Synthesis of partially saturated nitrogen heterocycles through stereo- and regioselective
dearomatization of heteroarenes.
Nitrogen-containing heterocycles are important in multiple areas of chemistry including
pharmaceutical, agrochemical and materials science due to their chemical properties and
biological significance. These heterocycles are often grouped as aromatic and non-aromatic
heterocycles. Aromatic heterocycles are widely available and recent advances in various cross
coupling and C-H activation chemistry have further improved the access to these heterocycles.
On the other hand, methods for the synthesis of non-aromatic heterocycles which often contain
stereogenic centers at sp3 hybridized carbon centers are less developed.
Our long-term goal is to develop new chemical transformations that will regio-, and
stereoselectively introduce functionality into the heteroarenes to enable synthesis of partially
saturated nitrogen heterocycles. Partially saturated heterocycles are excellent precursors to both
aromatic and non-aromatic azaheterocycles. For example, dihydropyridines can be
functionalization or reduced to yield tetrahydropyridines and piperidines and they can be oxidized
to yield pyridines.
The current proposal addresses the regioselective, stereoselective and catalytic addition
of nucleophiles and electrophiles to the heteroarenes for the synthesis of partially saturated six-
membered azaheterocycles. Specifically, we propose methodologies supported by significant
preliminary results and literature precedents for the transition metal catalyzed dearomatization
reactions of heteroarenes focusing on the regioselective dearomatization of six-membered
heteroarenes containing one or two nitrogen atoms. Dearomatization approaches proposed by
us include Rh, Pd, Ni and Cu catalyzed addition of boron nucleophiles as well as addition of
organometallic nucleophiles to activated N-alkyl and N-acyl heteroarenes. In addition to coupling
of nucleophiles, we propose dearomative coupling of heteroarenium salts with electrophiles using
Ni-photoredox system. Catalyst design approaches for controlling the regio- and stereoselectivity
of the addition reactions will also be explored.
Methods described by us are innovative as they involve previously unexplored
approaches, coupling partners and catalysts. The results obtained from these studies will be
significant as the saturated and partially saturated heterocycles are common structural motifs in
bioactive natural products and pharmaceuticals.
