In Situ Generation of Magnesium- and Calcium-Based Grignard Reagents for Amide Synthesis.

ABSTRACT

The alkaline-earth metals Mg and Ca are too inert for the direct metalation of primary and secondary amines. Consequently, activation prior to use is required. Alternatively, the Grignard reagents RMgX (R=alkyl, aryl, X=halide) can be applied in metalation of amines. However, such a straightforward procedure for the synthesis of alkylcalcium reagents is disadvantageous due to diverse side reactions, including Wurtz-type C-C coupling and ether degradation reactions. Therefore, suspensions of magnesium or calcium with amine can be treated in a smooth reaction with ethyl bromide in an ethereal solvent at room temperature. Intermediately formed RAeX (Ae=alkaline-earth metal, i. e., Mg, Ca) either metalates amines yielding the corresponding amides in an in situ Grignard metalation method (iGMM) or adds across C=N bonds of imines in an in situ Grignard addition method (iGAM). The amides R'2 N-AeX (Ae=Mg Hauser bases) undergo Schlenk-type ligand exchange reactions yielding homoleptic Ae(NR'2 )2 and potentially sparingly soluble AeX2 .