.

Herein, we demonstrate the first nickel-catalyzed double dehydrogenative condensation of secondary alcohols and ß-amino alcohols in one pot to the pyrrole derivatives. A series of 2,5- and 2,3,5-substituted pyrroles were obtained in ≤83% yield, releasing water and hydrogen gas as byproducts. Initial mechanistic studies, including defined Ni catalyst, deuterium labeling experiments, quantitative determination of hydrogen gas evaluation, and detection of water generation in the reaction mixture, were performed.

Iron-Catalyzed Ligand Free α-Alkylation of Methylene Ketones and ß-Alkylation of Secondary Alcohols Using Primary Alcohols.

Herein, we demonstrate a general and broadly applicable catalytic cross coupling of methylene ketones and secondary alcohols with a series of primary alcohols to disubstituted branched ketones. A simple and nonprecious Fe2(CO)9 catalyst enables one-pot oxidations of both primary and secondary alcohols to a range of branched gem-bis(alkyl) ketones. A number of bond activations and formations selectively occurred in one pot to provide the ketone products. Coupling reactions can be performed in gram scale and successfully applied in the synthesis of an Alzehimer's drug. Alkylation of a steroid hormone can be achieved. A single catalyst enables sequential one-pot double alkylation to bis-hetero aryl ketones using two different alcohols. Preliminary mechanistic studies using an IR probe, deuterium labeling, and kinetic experiments established the participation of a borrowing-hydrogen process using Fe catalyst, and the reaction produces H2 and H2O as byproducts.

Nickel-Catalyzed Synthesis of N-Substituted Pyrroles Using Diols with Aryl- and Alkylamines.

Herein, nickel-catalyzed sustainable strategy for the synthesis of N-substituted pyrroles using butene-1,4-diols and butyne-1,4-diols with a series of aryl-, alkyl-, and heteroarylamines is reported. The catalytic protocol is tolerant of free alcohol, halide, alkyl, alkoxy, oxygen heterocycles, activated benzyl, and the pyridine moiety and resulted in up to 90% yield. Initial mechanistic studies involving defined nickel catalyst, determination of rate, and order of reaction including deuterium-labeling experiments were performed for pyrrole synthesis.

Nickel-catalysed alkylation of C(sp3)-H bonds with alcohols: direct access to functionalised N-heteroaromatics.

The first base-metal catalysed coupling of primary alcohols with methyl-N-heteroaromatics is reported. The use of an earth abundant and nonprecious NiBr2/L1 system enables access to a series of C(sp3)-alkylated N-heteroaromatics. Mechanistic studies have established the participation of a hydrogen-borrowing strategy for α-alkylation.