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

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 = 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'2N-AeX (Ae = Mg: Hauser bases) undergo Schlenk-type ligand exchange reactions yielding homoleptic Ae(NR'2)2 and potentially sparingly soluble AeX2.