Alexander J. Grenning

We report the discovery of a fundamentally unique nucleophilic aromatic substitution (S _N Ar) reaction. It was found that a-arylmalononitriles and haloheterocycles undergo a mild, additive- and base-free C–C bond forming reaction via in situ co-activation (ISCA) to a carbanion and a pyridinium, which rapidly react through a neutral and low-barrier Meisenheimer complex to ultimately yield the S _N Ar product. This study includes a background analysis of ISCA-S _N Ar and a-aryl-a-heteroarylmalononitriles, discovery and optimization of efficient coupling conditions, a study of various physical organic parameters governing the transformation, scope of the reaction, and select malononitrile functional group interconversions. These detailed studies lay the groundwork for developing this, and related reactions, for use in high-value organic synthesis.

Described is a synthesis of quinolones with 3°- or 4°-3-alkylquinolones via a nucleophilic aromatic substitution and heteroaromatic Claisen rearrangement sequence. This particular substitution pattern is nearly absent in the literature as the motif is challenging to prepare by the conventional condensation-based approach. We report the optimization of a nucleophilic aromatic substitution reaction between 2°-allyl alcohols and 4-sulfonylquinolines and a 3°- or 4°-generating Claisen rearrangement. Key studies include improving and understanding the energetics and stereoselectivity of [3,3], the scope and limitations for the two-step sequence, and a proof-of-concept synthesis of “quaternary endochin-like quinolones” (4°-ELQs), a unique direction for the development of novel antiinfective agents.

Cyclobutanes, azetidines, and oxetanes have become more prevalent as structural features on pharmaceutical leads and drugs due to their unique physicochemical and biological properties. Substitution of (hetero)cyclobutanes in a stereocontrolled fashion with pharmaceutically relevant functionality is still a modern challenge. Described herein is a method for constructing quaternary (hetero)cyclobutanes and linking them to other (hetero)cycles via an allylic alkylation/exocyclic strain-release Cope rearrangement. The one- or two-step sequence can yield uniquely linked heterocycles bearing an alkylidenemalononitrile functional group, which can be readily transformed into amides diastereoselectively. This study includes optimization and scope studies of the allylic alkylation/[3,3] sequence, enantioselective optimization using asymmetric allylic alkylation, and functional group interconversion studies to yield densely substituted drug-like scaffolds.

Reported herein is a method for the 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 analogues of common (hetero)cyclohexane carboxylates. 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.

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).

Aliphatic 4-membered (hetero)cycles, such as cyclobutanes and azetidines, are becoming more prevalent as structural features on pharmaceutical leads and drugs. In particular, their rigidity and favorable physicochemical properties allow them to serve as bioisosteric replacements for common drug motifs. Substitution of (hetero)cyclobutanes in stereocontrolled fashion with pharmaceutically relevant functionality is still a modern challenge. Described herein is a method for constructing quaternary (hetero)cyclobutanes and linking them to other (hetero)cycles via an allylic alkylation/exocyclic strain-release Cope rearrangement. The one- or two- step sequence can yield uniquely linked heterocycles bearing an alkylidenemalononitrile functional group, which can be readily transformed into amides diastereoselectively. This study includes optimization and scope studies of the allyic alkylation/[3,3] sequence, enantioselective optimization using asymmetric allylic alkylation, and functional group interconversion studies to yield densely substituted drug-like scaffolds.

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.

The development of a three-component cine,ipso-disubstitution of nitrocoumarins is reported. The reaction leverages the electrophilicity of nitrocoumarins, the nucleophilicity of nitronates, and the leaving group ability of nitrite (NO₂^-) to yield complex polyfunctionalized biaryls that often display stable axial chirality.