Chiral phosphine lewis bases catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins

In the aza-Baylis-Hillman reaction of N-sulfonated imines (N-arylmethylidene-4-methylbenzenesulfonamides and others) with methyl vinyl ketone, ethyl vinyl ketone, and acrolein, we found that, in the presence of a catalytic amount of chiral phosphine Lewis base such as (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol LB1 (10 mol %) and molecular sieve 4A, the corresponding aza-Baylis-Hillman adducts could be obtained in good yields with good to high ee (70-95% ee) at low temperature (approximately -30 to -20 degrees C) or at room temperature in THF, respectively. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate or naphthyl acrylate gave the adducts in good to high yields (60-97%) with moderate ee (52-77%). The mechanistic insight has been investigated by 31P and 1H NMR spectroscopic measurements. The key enolate intermediate, which has been stabilized by intramolecular hydrogen bonding, has been observed by 31P and 1H NMR spectroscopy. An effective bifunctional Lewis base and Bronsted acid phosphine Lewis base system has been disclosed in this catalytic, asymmetric aza-Baylis-Hillman reaction.     

Reactions of arylaldehydes and N-sulfonated imines with dimethyl acetylenedicarboxylate catalyzed by nitrogen and phosphine lewis bases

[reaction: see text] In the reaction of arylaldehydes or N-sulfonated imines (0.5 mmol) with dimethyl acetylenedicarboxylate (DMAD) (0.6 mmol) catalyzed by pyridine or DMAP (20 mol %), we found that (E)-2-aryl-but-2-enedioic acid dimethyl ester 1 or (E)-2-[aryl-(toluene-4-sulfonylimino)methyl]-but-2-enedioic acid dimethyl ester 2 was formed in good yields at 60 degrees C in THF. A plausible mechanism has been proposed.     

An unexpected highly stereoselective double aza-Baylis-Hillman reaction of sulfonated imines with phenyl vinyl ketone

The aza-Baylis-Hillman reaction of N-sulfonated imine with phenyl vinyl ketone gave the double aza-Baylis-Hillman adduct in good yields with excellent stereoselectivities in the presence of Lewis base 1,4-diazabicyclo[2.2.2]octane.     

A general organic catalyst for asymmetric addition of stabilized nucleophiles to acyl imines

Cinchona alkaloid-derived thiourea catalysts promote nucleophilic additions to acyl imines for the asymmetric synthesis of secondary amine adducts. The hydroquinine-derived thiourea catalyst efficiently promotes the aza-Henry reaction of nitroalkane with acyl imines, affording β-nitroamines in good yields with enantioselectivities of 90-98% ee and diastereoselectivities up to 97%. The scope of the reaction also includes dimethyl malonate as a nucleophile to access β-amino esters in high enantiopurity. Under the optimized reaction conditions, secondary amine adducts of high enantiopurity are generated based on various aromatic and α,β-unsaturated acyl imines.     

New multifunctional chiral phosphines and BINOL derivatives co-catalyzed enantioselective aza-Morita-Baylis-Hillman reaction of 5,5-disubstituted cyclopent-2-enone and N-sulfonated imines

New multifunctional chiral phosphine (phosphine-amide type) and BINOL derivative co-catalyzed asymmetric aza-MBH reaction of 5,5-disubstituted cyclopent-2-enones with N-sulfonated imines afforded the corresponding optically active adducts in good to outstanding yields with moderate to good ee's under mild conditions. The steric hindrance environment of BINOL derivatives as well as the nucleophilicity of the phosphorus center and the acidity of free OH which could significantly affect the stereochemical and chemical outcomes had been discussed, indicating the co-catalyzed system is very important to this particular asymmetric aza-MBH reaction.     

A convenient route to enantiopure 3-aryl-2,3-diaminopropanoic acids by diastereoselective Mannich reaction of camphor-based tricyclic iminolactone with imines

A novel and convenient route to the asymmetric synthesis of 2,3-diamino acids via Mannich reaction of iminolactones 1a and 1b with N-protected imines has been achieved in good yields (up to 95%) and high diastereoselectivity (dr: >99:1). Hydrolysis of the Mannich adducts under acidic conditions furnished the desired 3-aryl-2,3-diaminopropanoic acids in good yields (up to 85%) with excellent enantiomeric excesses (99% ee).     

Abnormal aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butadienoate and penta-3,4-dien-2-one

[reaction: see text] The attempted aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butadienoate or penta-3,4-dien-2-one gave azetidine derivatives in the presence of DABCO. In the case of the aza-Baylis-Hillman reaction of N-tosylated imines with ethyl 2,3-butandieonate catalyzed by DMAP, novel dihydropyridine derivatives were formed.     

Asymmetric catalytic aza-Morita-Baylis-Hillman reaction using chiral bifunctional phosphine amides as catalysts

The asymmetric catalytic aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with α,β-unsaturated ketones has been successfully conducted by using chiral bifunctional phosphine amides as catalysts. A series of new chiral bifunctional phosphine amides were designed, synthesized, and systematically studied for this asymmetric reaction. The corresponding aza-MBH adducts were obtained in good yields (75-99%) and up to very good enantiomeric excesses (51-95% ee) under mild conditions.     

Chiral binaphthylthiophosphoramide-cu(I)-catalyzed asymmetric addition of diethylzinc to N-sulfonylimines

In the presence of a catalytic amount of chiral binaphthylthiophosphoramide L2 (6 mol %) and Cu(I) (3 mol %), the asymmetric addition of diethylzinc to N-sulfonylimines could be achieved in good yields with moderate to high ee (63-93% ee) at 0 degrees C in toluene. A novel chiral binaphthylthiophosphoramide ligand system for this asymmetric addition reaction has been explored.     

Highly efficient aza-Baylis-Hillman reaction of N-tosylated imines with MVK, acrolein, and phenyl acrylate or alpha-naphthyl acrylate: Lewis base effects and a convenient method to synthesize alpha,beta-unsaturated beta-amino carbonyl compounds

This paper describes several highly efficient aza-Baylis-Hillman reactions of N-tosylated imines with MVK, acrolein, and phenyl acrylate or alpha-naphthyl acrylate in the presence of a Lewis base. In most cases, the reaction can be completed within 1 h using the appropriate Lewis base catalyst. An efficient method to synthesize beta-amino ketones, aldehydes and esters in high yields and short reaction time has been developed.     

Novel bifunctional chiral thiourea catalyzed highly enantioselective aza-Henry reaction

A novel bifunctional chiral thiourea organocatalyst bearing a glycosyl scaffold and a tertiary amino group was synthesized starting from readily available alpha-D-glucose. This thiourea was proven to be an effective organocatalyst for the asymmetric aza-Henry reaction between N-Boc imines and nitromethane. The corresponding adducts were obtained in good to excellent yields with excellent enantioselectivities (up to 99.8% ee). In addition, the reaction of nitroethane also proceeded smoothly with excellent enantioselectivity, albeit with low to good diastereoselectivities.     

α-Amido sulfones: novel substrates for the practical and efficient aza-Morita-Baylis-Hillman reaction under neat conditions

α-Amido sulfones undergo aza-Morita-Baylis-Hillman reaction efficiently with alkyl acrylates under neat conditions in the presence of DABCO at room temperature. These sulfones generate aryl imines in the presence of DABCO and form the corresponding adducts in high yields (85-94%) within 9-12 h.     

Asymmetric hetero-Diels-Alder reactions of N-sulfinyl dienophiles using chiral bis(oxazoline)-copper(II) and -zinc(II) triflates

Asymmetric hetero-Diels-Alder (HDA) reactions of N-sulfinyl dienophiles using bis(oxazoline)-copper(II) and -zinc(II) triflates are described. The cycloadditions with cyclic and acyclic 1,3-dienes have been studied. In most cases, good enantioselectivities (70-98% ee) and yields (60-85%) were obtained with stoichiometric amounts of the Lewis acids. Cyclic dienes gave the endo adducts as major products, while acyclic dienes provided cis adducts. The HDA adducts have been transformed into N-protected alpha-amino acid methyl esters, amino alcohols, and homoallylic amines. A stereochemical model, which accounts for the enantiofacial selectivity of the HDA reaction by a tetrahedral metal center, has been proposed. Mechanistic studies revealed positive nonlinear effects, assumed to arise from the formation of less-reactive heterochiral complexes. Investigation of the temperature dependence of the enantioselectivity indicated that at least two selective reaction steps exist in the zinc-catalyzed reaction. Reactions run with 10 mol % chiral Lewis acid gave poor yields and selectivities. However, in combination with TMSOTf (100 mol %), high yields (68-86%) and enantioselectivities (97-98% ee) were obtained.     

Catalytic asymmetric addition of arylboronic acids to isatins using C2-symmetric cationic N-heterocyclic carbenes (NHCs) Pd2+ diaqua complexes as catalysts

A catalytic asymmetric addition of arylboronic acids to isatins has been achieved by using chiral cationic C(2)-symmetric N-heterocyclic carbene (NHC) Pd(2+) diaqua complexes as the catalysts. The reaction can be performed under convenient conditions to give the corresponding adducts in good to high yields (79-94%) and moderate to excellent enantioselectivities (up to 94% ee) in the presence of LiOAr as the promoter which was generated in situ.     

Synthesis of novel chiral oxazoline ligands and application in the highly enantioselective diethylzinc addition to N-diphenylphosphinoylimines

Two sets of novel chiral oxazoline ligands were designed and conveniently prepared from readily available l-aspartic acid and evaluated in enantioselective diethylzinc addition to N-diphenylphosphinoyl imines. In the presence of stoichiometric amounts of these ligands, high enantioselectivities (up to 95% ee) and yields (up to 85%) were achieved for several aromatic imines in toluene at room temperature. Furthermore, the effect of the structure of the ligand on the reaction was studied.     

Baylis-Hillman reactions of N-tosyl aldimines and aryl aldehydes with 3-methylpenta-3,4-dien-2-one

The attempted Baylis-Hillman reactions of N-tosyl aldimines and aryl aldehydes with 3-methylpenta-3,4-dien-2-one gave the corresponding Baylis-Hillman adducts 3 and 6 in moderate to good yields in the presence of DMAP in DMSO, respectively. In the case of the aza-Baylis-Hillman reactions of N-tosyl aldimines with 3-methylpenta-3,4-dien-2-one catalyzed by PBu3, the corresponding aza-Baylis-Hillman derivatives 4 and 5 were formed at the same time.     

Asymmetric Mannich reactions of beta-keto esters with acyl imines catalyzed by cinchona alkaloids

Cinchona alkaloids catalyze the enantioselective Mannich reaction of beta-keto esters with acyl aryl imines. The reaction requires 10 mol % of cinchonine or cinchonidine. The reaction products are obtained in good yields (81-99%), high enantioselectivities (80-96% ee), and in diastereoselectivities that range from 1:1 to >95:5. The cinchonine-catalyzed reaction provides access to highly functionalized building blocks used in the asymmetric synthesis of a dihydropyrimidone and beta-amino alcohol.     

Palladium-catalyzed asymmetric silaboration of allenes

An enantioselective silaboration of allenes was achieved using an achiral silylborane in the presence of a palladium catalyst bearing a chiral monodentate phosphine ligand. (R)-2-Bis(3,5-dimethylphenyl)phosphino-1,1'-binaphthyl gave the highest enantioselectivities in the addition of (diphenylmethylsilyl)pinacolborane to the internal C=C bond of terminal allenes at 0 degrees C, giving the corresponding beta-borylallylsilanes in high yields with high enantiomeric excesses. The enantioselectivity depended on the bulkiness of substituents of allenes: the enantiomeric excesses were found to be 91-93% ee (R = tert- and sec-alkyl), 88-90% ee (R = aryl), and 80-82% ee (R = prim-alkyl and Me) at 0 degrees C. Perfect chirality transfer was observed in the intramolecular cyclization reactions of the functionalized allylsilanes, affording highly enantioenriched cyclic alkenylboranes, which underwent Suzuki-Miyaura coupling with aryl halides.     

Enantioselective Michael addition of 3-aryl-substituted oxindoles to methyl vinyl ketone catalyzed by a binaphthyl-modified bifunctional organocatalyst

The enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles with methyl vinyl ketone promoted by binaphthyl-modified bifunctional organocatalysts was investigated. The corresponding Michael adducts, containing a quaternary center at the C3-position of the oxindoles, were generally obtained in high yields with excellent enantioselectivities (up to 91% ee).     

Chiral biscinchona alkaloid promoted asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones with Morita-Baylis-Hillman carbonates

A highly diastereo- and enantioselective asymmetric allylic alkylation reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and MBH carbonate by a chiral biscinchona alkaloid catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 97%) with very good diastereo- (up to 98:2 dr) and enantioselectivities (up to 95% ee).