Domino reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: general and stereoselective synthesis of gamma-alkylidenebutenolides

The Lewis acid catalyzed cyclization of oxalyl chloride with 1,3-bis(trimethylsilyloxy)-1,3-dienes 3, derived from 1,3-dicarbonyl compounds 1, provides a new and general approach for the synthesis of gamma-alkylidenebutenolides 4, a pharmacologically and synthetically important class of substances. A variety of butenolides were efficiently prepared in good yields and with very good regio- and stereoselectivities. An up-scaling of the reaction was possible. The use of the Lewis acid trimethylsilyl-trifluoromethanesulfonate (TMSOTf) proved to be superior to other activation conditions. Sterically undemanding gamma-alkylidenebutenolides could be prepared alternatively by reaction of the corresponding 1,3-dicarbonyl dianions with N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). In contrast to the dianion method, the Lewis acid catalyzed reaction also facilitated the cyclization of sterically hindered, base-labile, cyclic and functionalized substrates. From a methodology viewpoint, the dianion reaction represents the first cyclization of a bis-Weinreb amide and the first cyclization of an oxalic acid-synthon with an ambident dianion. The TMSOTf-catalyzed reactions are both the first cyclizations of 1,3bis(trimethylsilyloxy)-1,3-dienes with a C2 dielectrophile and the first cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes with a carboxylic acid dichloride or a related dielectrophile.     

An improved microwave assisted protocol for Yonemitsu-type trimolecular condensation

Due to the presence of the indole ring in a number of bioactive compounds, novel methods for the preparation of polyfunctionalized indole derivatives are of great interest. The combined use of Lewis acid catalysis and microwave irradiation furnished satisfactory results in the Yonemitsu-type trimolecular condensation of indoles with aldehydes and 1,3-dicarbonyl compounds, such as malonates and acetoacetates.     

Gold/copper-catalyzed activation of the aci-form of nitromethane in the synthesis of methylene-bridged bis-1,3-dicarbonyl compounds

Activation of the aci-form of nitromethane using Lewis acids for the attack of carbon nucleophiles was studied. 1,3-Dicarbonyl compounds in the presence of catalytic amounts of AuCl(3) or Cu(OTf)(2) in nitromethane solvent could be converted into methylene-bridged bis-1,3-dicarbonyl compounds.     

Nucleophilic substitution reactions of alcohols with use of montmorillonite catalysts as solid Brønsted acids

We have developed an environmentally benign synthetic approach to nucleophilic substitution reactions of alcohols that minimizes or eliminates the formation of byproducts, resulting in a highly atom-efficient chemical process. Proton- and metal-exchanged montmorillonites (H- and Mn+-mont) were prepared easily by treating Na+-mont with an aqueous solution of hydrogen chloride or metal salt, respectively. The H-mont possessed outstanding catalytic activity for nucleophilic substitution reactions of a variety of alcohols with anilines, because the unique acidity of the H-mont catalyst effectively prevents the neutralization by the basic anilines. In addition, amides, indoles, 1,3-dicarbonyl compounds, and allylsilane act as nucleophiles for the H-mont-catalyzed substitutions of alcohols, which allowed efficient formation of various C-N and C-C bonds. The solid H-mont was reusable without any appreciable loss in its catalytic activity and selectivity. Especially, an Al3+-mont showed high catalytic activity for the alpha-benzylation of 1,3-dicarbonyl compounds with primary alcohols due to cooperative catalysis between a protonic acid site and a Lewis acidic Al3+ species in its interlayer spaces.     

Sodium stearate-catalyzed multicomponent reactions for efficient synthesis of spirooxindoles in aqueous micellar media

A new type of Lewis base-surfactant-combined catalyst (LBSC), sodium stearate, was applied as a catalyst in three-component one-pot reaction involving isatin, malononitrile, and 1,3-dicarbonyl compounds to afford the corresponding spirooxindoles derivatives in good yields (91-97%) under aqueous micellar media.     

Heteropoly acid-catalyzed highly efficient alkylation of 1,3-dicarbonyl compounds with benzylic and propargylic alcohols

Various 1,3-dicarbonyl compounds reacted readily with benzylic and propargylic alcohols in the presence of 10 mol % of phosphomolybdic acid supported on silica gel (PMA/SiO₂) under mild reaction conditions to produce 2-benzylic- and 2-propargylic-1,3-dicarbonyl compounds in excellent yields and with high selectivity.     

A practical and convenient fluorination of 1,3-dicarbonyl compounds using aqueous HF in the presence of iodosylbenzene

A simple, practical, and convenient fluorination of 1,3-dicarbonyl compounds was achieved by direct use of aqueous hydrofluoric acid and iodosylbenzene (PhIO). The reaction of ethyl benzoylacetate with the reagent system of aqueous HF and PhIO in CH(2)Cl(2) gave ethyl 2-fluoro-2-benzolyacetate in 98% yield. Other 1,3-dicarbonyl compounds including β-keto esters and 1,3-diketones underwent the fluorination reaction to give the corresponding fluorinated products in good yields.     

Copper(II) Triflate Catalyzed Amination of 1,3-Dicarbonyl Compounds

A method to prepare α,α-acyl amino acid derivatives efficiently by Cu(OTf)(2) +1,10-phenanthroline (1,10-phen)-catalyzed amination of 1,3-dicarbonyl compounds with PhI?NSO(2) Ar is described. The mechanism is thought to initially involve aziridination of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, by the putative copper-nitrene/imido species generated from the reaction of the metal catalyst with the iminoiodane source. Subsequent ring opening of the resultant aziridinol adduct under the Lewis acidic conditions then provided the α-aminated product. The utility of this method was exemplified by the enantioselective synthesis of a precursor of 3-styryl-2-benzoyl-L-alanine.     

A new method for enol lactone synthesis by a Michael addition/cyclization sequence

Reactions of cyclic 1,3-dicarbonyl compounds with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles under the double catalytic activation conditions using both catalytic amounts of Lewis acid and amine catalysts provide a new direct synthetic route to enol lactones. Thus, 1,3-cyclohexanedione is allowed to react with 4-bromo-1-crotonoyl-3,5-dimethylpyrazole, in tetrahydrofuran at room temperature in the presence of both catalytic amounts (10 mol% each) of nickel(II) perchlorate hexahydrate and 2,2,6,6-tetramethylpiperidine, to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahydrobenzopyran-2(H),5-dione in a good yield. This reaction does not proceed or is too slow under the reaction conditions other than the double catalytic activation conditions.     

Catalytic fluorination of 1,3-dicarbonyl compounds using iodoarene catalysts

Catalytic fluorination of 1,3-dicarbonyl compounds with aqueous hydrofluoric acid proceeded efficiently with the aid of iodoarene catalysts in the presence of m-CPBA as a terminal oxidant. o-Iodotoluene, o-iodoanisole, and o-ethyliodobenzene showed a high catalytic efficiency to give 2-fluoro-1,3-dicarbonyl compounds in good yields.     

Lewis acid-mediated selective chlorinations of silyl enolate

A new method involving efficient, widely applicable, and highly selective alpha-chlorination of simple silyl enolate with Lewis acid and an alpha,alpha-dichloro-1,3-dicarbonyl controller unit was reported. Diastereoselectivity and enantioselectivity of the reaction were investigated. High reactivity and selectivity were achieved by using alpha,alpha-dichlorinated malonic ester.     

An unusual Mannich type reaction of tertiary aromatic amines in aqueous micelles

An efficient, unusual Mannich type reaction of tertiary aromatic amines, formaldehyde and 1,3-dicarbonyl compounds is described in aqueous micelles catalyzed by boric acid to afford dialkylaminoarylated 1,3-dicarbonyls. In this unusual Mannich type reaction, tertiary aromatic amines react with formaldehyde to generate an N-alkyl-N-(4-methylenecyclohexa-2,5-dienylidene)alkylaminium intermediate (aza quinone methide), which undergoes nucleophilic addition with 1,3-dicarbonyl compounds. The reaction is highly regioselective, and exclusively para functionalized products are formed in high yields.     

Synthesis of 1,3-diazapyrenes by the reaction of 1 H-perimidines with 1,3-dicarbonyl compounds

A method for the synthesis of 1,3-diazapyrenes has been developed based on the reaction of 1H-perimidines with 1,3-dicarbonyl compounds in polyphosphoric or 70% aq. sulfuric acid.     

Regio- and diastereoselective cyclization reactions of free and masked 1,3-dicarbonyl dianions with 1,2-dielectrophiles

Despite their simplicity and synthetic usefulness, cyclisation reactions of 1,3-dicarbonyl dianions with 1,2-dielectrophiles are problematic, since both dianions and 1,2-dielectrophiles are highly reactive compounds (low reactivity matching). In addition, 1,2-dielectrophiles are often rather labile, and reactions with nucleophiles can result in polymerisation, decomposition, formation of open-chained products, elimination or SET-reactions. These intrinsic limitations can be overcome by a proper reactivity tuning and by the use of electroneutral dianion equivalents (masked dianions) in Lewis acid catalysed reactions. The cyclisations reported herein allow for an efficient, regio- and stereoselective one-pot synthesis of biologically relevant ring systems.     

Cu(OTf)2 catalyzed cross-coupling reaction of 1,3-dicarbonyl derivatives with 2-oxo-1-pyrrolidine compounds

An efficient method for the cross-coupling reactions of 1,3-dicarbonyl compounds with 2-oxo-1-pyrrolidine compounds 1 was developed. Cu(OTf)₂ catalyzed C–C bond forming reactions using substrates 1 with 1,3-dicarbonyl compounds in chloroform, providing the corresponding compounds of 2-oxo-1-pyrrolidine bearing 1,3-dicarbonyl moiety in moderate to good yields.     

Synthesis of (1,3-adamantylene)bis-1,3-dicarbonyl compounds

Reactions of 1,3-dihydroxyadamantane with 1,3-dicarbonyl compounds in the presence of 5 mol % of In(OTf)₃ afforded a series of (1,3-adamantylene)bis-1,3-dicarbonyl compounds in yields of 25–83%.     

Direct generation of nucleophilic chiral palladium enolate from 1,3-dicarbonyl compounds: catalytic enantioselective Michael reaction with enones

Generation of chiral palladium enolates from 1,3-dicarbonyl compounds with the palladium aqua complex and its application to the highly efficient catalytic enantioselective Michael reaction with enones are described. The palladium aqua complexes are likely to supply Br?nsted base and Br?nsted acid successively during the reaction. The former activates the carbonyl compounds to give chiral palladium enolates, and the latter cooperatively activates enones. Using a catalytic amount (2-10 mol %) of the palladium complexes, the various 1,3-dicarbonyl compounds including diketones and beta-ketoesters were converted to the desired Michael adducts in good yields (69-92%) with excellent enantiomeric excesses (89-99% ee).     

Practical azidation of 1,3-dicarbonyls

An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed. The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant such as I(2) or 2-iodoxybenzoic acid (IBX)-SO(3)K/NaI. In particular, the latter method, as a new and well-balanced oxidizing agent, shows excellent functional group tolerance and substrate scope and thus allows access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds that would be more difficult to access by using traditional methods. Because the azide-containing products easily undergo 1,3-dipolar cycloaddition with alkynes, our report represents a novel route to analogues of sensitive complex molecules.     

Synthesis of functionalized 2-alkylidenetetrahydrofurans by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with epoxides

The Lewis acid mediated cyclization of epoxides with 1,3-bis(trimethylsilyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, results in the formation of 2-alkylidenetetrahydrofurans with a great variety of substitution patterns and functional groups. This includes the synthesis of 2,3'-bifuranylidenes and 7-oxabicyclo[4.3.0]nonanes. The cyclization of dienes with functionalized epoxides containing base-labile groups proceeds with good chemoselectivity. In all reactions, good regio- and E diastereoselectivities are observed. Based on the stereoselectivities observed for reactions of 1,2-disubstituted epoxides, a working hypothesis for the mechanism of the reaction is suggested.     

N-Phenacylpyridinium bromides in the one-pot synthesis of 2,3-dihydrofurans

A one-pot three-component process for the synthesis of highly functionalized 2,3-dihydrofurans from 1,3-dicarbonyl compounds, aromatic aldehydes, and N-phenacylpyridinium bromides has been developed. Benzylidene 1,3-dicarbonyl compounds could be generated in situ from aromatic aldehydes and 1,3-dicarbonyl compounds and then reacted smoothly with N-phenacylpyridinium bromides to produce 2,3-dihydrofurans in moderate to good yields. Piperidine/acetonitrile is the optimal condition for this process. To increase the efficiency of this reaction, this one-pot process was also conducted solvent-free under classical heating conditions and grinding conditions.