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Barl, Nadja Maria (2014): New Strategies for the functionalization of N-heterocycles using Li-, Mg- and Zn-organometallics. Dissertation, LMU München: Faculty of Chemistry and Pharmacy



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.