A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts for the occurrence of the rearrangement cascade in the former case.
Cyclisation of bromides 4a-f mediated by tributyltin hydride affords predominantly the trans piperidines 5a-f with modest diastereomeric ratios, while cyclisation with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99 : 1.
Pyridine derivatives R 0380Tris(trimethylsilyl)silane: An Unprecedented Enhancement in the Diastereoselectivity of Radical Cyclizations to Give 2,4-Disubstituted Piperidines. -The Bu3SnH mediated radical cyclization of unsaturated bromides (VI) leads to diastereomeric piperidines (VII) and (VIII) in high yields, but only with moderate trans-diastereoselectivity. The use of (Tms)3SiH instead of Bu3SnH enhances significantly the diastereoselectivity for the derivatives (VIIb,c). -(GANDON, L. A.; RUSSELL, A. G.; SNAITH*, J. S.; Org.
Tris(trimethylsilyl)silane. -Radical cyclization of bromides of type (I) and (III) offers a new and stereoselective approach to trans-substituted piperidines. The use of tris(trimethylsilyl)silane instead of Bu3SnH generally leads to better diastereoselectivity which results from selective rearrangement of the minor stereoisomer through a cascade process. -(GANDON, L. A.; RUSSELL, A. G.; GUEVELI, T.; BRODWOLF, A. E.; KARIUKI, B. M.; SPENCER, N.; SNAITH*, J. S.; J. Org. Chem. 71 (2006) 14, 5198-5207; Sch. Chem., Univ. Birmingham, Edgbaston, Birmingham B15 2TT, UK; Eng.) -Jannicke 48-153
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.