Synthesis of 2,4-disubstituted piperidines via radical cyclization: unexpected enhancement in diastereoselectivity with tris(trimethylsilyl)silane.
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.
Gandon
Lucile A
LA
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
Russell
Alexander G
AG
Güveli
Tatyana
T
Brodwolf
Angela E
AE
Kariuki
Benson M
BM
Spencer
Neil
N
Snaith
John S
JS
D003500:Cyclization; D005609:Free Radicals / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D012821:Silanes / Q000737:chemistry*; D013237:Stereoisomerism
D005609:Free Radicals; D010880:Piperidines; D012821:Silanes; C510691:tris(trimethylsilyl)silane