Asymmetric palladium-catalyzed benzylic nucleophilic substitution: high enantioselectivity with the DUPHOS family ligands

The asymmetric palladium-catalyzed benzylic reaction of 1-(2-naphthyl)ethyl acetate and its 6-methoxy substituted analogue with dimethyl malonate anion led to substitution products with up to 90% ee when the iPr-DUPHOS chiral ligand was used.     

Oxidative Addition of Dimethyl Malonate to Styrenes Mediated by Cerium(Iv) Ammonium Nitrate: Some Novel Observations

The oxidative addition of dimethyl malonate to ring substituted styrenes leads to the formation of substituted dimethyl (2-oxo-2-phenylethyl) malonate and methyl 2-oxo-5-phenyltetrahydrofuran-3-carboxylate along with small amounts of substituted dimethyl [2-(nitrooxy)-2-phenylethyl] malonate and dimethyl 2-methoxy-2-phenylethyl) malonate. A tentative mechanism which supports the formation of these products is also presented.     

Palladium-catalyzed asymmetric alkylation of 2-azaallyl acetates for the synthesis of β-carboxyaspartic acid derivatives

Palladium-catalyzed asymmetric alkylation of 2-azaallyl acetate, N-(diphenylmethylene)acetoxyglycine ester with a sodium salt of malonate ester was successfully carried out. High enantioselectivities were achieved using sodium dimethyl methylmalonate (98%ee) or sodium dimethyl malonate (93%ee) as a nucleophile with t-butyl ester of 2-azaallyl acetate in the presence of (S)-BINAP in acetonitrile.     

Reactions of Zinc Enolates Formed from 1-Aryl-2-bromo-2-phenylethanone or 2-Bromoindanone and Zinc,with Dimethyl 2-(1-Arylmethylene)malonates

Zinc enolates formed from 1-aryl-2-bromo-2-phenylethanones and zinc react with dimethyl 2-(1-arylmethylene)malonates to afford dimethyl 2-(1,3-diaryl-3-oxo-2-phenylpropyl)malonates. The latter react with cyclohexylamine, piperidine, or morpholine to give the corresponding monosubstituted amides. The zinc enolate derived from 2-bromoindanone and zinc reacts with dimethyl 2-(4-bromobenzylidene)malonate, yielding dimethyl 2-[(4-bromophenyl)(1-oxoindan-2-yl)methyl]malonate. The final products largely form as a single diastereomer.     

Reactions of styryl and phenylethynyl sulfones with some CH-acids

Reactions of methyl and p-tolyl phenylethynyl sulfones with enolated of dimethyl malonate and malononitrile lead to the formation of sulfonyl-substituted derivatives of ethylidenemalonic acid. Methyl (E)-β-styryl sulfone reacts with sodium enolates of dimethyl malonate, malononitrile, and methyl cyanoacetate to give common Michael adducts.     

Synthesis of indenes via palladium-catalyzed carboannulation of diethyl 2-(2-(1-alkynyl)phenyl)malonate and organic halides

Highly substituted indenes have been prepared in good yields by the palladium-catalyzed carboannulation of diethyl 2-(2-(1-alkynyl)phenyl)malonate with aryl, benzylic, and alkenyl halides. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed.     

Nucleophilic displacement of activated aryl triflates a new synthesis of oxindoles and arylacetic acids

2-Nitroaryl triflates undergo efficient base-catalyzed nucleophilic displacement by dimethyl malonate anion to yield dimethyl nitroarylmalonates, which subsequently are converted in high yields to nitroarylacetic acids and oxindoles.     

A Novel Synthesis of Dimethyl Malonate by Carbonylation of Methyl Chloroacetate Catalyzed by Cobalt Complex

Dimethyl malonate (DMM) is an important organic synthesis intermediate. Traditional synthetic method by reaction of mono-chloroacetic acid with sodium cyanide1 is poisonous and complicated. Therefore, an interest in green synthesis routes of DMM has risen greatly. The several processes for preparing DMM by carbonylation of methyl chloroacetate catalyzed by Co2(CO)8 have been reported2~5. However, Co2(CO)8 is unstable and must be prepared under high pressure (12 Mpa). Moreover, the yield…     

Palladium-catalyzed nucleophilic benzylic substitutions of benzylic esters

A palladium complex generated in situ from [Pd(eta3-C3H5)(cod)]BF4 and DPPF is a good catalyst for benzylic alkylation of benzyl methyl carbonate with the carbanion of dimethyl malonates. The catalytic reaction is applicable to a wide range of the benzylations of benzylic esters with malonates. The catalytic activity was heavily affected by the bite angle of the bidentate phosphine ligand on palladium. DPEphos ligand is superior to DPPF in the case of palladium-catalyzed benzylic amination of benzylic esters.     

Tandem transformations of bromo-substituted β-(methylsulfonyl)styrenes in reactions with dimethyl malonate,methyl cyanoacetate,and methyl acetoacetate

β-Bromo-β-(methylsulfonyl)styrene reacted with dimethyl malonate and methyl cyanoacetate in the presence of sodium hydride to give sulfonyl-substituted cyclopropanes, and sulfonyl-substituted 2,3-dihydrofuran was also formed in the reaction with methyl acetoacetate. Reactions of α-bromo-β-(bromomethylsulfonyl) styrene with dimethyl malonate and methyl cyanoacetate led to the formation of 2,3-dihydro-λ⁶-thiophene S,S-dioxide derivatives. In the reaction of α-bromo-β-(bromomethylsulfonyl)styrene with methyl acetoacetate, 2,3-dihydro-λ⁶-thiophene S,S-dioxide and 2,5-dihydro-λ⁶-thiophene S,S-dioxide derivatives and methyl acetoacetate O-alkylation product, methyl 3-[(E)-2-(bromomethylsulfonyl)-1-phenylvinyloxy]but-2-enoate, were obtained at a ratio of 2.7: 1.2: 1. α-Bromo-β-(methylsulfonyl)styrene reacted with dimethyl malonate to produce dimethyl 2-[2-(methylsulfonyl)-1-phenylethylidene]malonate. The reaction of β-bromo-β-(bromomethylsulfonyl) styrene with dimethyl malonate and methyl cyanoacetate were strictly stereoselective, and they afforded tetrahydro-λ⁶-thiophene S,S-dioxide derivatives. The reaction of the same substituted styrene with methyl acetoacetate was not stereoselective, and the products were two diastereoisomeric tetrahydro-λ⁶-thiophene S,S-dioxides and sulfonyl-substituted 2,3-dihydrofuran at a ratio of 2.3: 2.7: 1.     

Novel synthesis of conjugated dienes attached to a quaternary carbon center via Pd(0)-catalyzed deconjugative allylation of alkenylidenemalonates

Palladium(0)-catalyzed deconjugative allylation of alkenylidenemalonates and alkylidenemalonates was achieved for the first time. Reactions of dimethyl 2-((E)-but-2-enylidene)malonate with various allylic acetates using LHMDS as a base in DMF in the presence of Pd(2)dba(3) (2.5 mol %) and PPh(3) (10 mol %) proceeded at room temperature to give the corresponding alpha-allylation products in good yields in a regio- and stereoselective manner. This reaction can also be used for allylation of dimethyl ethylidenemalonate or dimethyl 2-((E)-pent-2-enylidene)malonate and give the desired alpha-allylation products in good yields.     

Synthesis and structures of the CH acid salts obtained in the reactions of malonic acid esters and malononitriles with 2,4,6-trinitrohalobenzenes in the presence of triethylamine

Reactions of dimethyl malonate, diphenyl malonate, methyl cyanoacetate, and malononitrile with 1-chloro-2,4,6-trinitrobenzene or 1-fluoro-2,4,6-trinitrobenzene in the presence of triethylamine in organic solvents gave stable brightly colored crystalline triethylammonium salts of the corresponding 2,4,6-trinitrophenylmalonic acid derivatives.     

A new tris-annulation reagent prepared from a butadiene telomer,and its application to steroid synthesis

Reaction of 1,7-octadien-3-one with dimethyl malonate, followed by the reduction of the ketone produced dimethyl (3-hydroxy-7-octenyl)malonate, which was converted to 9-decen-5-olide after hydrolysis and decarboxylation. Reaction of vinylmagnesium chloride with the lactone and the subsequent acylation afforded 7-acetoxy-1,11-dodecadien-3-one. This is a new tris-annulation reagent. (±)-D-homo-19-norandrosta-4-en-3-one was synthesized by using this tris-annulation reagent.     

New dihydroxy bis(oxazoline) ligands for the palladium-catalyzed asymmetric allylic alkylation: experimental investigations of the origin of the reversal of the enantioselectivity

The origin of the reversal of the enantioselectivity in the palladium-catalyzed allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate anion using chiral dihydroxy bis(oxazoline) "BO" ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol was investigated. To determine the structural effects of the dihydroxy BO ligand on this unique phenomenon, new homochiral dihydroxy BO ligands were prepared from L-threonine and L-serine and were assessed in the transformation. The results obtained with these novel BO ligands, compared with the one obtained by using the dihydroxy BO ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, reveal that the reversal in the enantioselectivity observed with the dihydroxy BO ligand depends on the structure of the ligand. The effect of different bases used to generate the dimethyl malonate anion was also examined. The results are discussed in terms of the interaction of one hydroxy group in the intermediate pi-allyl palladium complex with the dimethyl malonate anion.     

Synthesis and Characterization of a Boronated Metallophthalocyanine for Boron Neutron Capture Therapy

Synthesis of the first fully characterized, water-soluble boronated phthalocyanine is reported. Reaction of 4-nitrophthalonitrile with dimethyl malonate in the presence of base yielded dimethyl (3,4-dicyanophenyl)malonate which was converted into dimethyl (3,4-dicyanophenyl)propargylmalonate by sequential treatment with potassium hydroxide and propargyl bromide. Formation of the o-carborane cage was accomplished by reaction of the alkyne with decaborane in acetonitrile at reflux. High-temperature solid state condensation of the resulting o-carboranylphthalonitrile with cobalt(II) chloride followed by ester deprotection and cation exchange provided the water-soluble closo-carbonylphthalocyanine product. The product contains 40 boron atoms (27% boron by weight) and may be useful as a tumor-seeking boron delivery agent for boron neutron capture therapy of cancer.     

The application of Pd-complexes of trans-2,5-dialkylpyrrolidinylbenzyldiphenylphosphines to enantioselective allylic alkylation

The preparation of cationic palladium (η³-C₃H₅) complexes 6 and 7, possessing an enantiopure trans-2,5-dialkylpyrrolidinyl unit, is described. These complexes were applied to the enantioselective alkylation of the test substrate, 1,3-diphenylpropenyl acetate 8, with dimethyl malonate in good to high conversions with enantioselectivities of up to 90% ee for the 2,5-diethylpyrrolidinyl substituted complex 7. Attempts to optimise reaction conditions included variation of solvent and temperature and the source of the malonate nucleophile.     

Complexing and catalytic properties of easily available chiral iminophosphite based on biphenyl-2,2"-diol

A chiral iminophosphite ligand based on biphenyl-2,2"-diol and its chelates with rhodium(i) and palladium(ii) were synthesized for the first time. Successful use of these compounds in asymmetric allylic substitution was demonstrated. The enantioselectivity of palladium-catalyzed alkylation of methyl pent-3-en-2-yl carbonate with dimethyl malonate reached 70%, that in the alkylation of 1,3-diphenylallyl acetate with dimethyl malonate was 88%. In the rhodium-catalyzed sulfonylation of 1,3-diphenylallyl acetate with sodium p-toluenesulfinite, the enantioselectivity was 56%.     

A Short Effective Preparation of Chiral N,3-Dimethyl-5,7-Dioxo-2-Phenylhexahydro-1,4-Oxazepines

Abstract

An improved two-stage procedure has been devised for the synthesis in 50% yield of the title compounds from ephedrine or pseudoephedrine enantiomers and dimethyl malonate using cyanuric chloride/pyridine to lactonise the intermediate ?-hydroxyacids.     

Palladium-catalyzed asymmetric intramolecular allylation forming optically active vinylcyclopropane and vinyldihydrofurans

Reaction of 2-butenylene dicarbonate with dimethyl malonate and methyl acetylacetate in the presence of a chiral ferrocenylphosphine-palladium catalyst gave optically active dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (70% ee) and methyl 2-methyl-5-vinyl-4,5-dihydrofuran-3-carboxylate (59% ee), respectively.     

Solvent-dependent dynamic kinetic asymmetric transformation/kinetic resolution in molybdenum-catalyzed asymmetric allylic alkylations

Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.