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

Abstract

AbstractThe 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, theGrignardreagents 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, includingWurtz‐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 situGrignardmetalation method (iGMM) or adds across C=N bonds of imines in an in situGrignardaddition method (iGAM). The amides R’2N‐AeX (Ae=Mg:Hauserbases) undergoSchlenk‐type ligand exchange reactions yielding homoleptic Ae(NR’2)2and potentially sparingly soluble AeX2.