Suman De Sarkar

NHC Catalyzed Oxidations of Aldehydes to Esters: Chemoselective Acylation of Alcohols in Presence of Amines

Not just one but two carbenes of the same structure act cooperatively in oxidative acylations of alcohols with aldehydes by using a readily available cheap organic oxidant. Alcohols are selectively acylated in the presence of amines by cooperative carbene catalysis. Quantum chemical calculations support the suggested mechanism.

Catalysis with N-Heterocyclic Carbenes under Oxidative Conditions

This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed.

NHC‐Catalyzed Michael Addition to α,β‐Unsaturated Aldehydes by Redox Activation

The formation of C C bonds undoubtedly belongs to the most important transformations in organic chemistry, and Michael reactions are important examples thereof. Two strategies have mainly been followed for the activation of Michael acceptors to conduct conjugate addition reactions: a) activation by using Lewis or Brønsted acids and b) activation by iminium ion generation. It has been shown independently by Bode and Glorius that a,bunsaturated aldehydes 1 react with N-heterocyclic carbenes (NHCs) 2 to umpoled intermediates of type A, which can then react as homoenolates at the b position with various electrophiles to give product B (Scheme 1).

Oxidative Amidation and Azidation of Aldehydes by NHC Catalysis

N-heterocyclic carbene catalyzed oxidative amidations of various aldehydes to the corresponding hexafluoroisopropylesters by using the readily available organic oxidant A are described. The hexafluoroisopropylesters prepared in situ are shown to be highly useful active esters for amide bond formation. In addition, oxidative azidation of aldehydes is presented. These mild organocatalytic processes do not use any transition metal.

Biomimetic carbene-catalyzed oxidations of aldehydes using TEMPO.

Pyruvate ferredoxin oxidoreductase (PFOR), which catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA and CO2, belongs to the family of 2-keto acid oxidoreductases. This CoA-dependent enzyme uses thiamine pyrophosphate (TPP) as an additional cofactor. The anaerobic decarboxylation is a reversible process, and the two electrons obtained during one turnover are transferred to ferredoxine via [Fe4S4] clusters. [1] The initial steps of the oxidative decarboxylation resemble those of the aerobic TPP-dependent 2-oxoacid dehydrogenases. Pyruvate reacts with A to form B after proton transfer, and B subsequently undergoes CO2 elimination to generate C (Scheme 1). Electron transfer to a [Fe4S4] cluster leads to radical cation D. Although intensive studies (X-ray and EPR) have been conducted on D, the structure of the radical cation is still under debate. Renewed electron transfer in the presence of CoASH eventually leads to CoASAc. In aerobic organisms lacking the [Fe4S4] clusters, C reacts with the dithiolane ring of a lipoyl group in a formal twoelectron transfer to an acetyl lipoamide thioester intermediate, which is further transformed in the presence of CoASH using another enzyme to CoASAc. The liberated dithiol is eventually reoxidized to the cyclic disulfide by a FADdependent dihydrolipoyl dehydrogenase. It is known in synthesis that reaction of aldehydes with thiazolium carbenes leads to intermediates of type C which react as “umpoled” nucleophiles with aromatic aldehydes (benzoin condensation) or with electron-poor olefins (Stetter reaction). Recently, N-heterocyclic carbene (NHC) catalyzed transformations have gained increasing attention. However, these investigations have focused on ionic processes. Guided by PFOR we planned to oxidize enamines of type C by organic single-electron transfer (SET) oxidants. The process would represent a biomimetic transition-metalfree organocatalytic oxidation of an aldehyde. As the oxidant we used 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO), which has been used successfully by our group in transition-metal-mediated reactions and in various radical processes. Hence, the oxidizing [Fe4S4] clusters in PFOR can be replaced by two oxidizing TEMPO units [Eq. (1)].

N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C–H tert-Alkylation with Removable Auxiliaries

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization.

Highly Stereoselective Synthesis of 1,2,3-Trisubstituted Indanes via Oxidative N-Heterocyclic Carbene-Catalyzed Cascades

Three stereocenters are formed in the carbene catalyzed cascade reaction of enals with various β-diketones to give the corresponding indane derivatives with excellent stereoselectivities. The products are readily transformed to the corresponding 1,2,3-trisubstituted indane derivatives, which represent privileged substructures in medicinal chemistry.

Enantioselective cyclopropanation of enals by oxidative N-heterocyclic carbene catalysis

Carbene catalysed redox activation of α,β-unsaturated aldehydes is applied for generation of α,β-unsaturated acyl azoliums which undergo cyclopropanation upon reaction with a sulfur ylide and an alcohol to give the corresponding cyclopropanecarboxylic acid esters. With chiral carbenes good to excellent diastereo and enantioselectivities are obtained.

meta - and para -Selective C–H Functionalization by C–H Activation

Transition metal-catalyzed C–H bond functionalization has recently emerged as an indispensable tool for transforming otherwise unreactive C–H bonds. In addition to various strategies for ortho-selective functionalization via chelation assistance, organometallic C–H activation has recently enabled novel functionalizations of (hetero)arenes at remote meta- or para-positions. The meta- and para-selectivity was governed either by the inherent substrate structure or by the transition metal catalyst. Herein we summarize the rapid recent progress in meta- and para-selective aromatic C–H functionalization until May 2015.

Ruthenium(II)‐Catalyzed CH Activation with Isocyanates: A Versatile Route to Phthalimides

A cationic ruthenium(II)-complex was utilized in the efficient synthesis of phthalimide derivatives by C-H activation with synthetically useful amides. The reaction proceeded through a mechanistically unique insertion of a cycloruthenated species into a C-Het multiple bond of isocyanate. The novel method also proved applicable for the synthesis of heteroaromatic unsymmetric diamides as well as a potent COX-2 enzyme inhibitor.