Intermolecular C–H Amination of Complex Molecules: Insights into the Factors Governing the Selectivity

Transition-metal-catalyzed C–H amination via nitrene
insertion allows the direct transformation of a C–H into a
C–N bond. Given the ubiquity of C–H bonds in organic
compounds, such a process raises the problem of regio- and chemoselectivity,
a challenging goal even more difficult to tackle as the complexity
of the substrate increases. Whereas excellent regiocontrol can be
achieved by the use of an appropriate tether securing intramolecular
addition of the nitrene, the intermolecular C–H amination remains
much less predictable. This study aims at addressing this issue by
capitalizing on an efficient stereoselective nitrene transfer involving
the combination of a chiral aminating agent 1 with a
chiral rhodium catalyst 2. Allylic C–H amination
of terpenes and enol ethers occurs with excellent yields as well as
with high regio-, chemo-, and diastereoselectivity as a result of
the combination of steric and electronic factors. Conjugation of allylic
C–H bonds with the π-bond would explain the chemoselectivity
observed for cyclic substrates. Alkanes used in stoichiometric amounts
are also efficiently functionalized with a net preference for tertiary
equatorial C–H bonds. The selectivity, in this case, can be
rationalized by steric and hyperconjugative effects. This study, therefore,
provides useful information to better predict the site of C–H
amination of complex molecules.