Syn-Selective anti-Markovnikov Intramolecular Hydroamination

Key words

rhodium(I) - anti-Markovnikov - hydroamination

Significance

Using a Rh(I)/DPPB catalyst system, aminoolefins undergo a remarkably selective anti-Markovnikov hydroamination reaction to generate 3-arylpiperidines in good yields. When the aminoolefin is appropriately substituted (R ≠ H), products are obtained with high degrees of syn-selectivity; presumably due to equatorial placement of the substituents in a chair-like transition state. The N-methyl substituent is necessary for the reaction to proceed; however, this group can be easily cleaved (see scheme).

Comment

Hydroamination reactions have been studied for decades, with many advances improving the efficiency of the reaction. However, the main limitation of hydroamination is a lack of Markovnikov/anti-Markovnikov selectivity (see review below), which is overcome using the rhodium catalyst system reported. The products of this reaction are medicinally interesting, as 3-arylpiperidines have found activity as dopamine autoreceptor antagonists which stimulate dopamine turnover without inducing hypoactivity. Development of an enantioselective anti-Markovnikov hydroamination would provide rapid access to this class of bioactive compounds.

Review

S. Hong, T. J. Marks Acc. Chem. Res. 2004, 37, 673-686.