Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines

• Published in: Journal of organic chemistry 2018-03, Vol.83 (6), p.3109-3118
• Main Authors: Nguyen, Alex L, Khatri, Hari R, Woods, James R, Baldwin, Cassidy S, Fronczek, Frank R, Colby, David A
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.7b03014

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.