1109
J. Org. Chem. 1993,58,1109-1117
a-Lithioamine Synthetic Equivalents: Syntheses of Diastereoisomers from Boc Derivatives of Cyclic Amines Peter Beak' and Won Koo Lee Department of Chemistry, University of Illinois, Urbana, Illinois 61801 Received August 4, 1992
Sequences of a'-lithiations and electrophilic substitutions of Boc-pyrrolidines,Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrogen are reported, and the pathways of the reactions are discussed. By this methodology monosubstituted 2 and disubstituted 2,4,2,6, and 2,5 Boc-piperidinesare obtained as singleor separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations. Both cis and trans 2,6-disubstituted diastereoisomers can be prepared, and control of diastereoselectivity is demonstrated by syntheses of solenopsin A, a 2,6-trans-disubstituted piperidine, and of Boc-dihydropinidine, a 2,6-cis-disubstituted piperidine. In the case of 3-methoxy-Boc-piperidine elimination of methoxide occurs upon lithiation, and with cis-2,4-disubstitutedBoc-piperidines the electrophile is introduced with trans stereochemistryat C-6. These reactions are suggested to involve twist boat conformationsconsistent with an X-ray crystal structureof 2-methyl-6-(trimethylstannyl)4-phenyl-N-Boc-piperidine.Boc-pyrrolidine lithiates more rapidly than Boc-piperidine, provides 2-substituted products with electrophiles, and on further lithiation-substitution gives 2,548- and -trans-substituted products. Boc-perhydroazepine provides 2-substituted products by the sequence and on further lithiation-substitution gives 2,7-trans-disubstituted products. Introduction The elaboration of amines by the sequence of substitution of an activating group on nitrogen, a'-lithiation to give a dipole stabilized carbanion, electrophilic substitution, and removal of the activating group is illustrated for the conversion of 1 to 3 via the a-lithioamine synthetic equivalent 2. The advantages of this methodology over classical amine syntheses has led to investigation of the approachfor a number of systems.' For saturated amines the sequence has been investigated most fully with the amide, formamidine, oxazoline,or nitroso functions as the activating groups.' Early work showed the amide to be effectivein the combination of induction and complexation which is involved in dipole stabilization, and the stereochemical course of the sequence was investigated for piperidide derivatives.l**However, the conditions required for the addition and removal of the amide were strenuous, and in recent years the formamidine group has been more fully developed for synthetic application^.^^^ The experience in these studies has been that derivatives of cyclic secondaryamines, particularly piperidine, are a demanding and informative test of the methodology.24
INJ- Iy J-
R
R
R
k
z
1
2
Li'
-
