Akash Gogate

Reported herein is a method for syn-selective 1,3-bis-trifluoromethylation of (hetero)cycloalkylidenemalononitriles. The malononitrile-containing intermediate can be readily converted into carboxylates (and derivatives thereof) by oxidative decyanation. The products of this two-step sequence are 1,3-bis-trifluoromethylated physicochemically-altered analogs of common (hetero)cyclohexane carboxylate. This study includes optimization of the bis-trifluoromethylation reaction, scope studies, synthesis of various new bis-trifluoromethylated (hetero)cycloalkane carboxylates, representative transformations relevant to pharmaceutical synthesis, mechanistic studies, and some computational analyses of the newly accessible scaffolds.

We report that the direct mixing of α-arylmalononitriles and haloheterocycles triggers in situ co-activation (ISCA) to generate a reactive carbanion and pyridinium ion pair for nucleophilic aromatic substitution (S _N Ar).

Described herein is a strategy for preparing 3° and 4° carbon-containing 3-alkylquinolones: molecules previously inaccessible and/or underexplored in synthetic- and medicinal chemistry. It was found that ~equimolar amounts of 4-(arylsulfonyl) quinolones and 2° allyl alcohols can react via nucleophilic aromatic substitution and allyl quinolyl ether Claisen rearrangement to yield the targeted quinolones. Key findings are fundamental and applied, including optimization of conditions and substrate for mild and high yielding [3,3] rearrangement, transition state analysis and enantiospecificity of the [3,3] step, and scope and limitations for the sequence. The work culminates in the synthesis of unique and previously unexplored antiparasitic endochin-like quinolones (ELQs) bearing 4°-carbons.