The first sequential reaction promoted by manganese: complete stereoselective synthesis of (E)-alpha,beta-unsaturated esters from 2,2-dichloroesters and aldehydes

Alpha,beta-unsaturated esters were obtained with complete control of stereoselectivity utilizing a sequential reaction of dichloroesters with a variety of aldehydes, promoted by active manganese. This methodology is generally applicable, and the C-C double bond can be di- or trisubstituted. A mechanism based on a successive aldol-type reaction/beta-elimination is proposed to explain these results.     

Stereoselective synthesis of (Z)-alpha-halo-alpha,beta-unsaturated esters, and amides from aldehydes and trihaloesters or amides promoted by manganese

Preliminary results of a Mn-promoted sequential process directed toward the stereoselective synthesis of different (Z)-alpha-halo-alpha,beta-unsaturated compounds are described.     

An easy, efficient, and completely stereoselective synthesis of (E)-alpha,beta-unsaturated esters via sequential aldol-type/elimination reactions promoted by samarium diiodide or chromium dichloride

(E)-Alpha,beta-unsaturated esters can be obtained with complete stereoselectivity by reaction of different aldehydes and ethyl dibromoacetate promoted by SmI(2) or CrCl(2). The transformation takes place as two sequential reactions: an aldol-type reaction and a beta-elimination reaction.     

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.     

Stereoselective synthesis of (E)-trisubstituted alpha,beta-unsaturated amides and acids

Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a range of trisubstituted (E)-alpha,beta-unsaturated amides in >95% de, that may be subsequently converted into their corresponding (E)-alpha,beta-unsaturated acids or (E)-alpha,beta-unsaturated oxazolines in good yield. syn-Aldols derived from alpha,beta-unsaturated aldehydes gave their corresponding trisubstituted (E)-alpha,beta-unsaturated-amides with poorer levels of diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a 1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted (E)-alpha,beta-unsaturated amide. The (E)-selectivity observed during the E1cB-type elimination step has been rationalised using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol.     

Synthesis of (E)-alpha,beta-unsaturated amides with high selectivity by using samarium diiodide

Stereoselective beta-elimination of 2-chloro-3-hydroxyamides 1 is achieved by using samarium diiodide to yield alpha,beta-unsaturated amides 2, in which the C=C bond is di- tri-, or tetrasubstituted. The starting compounds 1 are easily prepared by reaction of the corresponding lithium enolates of alpha-chloroamides with aldehydes or ketones at - 78 degrees C. The influence of the reaction conditions and the structure of the starting compounds on the stereoselectivity of the beta-elimination reaction is also discussed.     

Efficient allylation of aldehydes promoted by carboxylic acids

A variety of carboxylic acids have been screened for mediating the allylation of aldehydes with allytributyltin in different solvents. A novel, general, and practical method of allylation of aldehydes promoted by carboxylic acids under mild reaction conditions has been developed. Among them, p-nitrobenzoic acid afforded high to quantitative yields of the homoallylic alcohol products, and can be easily recovered after workup by aqueous HCl. Glyoxylic acid self-catalyzed the allylation without adding any other promoter or catalyst to give the corresponding allylation product in good yield. The regioselectivity of the crotylation of aldehydes is tunable by controlling the acidity of the carboxylic acids. The crotylation of aldehydes produced the alpha-adduct as major products in moderate to good yields with CF(3)CO(2)H as a promoter. A possible mechanism for the allylation is also discussed.     

Highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides from 1-bromo-1-fluoroalkenes via palladium-catalyzed carbonylation reactions

The highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z approximately 1:1), which are readily available starting materials, have been found to isomerize to high E/Z ratios after storage at -20 degrees C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E >/= 98:2) ratio of the alpha-fluoro-alpha,beta-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z approximately 1:1) were reacted with HCOOH/NBu(3)/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining (Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed carboalkoxylation reactions at 70 degrees C, and the (E)-alpha-fluoro-alpha,beta-unsaturated esters were stereospecifically obtained. This methodology was also successfully applied for the stereospecific synthesis of (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides: the palladium-catalyzed carboamidation reaction of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides, respectively.     

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.     

Self-assisted tandem Michael-aldol reactions of alpha,beta-unsaturated ketones with aldehydes

The tandem Michael-aldol reaction of 1-[2-(methylsulfanyl)-phenyl]prop-2-en-1-one (1) or the seleno congener 4 with p-nitrobenzaldehyde in the presence of BF3.Et2O gave the Baylis-Hillman adduct 2 or 5 and onium salt 3 or 6, respectively, and selenochromanone 7 from 4.     

Sequential aldol condensation-transition metal-catalyzed addition reactions of aldehydes, methyl ketones, and arylboronic acids

Sequential aldol condensation of aldehydes with methyl ketones followed by transition metal-catalyzed addition reactions of arylboronic acids to form β-substituted ketones is described. By using the 1,1'-spirobiindane-7,7'-diol (SPINOL)-based phosphite, an asymmetric version of this type of sequential reaction, with up to 92% ee, was also realized. Our study provided an efficient method to access β-substituted ketones and might lead to the development of other sequential/tandem reactions with transition metal-catalyzed addition reactions as the key step.     

Stereoselective synthesis of (E)-alpha,beta-unsaturated esters via carbene-catalyzed redox esterification

[reaction: see text] Stereoselective, carbene-mediated redox esterification of alkynyl aldehydes provides mild and atom economical access to (E)-configurated, alpha,beta-unsaturated carboxylic esters. The organocatalytic method relies on the generation of activated carboxylates via extended/conjugated umpolung in the presence of catalytic amounts of carbene precursor and base.     

Stereoselective synthesis of (Z)-alpha-haloacrylic acid derivatives, and (Z)-haloallylic alcohols from aldehydes and trihaloesters or amides promoted by Rieke manganese

A Mn*-promoted sequential process directed toward the synthesis of (Z)-alpha-halo-alpha,beta-unsaturated esters or amides is described. In both cases, the process takes place with complete Z-stereoselectivity. In addition, (Z)-alpha-chloro-alpha,beta-unsaturated ketones and carboxylic acids, and (Z)-haloallylic alcohols were readily prepared from (Z)-alpha-halo-alpha,beta-unsaturated amides derived from morpholine, or esters. A mechanism has been proposed to explain the sequential process and the stereoselectivity observed.     

One-pot synthesis of aldehydes or ketones from carboxylic acids via in situ generation of Weinreb amides using the Deoxo-Fluor reagent

A one-pot, high yield conversion of carboxylic acids to the corresponding aldehydes and ketones is described. The highlight of this methodology is the in situ generation of Weinreb amides with the Deoxo-Fluor reagent, which undergo nucleophilic reaction with DIBAL-H and Grignard reagents.     

Proline promoted synthesis of ring-fused homodimers: self-condensation of alpha,beta-unsaturated aldehydes

1,2,4-Trisubstituted cyclohexadienals can be prepared synthetically by self-condensation of beta-methyl substituted alpha, beta-unsaturated aldehydes. While molecules with this structural scaffold have been observed in nature, the biological roles of these compounds have yet to be thoroughly investigated. Here we investigate the use of L-proline and its derivatives to effect synthesis of these ring-fused homodimers. The scope of this reaction is investigated with different substrates and proline derivatives. Mechanistic hypotheses are put forth supported by NMR and mass spectrometry studies. The method will enable diversification of this scaffold in sufficient quantities for biological investigations.     

POCl3 promoted metal-free synthesis of tertiary amides by coupling of carboxylic acids and N,N-disubstituted formamides

Herein we report a robust and synthetically useful catalyst-free amination methodology by the coupling of carboxylic acids and N-substituted formamides using POCl₃ as a promoter. Versatile amides with a wide array of substituent groups were prepared within only 1?h in good to excellent yields. And even multi-substituted aromatic carboxylic acids could give the desired products with satisfactory results.     

Asymmetric, organocatalytic, three-step synthesis of gamma-hydroxy-(E)-alpha,beta-unsaturated sulfones and esters

Efficient and enantiocontrolled synthesis of gamma-hydroxy-alpha,beta-unsaturated sulfones and esters are reported through the reaction of enantioenriched alpha-selenyl aldehydes with EWG-stabilized carbanions and then a one-pot selenide oxidation, in situ epoxide formation, and final in situ epoxide opening.     

Diastereoselective intermolecular cobalt-catalyzed reductive aldol reactions of alpha,beta-unsaturated amides with ketones

Under cobalt catalysis, diethylzinc mediates the conjugate reduction of alpha,beta-unsaturated amides to produce ethylzinc enolates that react with ketones in situ to produce tertiary alcohol-containing aldol products with up to >19:1 diastereoselectivity.     

Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: stereoselective synthesis of alpha-methyl-beta-hydroxy acids, esters, ketones, and 1,3-Syn and 1,3-anti diols

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.     

Highly stereoselective three-component reactions of phenylselenomagnesium bromide,acetylenic sulfones,and saturated aldehydes/ketones or alpha,beta-unsaturated enals or enones

beta-Phenylseleno-alpha-tolylsulfonyl-substituted alkenes were synthesized via the three-component conjugate-nucleophilic addition of acetylenic sulfones, phenylselenomagnesium bromide, and carbonyl compounds, such as aldehydes, aliphatic ketones, or alpha,beta-unsaturated enals or enones. The reaction is highly regio- and stereoselective with moderate to good yields. Functionalized allylic alcohols were obtained in the case of aldehydes and aliphatic ketones. In the case of alpha,beta-unsaturated enones, functionalized allylic alcohols or functionalized gamma,delta-unsaturated ketones were obtained, depending on the structures of the ketones.