Selective functionalization of N-heterocyclic substrates using the TMPLi/ZnCl2 system

According to recent analyses of the US Food and drug administration, 59% of the approved drugs contain a nitrogen heterocycle.1 Lithium amides play an important role in the directed functionalization N-heterocycles, however, the high reactivity of organolithium reagents is a drawback when dealing with substrates bearing sensitive functional groups. In addition, a number of N-heterocyclic rings are prone to nucleophilic attack of reactive organometallic species leading to undesirable products. The complexation of organic substrates with ZnCl2 prior to the addition of the base has already proved to be an interesting strategy to overcome this problem since the corresponding organozinc derivatives are much more stable.2 Given our interest in the functionalization of aromatic and heterocyclic compounds with organometallic reagents,3 herein we wish to report the selective metalation of a number of important N-heterocyclic compounds using the base TMPLi (TMP = 2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl2.2LiCl. Interestingly, after reaction of the organozinc intermediates with different electrophiles, the functionalized derivatives, some of them new compounds, were obtained in reasonable to good yields. Finally, application of the strategy to synthesize an analogue of antitumoral Verubulin illustrates that this approach has a great potential for application in Medicinal Chemistry (Scheme 1).