Introduction of Cyclopropyl and Cyclobutyl Ring on Alkyl Iodides through Cobalt-Catalyzed Cross-Coupling

Abstract

A cobalt-catalyzed cross-coupling between alkyl iodides and cyclopropyl, cyclobutyl and alkenyl Grignard reagents is disclosed. The reaction allows the introduction of strained rings on a large panel of primary and secondary alkyl iodides. The catalytic system is simple, non-expensive and the reaction is general, chemoselective and diastereoconvergent. The alkene resulting from the cross-coupling can be transformed to substituted cyclopropanes using a Simmons-Smith reaction. The formation of radical intermediates during the coupling is hypothesized.

Iron and cobalt catalysis: new perspectives in synthetic radical chemistry

“…Using the same catalytic system they also showed that α-halogeno βlactams could be functionalised by aryl Grignard reagents (Scheme 44). 128,129 Scheme 44. Functionalisation of α-halogeno β-lactams…”

Cobalt-Catalyzed Cross-Couplings between Alkyl Halides and Grignard Reagents

“…28 Very recently, the introduction of phenyl bioisosteres consisting of strained cycles such as cyclopropanes or cyclobutanes through cobalt-catalyzed cross-coupling was accomplished. 29 2-Cobalt-catalyzed arylation of alkyl halides 2-1 Arylation of α-bromo glycosides 24 Carbohydrate analogues, such as C-aryl glycosides, are of particular interest in medicinal chemistry due to their enhanced resistance to metabolic processes in comparison to O-glycosides. 30 The introduction of anomeric aryl substituents through metal-catalyzed crosscoupling, on readily accessible α-bromo glycosides, can appear as a straightforward and versatile strategy.…”

Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents

“…Based on our previous results on the cross-coupling between alkyl iodides and cyclopropyl Grignard reagents, the use of a cobalt catalyst, Co(acac)2, associated to N,N,N',N'-tetramethylethylenediamine (L = TMEDA), was first selected. 16 Unfortunately, under these conditions, no conversion of the alkyl iodide 5a was observed after 1 h at 0 °C (Table 1, entry 1). To ensure full conversion of 5a, the reaction time was increased to 16 h and the temperature was raised to 50 °C.…”

“…To identify a catalytic system able to promote the alkylation of a BCP Grignard reagent, the reaction between the primary alkyl iodide 5a and the BCP Grignard reagent, substituted by a t -Bu group at C3, 3a , was first examined. On the basis of our previous results on the cross-coupling between alkyl iodides and cyclopropyl Grignard reagents, the use of a cobalt catalyst, Co­(acac) 2 , associated with N , N , N′ , N′ -tetramethylethylenediamine (L = TMEDA), was first selected . Unfortunately, under these conditions, no conversion of the alkyl iodide 5a was observed after 1 h at 0 °C (Table , entry 1).…”