An (E)-selective synthesis of trisubstituted (E)-alpha,beta-unsaturated acid derivatives

Potassium alkoxides of N-acyloxazolidin-2-one derived syn-aldolates undergo a novel tandem intramolecular cyclisation elimination reaction to afford trisubstituted (E)-alpha,beta-unsaturated amides in high d.e., which may be converted into their corresponding acids or oxazolines in good yield.     

Nickel-catalysed reactions with trialkylboranes and silacyclobutanes

Nickel catalysis enables us to develop new reactions with trialkylboranes and silacyclobutanes of modest reactivity. A combination of Ni(cod)(2) and tri-tert-butylphosphine catalyses alkylation reactions of aldehydes and alpha,beta-unsaturated esters with various trialkylboranes of modest reactivity, suppressing conceivable beta-hydride elimination from alkylnickel intermediates. A nickel catalyst is also useful for 1,4-addition of bis(pinacolato)diboron to alpha,beta-unsaturated esters and amides. Nickel-catalysed reaction of silacyclobutanes with aldehydes results in ring opening to afford the corresponding alkoxyallylsilanes. In contrast, the ring expansion reaction of benzosilacyclobutene with aldehydes yields benzoxasilacyclohexenes. A nickel catalyst prepared from Ni(cod)(2) and tricyclohexylphosphine realises direct silylation of terminal alkenes with silacyclobutane furnishing vinylsilanes.     

Direct reaction of dibromoacetic acid with aldehydes promoted by samarium diiodide: an easy, efficient, and rapid synthesis of (E)-alpha,beta-unsaturated carboxylic acids with total stereoselectivity

A promoted SmI2 direct reaction of dibromoacetic acid with different aldehydes, followed by an elimination reaction also promoted by samarium diiodide, affords (E)-alpha,beta-unsaturated carboxylic acids 2 with total stereoselectivity. A mechanism to explain this transformation is proposed.     

Generation and tandem reactions of 1-alkenyl-1,1-heterobimetallics: practical and versatile reagents for organic synthesis

A practical and straightforward method for generation of versatile 1-alkenyl-1,1-heterobimetallic intermediates and their application to construction of functionalized building blocks are disclosed. Beginning with readily available air-stable 1-alkynyl-1-boronate esters, hydroboration with dicyclohexylborane generates 1-alkenyl-1,1-diboro species. In situ transmetallation with dialkylzinc reagents furnishes 1-alkenyl-1,1-heterobimetallic intermediates. Direct treatment with aldehydes followed by workup allows isolation of B(pin)-substituted allylic alcohols in 70-95% yield. The B(pin)-substituted allylic alcohols react with NBS to afford (E)-alpha,beta-unsaturated aldehydes in 51-77% yield via a semipinacol-type rearrangement. In situ treatment of 1-alkenyl-1,1-heterobimetallic intermediates with aldehydes followed by TBHP oxidation enables the preparation of alpha-hydroxy ketones. Under optimized conditions, addition of 1-alkenyl-1,1-heterobimetallic intermediates to a variety of protected alpha- and beta-hydroxy aldehydes proceeds with good to excellent control over diastereoselectivity to furnish differentially protected dihydroxy ketones. The 1-alkenyl-1,1-heterobimetallic intermediates have also been employed in tandem aldehyde addition/Suzuki cross-coupling reactions to provide densely functionalized allylic alcohols in good to excellent yields.     

Single-isomer trisubstituted olefins from a novel reaction of (E)-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters and amides

(E)-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters are converted to single isomer trisubstituted olefins bearing three different carbon substituents by cross-coupling under reflux. Mechanistic investigations suggest that this process transfers a hydrogen from the boronic acid to the alpha-position of the substrate and then introduces an aryl group to the beta-position of the intermediate template while replacing chloride. The reaction is highly stereoselective, showing preference for the E-isomer. The process proceeds through (E)-beta-chloro-alpha-aryl-alpha,beta-unsaturated esters that are transformed efficiently into the corresponding E-products through stereoselective Suzuki-type reactions giving single isomers. The observed stereochemistry is apparently enabled by the intermediacy of a palladium allenoate. The reaction involves a catalytic cycle in which Pd(II) is reduced to Pd(0) through the formation of biaryl-coupled products.     

CrCl2-promoted stereospecific and stereoselective alkyl- and silylcyclopropanation of alpha,beta-unsaturated amides

An efficient chromium-promoted alkyl- or silylcyclopropanation of alpha,beta-unsaturated amides is described. These reactions can be carried out on (E)- or (Z)-alpha,beta-enamides in which the C-C double bond is di-, or trisubstituted. This process takes place with total stereospecificity and the new stereogenic center is generated with high or total stereoselectivity. Some synthetic applications of the obtained silylcyclopropyl amides are also reported. Two mechanisms based on the generation of carbenoid or carbene complexes have been proposed to explain this cyclopropanation reaction.     

Highly diastereoselective tandem photoenolization-hetero-Diels-Alder cycloaddition reactions of o-tolualdehydes in the solid state

The (E)-photoenols generated in situ by photolysis of o-tolualdehydes 1-5 in the solid state react with the precursor aldehydes as dienophiles in a hetero-Diels-Alder cycloaddition fashion to afford trans-3-arylisochromanols in excellent yields and in a high diastereoselectivity. An examination of the reactivity of three different classes of rationally designed aldehydes shows that the tandem enolization-Diels-Alder cycloaddition occurs in the solid state efficiently for aldehydes whose (E)-photoenols (i) are more stable than their corresponding benzocyclobutenols and (ii) are not sterically congested. However, rapid cyclization to benzocyclobutenols is found to be the sole pathway for sterically encumbered (E)-enols derived from aldehydes 6-8. Given that the execution of heteromolecular reactions in the solid state is a challenge, the results obtained with simple crystalline o-tolualdehydes are remarkable and the strategy involving in situ generation of a dienol in the crystal lattice of a dienophile to achieve hetero-Diels-Alder reaction in a highly diastereoselective manner is heretofore unprecedented. In the context of enormous interest in tandem/domino reactions in contemporary synthetic organic chemistry, the results observed with o-tolualdehydes exemplify successful execution of tandem reactions in the solid state.     

Extremely Efficient Chiral Induction in Conjugate Additions of p-Tolyl alpha-Lithio-beta-(trimethylsilyl)ethyl Sulfoxide and Subsequent Electrophilic Trapping Reactions

Reaction of p-tolyl alpha-lithio-beta-(trimethylsilyl)ethyl sulfoxide with alpha,beta-unsaturated esters gave the conjugate addition products as a single diastereomer. The intermediate enolates were subsequently trapped with various alkyl halides or aldehydes to give the products with extremely high stereoselectivity. The reaction with alpha,beta-unsaturated ketones also proceeded with high diastereoselectivity. Protolysis of the enolates derived from the alpha-methyl-alpha,beta-unsaturated esters gave the products with high stereoselectivity. The stereo- and regioselective elimination of the sulfinyl group gave chiral homoallylic carboxylates.     

Samarium Triflate as Mild and Efficient Catalyst for Aza-Diels–Alder Reaction: A Facile Synthesis of cis-Fused Pyrano- and Furanoquinolines

Three-component coupling reactions of aldehydes, amines, and cyclic enol ethers have been carried out in the presence of samarium triflate to afford the corresponding pyrano and furanoquinolines in excellent yields with high endo-selectivity. The reaction conditions are mild and amenable to scale-up.     

Room temperature ionic liquids promoted three-component coupling reactions: a facile synthesis of cis-isoquinolonic acids

Room temperature ionic liquids are found to catalyze efficiently the three component-coupling reactions of aldehydes, amines and homophthalic anhydride under mild and convenient conditions to afford the corresponding cis-isoquinolonic acids in excellent yields with high cis-selectivity.     

Regiocontrolled, palladium-catalyzed bisfunctionalization of allenyl esters. Multicomponent coupling approaches to highly substituted alpha,beta-unsaturated delta-lactones

A palladium-catalyzed regioselective bisfunctionalization of allenyl esters with boronic acids (nucleophiles) and aldehydes (electrophiles) was demonstrated. The three-component coupling afforded alpha,beta-unsaturated delta-lactones under mild conditions and with excellent chemo-, regio-, and diastereoselectivity. Aromatic, heteroaromatic and vinylic boronic acids (R1B(OH)2) reacted with ethyl 2,3-butadienoate and benzaldehyde to afford the corresponding 4-R(1),6-Ph-disubstituted alpha,beta-unsaturated delta-lactones in 62-78% yields. Lactones derived from aromatic, heteroaromatic, and vinylic aldehydes were isolated in 51-58% yields, while aliphatic aldehydes were less reactive. The regiochemistry of bisfunctionalization of allenyl ester homologues remained controlled by the ester substituent, and the reactions afforded cis-4,5,6-trisubstituted alpha,beta-unsaturated delta-lactones and esters of (Z)-syn-3,4,5-trisubstituted-5-hydroxy-2-pentenoic acids in combined 47-65% yields. The superior performance of a pi-allylpalladium(II) dimer catalyst featuring an auxiliary allyl ligand derived from beta-pinene, among diverse palladium(II) catalysts, was demonstrated. A catalytic cycle involving an unsymmetrical bis-pi-allylpalladium complex as the key intermediate was proposed, and the communication highlights the synthetic potential of such intermediates. However, the efficiency of asymmetry transfer remained low (<20%).     

Stereospecific and stereoselective alkyl and silylcyclopropanation of alpha,beta-unsaturated amides

A novel chromium-promoted alkyl- and silyl cyclopropanation of (E)- or (Z)-alpha,beta-unsaturated amides in which the C-C double bond is di-, or trisubstituted is described. This process takes place with total stereospecificity, and the new stereogenic center is generated with high or total stereoselectivity. A mechanism is proposed to explain the cyclopropanation reaction.     

A novel pyrrolidine imide catalyzed direct formation of alpha,beta-unsaturated ketones from unmodified ketones and aldehydes

A method for direct, stereoselective preparation of (E)-alpha,beta-unsaturated ketones from ketones and aldehydes, promoted by a novel pyrrolidine imide organocatalyst, has been developed in moderate to high yields. Unlike the Claisen-Schmidt condensation and Lewis acid catalyzed tandem aldol-dehydration processes, this method provides mild reaction conditions to access alpha,beta-unsaturated ketones from simple, unmodified ketones. [reaction: see text]     

Aza-Diels-Alder reactions in ionic liquids: a facile synthesis of pyrano- and furanoquinolines

Room temperature ionic liquids are found to catalyze efficiently the three component-coupling reactions of aldehydes, amines and cyclic enol ethers such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran under mild and convenient conditions to afford the corresponding pyrano- and furanoquinolines in excellent yields with high endo-selectivity. Interestingly, 2,3-dihydrofuran afforded selectively endo-products under the similar reaction conditions.     

Efficient and stereoselective synthesis of beta-trifluoromethyl alpha,beta-unsaturated esters via iron(III) porphyrin-catalyzed olefination of ketones

beta-Trifluoromethyl alpha,beta-unsaturated esters were efficiently prepared by reactions of fluorine-containing ketones with diazo compounds via metalloporphyrin-catalyzed olefination in the presence of triphenylphosphine. The commercially available Fe(III)(TPP)Cl (TPP: tetraphenylporphyrin) is effective for catalyzing the olefination of a variety of trifluoromethyl ketones with different diazoacetate esters under mild conditions. The reactions proceeded with high yields (up to 95% isolated yield) and high stereoselectivity (up to 99% (E)-selectivity).     

Diastereoselective and enantiospecific synthesis of gamma-substituted alpha,beta-unsaturated nitriles from O-protected allylic cyanohydrins

gamma-Functionalized alpha,beta-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from enantioenriched cyanohydrin-O-phosphates and carbonates derived from alpha,beta-unsaturated aldehydes, either by palladium or iridium-catalyzed nucleophilic allylic substitution reactions with different nucleophiles. Appropriate reaction conditions for dibenzylamine, benzylamine, sodium azide, NaOAc, tetra-n-butylammonium acetate (TBAA), the corresponding sodium salts of phenol and N-hydroxysuccinimide and the carbonucleophile sodium dimethyl malonate are described. Different substituted O-protected cyanohydrins, such as carbonates and phosphates, derived from crotonaldehyde, (E)-hex-2-enal, oct-2-enal, 2-methylbut-2-enal, and cinnamaldehyde are used as allylic substrates. The substitution takes place with total retention of the configuration for the (E)-gamma-functionalized nitriles and with inversion of the configuration for the Z-isomers. In general, cyanohydrin-O-phosphates are the materials of choice to get the highest E-diastereoselectivity. Dibenzylamine is the best nucleophile for the synthesis of gamma-nitrogenated alpha,beta-unsaturated nitriles in the presence of either palladium or iridium catalysts when aliphatic compounds and cinnamaldehyde derivative are used (up to 98% dr). For the synthesis of gamma-oxygenated alpha,beta-unsaturated nitriles sodium or TBAA the reagents are selected to avoid epimerizations in up to 76% dr. Finally, the Tsuji-Trost reaction with sodium malonate works only under palladium catalysis in up to 70% dr.     

A convenient preparation of 3,3,3-trifluoro-1-propynylamines and their Lewis acid catalyzed reaction with carbonyl compounds leading to (z)-alpha-(trifluoromethyl)-alpha,beta-unsaturated amides

N,N-Dialkyl(3,3,3-trifluoro-1-propynyl)amines were readily prepared by a three-step procedure starting from commercially available 2,2,3,3,3-pentafluoropropanol. These fluorinated alkynylamines reacted smoothly with a variety of aldehydes or ketones in the presence of a catalytic amount of Lewis acid and molecular sieves 4A at ambient temperature to produce the corresponding alpha-(trifluoromethyl)-alpha,beta-unsaturated amides in good to excellent yields with high Z-stereoselectivity.     

Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions.

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.     

Indium(I) bromide-mediated coupling of dibromoacetonitrile with aldehydes followed by Boord elimination of bromine and oxygen of β-bromo alkoxides for preparation of 3-organyl-2-alkenenitriles

The organoindium compound derived from indium monobromide and dibromoacetonitrile reacts with carbonyl compounds to afford the corresponding 2-bromo-2-cyano-indium(III) alkoxide. The action of a second equivalent of indium monobromide onto the alkoxides derived from aldehydes promotes the Boord elimination of the β-related oxygen and bromine atoms leading to 2-alkenenitriles.     

Stereoselectivity in the aldol reaction: The use of chiral and achiral oxazolines as their boron azaenolates

Chiral oxazolines, as their boron enolates derived from various boron triflates, react with aldehydes to give erythro-selectivity (97% + %) with enantiomeric purities of 50–60%. Achiral oxazolines as their boron enolates derived from diisopinocampheylborane give, on reaction with aldehydes, β-hydroxy esters with high threo-selectivity (90+%) in 77–85% ee. A variety of structurally different oxazolines were also studied and many show high erythro -selectivity.