Nickel‐Catalyzed Synthesis of Pyrimidines via Dehydrogenative Functionalization of Alcohols

Abstract

Herein we report a comparative study of nickel‐catalyzed syntheses of pyrimidines via dehydrogenative multi‐component coupling of alcohols and amidines using two different classes of nickel catalysts (1 a/1 b and 2 a/2 b) differing with respect to their mode of action during catalysis. The catalysts 1 a and 1 b are two tetracoordinate Ni(II)‐complexes containing two apparently redox‐inactive tetraaza macrocyclic ligands while the catalysts 2 a and 2 b are square planar Ni(II)‐complexes featuring redox‐active diiminosemiquinonato type scaffolds. Catalyst 1 a and 1 b dehydrogenate alcohols via a two‐electron hydride transfer pathway involving energetically demanding nickel‐centered redox events while in the presence of 2 a and 2 b dehydrogenation of alcohols proceeds via a one‐electron hydrogen atom transfer (HAT) pathway via synergistic participation of metal and ligand centered redox processes avoiding high energy nickel centered redox events. Detailed substrate screening and control experiments were performed to unveil the reaction sequence and understand the advantages/disadvantages of these two pathways.

Recent Progress in the Synthesis of Heterocycles through Base Metal‐Catalyzed Acceptorless Dehydrogenative and Borrowing Hydrogen Approach

“…6 mol% of the catalyst in conjugation with 12 mol% of the TMAO and CPME as a solvent at 160°C is effective to couple the two substrates at oxygen atmosphere to give Pyrrolo[1,2-α] quinoxalines ( 91 aniline (92) and in doing so, present protocol utilizes 3 equiv. of alcohol.…”

“…of alcohol. The condensation between corresponding aniline (92) and aldehyde (2 a) results in imine ( 93) which upon nucleophilic attack by pyrrole (C-2 position) gives the cyclized product (94). The reaction utilizes O 2 atmosphere whose primary role was found to oxidize the intermediate to the desired product 91 (Figure 23).…”

“…The same group [92] also accomplished the synthesis of pyrimidines by using two different Ni‐based tetradentate catalysts ( Ni‐3 and Ni‐2 ). In this multicomponent synthesis they employed amidines ( 98 ), primary alcohols ( 1 a ) and secondary alcohols ( 1 ) as a coupling partner (Scheme 44 and 45).…”

Catalytic Synthesis of Luminescent Pyrimidines via Acceptor-less Dehydrogenative Coupling

“…They can thus be used to prepare a variety of highly substituted pyrimidines with only hydrogen gas and water as byproducts. [23][24][25][26][27][28][29] We herein report the application of this synthetic methodology for the preparation of a series of emissive, push-pull pyrimidines (Figure 1). In addition to the catalytic preparation and full characterization of a series of novel pyrimidines, we furthermore describe their optical properties, along with computational modelling and solid-state structures of selected representatives, demonstrating the utility of ADC pathways for the preparation of asymmetric D-A-D' and D-A-A pyrimidine p-systems.…”

Synthesis of 1,2,4,5‐tetrasubstituted imidazoles and 2,4,5,6‐tetrasubstituted pyrimidines: three‐component, the one‐pot reaction of arylamidines, malononitrile, and arylglyoxals or aryl aldehydes

“…[17] Besides, many imidazole and pyrimidine-based agents have been extensively studied as drug candidates and some of them are used clinically such as nilotinib, [18] metronidazole, [19] voriconazole, [20] eprosartan, and losartan. [21] Due to the wide range of applications of imidazole and pyrimidine cores, a variety of methods have been reported to the synthesis of them including various multi-component methods, [22][23][24][25][26] cyclization reaction, [22,[27][28][29] metal-catalyzed, [30][31][32][33] multistep approaches, [34,35] Diels-Alder reaction, [36] and various other methods. [37,38] However, the above-mentioned methods for synthesis of imidazole and pyrimidine derivatives suffer from one or more disadvantages, for example difficult reaction conditions, low yields, complex work-up and purification, multiple synthetic steps, and usage of expensive catalysts and reagents.…”