Department of BioMolecular Sciences , University of Mississippi , University , Mississippi 38677 , United States.
Department of Medicinal Chemistry and Molecular Pharmacology , Purdue University , West Lafayette , Indiana 47907 , United States.
J Org Chem. 2018 Mar 16;83(6):3109-3118. doi: 10.1021/acs.joc.7b03014. Epub 2018 Feb 27.
Although there are many synthetic methods to produce fluorinated and trifluoromethylated organic structures, the construction of difluoromethylated compounds remains a synthetic challenge. We have discovered that unactivated imines will react with difluoroenolates under exceedingly mild conditions when using magnesium salts and organic bases. We have applied this approach to the iminoaldol reaction to produce difluoromethylene groups as α,α-difluoro-β-amino-carbonyl groups. This method provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones without the need of protecting groups or the use of activated imines. Moreover, we have applied this strategy to create analogues of the dual orexin receptor antagonist, almorexant, in only two synthetic steps.
尽管有许多合成方法可以制备氟化和三氟甲基有机结构，但二氟甲基化合物的构建仍然是一个合成挑战。我们发现，在使用镁盐和有机碱时，未活化的亚胺在非常温和的条件下与二氟烯醇盐反应。我们将这种方法应用于亚胺醇醛缩合反应，将二氟亚甲基基团作为α,α-二氟-β-氨基羰基基团生成。这种方法提供了具有合成用途的难以获得的α,α-二氟-β-氨基酮，而无需使用保护基团或使用活化的亚胺。此外，我们还应用该策略仅通过两个合成步骤来制备双重食欲素受体拮抗剂阿莫雷克斯的类似物。
