Reductive Alkylation of Thioannides with Grignard Reagents in the Presence of Ti(OiPr)4: Insight and Extension

• Published in: Organometallics Vol. 33; no. 20; pp. 5643 - 5653
• Main Authors: Hermant, Fabien, Urbanska, Ewelina, de Mazancourt, Sarah Seizilles, Maubert, Thomas, Nicolas, Emmanuel, Six, Yvan
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 27.10.2014
• Subjects: Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Physical Sciences; Science & Technology; PRIMARY CYCLOPROPYLAMINES; ORGANIC-CHEMISTRY; ALKENES; DIASTEREOSELECTIVE SYNTHESIS; CONVENIENT METHOD; COMPLEXES; TITANIUM(IV) ALKOXIDES; SELECTIVITY ISSUES; KULINKOVICH CYCLOPROPANATION; TI(O-I-PR)/2 I-PRMGX
• ISSN: 0276-7333; 1520-6041
• DOI: 10.1021/om500603v

The reductive alkylation of thioamides by Grignard reagents in the presence of Ti(OiPr)(4) is the subject of a study involving 20 different substrates. The influence of various parameters has been evaluated, showing notably that the yields of this moderately efficient process can be improved in several cases by applying a slow addition of the Grignard reagent. The results presented in this contribution also provide new insight into the reactivity of the proposed key intermediates, namely, a metalated iminium species and, ultimately, an alpha-metalated amine. Interestingly, by control of the temperature and the amount of Grignard reagent engaged, the reaction can be directed toward the selective formation of the former titanium intermediate complex. This represents an extension of the original method, allowing the synthesis of various previously inaccessible substituted amines by subsequent addition of a nucleophilic reagent. This role can be played not only by organomagnesium compounds but also by alkyllithium reagents, alkyltitanium(IV) complexes, and lithium aluminum hydride. The properties of the alpha-metalated amine final intermediate have also been explored, demonstrating that this complex is a poor nucleophile but can act as a radical precursor, which is especially evidenced when the resulting radical species are stabilized. Overall, this chemistry thus proves unexpectedly rich and can plausibly lay the basis for the development of new applications in the future.