Mild Synthesis of β‐Amino‐α,α‐difluoro Ketones from Acylsilanes and Trifluoromethyltrimethylsilane in a One‐Pot Imino Aldol Reaction

Abstract

Abstractβ‐Amino‐α,α‐difluoro ketones have been very conveniently prepared in a one‐pot procedure from acylsilanes, trifluoromethyltrimethylsilane and imines. The key intermediate in this reaction is a difluoroenoxysilane. The Lewis acid promoted imino aldol reaction was performed with BF3·OEt2 or under very mild conditions using a catalytic amount of Yb(OTf)3. The reaction with chiral benzylimines occurred in good yield with 52–78 % de. Palladium‐catalyzed hydrogenolysis furnished an unprotected β‐amino‐α,α‐difluoro ketone or a β‐amino‐α,α‐difluoro alcohol. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Methods for the Synthesis of α,α‐Difluoroketones

“…Imines can also be used as electrophiles for trapping difluoroenol silanes in Mannich‐type reactions (Scheme ). Non‐activated imines are best activated by a Lewis acid such as BF 3 · Et 2 O, although imines bearing an electron‐withdrawing group on nitrogen are most effective in this process . Aromatic imines generally form Mannich adducts 77 in higher yield than aliphatic imines.…”

“…Nonactivated imines are best activated by a Lewis acid such as BF 3 ·Et 2 O, although imines bearing an electron-withdrawing group on nitrogen are most effective in this process. [79] Aromatic imines generally form Mannich adducts 77 in higher yield than aliphatic imines. Acceleration of Mannich processes by "on water" effects in a similar fashion to aldol reactions has been reported.…”

α,α‐Difluoro‐α‐(trimethylsilyl)acetamides as Versatile Reagents for the Preparation of Difluorinated Aldol and Mannich Adducts

“…During the study of a one‐pot three‐component tetra‐ n ‐butylammonium diphenyltrifluorosilicate (TBAT)‐catalyzed Mannich reaction starting from Ruppert–Prakash reagent, acylsilanes and various activated imines, we noticed that the ammonium difluoroenolate, which is supposedly generated during the one‐pot process, was unreactive towards N ‐( tert ‐butanesulfinyl)imines . A careful examination of the litterature indeed shows that the addition to sulfinylimines has been mostly accomplished either from difluoroenol ethers, under Lewis or Brønsted acid activation,,, or via imino‐Reformatsky reactions ,,. The addition of difluoroenoxysilanes to sulfinylimines promoted only by a Lewis base, without any activation of the electrophile, has never been reported.…”

A general and efficient Lewis acid catalysed Mukaiyama-aldol reaction of difluoroenoxysilanes and ketones

“…Recently, catalytic functionalization of difluoroenoxysilanes, readily accessed from a-CF 3 ketones [30][31], has emerged as a fruitful method for the selective introduction of an a-difluorinated ketone moiety as a synthetic handle for various reactions [32]. To date, they have been found utility in aldol [33][34][35][36][37][38][39], Mannich [40][41][42][43][44][45][46][47][48], Michael [49] and olefination reaction [50]. Particularly, the aldol reaction of difluoroenoxysilanes and carbonyl compounds is very attractive for the synthesis of b-hydroxy a,a-difluoro ketones [51][52][53] as valuable synthons to access difluorinated products such as 1,3-diols, 1,3aminoalcohols and b-hydroxy acid derivatives [35,38].…”