New and Stereospecific Synthesis of α-Ethylenic Ketones

Abstract

H. Kise et al¹ have shown that the reaction of β-propiolactones 1 with ylides 2 give phosphonium carboxylate betaïne 3. We now report that, carried out under different conditions, reaction of lactones 1 with the same ylides proceeds through pathway (b). Thermolysis of 4 affords α-ethylenic ketones 5. The mecanism of this new extrusion reaction of triphenylphosphine oxyde probably involves the generation of an oxaphosphene as an intermediate.     

γ-Methylenation of α,β-Unsaturated Ketones

γ-Methylene derivatives of α,β-unsaturated ketones are obtained readily by a one-pot procedure exploiting the reaction of O-silylated dienolates with commercially available formaldehyde N, N-dimethyliminium chloride in anhydrous N, N-dimethylformamide, in situ oxidation of the Mannich reaction product with hydrogen peroxide, and elimination of N,N-dimethylhydroxylamine from the resultant N-oxide.     

Synthesis of α,β-Unsaturated Ketones via Enamines

Acylation of an enamine followed by acid hydrolysis constitutes the well-known Stork's reaction of synthesizing β-diketones.^1,2 This article reports that the acylated enamine 1 which corresponds to monoenamine of a β-diketone can be hydrogenated to a Mannich base 2 which on elimination by heating or treatment with acid yields the α, β-unsaturated ketone 3; further hydrogenation gives saturated ketone 4 in good yield (Scheme 1). A similar transformation effected by hydroboration has been reported by Montury and Góre.     

α-Halo Ketones in C-, N-, O-, and S-Alkylation Reactions

The review summarizes and analyzes both theoretical aspects and practical applications of C-, N-, O-, and S-alkylation with -halo ketones of aliphatic, alicyclic, aromatic, and heterocyclic compounds. Some reactions of -halo ketones with difunctional nucleophiles are also discussed.     

One‐Pot Synthesis of α‐Formyloxy Ketones from Enolizable Ketones

One‐pot synthesis of α‐formyloxy tones as well as α‐acetoxy ketones from enolizable ketones and [hydroxy(tosyloxy) iodo] benzene (HTIB)/polymer supported [hydroxy(tosyloxy) iodo] benzene (PSHTIB) in N,N–dimethylformamide (DMF)/N, N–dimethylacetamide (DMA) in high yields is described.     

Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. ¹H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.     

One‐Pot,Four‐Component Reaction of Aryl Aldehydes,Aryl Ketones,Phosphorus Trichloride,and Acetonitrile Catalyzed by Acetyl Chloride: Synthesis of β‐Acetamido Ketones

The one‐pot, four‐component reaction of aryl aldehydes, aryl ketones, phosphorus trichloride, and acetonitrile, catalyzed by acetyl chloride, affords β‐acetamido ketones in good to excellent yields. Silicaphosphine (silphos), [P(Cl)_3‐n(SiO₂)_n], can also be used effectively as a solid‐supported reagent instead of phosphorus trichloride.     

Amine-Free,Directing-Group-Free and Redox-Neutral α-Alkylation of Saturated Cyclic Ketones

The activation of the α-C−H bond of ketones typically requires an amine and a directing group to guide the reaction selectivity in amine-catalysis carbonyl chemistry. For an α-C−H bond activation of ketone, directing groups are also required to control the reaction selectivity. Reported herein is the first α-alkylation of cyclic ketones in the absence of an amine catalyst and directing group. ¹H NMR, XPS, EPR studies and DFT calculations indicate that an α-carbon radical intermediate is formed through direct and selective activation of the inert α-C−H bond of ketones chelating on the surface of colloidal quantum dots (QDs). Such an interaction is essential for weakening the C−H bond, as exemplified, using CdSe QDs as the sole photocatalyst to execute α-C−H alkylation of cyclic ketones under visible-light irradiation. Without an amine catalyst and directing group, the high step- and atom-economy transformation under redox-neutral condition opens a new way for α-C−H functionalization of ketones in carbonyl chemistry.     

Reactions of β-Sulfinyl α,β-Unsaturated Ketones with Dienes

β-Sulfinyl α,β-unsaturated ketones (2a-f) reacted in a regioselective manner with dienes such as butadiene (3a) and 1,3-pentadiene (3b) to give 1,4-cyclohexadiene derivatives (4-8) with the concomitant elimination of sulfenic acid, while the ketones (2a-c) reacted with cyclopentadiene (3c) to yield the norbornenes (9).     

The Reaction of α,α-Dichlorobenzyltrimethylsilane with Aldehydes and Ketones

The reaction of α,α-dichlorobenzyltrimethylsilane with carbonyl compounds in the presence of fluoride ion fails to give reasonable yields of the α,α-dichlorobenzyl adducts except when carried out in the presence of zinc iodide and in HMPA as solvent. Under these conditions moderate yields of the adducts can be obtained with cyclohexanone, cyclohexenone, benzaldhyde and trans cinnamaldehyde. These reactions were compared with those of α,α-dichlorobenzyllithium.     

Transition-Metal-Free Superbase-Promoted Stereoselective α-Vinylation of Ketones with Arylacetylenes: A General Strategy for Synthesis of β,γ-Unsaturated Ketones

A wide variety of β,γ-unsaturated ketones of E configuration have been obtained in good to excellent yields via KO(t)Bu/DMSO promoted α-vinylation of aliphatic, cycloaliphatic, and alkyl aromatic (heteroaromatic) ketones with diverse arylacetylenes.     

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.     

Catalytic Asymmetric Conjugate Addition of Indolizines to α,β-Unsaturated Ketones

A catalytic enantioselective conjugate addition of indolizines to enones is described. The chiral phosphoric acid (S)-TRIP activates α,β-unsaturated ketones, thereby promoting an enantioface-differentiating attack by indolizines. Using this reaction, several alkylated indolizines were synthesized in good yields and with enantiomeric ratios of up to 98:2.     

Regiospecific Synthesis of α-Alkylated Ketones

Several solutions have been developed to avoid the troublesome di- and polyalkylation encountered in ketone enolate alkylations¹, including use of the covalent Li enolate, or “additives” to tighten the metal-oxygen bond (M = Si^2,3,4, Sn^5,6, Al⁶, B^7,8,9).     

Interaction of α,β-Unsaturated Ketones of the Adamantane Series with N,N'-Binucleophiles

The influence has been established of the structure of the initial ketone, the reactants, and the reaction conditions on the direction of the interaction of ,-unsaturated ketones of the adamantane series with hydrazine, phenylhydrazine, semicarbazide, thiosemicarbazide, urea, and thiourea. It was found that on interaction with hydrazine and phenylhydrazine both intermediate hydrazones and the final cyclization products, pyrazolines, were formed. Reaction with semicarbazide and thiosemicarbazide leads only to the synthesis of derivatives at the carbonyl group, semicarbazones and thiosemicarbazones, but with urea and thiourea leads to products of addition at the double bond.     

Polyaniline-Anchored Metal Salts for Michael Reaction of α,β-Unsaturated Ketones

A catalyst consisting of polyaniline-anchored metal salts is used as a Lewis acid to promote the Michael reaction of α,β-unsaturated ketones. The reaction is performed efficiently with imidazole, acetyl acetone, and ethyl acetate as Michel donors and chalcones as the acceptors under ultrasound irradiation.     

Chemoselective Catalytic Hydrogenation of α,β-Unsaturated Ketones and α,β-Unsaturated Carboxylic Esters

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Stereoselective Cycloaddition of N-Acyliminium Ions with α,β-Unsaturated Ketones and Esters

The [4+2] reactions of N‐acyliminium ions, produced from 2‐aryl‐3‐hydroxy‐2,3‐dihydroisoindol‐1‐ones or 5‐hydroxy‐1‐phenyl‐2,5‐dihydro/2,3,4,5‐tetrahydropyrrol‐2‐ones in the presence of BF₃OEt₂, with α,β‐unsaturated ketones or esters were examined, and the dependence of these reactions on the substituents at double bonds was clarified. For β‐aryl substituted α,β‐unsaturated ketones and esters such as 4‐aryl‐3‐buten‐2‐ones, chalcones and methyl cinnamate, the [4+2] reactions could proceed smoothly at room temperature to afford 6‐acyl‐5,6,6a,11‐tetrahydroisoindolo[2,1‐a]quinolin‐11‐ones and 4‐acyl‐1,3a,4,5‐tetrahydropyrrolo[1,2‐a]quinolin‐ 1‐ones or 4‐acyl‐1,2,3,3a,4,5‐hexahydropyrrolo[1,2‐a]quinolin‐1‐ones in moderate to high yields; while for simple α,β‐unsaturated ketones and esters such as methyl crotonate and ethyl 3‐methylbut‐2‐enoate, except mesityloxide, the [4+2] reactions were difficult to proceed. The cycloaddition reactions were highly stereoselective, and only one stereoisomer was produced in each reaction.     

Reaction of N-Tosylated Imines with α,β-Acetylenic Ketones via Organozinc Species

A new procedure for stereoselective synthesis of trisubstituted alkenes by an one-pot, three-component reaction of N-tosylated imines with α,β-acetylenic ketones and organozinc species CF₃COOZnEt was described. This reaction system provides β-branched Morita–Baylis–Hillman adducts with excellent yields in absence of any catalyst.