Mild and efficient catalytic method for α-trimethylsilyl ketones

A mild, efficient and convenient method for the synthesis of α-silyl ketones from corresponding aldehydes and trimethylsilyldiazomethane in the presence of a catalytic amount of indium(III) chloride has been developed


Introduction
α-Silyl ketones are useful building blocks in organic synthesis because they are substrates for many regio-and stereoselective reactions to construct carbon-carbon and carbon-heteroatom bonds in high stereoselectivities. 1 Generally, α-silyl ketones can be synthesized through several methods including condensation of esters or acyl halides with α-silylated organolithium 2 or organomagenesium 3 reagents, reaction of α-silyl esters with Grignard reagents, 4 oxidation of vinylsilanes followed by rearrangement, 5 and deprotonation-silylation of corresponding hydrazones, 6 and O→C silyl migration strategy starting from α-bromoketones. 7Some of these methods are versatile yet milder and more efficient methods are highly needed.
We envision that an appropriate Lewis-acid may be used as catalyst in the reaction of trimethylsilyldiazomethane and aldehydes to form α-silyl ketones.In this method, a Lewis acidactivated aldehyde A would undergo a nucleophilic addition by trimethylsilyldiazomethyl carbon in B to afford diazonium intermediate C.This intermediate then will undergo a 1,2-hydride shift with a concomitant extrusion of nitrogen to form the desired α-silyl ketone product and the regenerated catalyst (Scheme 1).Many homologation reactions of cyclic ketones with diazomethane and its derivatives, all of which share the same mechanistic paradigm, have been reported in the literature 8 but the homologation of aldehyde with trimethylsilyldiazomethane to selectively generate α-silyl ketones is rare. 9Probably, this is because not only the α-silyl ketones have a strong propensity to rearrange into the corresponding silyl enol ether but also the zwitterionic intermediate D tends to form a carbene intermediate E due to the formation of a strong silicon-oxygen bond, thereby generating silyl enol ether.Furthermore, relatively unstable α-silyl ketone products may further undergo secondary transformations to generate the corresponding protodesilylated methyl ketones, which must be suppressed to maximize the yield of α-silyl ketones.In this article, we report an indium(III) chloride-catalyzed reaction between aldehydes and trimethylsilyldiazomethane as a useful method for the selective synthesis of α-silyl ketones where indium(III) chloride was found to be a uniquely effective catalyst compared to many other Lewis acids.

Results and Discussion
First, we selected 4-cis-decenal 1 as a model substrate to examine the reaction scope and the performance of different Lewis acids (Table 1).These reactions were carried out at room temperature using 2 mol% Lewis acid in methylene chloride.All Lewis acids tested afforded either α-silyl ketone 2 and/or silyl enol ether 3 in 30 minutes.A boron-based Lewis acid such as BF 3 •Et 2 O exhibited a high reactivity to generate 2 and small amount of methyl ketone 4, which, we believe, resulted from α-silyl ketone 2 via a protodesilylation under the reaction conditions (entry 1).Metal triflates such as Hf(OTf) 3 , In(OTf) 3 and Sc(OTf) 3 afforded silyl enol ether 3 as the major product , which is assumed to be a secondary product from α-silylketone 2 via C→O silyl migration catalyzed by the Lewis acids.It is worthwhile to note that Sc(OTf) 3 -catalyzed reaction generated silyl enol ether exclusively in quantitative yield (entry 8).8c,10 Other triflates such as Mg(OTf) 2 and Zn(OTf) 2 did not promote the formation of the silyl enol ether, yet low yield of 2 and formation of 4 was observed with these catalysts (entries 7 and 12).Halide-based Lewis acids, in general, showed better catalytic performance than the corresponding triflates, and among the Lewis acids examined, indium(III) chloride (InCl 3 ) was found to be the best catalyst, leading to complete conversion and high selectivity for the desired α-silyl ketone 2, minimizing its rearrangement to silyl enol ether 3 or protodesilylation to methyl ketone 4. Next, we turned our attention to expanding the substrate scope using the optimized conditions (Table 2).The results show that this indium chloride-catalyzed reaction tolerates diverse functional groups including alkene (entries 1,2 and 4), alkyne (entry 3), ether (entries 9-11), acetal (entry 12), and ketone (entries 13).In case of the reaction with benzaldehydes, however, α-silyl ketone products were obtained in slightly lower yields due to the formation of an epoxide byproduct (entries 6-8).Although Fournier and coworkers recently reported that the reaction between ethyl diazoacetate and 2-aminobenzaldehydes in the presence of BF 3 •OEt 2 afforded indole through [1,2]-aryl shift, 11 no [1,2]-aryl shift was observed under current conditions with these aldehydes.The alkoxy group on the α-position of the aldehyde did not cause deleterious effect for the methylene insertion, thus α-silyl ketone 6j and 6k were obtained in excellent yields (entries 10 and 11).The substrate with both aldehyde and ketone moiety gives α-silyl ketone 6m without the participation of the ketone moiety (entry 13).An α-branched aldehyde 2-methylpentanal also efficiently afforded the corresponding α-silyl ketone 6n without incident (entry 14).The synthetic utility of this method was further demonstrated by one-pot synthesis of α-silyl ketones followed by their conversion to silylated cyclopropene 7 or to a cyclic allylsilane 8 (Scheme 2). 12Scheme 2. Formation of α-silyl ketones and their C-Si and C-H insertion reactions.

Conclusions
In summary, we have developed an indium(III) chloride-catalyzed reaction between aldehydes and trimethylsilyldiazomethane as a new and effective method for the synthesis of α-silyl ketones.Indium(III) chloride was found to be uniquely effective and selective to provide high yield of the desired α-silyl ketones by minimizing protodesilylation and/or C→O silyl migration compared to other Lewis acids.

Experimental Section
General.All reactions were carried out under air, unless otherwise indicated.Compounds were purchased from Aldrich unless otherwise noted.CH 2 Cl 2 , THF, Et 2 O were purified based on standard procedures.Analytical thin layer chromatography (TLC) was performed on 0.25 mm E. Merck precoated silica gel 60 (particle size 0.040-0.063mm). 1 H NMR and 13 C NMR spectra were recorded on a Bruker DRX-500 spectrometer. 1 H and 13 C chemical shifts were referenced to internal solvent resonances and reported relative to SiMe 4 ; multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet) and br (broad).Coupling constants, J, are reported in Hz (Hertz).Electrospray ionization (ESI) mass spectra were recorded on a Micromass LCT equipped with a time-of-flight analyzer on a Waters Micromass Q-Tof Ultima in the University of Illinois at Urbana-Champaign.Electron impact (EI) mass spectra were obtained using a Micromass AutoSpecTM.