Synthesis of functionalized alpha,alpha-disubstituted beta-alkynyl esters from allenoates through an alkynylenolate intermediate

Highly substituted alpha,alpha-disubstituted beta-alkynyl esters are readily prepared from allenyl esters and either alkyl halide, acid chloride, or alkyl chloroformate, mediated by an amide base. This highly efficient and mild process tolerates various functional groups and provides alpha,alpha-disubstituted beta-alkynyl esters in good to excellent yields. This method is especially suitable for the synthesis of 1,n-enynes or 1,n-diynes (n > 4). Electrophilic cyclization of 1,5-enyne gives a highly functionalized gamma-iodolactone, whereas its platinum-catalyzed cycloisomerization affords 1,3-cyclohexadiene.     

1-(2,4,6-triisopropylphenyl)ethylamine: a new chiral auxiliary for the asymmetric synthesis of gamma-amino acid derivatives

The title compound has proven to be an excellent chiral auxiliary for nitrones in SmI2-mediated reductive coupling with alpha,beta-unsaturated esters. A variety of such nitrones, prepared from aldehydes and enantiopure N-hydroxy-1-(2,4,6-triisopropylphenyl)ethylamine, afforded gamma-N-hydroxyamino esters in high yields and diastereomeric purity. These adducts, readily available as either enantiomer, could be transformed into gamma-N-acetoxyamino esters, N-Boc-gamma-amino esters, and gamma-lactams.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

A new procedure for preparation of carboxylic acid hydrazides

The standard method for preparing carboxylic acid hydrazides is hydrazinolysis of esters in alcoholic solutions. However, when applied to alpha,beta-unsaturated esters, the main product typically is the pyrazolidinone resulting from an undesired Michael-type cyclization. Other alternative methodologies reported for direct preparation of hydrazides from acids are inefficient. We developed an efficient and general process, involving preforming activated esters and/or amides followed by reaction with hydrazine, for the preparation of hydrazides including those of alpha,beta-unsaturated acids. This process gives the desired hydrazides in excellent yield and purity under mild conditions.     

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.     

Activation of organozinc reagents with t-Bu-P4 base for transition metal-free catalytic SN2' reaction

The t-Bu-P4 base was found to be an excellent catalyst for activating organozinc reagents and was used to promote the S(N)2' reaction of alpha,beta-unsaturated esters bearing a gamma-chloride using various organozinc reagents: these reactions proceeded in high yields with excellent chemo-and regioselectivity.     

A novel chiral sulfonium yilde: highly enantioselective synthesis of vinylcyclopropanes

A newly designed chiral sulfonium allylide, generated in situ from the corresponding sulfonium salt in the presence of KOBu(t), reacted with alpha,beta-unsaturated esters, ketones, amides, and nitriles to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters, ketones, amides, and nitriles with outstanding diastereoselectivity and excellent enantioselectivity in good to high yields. A mechanistic rationale is proposed.     

Olefination of ketones using a gold(III)-catalyzed Meyer-Schuster rearrangement

An atom-economical and efficient olefination strategy for ketones is described. Ethoxyacetylide addition followed by a gold-catalyzed Meyer-Schuster rearrangement affords alpha,beta-unsaturated esters, generally in excellent overall yield from the starting ketones. The alkynophilicity of Au3+ promotes an interaction with the electron-rich acetylenes that catalyzes the Meyer-Schuster rearrangement selectively over other conceivable pathways.     

alpha,beta-Unsaturated and cyclopropyl acyl radicals, and their ketene alkyl radical equivalents. Ring synthesis and tandem cyclisation reactions

Treatment of the alpha,beta-unsaturated selenyl esters 12 and 14 with Bu(3)SnH-AIBN produces the corresponding 2-cyclohexenones 13 and 15 respectively via presumed alpha-ketene alkyl radical intermediates, viz. 10. By contrast, the 2,7-diene esters 34 and 39 undergo tandem radical cyclisations producing diquinanes, e.g.(76%), and the corresponding allene-substituted alpha,beta-unsaturated selenyl ester 48 gives the cyclooctadienone 56 on treatment with Bu(3)SnH-AIBN in refluxing benzene. The selenyl ester 19 derived from chrysanthemic acid produces a mixture of the gamma,delta-unsaturated aldehyde 22 and the corresponding dimer 25a on treatment with Bu(3)SnH-AIBN. Furthermore, in the presence of methanol the only product from this reaction was the bis(methyl ester) dimer 25b, thereby lending further credence to the involvement of ketene alkyl radical intermediates in these reactions, and in the aforementioned reactions involving 2,6- and 2,7-diene selenyl esters. Treatment of the cyclopropane selenyl esters and , containing keto- and oxy-group functionality in their side-chains, with Bu(3)SnH-AIBN led to excellent syntheses of the enol lactone 66 (76%) and the trans-fused bicyclo[6.1.0]nonane 67 (80-95%) respectively.     

Novel method for high-performance liquid chromatography of azo derivatives of conjugated and unconjugated bilirubin

A method for the separation and quantitation of ethyl anthranilate or p-iodoaniline azo derivatives of bile pigments was developed using reversed-phase high-performance liquid chromatography. A convenient separation was achieved in 15 min, permitting the quantitation of the unconjugated azo-dipyrrole (alpha o) and its glucuronide (delta), xyloside (alpha 2) and glucoside (alpha 3) conjugates. The pathological beta- and gamma-azo pigments, derived from bilirubin glucuronide isomers that occur in cholestatic bile or plasma, are also detected in this system. The results of this method as applied to bile from 25 healthy dogs were in excellent agreement with the values obtained by reversed-phase chromatography of bilirubin and its mono- and dimethyl esters produced from the corresponding conjugates by alkaline methanolysis. This system permits the sensitive and convenient determination of bilirubin and its conjugation pattern in biological fluids.     

Ph3As-catalyzed wittig-type olefination of aldehydes with diazoacetate in the presence of Na2S2O4

In the presence of sodium hydrosulfite and a catalytic amount of AsPh3 and Fe(TCP)Cl, aldehydes react with ethyl diazoacetate to give the corresponding alpha,beta-unsaturated esters in high yields with excellent stereoselectivities (E/Z > 50/1).     

Catalytic enantioselective conjugate reduction of lactones and lactams

A dramatic acceleration of the enantioselective copper-catalyzed conjugate reduction of alpha,beta-unsaturated lactones, lactams, and esters is reported upon addition of alcohol additives. Good to excellent yields and enantioselectivities were realized using a catalyst generated in situ from CuCl(2).H(2)O, t-BuONa, p-tol-BINAP, and PMHS, and this methodology was applied to the synthesis of (-)-Paroxetine.     

Functionalization of alpha,beta-unsaturated esters and ketones: a facile and highly stereoselective one-pot approach to N-protected alpha,beta-dehydroamino acid derivatives

A new, facile, and highly stereoselective protocol toward alpha,beta-dehydroamino acid derivatives has been developed. The one-pot synthesis was very convenient to perform by using the aminohalogenation reaction of alpha,beta-unsaturated esters and ketones followed by treatment with specific bases. Only two [2.2.2] bicyclic organic bases were found to be effective for this transformation. Good yields (58-68%) and excellent Z-selectivity were obtained for 12 examples. [reaction: see text]     

Virtually complete E-selective alpha,beta-unsaturated ester synthesis by Hg(OTf)2-catalyzed hydration of sec-ethoxyalkynyl acetate

The reaction of alkyl-substituted sec-ethoxyalkynyl acetates with water catalyzed by Hg(OTf)2 afforded alpha,beta-unsaturated esters in excellent yield with high catalytic turnover up to 1000 times under very mild reaction conditions with virtually complete E-selectivity, superior even to that of the HWE reaction.     

Synthesis, structure, and E-Z isomerization of beta-(hetero)aryl-alpha-nitro-alpha,beta-enals

The first general methodology for the gram-scale preparation of previously overlooked beta-(hetero)aryl-alpha-nitro-alpha,beta-enals (3) is reported. Condensation of (hetero)aromatic aldehydes with 2-nitroethanol gave the E-isomers of uncommon beta-(hetero)aryl-alpha-hydroxymethyl-alpha,beta-unsatured-nitroalkenes (2), as determined by NOE and X-ray studies. alpha-Nitro-alpha,beta-enals 3 were subsequently obtained by hypervalent iodine oxidation of 2 as E-Z-mixtures in solid form. They showed varied stability and solvent-dependent thermal-promoted and photopromoted E-Z interconversion. Starting with furfural, experimental conditions were developed to prepare the corresponding nitroenal 3a enriched in either the E or the Z isomer: E-3a/Z-3a approximately 90/10 and 20/80, respectively. In contrast with other structurally related compounds, nitroenals 3 have their (hetero)aryl-vinyl unit and their formyl and nitro groups all in a planar arrangement, both in solid form and in solution; accordingly, they are colored compounds with predicted high dipole moments. As deduced from solution-NMR and X-ray data, the C=C and the C=O double bonds in 3 are exclusively s- cis-oriented; this disposition corresponds in fact to the DFT-computed most stable conformer.     

Conjugate addition of arylsilanes to unsaturated carbonyl compounds catalyzed by rhodium in air and water

ArSiCl3 and Ar2SiCl2, believed to be unstable in aqueous media, reacted efficiently with alpha,beta-unsaturated ketones and esters in air and water (in the presence of sodium fluoride and a rhodium catalyst), giving good to excellent yields of the desired conjugate addition products.     

One-pot organocatalytic domino Michael/alpha-alkylation reactions: direct catalytic enantioselective cyclopropanation and cyclopentanation reactions

The development of one-pot organocatalytic domino Michael/alpha-alkylation reactions between bromomalonates or bromoacetoacetate esters and alpha,beta-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99 % ee. The catalytic domino Michael/alpha-alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cyclopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of beta-malonate esters (91-97 % ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.     

Catalytic intermolecular allylic C-H alkylation

The first electrophilic Pd(II)-catalyzed allylic C H alkylation is reported, providing a novel method for formation of sp3-sp3 C C bonds directly from C H bonds. A wide range of aromatic and heteroaromatic linear (E)-alpha-nitro-arylpentenoates are obtained as single olefin isomers in excellent yields directly from terminal olefin substrates and methyl nitroacetate. The use of DMSO as a pi-acidic ligand was found to be crucial for promoting functionalization of the pi-allylPd intermediate. Products from this reaction are valuable synthetic intermediates and are readily transformed to amino esters via selective reduction and optically enriched alpha,alpha-disubstituted amino acid precursors via asymmetric conjugate addition.     

Palladium-catalyzed enantioselective conjugate addition of arylboronic acids

[reaction: see text] The first asymmetric palladium-catalyzed conjugate addition of arylboronic acids to alpha,beta-unsaturated aldehydes, ketones, and esters is described. For cyclic substrates, excellent chemo-, regio-, and enantioselectivities are achieved when a Pd(O2CCF3)2/DuPHOS catalyst is applied.     

Intermolecular cross-double-michael addition between nitro and carbonyl activated olefins as a new approach in C-C bond formation

A novel intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins has been developed through Lewis base catalysis. The reaction took place with a large group of beta-alkyl nitroalkenes and alpha,beta-unsaturated ketone/esters, producing an allylic nitro compound in good to excellent yields.