Vashchenko B. Synthesis of sultams and sultones by carbanion and reductive cyclizations of functionalized nitriles.

The dissertation work is devoted to the study of new approaches to the use of bifunctional nitriles (in particular, aminonitriles, cyanohydrins, and cyanoalkylsulfonyl fluorides) for the synthesis of sp3-enriched sultams and sultones, which mostly had a spirocyclic bicyclic structure. Carbanion-mediated sulfonamide (sulfonate) intramolecular cyclization (CSIC) of hydroxy- and aminonitriles, as well as reductive cyclization of cyanoalkylsulfonyl fluorides were chosen as the main synthetic approaches. A method of Et3N-catalyzed sulfonylation of aminonitriles with methyl 2-(chlorosulfonyl)acetate was developed with the formation of sulfonamides in the first step (they could be observed by 1H NMR spectroscopy). The latter ederivatives without isolation from the reaction mixture rapidly proceeded in the next step of the process, i.e. the formation of carbanions with further intramolecular condensation by the Thorpe reaction, which resulted in the one-pot formation of methyl 4-amino-1,1-dioxo-1λ6-isothiazolidine-5-carboxylates (β-enamino γ-sultam α-carboxylates). The impact of stereoelectronic factors on the total yield of sultam carboxylates was studied, e.g. the size of the substituents in the starting aminonitriles at three variation points (tetrasubstituted carbon atom and nitrogen atom) and the presence of additional electron acceptor properties. It is shown that the lowest yields of sultams are observed for C/N-phenyl-substituted aminonitriles and the most conformationally bulky cycloheptylidene substituent. Additionally, X-ray structural analysis showed that the amino group has an sp2-hybridized character, is flattened, and lies in the plane of the sultam carboxylate fragment, while one of the protons of the nitrogen atom of the enamine fragment forms a hydrogen bond with the carbonyl group of the ester group. 7 Cyanohydrins were sulfonylated with methyl 2-(chlorosulfonyl)acetate and the corresponding acetonitrile. Analogously to the case of aminonitriles, it was found that the sulfonates formed in the first step (could be observed by NMR spectroscopy) were immediately subjected to the carbanion cyclization reaction to give the corresponding β-enamino-γ-sultones in the one-pot manner. It was shown that the influence of the steric factor in the sulfonylation of cyanohydrins was insignificant, and the yield of products was mostly determined by the relative stability of the sulfonyl chloride. The scope and limitations of the one-pot sulfonylation – cyclization were studied. In particular, the use of phenylmethane sulfonyl chloride in the reaction with cyanohydrins under typical conditions mostly leads to the formation of the corresponding non-cyclized cyano alkane sulfonates. Further carbanion cyclization proceeded upon the treatment with t-BuOK in DMF and resulted in the formation of α-phenyl β-enamino γ-sultones with yields up to 77%. An X-ray structural study of single crystals of phenyl sultone showed a pyramidal configuration of the Nitrogen atom, as well as non-coplanarity of the phenyl and sultam cycles.