Palladium-catalyzed C-C bond cleavage of N-cyclopropyl acylhydrazones.

Despite their utility as directing groups, the C-C bond cleavage of cyclopropanes utilizing hydrazones has not been explored. Herein, Pd-catalyzed C-C bond cleavage reaction of N-cyclopropyl acylhydrazones, followed by cycloisomerization to yield pyrazoles, has been developed. The protocol enables the synthesis of various α-pyrazole carbonyl compounds, which have a potential of biological activity. Control experiments and DFT calculations suggest that ß-carbon elimination of a stable 6-membered chelate palladium complex occurs, generating a conjugated azine as a reaction intermediate for the following cycloisomerization.

P(III)-Mediated Formal Reductive N-H Bond Insertion Reaction of Hydrazones to α-Keto Esters.

A diazo-, metal-, and base-free multi-substituted hydrazone synthesis via a formal reductive N-H bond insertion reactions of hydrazones to α-keto esters has been developed. The protocol features a broad substrate scope and good functional group tolerance, providing N-H bond insertion products in moderate to excellent yields. Moreover, P(III)-mediated N-H functionalization of pharmaceutical containing hydrazone moiety was also successfully achieved.

Synthesis of oxime ethers via a formal reductive O-H bond insertion of oximes to α-keto esters.

This study describes an efficient approach to access oxime ethers via P(III)-mediated O-H bond insertion reaction of oximes with α-keto esters. The strategy involves the protonation of in situ generated Kukhtin-Ramirez adducts, followed by SN2-type reaction. Important features include a good functional group tolerance, operational simplicity, and application to gram scale synthesis and the synthesis of an acaricide.

Synthesis, Structure, and Characterization of Thiacalix[4]-2,8-thianthrene.

Sulfur-containing macrocycles have attracted substantial interest because they exhibit unique characteristics due to their polygonal ring-shaped skeleton. In this study, a thianthrene-based cyclic tetramer with the sulfur linker, thiacalix[4]-2,8-thianthrene (TC[4]TT), was successfully prepared from a cyclo-p-phenylenesulfide derivative using acid-induced intramolecular condensation. Single crystal X-ray diffraction revealed that TC[4]TT adopts an alternative octagonal form recessed to the inner side. Its internal cavity included small solvents, such as chloroform and carbon disulfide. Due to its polygonal geometry, TC[4]TT laminated in a honeycomb-like pattern with a porous channel. Furthermore, TC[4]TT showed fluorescence and phosphorescence emission in a CH2Cl2 solution at ambient and liquid nitrogen temperatures. Both emission bands were slightly redshifted compared with those of the reference compounds (di(thanthren-2-yl)sulfane (TT2S) and thianthrene (TT)). This work describes a sulfur-containing thiacalixheterocycle-based macrocyclic system with intriguing supramolecular chemistry based on molecular tiling and photophysical properties in solution.

Copper-Catalyzed Aerobic C(sp3)-H Oxidation of ß-(Alkoxy)imino Carbonyl Compounds.

Direct oxidation of the C(sp3)-H bond of ß-(alkoxy)imino carbonyl compounds using copper acetate and molecular oxygen has been established. The protocol features a broad substrate scope and generates 1-imino-2,3-dicarbonyls in good to excellent yields.

Synthesis of isolable ß-chloroenamines from N-alkoxylactams with organometallic reagents.

An efficient approach to access isolable ß-chloroenamines via nucleophilic addition/dehydration of α-chloro N-alkoxylactam with organolithium and Grignard reagents is reported. This approach is amenable to the synthesis of ß-chloroenamines by incorporating various C(sp) and C(sp2) units, such as alkyne, aryl, and heteroaryl moieties. The sequential reaction has a broad substrate scope and can be carried out for a scalable synthesis of ß-chloroenamines. Control experiments suggested that both chloro and alkoxy groups act as inductive electron-withdrawing substituents to improve the stability of the enamines.

Synthesis of Spiro[indole-3,3'-pyrrolidine]-2'-(thi)ones.

Spiro[indole-3,3'-pyrrolidine]-2'-ones were synthesized via one-pot chloroformylation-dearomatizing spirocyclization of tryptamine derivatives. Moreover, the "thio" equivalent spiro[indole-3,3'-pyrrolidine]-2'-thiones, for which the synthesis and properties were previously unreported, were synthesized. The procedures are easily implemented, have a broad scope, and are transition-metal-free and cheap. To demonstrate the utility of the synthetic methodology, the spiro[indole-3,3'-pyrrolidine]-2'-ones were converted into heterocyclic scaffolds, such as an optically active spiroindoline and spirooxindole.

Janus-Type AIE Fluorophores: Synthesis and Properties of π-Extended Coumarin-Bearing Triskelions.

Janus-type triskelion-shaped fluorophores comprising coumarins bearing various electron-donating substituents (1aad, 1add, 1ccd, and 1cdd) were successfully synthesized via an intramolecular Ullmann coupling. Density functional theory (DFT) calculations indicated that all the compounds presented two different molecular surfaces, similar to Janus-type molecules. The absorption and fluorescence spectra of asymmetrical derivatives 1aad, 1add, 1ccd, and 1cdd exhibited a bathochromic shift due to their narrow highest occupied molecular orbital (HOMO) -lowest unoccupied molecular orbital (LUMO) gap. Natural transition orbital (NTO) analysis indicated that the excited state orbital overlaps differ among the C3 symmetrical and asymmetrical dyes. These triskelion-shaped fluorophores were found to form molecular nanoaggregates in THF/H2O mixtures and demonstrated aggregation-induced emission (AIE) enhancement characteristics as a result of restricting their molecular inversion. These results indicate that Janus-type AIE fluorophores are potentially applicable as solid-state fluorescent chiral materials, which can be optimized by controlling their molecular rearrangement in the solid state.

Synthesis and crystal structure of a sulphur-bridged molecular hoop consisting of 5,7,12,14-tetrathiapentacene.

A cyclic dimer consisting of 5,7,12,14-tetrathiapentacene (TC[2]TTP) forms a new extended series of thiacalix[n]arenes, and was successfully synthesized by an intramolecular Friedel-Crafts-type condensation of the macrocyclic precursor. TC[2]TTP was characterized using 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry. Its hoop-shaped molecular structure was determined by X-ray crystallography. The two-tub-shaped TTP formed a hexagonal geometry via a sulphur linker, and TC[2]TTP adopted a honeycomb structure with columnar stacking in the crystal structure. Furthermore, TC[2]TTP exhibited crystal polymorphism, which incorporated appropriate organic solvents such as CHCl3, benzene, and toluene into its internal cavity. This suggests that TC[2]TTP is a candidate for the components of cavity-assembled porous solids based on molecular tiling.

Construction of pyrazolodiazepines using AuI, a dual functional gold catalyst.

N,N'-5,7-Fused compounds are important molecules exhibiting medicinal potential. Herein, we report a practical and robust method for synthesising pyrazolodiazepines from N-piperidinyl alkynylhydrazides using a AuI catalyst. The broad substrate scope of alkynylhydrazides and synthetic application of pyrazolodiazepines are demonstrated. In addition, control experiments provide detailed information on the reaction mechanism, in which AuI promotes both the sequential intramolecular nucleophilic addition and the double nucleophilic substitution reaction as a π-acidic and nucleophilic dual functional catalyst.

Anhydrous Hydrogen Iodide-Mediated Reductive Indolization of In Situ-Generated Cyclopropyl Hydrazones.

Fischer-type indolization of N-aryl-C-cyclopropyl hydrazones generated in situ followed by chemoselective reduction using tert-butyl iodide as an anhydrous HI generator was developed. This protocol provides indoles bearing carboxylic acid derivative units. A series of control experiments indicated the HI-mediated formation and reduction of spirocyclopropyl indolenines. Anhydrous HI functions as a Brønsted acid as well as a reducing agent, facilitating the successful conversion of unstable reaction intermediates and iodinated mixtures in equilibrium.

Synthesis of multi-substituted 1,2,4-triazoles utilising the ambiphilic reactivity of hydrazones.

The synthesis of N-alkyl-1H-1,2,4-triazoles from N,N-dialkylhydrazones and nitriles via formal [3+2] cycloaddition including the C-chlorination/nucleophilic addition/cyclisation/dealkylation sequence was developed. This sequential reaction utilising the in situ generation of hydrazonoyl chloride based on the ambiphilic reactivity of hydrazones afforded a variety of multi-substituted N-alkyl-triazoles in high yields. The synthetic utility of multi-substituted triazoles was also demonstrated by further transformations.

Sc(OTf)3-Catalyzed Iodocyclization/Ritter-Type Amidation of N-Alkoxypropiolamides: A Synthetic Strategy for Isoxazol-3(2H)-ones.

A Sc(OTf)3-catalyzed iodocyclization/Ritter-type amidation of N-alkoxypropiolamides for the synthesis of 4-iodoisoxazol-3(2H)-ones bearing an amide group has been developed. This domino protocol allows the construction of a valuable heterocycle, isoxazol-3(2H)-one, as well as the introduction of two functional groups. The reaction has a broad substrate scope and can be carried out on a large scale. Control experiments suggest that Sc(OTf)3 acts as a dual activator for both the iodocyclization and amidation steps. In addition, the N-alkoxy group in the substrate suppresses some of the side reactions.

Sequential Nucleophilic Arylation/Ring-Contractive Rearrangement of N-Alkoxylactams.

A nucleophilic addition/ring-contractive rearrangement of α-bromo N-alkoxylactams with organometallic reagents was developed, providing an efficient access to α-acylpyrrolidines incorporating various C(sp2) units such as aryl, heteroaryl, and alkenyl groups. The sequential reaction proceeds through a five-membered chelate formation using nucleophilic addition followed by ring contraction via the formation of N,O-hemiaminal with good yields and a broad substrate scope. Moreover, a preliminary result with the use of the chiral N-alkoxylactam for the diastereoselective reaction is described.

Synthesis of Pyrazoles Utilizing the Ambiphilic Reactivity of Hydrazones.

A Brønsted acid-mediated synthesis of pyrazoles from conjugated hydrazones through a ß-protonation/nucleophilic addition/cyclization/aromatization sequence was developed. This protocol utilizing the ambiphilic reactivity of hydrazones enables not only self-condensation but also cross-condensation, affording multisubstituted pyrazoles in high yields, with a broad substrate scope. This sequential reaction proceeds under mild conditions via a simple operation. Moreover, the method can be applied to the synthesis of a nonsteroidal anti-inflammatory drug, Lonazolac.

Copper-Catalyzed Sequential Cyclization/Migration of Alkynyl Hydrazides for Construction of Ring-Expanded N-N Fused Pyrazolones.

A copper-catalyzed sequential cyclization/migration reaction of alkynyl hydrazides for the synthesis of ring-expanded N-N fused pyrazolones was developed. Control experiments indicate that the copper-ligand complex plays an essential role in the reaction. This approach features a broad scope including some functional group tolerance as well as a nucleophilic addition/1,3-migration/formal 1,2-migration sequence. This protocol provides simple manipulation and less waste due to high yield and atom economy. The synthetic utility of N-N fused pyrazolones was also demonstrated by further transformations.

γ-C (sp3)-H bond functionalisation of α,ß-unsaturated amides through an umpolung strategy.

The nucleophilic γ-phenylation and γ-alkylation of α,ß-unsaturated amides have been developed. This umpolung reaction allows the regioselective introduction of phenyl and alkyl groups to a vinylketene N,O-acetal, which is generated in situ from an α,ß-unsaturated N-alkoxyamide, followed by N-O bond cleavage in a two-step, one-pot process.

Copper-Catalyzed Cycloisomerization of Cyclopropenylimine for Synthesis of Pyrroles.

Copper-catalyzed cycloisomerization of 3-iminocyclopropenes for synthesis of pyrroles has been developed. The reaction allows regioselective construction of pyrroles with various substitution patterns, including fully substituted pyrroles. The method was successfully applied to synthesis of steroidal pyrroles as well as a N-fused pyrrole.

Hydration of Polycationic [5]Radialene with Quintuple 1,3-Dithiol-2-ylidenes Leads to a New Class of π-Extended Tetrathiafulvalene Scaffold.

[5]Radialene with quintuple 4,5-benzo-1,3-dithiol-2-ylidenes (DTs) easily forms a stable polycationic salt (1)4+ (BF4 - )4 owing to its aromatic character in the central cyclopentadienide ring. In this work, it was found that the polycationic salt (1)4+ underwent a hydration reaction in moist polar solvent to give several unexpected products, namely, an oxygen adduct dicationic salt (2)2+ , a tetrathiafulvalene (TTF) vinylogue (3) with 1,4-dithiine-2(3H)-one moieties, and an oxygen adduct of π-extended TTF with a cyclopentenone core (4). Their molecular structures were fully determined by X-ray crystal-structure analysis. In this reaction, irreversible hydration to the polycationic salt might either initiate the ring expansion and lead to the successive hydration at the specific cationic DT ring (for 3), or promote the transannular reactions to the next DT ring followed by elimination of the DT ring (for 4). Cyclic voltammetry and differential pulse voltammetry measurements for compound 3 indicated the occurrence of multi redox process resulting from electronic delocalization on the vinylogous TTF moiety. The electronic structures of the cationic species of 3 were also investigated by electronic spectra.

Chiral isoxazolidine-mediated stereoselective umpolung α-phenylation of methyl ketones.

An effective asymmetric α-phenylation of methyl ketones with triphenylaluminium in the presence of (+)-benzopyranoisoxazolidine has been developed. The reaction proceeds via the in situ formation of a chiral N-alkoxyenamine and the subsequent diastereoselective nucleophilic phenylation to provide α-phenylated products in moderate to good yields, with high enantioselectivities.