The ortho and meta Magnesiation of Functionalized Anilines and Amino-Substituted Pyridines and Pyrazines at Room Temperature

摘要

The directed lithiation of anilines or aminopyridines is an important method for preparing functionalized amino-substituted arenes and N-heterocycles. These scaffolds may have pharmaceutical applications as antiviral agents or antibiotics. Although directed ortho lithiations give access to various aminated aromatics, the use of strong lithium bases such as nBuLi or tBuLi is incompatible with standard carbonyl functionalities, such as an ester or a nitrile, as well as with sensitive heterocyclic moieties. Generally the amino group was protected with a pivaloyl, a tert-butoxycarbonyl, or a trifluoroacetyl group leading to substrates of type ArNH-COR, which, after treatment with two equivalents of base, afforded an orfho-lithiated bimetallic intermediate. Low temperatures were usually required for these lithiations. Also, the directed lithiation of trifluoroacetamides led to extensive side products. Recently, we have shown that aryl magnesium reagents are readily prepared by metalation with TMPMgCl-LiCl (1; TMP = 2,2,6,6-tetramethylpiperidyl) and that this magnesiation is compatible with sensitive functional groups. However, the magnesiation of anilines proved to be sluggish and inefficient with most directing groups. After extensive experimentation, we found that trifluoroacetamides of type 2 are readily deprotonated with MeMgCl (1.1 equiv) and ring-metalated at room temperature with TMPMgCl-LiCl (1; 1.2 equiv), leading to dimagnesiated intermediates of type 3, which were efficiently trapped with a range of electrophiles (E) to provide substituted anilides of type 4 (Scheme 1).