New Strategies for the functionalization of N-heterocycles using Li-, Mg- and Zn-organometallics

The first part of this work focused on the development of a
convenient and general regioselective functionalization of all ring
positions of the 7-azaindole scaffold. To this end, starting from
simple 2-amino-5-bromopyridine an appropriately substituted
azaindole precursor was prepared which allowed us to functionalize
the 7-azaindole ring in a predictable manner using a combination of
directed metalation, halogen/magnesium and sulfoxide/magnesium
exchange. Furthermore, the general preparation of various
heteroarylmethylzinc reagents by LiCl-promoted zinc insertion into
the corresponding chloromethyl heteroarenes, along with a facile
and straightforward synthesis of these chloromethyl precursors
displayed a major part in this work. The obtained zinc compounds
were subjected to Pd-catalyzed cross-couplings, Cu-mediated
acylations, Cu-catalyzed allylations and addition reactions to
aldehydes. In addition, they proved to be versatile intermediates
for the construction of fused N- and O-heterocycles and gave access
to an analogue of a reported CB1 modifier. Finally, a
lithiation/transmetalation strategy for the metalation of sensitive
functionalized arenes and heteroarenes was developed, using the
strong amide base TMPLi in the presence of metal salts such as
ZnCl2, MgCl2, CuCN and LaCl3. This in situ trapping method not only
allowed the metalation and functionalization of sensitive
heteroarenes, but also provided metalated intermediates with a
different regioselectivity to the one produced with moderately
powerful bases such as TMPZnCl•LiCl or TMPMgCl•LiCl, giving access
to higly functionalized organometallics difficult to prepare
otherwise.