Towards an Asymmetric Organocatalytic α-Azidation of β-Ketoesters

Abstract

Detailed investigations concerning the organocatalytic (asymmetric) α-azidation of prochiral β-ketoesters were carried out. It was shown that the racemic version of such a reaction can either be carried out under oxidative conditions using TMSN3 as the azide-source with quaternary ammonium iodides as the catalysts, or by using hypervalent iodine-based electrophilic azide-transfer reagents with different organocatalysts. In addition, the latter strategy could also be carried out with modest enantioselectivities when using simple cinchona alkaloid catalysts, albeit with relatively low yields.

Insight into trifluoromethylation – experimental electron density for Togni reagent I

“…Triuoromethylation is not the only application for hypervalent iodine compounds; they have also been used as alkynylating 14 or azide transfer reagents. 15,16 The syntheses of hypervalent iodanes and their application in organouorine chemistry have been reviewed, 17 and a special issues of the Journal of Organic Chemistry has been dedicated to Hypervalent Iodine Catalysis and Reagents. 18 Recently, Pietrasiak and Togni have expanded the concept of hypervalent reagents to tellurium.…”

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

“…[25] Given the abundance of alkyl carboxylic acids in natural products and drug molecules,w ea nticipate that, by combining with Masamune reaction, this protocol could provide an ew opportunity to access previously difficult-to-access medicinally relevant a-azido carbonyls. [26] As in the previously reported catalytic oxidative methods, [9][10][11][12][13] our protocol could not be applied to the oxidative aazidation of monocarbonyls.Alternatively,wedeveloped the hypoiodite-catalyzed decarboxylative [27] a-azidation [9b] of boxocarboxylic acids or malonic acid monoesters to give the corresponding a-azido monocarbonyls (Scheme 4, for details see Table S3). Decarboxylative functionalization of b-oxocarboxylic acids has been widely used in various synthetic protocols because of the ease of releasing carbon dioxide under mild conditions to generate the corresponding enolates in as ite-specific fashion.…”

“…[31] To the best of our knowledge,o nly two enantioselective methods have been developed for the direct enantioselective a-azidation of carbonyl compounds with azidobenziodoxole [32] as ah ypervalent iodine-based azide source using transition metal [8c, 33] or organocatalysis. [13] Mechanistic consideration described above and in Supporting Information revealed that, to render the reaction asymmetric, a-iodination step should proceed enantioselectively.H owever, a-iodo intermediates 9 were found to be stereolabile and readily epimerized as could not be isolated in enantioenriched form ( Figure S10). By taking advantage of the catalytic mechanism (Scheme 6c), in which nucleophilic azidation might proceed smoothly after the ratedetermining a-iodination step,w ec ould apply our chiral hypoiodite catalysis to the enantioselective a-azidation of cyclic b-oxoesters 1 with NaN 3 as an azide source by using chiral binaphthyl-based quaternary ammonium iodide 3e [17] (Scheme 7, for details,s ee Table S7).…”

“…[8] Recently,o xidative umpolung a-azidation reactions have also been developed using iodine-based catalysis. [9][10][11][12][13] Fori nstance,i n2 012, Kirsch and colleagues first achieved the hypoiodite-catalyzed oxidati-ve [9a] or decarboxylative [9b] oxidative a-azidation of 1,3dicarbonyls by using sodium azide in the presence of ac atalytic amount of sodium iodide (Scheme 1b). However, to induce high chemoselectivity,astoichiometric amount of IBX-SO 3 K, asulfonylated derivative of 2-iodoxybenzoic acid (IBX), was required as an oxidant, and organic wastes derived from the oxidant were generated.…”

“…[11] However,t rimethylsilyl azide (TMSN 3 )a sa n expensive and volatile azide source was used under harsh conditions (80 8 8C). On the other hand, Nagasawa [12] and Waser [13] independently reported room-temperature oxidative azidation protocols using hydrogen peroxide or its urea complex (urea hydrogen peroxide,U HP) as an oxidant (Scheme 1d). However,these methods also required TMSN 3 as an azide source.Inaddition, generally,the best results were obtained for the reaction of highly reactive cyclic 1,3dicarbonyl compounds.…”