Radical one-pot α,ß-dual and ß-mono-oxymethylation of alkylidenemalonate.

Dimethylzinc-mediated radical conjugate addition reaction of dimethyl alkylidenemalonates with iodomethyl pivalate gave a high yield of the α,ß-dual oxymethylation product in one pot under air and the ß-pivaloyloxymethylation product under argon.

High performance of N-alkoxycarbonyl-imines in triethylborane-mediated tin-free radical addition.

Triethylborane-mediated tin-free radical alkylation of N-alkoxycarbonyl-imines, such as N-Boc-, N-Cbz-, and N-Teoc-imines, proceeded smoothly at a low temperature (-78 to -20 °C) to give the corresponding adducts in high yield. Although the formation of isocyanate was the major unfavorable reaction at room temperature, a one-pot conversion of N-Boc-imine to N-ethoxycarbonyl-adduct was possible through the corresponding isocyanate generated in situ. The higher performance of N-alkoxycarbonyl-imine than those of N-Ts- and N-PMP-imines is rationalized by a moderate electron-withdrawing character of an alkoxycarbonyl group that makes both addition of alkyl radical and trapping of the resulting aminyl radical by triethylborane efficiently fast.

General entry to asymmetric one-pot [N + 2 + n] cyclization for the synthesis of three- to seven-membered azacycloalkanes.

Enantio- and diastereoselective one-pot synthesis of three- to seven-membered cis-azaheterocycles was achieved using a triggered asymmetric conjugate addition reaction of lithium amide with an enoate, followed by alkylation of the resulting lithium enolate with α,ω-dihaloalkane and N-alkylation. Isomerization of cis-azaheterocycles with a base yielded the trans-product, constituting a one-pot synthesis of cis-azacycles and a two-step synthesis of trans-azacycles. The four-step asymmetric synthesis of nemonapride highlights the general utility of the method.

Phosphazene Base-Catalyzed Intramolecular Hydroamidation of Alkenes with Amides.

A method for the synthesis of cyclic amides via phosphazene base-catalyzed intramolecular hydroamidation of amide alkenes was developed. The reaction using a catalytic amount of P4-base had a good functional group tolerance and a broad substrate scope and could also be used to synthesize lactam, cyclic urea, and oxazolidinone compounds. This catalytic system was expanded to a one-pot intramolecular hydroamidation and intermolecular hydroalkylation. Deuterium labeling and radical trapping experiments provided mechanistic insights into the catalytic cycle of the hydroamidation reaction.

Chiral N-heterocyclic carbene-copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides: steric and electronic effects on γ-selectivity.

Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve γ-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High γ-selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed σ-allyl copper intermediate enhance the rate of the reductive elimination to give γ-products as major isomers.

Stereoselective formal synthesis of (+)-allokainic acid via thiol-mediated acyl radical cyclization.

Stereoselective formal synthesis of (+)-allokainic acid was accomplished starting from L-glutamate by using a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly diastereoselective manner to give trans-4,5-disubstituted pyrrolidin-3-one without the production of the cis-isomer. The pyrrolidinone was then converted into the established synthetic intermediate of (+)-allokainic acid via the iron-catalyzed coupling reaction with an isopropenyl Grignard reagent.

Stereoselective radical addition of an acetal to sterically tuned enantiomerically pure N-sulfinyl imines.

Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enantiomerically pure N-sulfinyl imines using dimethylzinc-air and boron trifluoride diethyl etherate. Higher levels of stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol with high enantiomeric purity were obtainable from the sulfonamide product.

Chiral amidophosphane-rhodium(i)-catalyzed asymmetric conjugate arylation of acyclic enones with arylboronic acids.

A catalytic asymmetric conjugate arylation of acyclic alpha,beta-unsaturated ketones with arylboronic acids was catalyzed by 3 mol% of chiral amidomonophosphane 1-rhodium(I) in the presence of potassium hydroxide in a mixture of 1,4-dioxane and water at 70 degrees C to afford 1,4-conjugate arylated acyclic ketones with high enantiomeric excess in high chemical yield. Thirteen examples of the reaction demonstrate the general applicability of the catalytic system.

Chemoselective conjugate addition of dimethylzinc-mediated ether and acetal radicals to alkylidenemalonates and asymmetric reactions.

Cyclic and acyclic ether or acetal radicals were generated directly from ethers or acetals by the action of dimethylzinc-air, and their subsequent conjugate addition reaction with alkylidenemalonates afforded the corresponding conjugate adducts in reasonably high yields. The reaction with benzylidenemalonates bearing formyl and imino groups gave chemoselectively the conjugate addition products. The asymmetric reaction of bis(8-phenylmenthyl) benzylidenemalonate proceeded diastereoselectively to provide the adduct with 93:7 dr.

Asymmetric radical addition of ethers to enantiopure N-p-toluenesulfinyl aldimines, mediated by dimethylzinc-air.

Asymmetric radical addition of ethers to enantiopure aromatic N-p-toluenesulfinyl aldimines has been achieved. The requisite radicals were generated by dimethylzinc-air. Lewis acid activation of the N-p-toluenesulfinyl aldimines followed by radical addition gives a mixture of sulfinamide and sulfonamide products. Subsequent treatment of the mixture with dry m-CPBA affords the sulfonamide product in enantiomerically enriched form. [reaction: see text]

Tin-free intermolecular addition of primary alkyls to imines via the dimethylzinc-air radical process.

[reaction: see text] A dimethylzinc-air initiator was applied to the generation of primary alkyl radicals from alkyl iodides. The addition of the generated primary alkyl radicals to N-tosylimines was accelerated by the action of boron trifluoride-diethyl etherate and copper(II) triflate to give the corresponding adducts in good yields after 2-3 h. Air oxygen was essential for the reaction to proceed, showing involvement of a radical process in the reaction.

Initiator-dependent chemoselective addition of THF radical to aldehyde and aldimine and its application to a three-component reaction.

[reaction: see text] The product distribution of the three-component reaction of aldehydes, arylamines, and THF was dependent on a radical initiator, preferentially giving the corresponding THF adducts of imines with dimethylzinc and adducts of aldehyde with triethylborane.

Radical addition of ethers to imines initiated by dimethylzinc.

Ethers undergo addition to imines in the presence of dimethylzinc and air through a radical process. [reaction: see text]

Asymmetric construction of three contiguous stereogenic centers by conjugate addition-alkylation of lithium ester enolate.

A chiral ligand- and lithium amide-assisted asymmetric conjugate addition of lithium enolate of propionate to cyclopentenecarboxylate gave the corresponding lithium enolate, whose allylation gave the key intermediate of the marine alkaloid halichlorine as a single diastereomer with moderate enantioselectivity.

Asymmetric construction of quaternary carbon centers by sequential conjugate addition of lithium amide and in situ alkylation: utility in the synthesis of (-)-aspidospermidine.

Chiral diether ligand-controlled asymmetric conjugate addition of a lithium amide to cyclopentenecarboxylate and subsequent in situ alkylation gave a chiral cyclopentane derivative bearing a quaternary carbon with high enantio- and diastereoselectivity. The cyclopentane derivative was converted successfully to (-)-aspidospermidine.

Asymmetric construction of binaphthyl by the chiral diether-mediated conjugate addition of naphthyllithium to naphthalenecarboxylic acid 2,6-di-t-butyl-4-methoxyphenyl ester.

Two ways for the synthesis of binaphthyl were examined based on a chiral ligand-mediated asymmetric conjugate addition of 1-naphthyllithium to naththalene-2-carboxylic acid 2,6-di-t-butyl-4-methoxyphenyl esters. The one pot method by conjugate addition-elimination gave a relatively higher enantioselectivity than the two step synthesis based on addition and subsequent oxidative aromatization.

Steric tuning of the amidomonophosphane-rhodium(I) catalyst in asymmetric addition of arylboroxines to N-phosphinoyl aldimines.

Highly enantioselective rhodium-catalyzed addition of arylboroxines to N-phosphinoylaldimines was realized by the steric tuning of a diphenylphosphorus moiety to a di(o-tolyl)phosphorus moiety of a chiral amidomonophosphane. The presence of MS 4 A in a 5:1 solvent mixture of dioxane-propanol was essential to afford the corresponding diarylmethylamines in high yield.

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides: a possible intermediate characterized.

Two 1:1 noncovalent mixed aggregates between a lithium enolate and two diastereomeric lithium amides have been identified spectroscopically in THF. The NMR data, as well as DFT theoretical calculations, shine some light on a puzzling reversal of induction, observed when switching from one diastereomer of the amide to the other in the enantioselective Michael addition of the lithium enolate to an unsaturated ester.

Consecutive cyclization of allylaminoalkene by intramolecular aminolithiation-carbolithiation.

Consecutive cyclization of allylaminoalkenes by tandem aminolithiation-carbolithiation proceeded smoothly by using a lithium amide as a lithiating agent as well as protonating agent to give bicyclic amines, octahydroindolizine and hexahydro-1 H-pyrrolizine, in reasonably high yield and diastereoselectivity.