Calculation-assisted regioselective functionalization of the imidazo[1,2-a]pyrazine scaffold via zinc and magnesium organometallic intermediates.

Straightforward calculations such as determinations of pKa values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored fused N-heterocycle imidazo[1,2-a]pyrazine. Thus, regioselective metalations of 6-chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl·LiCl and TMP2Zn·2MgCl2·2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMP2Zn·2MgCl2·2LiCl as base for the first metalation allowed an alternative regioselective metalation. Nucleophilic additions at position 8 as well as selective Negishi cross-couplings complete the set of methods for selectively decorating this heterocycle of the future.

Regioselective Magnesiations of Fluorinated Arenes and Heteroarenes Using Magnesium-bis-Diisopropylamide (MBDA) in Hydrocarbons.

We report a convenient preparation of a new and storable magnesium amide (iPr2 N)2 Mg (magnesium-bis-diisopropylamide; MBDA) which proved to be especially suitable for the non-cryogenic magnesiation of fluoro-substituted arenes and heteroarenes providing arylmagnesium amides (ArMgDA) or bis-heteroaryl magnesiums (HetAr)2 Mg in hydrocarbons. Further reactions with electrophiles (aldehydes, ketones, allylic bromides, aryl halides (Negishi cross-coupling)) furnished a range of polyfunctional fluoro-substituted unsaturated building blocks. Several postfunctionalizations were described as well as NMR-studies confirming the dimeric structure of the base.