Stereochemistry of the Kulinkovich Cyclopropanation of Nitriles

Abstract

The stereochemistry of the Kulinkovich cyclopropanation of nitriles with alkenes has been examined by employing (E)-disubstituted alkenes and deuterium-labeled homoallylic alcohols as a stereochemical probe. An intramolecular cyclopropanation proceeds with preservation of the olefin configuration. On the other hand, intermolecular counterparts occur with both preservation and reversal of the olefin configuration, which corresponds to retention and inversion of configuration at the Ti–C bond, respectively, in the cyclopropane-forming step. These uncommon stereochemical outcomes contrast with that of the Kulinkovich cyclopropanation of tertiary amides.

Asymmetric Kulinkovich Hydroxycyclopropanation of Alkenes Mediated by Titanium(IV) TADDOLate Complexes

“…25 Following this seminal work, Cha further revealed that both retention and inversion of configuration at the Ti-C bond occurred in intermolecular coupling between a homoallylic alcohol and a nitrile. 26 In the event of asymmetric cyclopropanation with alkoxide 13-d, the formation of diastereomeric cyclopropanols 1c-d and 1c-d′ could be expected as a result of retention or inversion of configuration at Ti-C bond respectively (Scheme 4). It is remarkable that both diastereomers 1c-d and 1c-d′ must behave as a pair of enantiomers during HPLC analysis with a chiral column, since isotopic substitution cannot strongly affect retention times.…”

Titanium‐Mediated Synthesis of 1,4‐Diketones from Grignard Reagents and Acyl Cyanohydrins

“…The first step would imply the insertion of the nitrile moiety of 3 into the titanacyclopropane intermediate A (obtained from Ti(OiPr) 4 and 2 equiv of EtMgBr) to provide the five-membered titanacycle C. The diketone 5 might be directly obtained from an intramolecular direct insertion of the ester C=O bond into the remaining titanium-carbon bond, however this possibility is unlikely because of obvious geometric constrictions. [17][18][19] For instance, the addition of Grignard reagents to five-membered oxatitanacyclopentanes has been proposed by Kulinkovich et al to explain the need for excess Grignard in the synthesis of cyclopropanols. Several related metallacycle ring-openings have already been proposed in the literature.…”

“…Several related metallacycle ring-openings have already been proposed in the literature. [18] The Table 1, entry 4). [17] Recently, the azatitanacyclopent-2-ene ring-opening has been postulated by Cha et al to explain the nonselective cyclopropanation of nitriles.…”

“…Several related metallacycle ring-openings have already been proposed in the literature. [17][18][19] For instance, the addition of Grignard reagents to five-membered oxatitanacyclopentanes has been proposed by Kulinkovich et al to explain the need for excess Grignard in the synthesis of cyclopropanols. [17] Recently, the azatitanacyclopent-2-ene ring-opening has been postulated by Cha et al to explain the nonselective cyclopropanation of nitriles.…”

“…[17] Recently, the azatitanacyclopent-2-ene ring-opening has been postulated by Cha et al to explain the nonselective cyclopropanation of nitriles. [18] Table 1, entry 4). Finally, the diketone 5 can be obtained by hydrolysis of E. This indicates the divergent synthesis of 4 and 5 from the common intermediate D. Nevertheless, the astonishing difference in reactivity between cyanoesters 1 and 3 remains unexplained at the moment.…”