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

Straightforward calculations such as determinations of p 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-]pyrazine. Thus, regioselective metalations of 6-chloroimidazo[1,2-]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl·LiCl and TMPZn·2MgCl·2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMPZn·2MgCl·2LiCl as base for the first metalation allowed an alternative regioselective metalation.

Transition-Metal Free Electrophilic Aminations of Polyfunctional O-2,4,6-Trimethylbenzoyl Hydroxylamines with Zinc and Magnesium Organometallics.

We reported a new electrophilic amination of various primary, secondary and tertiary alkyl, benzylic, allylic zinc and magnesium organometallics with O-2,4,6-trimethylbenzoyl hydroxylamines (O-TBHAs) in 52-99 % yield. These O-TBHAs displayed an excellent long-term stability and were readily prepared from various highly functionalized secondary amines via a convenient 3 step procedure. The amination reactions showed remarkable chemoselectivity proceeding without any transition-metal catalyst and were usually complete after 1-3 h reaction time at 25 °C.

Exploiting Coordination Effects for the Regioselective Zincation of Diazines Using TMPZnX⋅LiX (X=Cl, Br).

A new method for regioselective zincations of challenging N-heterocyclic substrates such as pyrimidines and pyridazine was reported using bimetallic bases TMPZnX⋅LiX (TMP=2,2,6,6-tetramethylpiperidyl; X=Cl, Br). Reactions occurred under mild conditions (25-70 °C, using 1.75 equivalents of base without additives), furnishing 2-zincated pyrimidines and 3-zincated pyridazine, which were then trapped with a variety of electrophiles.

Reliable Functionalization of 5,6-Fused Bicyclic N-Heterocycles Pyrazolopyrimidines and Imidazopyridazines via Zinc and Magnesium Organometallics.

DFT-calculations allow prediction of the reactivity of uncommon N-heterocyclic scaffolds of pyrazolo[1,5-a]pyrimidines and imidazo[1,2-b]pyridazines and considerably facilitate their functionalization. The derivatization of these N-heterocycles was realized using Grignard reagents for nucleophilic additions to 5-chloropyrazolo[1,5-a]pyrimidines and TMP Zn ⋅ 2 MgCl  ⋅ 2 LiCl allowed regioselective zincations. In the case of 6-chloroimidazo[1,2-b]pyridazine, bases such as TMP Zn ⋅ MgCl  ⋅ 2 LiCl, in the presence or absence of BF  ⋅ OEt , led to regioselective metalations at positions 3 or 8.

Preparation of Primary and Secondary Dialkylmagnesiums by a Radical I/Mg-Exchange Reaction Using sBu Mg in Toluene.

The treatment of primary or secondary alkyl iodides with sBu Mg in toluene (25-40 °C, 2-4 h) provided dialkylmagnesiums that underwent various reactions with aldehydes, ketones, acid chlorides or allylic bromides. 3-Substituted secondary cyclohexyl iodides led to all-cis-3-cyclohexylmagnesium reagents under these exchange conditions in a highly stereoconvergent manner. Enantiomerically enriched 3-silyloxy-substituted secondary alkyl iodides gave after an exchange reaction with sBu Mg stereodefined dialkylmagnesiums that after quenching with various electrophiles furnished various 1,3-stereodefined products including homo-aldol products (99 % dr and 98 % ee).