Ionic liquid-promoted one-pot oxidative Michael addition of TMSCN to Baylis-Hillman adducts

The first example of ionic liquid-promoted one-pot oxidative conjugate hydrocyanation of Baylis-Hillman adducts with trimethylsilyl cyanide (TMSCN) is reported. The oxidation of Baylis-Hillman adducts with IBX/[bmim]Br or isomerization-oxidation with NaNO₃/[Hmim]HSO₄ systems affords β-ketomethylene compounds or [E]-cinnamaldehydes, respectively. These α,β-unsaturated carbonyl compounds undergo Michael addition with TMSCN in the same vessel to afford the corresponding thermodynamically more stable β-cyanated products. Thermodynamically less stable 1,2-addition products were not formed. The present regioselective reactions are promoted by ionic liquids, which can be recycled easily for further use without any loss of efficiency.     

Unusual reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et3N

The reaction of β-hydroxy α-diazo carbonyl compounds with TsNHNCHCOCl/Et₃N gave β-(p-tolylsulfonyl) α,β-unsaturated carbonyl compounds or β-(p-tolylsulfonyl) α-diazo esters. The reaction mechanism is discussed.     

A highly stereospecific synthesis of (E)-α,β-unsaturated esters

CrCl₂-induced olefination of aldehydes using methyl dichloroacetate exclusively generates (E)-α,β-unsaturated esters in excellent yields. The intermediate α-chloro-β-hydroxy adducts could also be isolated in good yields under conditions of limited reagent.     

A facile method for the synthesis of enantiopure α-unsubstituted β-hydroxy esters

One-pot deacylation–debromination reactions involving the transesterification of the initial chiral α-bromo-β-hydroxy thioimide aldol adducts and subsequent Al–Hg mediated reductive cleavage of the C–Br bond allow for a facile synthesis of enantiopure β-hydroxy esters.     

Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic acid enolate and α,β-enones

An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding α-hydroxy acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me₂opba complex as catalyst give chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic acid acts as an umpoled chiral equivalent of the benzoyl anion.     

Palladium catalyzed Heck reaction of arenediazonium tetrafluoroborate salts with Baylis-Hillman adducts: production of α-benzyl-β-keto esters

A novel experimental procedure to obtain α-benzyl-β-keto esters from the Heck reaction between arenediazonium tetrafluoroborate salts and Baylis-Hillman (BH) adducts in the presence of Pd(OAc)₂ as catalyst is described. The methodology is simple, straightforward and the use of arenediazonium salts as opposed to conventional arylhalides/triflates over the usual Heck reaction is highlighted.     

NaIO4-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides with high diastereoselectivity: a short route to (−)-cytoxazone and droxidopa

The NaIO₄-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides was achieved using lithium bromide as the bromine source under acidic conditions at rt to afford the corresponding chiral α-bromo-β-hydroxy carboxamides. Excellent yields (77-90%) and diastereoselectivities (up to 10:1) along with exclusive control over regio- as well as anti-selectivity are the main features with a good scope of substrates. The method has successfully been applied in the enantioselective syntheses of two biologically important molecules, viz (−)-cytoxazone and l-threo-DOPS (droxidopa).     

Synthesis of enantiomerically pure α-amino-β-hydroxy-cyclobutanone derivatives and their transformations into polyfunctional three- and five-membered ring compounds

Ketenes readily cycloadded to (R)-tert-butyldihydrooxazole 2a-d to yield enantiomerically pure bicyclic cyclobutanones. The cycloadditions proceeded with unusual regiochemistry giving predominantly or exclusively protected α-amino-β-hydroxycyclobutanone derivatives. The adducts could be converted into a variety of interesting enantiopure intermediates equipped with many functional groups: α-amino-β-hydroxy cyclopropane carboxylic acid derivatives, α-amino-β-hydroxy succinic acid derivatives, α-amino-β-hydroxy lactones and lactams derivatives.     

Aldol reaction of aluminium enolate resulting from 1,4-addition of Me2AlSPh to α,β-unsaturated carbonyl compound. A 1-acylethenyl anion equivalent

Me₂AlSPh or Me₂AlSeMe adds to α,β-unsaturated carbonyl compounds in 1,4-fashion. The resulting aluminium enolates react with aldehydes effectively to afford the adducts of the title anion after formal PhSH (or MeSeH)-elimination.     

Further studies on the synthesis of α-fluoro carbonyl compounds [1]

The trimethylsilyl enol ethers of cycloalkanones and acid esters are converted in high yields (70–90%) to the corresponding α-fluoro carbonyl derivative using XeF₂ in CH₂Cl₂. Non-cyclic α-hydroxy ketones such as ethyl mandelate are efficiently transformed to the α-fluoro product by DAST and by Ishikawa's reagent. Nucleophilic displacement of halogen by fluoride failed in cyclic systems, giving instead, α,β-unsaturated ketones in DMF or CH₃CN (18-crown-6) and 1,2-diones in DMSO, with KF acting as a base. Attempts at DMSO oxidation of I(Br)F adducts failed to give the α-fluoro ketones, but resulted in dehydrohalogenation to the $\text{trans}$-vinyl fluorides.     

Diastereoselective synthesis of 2-fluoroaziridine-2-carboxylates by Reformatsky-type aza-Darzens reaction

The reaction of ethyl dibromofluoroacetate with imines using zinc metal gave 2-fluoroaziridine-2-carboxylates via aza-Darzens reaction of the primary product of the Reformatsky reaction with high diastereoselectivity in excellent yields (quantitative yield and Dr = 85:15). This chemoselective formation of 2-fluoroaziridines was achieved by using CH₃CN as a solvent. Interestingly, the reaction proceeded without activation of zinc metal, which was necessary for the Reformatsky reaction of bromodifluoroacetate. None of α-bromo-α-fluoro-β-lactams, four-membered cyclization products, and noncyclized 3-amino-2-bromo-2-fluorocarboxylic esters, usual Reformatsky adducts, were formed.     

Zur Herstellung von 1,2,3-Tricarbonylverbindungen aus 1,3-Dicarbonylverbindungen. 27. Mitteilung über Reduktone und Tricarbonylverbindungen [1]

The synthesis of 22 substituted tricarbonyl compounds is reported. They were obtained either by oxidation of β-dicarbonyl compounds with SeO₂ or nitrous oxides or by oxidation of the α-bromo-β-dicarbonyl compounds with DMSO. The procedures using SeO₂ or DMSO are more rapid and give in general better yields than other methods described in the literature.     

New transformations involving squarate esters. Multi-channel rearrangement options available to 2-(dimethoxy-methyl)-1-cycloalken-1-yl adducts

The Vilsmeier-Haack reaction of cyclic ketones with PBr₃ and DMF is an effective means for generating β-bromo-α,β-unsaturated aldehydes, which are readily transformed into their dimethyl acetals. These bromides are conveniently amenable to halogen-metal exchange in the presence of tert-butyllithium. The resultant organometallic intermediates, when treated with an equimolar amount of diisopropyl squarate, undergo 1,2-addition to deliver α-hydroxy ketone adducts that have proven to be sensitive to different rearrangements when in the presence of silica gel or boron trifluoride etherate. Although both processes involve net ring expansion of the cyclobutene ring with loss of methanol, the similarity stops there. In the first instance, spirocyclic diketones are produced by 1,2-shift of either of two ring carbons. In the second, extensively conjugated lactones are generated. The behavior of the adduct originating from a lithiated quinone bisketal has also been scrutinized.     

gem-Difluoromethylation of α- and γ-ketoesters: preparation of gem-difluorinated α-hydroxyesters and γ-butyrolactones

PhSCF₂SiMe₃ has been demonstrated as difluoromethyl carbanion synthon (⁻CF₂H). It reacts chemoselectively with α- and γ-ketoesters at the keto group in the presence of a catalytic amount of TBAF in THF to give the corresponding α-hydroxy ester adducts as well as γ-gem-difluorophenylsulfanylmethylated-γ-butyrolactones in good yields. Reductive cleavage of the phenylsulfanyl group of these products employing Bu₃SnH/AIBN gives the corresponding gem-difluoromethylated α-hydroxyesters and γ-butyrolactones in good yields.     

A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: key intermediates for taxol side chain and phenylnorstatine

Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo-α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.     

Diastereoselective synthesis of enantioenriched homopropargyl amino alcohols from α-dibenzylamino aldehydes and their use as chiral synthons

Homochiral α-dibenzylamino aldehydes, prepared from the corresponding α-amino acids, react with propargyl bromide and zinc in DMF/THF (1:1) or DMF/Et₂O (1:1) at 20 °C to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Diastereomers were always formed as major products in this reaction. These compounds are versatile intermediates for a variety of synthetic targets: γ-amino-β-hydroxy-ketones, 4-amino-1,3-diols, 1,7-diamino-2,6-diols, and ω-amino-δ-hydroxy esters.     

An efficient room temperature preparation of bromo difluorovinylzinc reagent (CF2CBrZnCl) and a high yield one-pot synthesis of α-bromo-β,β-difluorostyrenes

A high yield room temperature preparation of the1-bromo-2,2-difluorovinylzinc reagent [CF₂CBrZnCl] (>89%) was achieved via insitu metallation of CF₃CH₂Br or CF₂CHBr with LDA in presence of ZnCl₂. Palladium catalyzed cross-coupling of this zinc reagent with aryl iodides provides α-bromo-β,β-trifluorostyrenes (ArCBrCF₂) in 64-86% isolated yields, in an essentially ‘one-pot’ procedure.     

IBX/Sc(OTf)3-promoted one-pot oxidative conjugate addition of allyltrimethylsilane to Baylis-Hillman adducts

Baylis-Hillman adducts undergo smooth one-pot oxidative Michael addition with allyltrimethylsilane in the presence of 2-iodoxybenzoic acid (IBX)/Sc(OTf)₃ under mild conditions to afford homoallyl β-ketoesters in good yields with high 1,4-selectivity.     

Synthesis of fluorinated materials catalyzed by proline or antibody 38C2 in ionic liquid

The utility of reusable ionic liquid-proline (or aldolase antibody 38C2) reaction system, proceeding the aldol reactions, is described. Further, obtained α-chloro-β-hydroxy compounds were transformed to the optically active α,β-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was able to reuse in Michael additions and the reaction of fluoromethylated imines.     

Mo(CO)6-mediated synthesis of calix[4]arenes carrying β-hydroxy ketones or α,β-unsaturated-β-amino ketones

Mo(CO)₆-mediated ring opening reactions of calix[4]arene isoxazolines/isoxazoles provide a new synthetic methodology for calix[4]arenes carrying bifunctional β-hydroxy ketones or α,β-unsaturated-β-amino ketones. Mo(CO)₆ is a highly selective and convenient reagent for the ring opening process of these supramolecular isoxazolines/isoxazoles.