Isai Ramakrishna

Copper-Catalyzed 8-Amido Chelation-Induced Remote C-H Amination of Quinolines.

A copper-catalyzed 8-amide chelation-induced remote C-H amination of quinolines has been developed. This direct amination with readily available azodicarboxylates proceeded with perfect C5-regioselectivity offering amino-substituted 8-aminoquinolines, important bioactive molecular scaffolds, in very high yields (up to 96%). A single-electron transfer (SET)-mediated mechanism with kH /kD =1.1 was proposed after trapping of the radical intermediate.

Nitrosocarbonyl–Henry and Denitration Cascade: Synthesis of α-Ketoamides and α-Keto Oximes

An unprecedented Henry reaction of in situ generated nitrosocarbonyl intermediates and concomitant denitration cascade has been developed. The reaction is catalyzed by organic base at room temperature offering α-ketoamides, a demanding scaffold for drug discovery, in high yields. An alteration of substitution pattern also produced α-keto oximes, a high-value synthon. The protocol features operational simplicity and broad substrate scope.

Advanced Nitroso Aldol Reaction: Metal-Free Cross-Coupling of Anilines with Silyl Enol Ethers en Route to α-Amino Ketones

A practical and step-economical nitroso aldol reaction has been developed based on metal-free direct cross-coupling of ready-stock anilines with silyl enol ethers at room temperature affording α-amino ketones in high yields (up to 82%). The protocol features a one-pot cascade of nitroso compound generation, selective C-N bond formation, and N-O bond cleavage using solely inexpensive and user-friendly Oxone and displays remarkable functional group tolerance. The method was further extended to prepare densely functionalized indoles that are otherwise difficult to synthesize.

Cross-Aldol Reaction of Activated Carbonyls with Nitrosocarbonyl Intermediates: Stereoselective Synthesis toward α-Hydroxy-β-amino Esters and Amides

A practical and flexible strategy toward α-hydroxy-β-amino esters and amides, which are important biological motifs, based on an organocatalytic cross-aldol reaction of in situ-generated nitrosocarbonyl intermediates followed by hydrogenation is presented. The protocol features operational simplicity, high yields, a wide substrate scope, and high regio- and diastereoselectivity profiles. The utility of this method was showcased through the synthesis of bestatin analogues and indole formation.

Synthesis of Chiral 1,2-Oxazinanes and Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes

The first catalytic enantioselective nitroso aldol reaction of distal dialdehydes is reported. The reaction is catalyzed by simple l-proline at room temperature and subsequent reduction delivered biologically potent and synthetically versatile N-O bond containing five- and six-membered heterocycles, 1,2-oxazinanes, and isoxazolidines in high yields and excellent enantioselectivities (up to >99% ee). The method was further exploited to prepare chiral 3-hydroxypiperidines and -pyrrolidines that are otherwise difficult to access.

Divergent Reactivity of gem-Difluoro-enolates toward Nitrogen Electrophiles: Unorthodox Nitroso Aldol Reaction for Rapid Synthesis of α-Ketoamides

An amination reaction of in situ generated gem-difluoro-enolates has been explored with electrophilic nitrogen sources. While their exposure to azodicarboxylates smoothly produced fluorinated α-amino ketones, reaction with nitrosoarenes (nitroso aldol reaction) furnished α-ketoamides in very high yields (up to 94%). The reaction is very fast (typically completed within 5 min) and scalable and tolerates various sensitive functional groups. Synthetic utility of this process was highlighted through the production of diverse nitrogen heterocycles and an orexin receptor antagonist.