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An active nickel catalyst prepared in situ from a Ni(II) compound, phosphine ligand, and zinc powder was found to be an efficient catalyst system for the hydrocyanation of various alkenes using acetone cyanohydrin as a safer cyano source. The combination of NiCl2·6H2O and 1,3-bis(diphenylphosphino)propane was the most efficient catalyst precursor in DMF. Under the optimized conditions, various styrenes, heterocyclic alkenes, and aliphatic alkenes were converted to their corresponding nitriles in excellent yields.

Oxidative ring-opening reactions of benzene-fused bicyclic cyclopropyl silyl ethers, promoted by copper(II) tetrafluoroborate, were investigated. The regioselectivity of cyclopropane ring-opening as well as product distributions were found to be highly dependent on the nature of the solvent. In alcohols, dimeric substances arising from external bond cleavage are major products. Radical rearrangement products are also formed in solvents such as ether and ethyl acetate. On the contrary, nucleophile addition to carbocation intermediates, generated by internal bond cleavage, occurs mainly in reactions taking place in acetonitrile. It is proposed that the observed solvent effects that govern the reaction pathways followed are a consequence of varying solvation of copper intermediates, which governs their reactivity and redox properties. In addition, the influence of counteranions of the copper salts, organonitriles, cyclic dienes, and substrate structures on the pathways followed in these reactions was also ex...

Various 1-methyl-, 1-triisopropylsilyl-, and 1-benzylindoles are carboxylated under CO2 pressure (3.0 MPa) with the aid of 1.0 molar equiv of Me2AlCl to give 1-substituted indole-3-carboxylic acids in good to excellent yields. Mechanistic studies suggest that the intermediate, an indol-3-ylaluminum ate complex, was reversibly formed by electrophilic addition of Me2AlCl to the substrate followed by deprotonation of the resulting adduct. This method is successfully extended to alkoxycarbonylation with ethyl chloroformate and carbamoylation with naphthalen-1-yl isocyanate, which afford ethyl indole-3-carboxylates and N-naphthalen-1-ylindole-3-carboxamides, respectively.

We have developed a novel method for synthesizing trisubstituted cyclopropane derivatives by a palladium-catalyzed intramolecular allylic alkylation of α-aryl esters. By using α-aryl α-(methoxycarbonyl) γ-vinyl γ-lactones as substrates, decarboxylative formation of π-allylpalladium(II) intermediates followed by an intramolecular allylic alkylation of the ester enolates proceeded in the presence of 5 mol% of a palladium catalyst, producing 1-aryl-1-(methoxycarbonyl)-2-vinylcyclopropanes in good to excellent yields and high diastereoselectivities. The relative configuration of the major isomer was determined by transforming the product into a known intermediate of milnacipran synthesis. When we extended our method to asymmetric catalysis, we obtained methyl (1S,2S)-1-phenyl-2-vinylcyclopropanecarboxylate in up to 55% ee by using (S)-[2′-(diphenylmethoxy)-1,1′-binaphthalen-2-yl](diphenyl)phosphine as a chiral monodentate phosphorus ligand.

The Rh-catalyzed formal carbenoid insertion into an amide C—N bond delivers azabicyclo[X.Y.Z.]alkane derivatives in good to high yields and proceeds via the formation of Rh-associated N-ylides, followed by an acyl group-selective Stevens [1,2]-shift through a concerted addition/elimination process on the sp2-hybridized carbon.

A novel protocol for the cascade cyclization of allenes derivatives to form three types of 3,4-fused tricyclic indoles is reported.

A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted intramolecular Friedel–Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence involving an acid-promoted intramolecular Friedel–Crafts allenylation of anilines, an acid-promoted intramolecular C–N bond formation, deprotection of the Boc group, and air oxidation proceeded in a single pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31–84% yield.

We developed a novel method of synthesizing nitrogen-containing fused-polycyclic compounds using tyramine derivatives as substrates. The method is based on the dearomatization of phenols via an intramolecular ipso-Friedel–Crafts allenylation and sequential bond-forming–cleavage reactions initiated by the construction of an indole skeleton. Structurally diverse fused-heterocycles were produced in reaction sequences requiring only a few steps.

A new method to synthesize spiro[4.5]cyclohexadienone derivatives with an exo-cyclic olefin unit is developed.

Herein we report an enantioselective synthesis of ( R )-Sumanirole wherein an organocatalytic asymmetric aziridination of 2-nitrocinnamaldehyde was the key step.

A direct access to compound (VIII) which bears the core skeleton of belaperidone by using the title reaction is also presented.

A-nor B-aromatic steroidal skeleton was efficiently constructed by means of o -quinodimethane chemistry with exclusive stereoselectivity. The benzocyclobutene substrate for generation of the o -quinodimethane intermediate and subsequent [4+2] cycloaddition could be synthesized via ( E )-selective Julia–Kocienski olefination and diastereoselective Grignard addition reactions. The synthesized tricyclic steroid-like compound with a trans -diol substructure would be utilized for divergent syntheses of potentially antitumor OSW-1 analogues with the truncated steroidal aglycone.

Two different cascade cyclization processes are developed using aryl group-substituted propargyl alcohol derivatives with a p-hydroxy-/p-methoxybenzylamine unit as substrates.

The synthesis of alkaloid (I) is achieved in six steps in 60% overall yield from dihydroxymethylchromanone.

A novel Pd-catalyzed Heck insertion to an allene followed by an intramolecular ipso-Friedel—Crafts allylic alkylation cascade is described to convert functionalized phenols (I) and (IV) to spiro[4.5]cyclohexadienones.

The Lewis acid catalyzed reaction yields 3,4-disubstituted phenols from dienones in a highly efficient rearrangement or from allylic substituted phenoles in a cascade reaction.

An acid-promoted novel cascade cyclization is described. Using 8 equiv of trifluoroacetic acid or a catalytic amount of Lewis acid as the promoter, structurally diverse polycyclic cyclopenta[b]indoles were obtained in moderate to excellent yield. This cascade process was extremely effective for the synthesis of 8-membered ring-fused cyclopenta[b]indole derivatives.

We developed a novel synthetic method for allenyl spiro[4.5]cyclohexadienone derivatives based on a base-promoted intramolecular ipso-Friedel–Crafts addition of phenols to propargyl bromides. The present spirocyclization proceeded in a CH2Cl2–tert-BuOH mixed solvent system using potassium tert-butoxide as the base, and produced the corresponding spiro[4.5]cyclohexadienone derivatives with an allene motif in up to 99% yield. This-type allenyl spirocycle was also accessible through Pd-catalyzed intramolecular ipso-Friedel–Crafts alkylation when a propargyl carbonate derivative with a naphthol unit was used as a substrate. Acid-promoted skeletal rearrangement of the reaction adducts was also examined.

Treatment of the substrates with TFA is found to provide a new access to the heterocyclic systems via intramolecular ipso-Friedel—Crafts-type addition, rearomatization, and intramolecular aza-Prins reaction.

The Friedel—Crafts-type carboxylation of arenes is achieved by activation of carbon dioxide with silylium borates.

trans-Fused decahydroisoquinoline derivatives without a phenol ring (I) are found to bound the opioid receptor in the micromolar range.

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso -Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (−)-9-NapBN (−)- 3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand ( R , R )- 3k , the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).

Complementary synthesis of two kinds of fluorinated bridged biphenyls has been developed by the combination of oxidative carbon–carbon bond formation and deoxyfluorination.

Efficient monocyclic 1,2-diazepine formation via a tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate is demonstrated. The reaction proceeds through an oxy anion-accelerated 4π-ring opening of cyclobutene followed by an 8π-ring closure of the resultant oxy anion-substituted diazo-diene under mild conditions to furnish a 1,2-diazepine via formal diazomethylene insertion into the C–C bond of cyclobutenone.

An innovative method for the synthesis of tricyclic indole derivatives which are of potential interest as scaffolds for drug design under mild and simple reaction conditions is developed.

The highly efficient synthesis of C8-prenylated derivatives of quercetin and hesperetin is accomplished using a regioselective Claisen rearrangement of ethers such as (III) and (VII) as the key steps.

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel–Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee.

The Lewis acid mediated carboxylation of thiophenes and benzothiophenes bearing alkyl or aryl substituents at the 2- or 3-positions affords the corresponding 2- or 3-carboxylic acids in up to 90% yield.

The process employs primary and secondary amine organocatalysts allowing the synthesis of mono and bicyclic lactam frameworks.

Novel mono-protected catechol derivatives of perhydrophenanthrene are synthesized utilizing hypervalent iodine oxidation and original o-quinodimethane chemistry of benzocyclobutenes.

An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor.

This review describes the development of a new class of chiral secondary phosphine oxide preligands: Amino acid-derived P-chiral diaminophosphine oxides, DIAPHOXs, and their application to several transition metal-catalyzed asymmetric reactions. The Pd-DIAPHOX catalyst system was successfully applied to enantioselective construction of quaternary stereocenters through Pd-catalyzed asymmetric allylic alkylation with β-keto esters as prochiral nucleophiles, asymmetric allylic substitutions with nitromethane, asymmetric allylic amination with various substrates, and enantioselective synthesis of axially chiral allenes. Ir-catalyzed asymmetric allylic amination and alkylation of terminal allylic carbonates were also examined using structurally optimized DIAPHOX preligands, and the corresponding branched products were obtained in a highly regio- and enantioselective manner. Furthermore, the developed processes were successfully applied to the enantioselective synthesis of biologically active compounds.

The novel method starts with the asymmetric allylic amination of diester (I) using a Pd/DIAPHOX catalyst system and a diastereoselective intramolecular Mannich reaction of ketoester (IV).

Symmetrical and nonsymmetrical triplet drugs with 1,3,5-trioxazatriquinane skeleton are synthesized.

The first method for the nucleophilic deoxyfluorination of one of the two hydroxyl groups of catechols and related compounds is reported.

A novel phenylalanine derived-bidentate chiral diaminophosphine oxide preligand DIAPHOX is developed and successfully applied to Pd-catalyzed asymmetric allylic alkylation and amination.

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived catalyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleophiles, asymmetric conjugate addition to β-aryl nitroalkenes proceeded with good diastereoselectivity to provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with up to 95% ee.

It allows and efficient and regioselective access to a number of aromatic carboxylic acids.

Treatment of the Boc protected allylamines (4) with rhodium catalysts in the presence of alcohols produces N-Boc substituted α-alkoxy amines (5) in high yields, which can be used as a synthetic equivalents of activated imines having an easily deprotectable Boc group.