Acetyltrimethylsilane, Trifluoromethyltrimethylsilane, and Prenyl Esters:  A Three-Component System for the Synthesis of gem-Difluoroanalogues of Monoterpenes

Abstract

The preparation of 3,3-difluoro-6-methylhept-5-en-2-one 1, a key intermediate for the synthesis of 4,4-difluoroterpenes, and applications in linalool and geraniol series are described. The process involves 1,1-difluoro-2-trimethylsilyoxypropene, an enol silyl ether prepared from acetyltrimethylsilane and trifluoromethyltrimethylsilane, and its reaction in situ with prenyl benzoate, under catalysis by trimethylsilyl trifluoromethanesulfonate. Optimized conditions leading to either the desired enol silyl ether or the unprecedented methyl(trifluoromethyl)trimethylsilyl carbinol 4 have been achieved. The prenylation of the enol silyl ether gives a 9/1 mixture of regioisomers, in favor of the expected ketone 1. Treatment of 1 with vinylmagnesium bromide leads to (+/-)-4,4-difluorolinalool 7. Reaction with the lithium enolate of ethyl diethylphosphonoacetate, and then LAH reduction, converts 1 to 4,4-difluorogeraniol 11, with complete stereoselectivity.

Amide Enolate Additions to Acylsilanes: In Situ Generation of Unusual and Stereoselective Homoenolate Equivalents

“…Aliphatic dimethylphenyl acylsilanes have been previously reported to be effective Brook rearrangement precursors due to the increased stabilization of the pentavalent silyloxy anion intermediate (33) from the aromatic substituent on silicon. [52][53][54][55][56][57][58][59][60] The β-hydroxy amide products were not observed when using dimethylphenyl acylsilanes under our developed reaction conditions (entries 8-9). As an alternative to aliphatic acylsilanes, tert-butyl trimethylsilylglyoxylate (69) 61 did prove to be effective for this transformation, providing the γ-carboxy-β-hydroxy amide (78) in moderate yield (entry 10).…”

“…Encouraged by these results, a range of electrophiles was surveyed. Primary, allylic and benzylic halides all afford the corresponding tertiary alcohols (53)(54)(55)(56)(57) in good yields (entries 1-5). The β-silyloxy homoenolate intermediate also undergoes facile addition to aldehydes and ketones (entries 6 and 7).…”

Recent Progress in One-Pot Syntheses of Fluorinated Building Blocks

“…These compounds with gemdifluorocarbonyl structures also have some bioactivities and synthetic utilities. Since monoterpene could be employed as pheromones [23], flavors [24], etc., 3,3-difluoro-6-methylhept-5-en-2-one 5 was prepared as the difluoroanalogue of a key intermediate towards monoterpene synthesis [16]. Since monoterpene could be employed as pheromones [23], flavors [24], etc., 3,3-difluoro-6-methylhept-5-en-2-one 5 was prepared as the difluoroanalogue of a key intermediate towards monoterpene synthesis [16].…”

“…For example, difluoroanalogue 4 [15] of ar-turmerone is a sesquiterpene displaying an antitumor activity [22]. Difluoroegomaketone with potential bovine respiratory toxicity [25], which contains the moiety of difluoroaldol 6, could be also prepared by using this one-pot methodology [17]. Difluoroegomaketone with potential bovine respiratory toxicity [25], which contains the moiety of difluoroaldol 6, could be also prepared by using this one-pot methodology [17].…”

Efficient Synthesis of Acylsilanes Using Morpholine Amides

“…This important 1,2-silyl migration from carbon to oxygen was initially described by Brook, and subsequent investigations of this process have firmly established its utility . For example, acylsilanes have been employed in the synthesis of enolsilanes and alcohols and provide direct access to homoenolates upon addition of vinyl or alkynyl organometallic reagents . More recently, acylsilanes undergoing the Brook rearrangement have been the cornerstone for the development of tandem annulation reactions, and the unique properties of the resulting anions have been exploited in the development of new catalytic acyl anion addition reactions …”