Electrochemically driven Michael reaction: synthesis of hydroquinone thioethers.

An original method for the synthesis of a diverse array of hydroquinone thioethers with yields of 36% to 99% under mild conditions is described. The process is voltammetrically controlled and involves electrogenerating active protonated -quinone followed by thiol addition.

Synthesis and evaluation of tetrahydropyrrolo[1,2-]quinolin-1(2)-ones as new tubulin polymerization inhibitors.

Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3,4,5-tetrahydropyrrolo[1,2-]quinoline-1(2)-ones 3 as inhibitors of tubulin polymerization. We evaluated their effects on microtubule dynamics and on the proliferation of A549 cells, using flow cytometry-based cell cycle analysis. The results were verified with phase-contrast microscopy in three cancer cell lines: A549, HeLa and MCF-7.

Converting Strain Release into Aromaticity Loss for Activation of Donor-Acceptor Cyclopropanes: Generation of Quinone Methide Traps for C-Nucleophiles.

Here, we present a new approach for the activation of donor-acceptor cyclopropanes in ring-opening reactions, which does not require the use of a Lewis or Brønsted acid as a catalyst. Donor-acceptor cyclopropanes containing a phenolic group as the donor undergo deprotonation and isomerization to form the corresponding quinone methides. This innovative strategy was applied to achieve (4 + 1)-annulation of cyclopropanes with sulfur ylides, affording functionalized dihydrobenzofurans.

Concise approach to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids. Synthesis of vigabatrin.

γ-Aminobutyric acid (GABA) and GABA derivatives have attracted increased attention over the years in the fields of medicinal chemistry and chemical biology due to their interesting biological properties and synthetic relevance. Here, we report a short synthetic route to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids, including the antiepileptic drug , from readily available donor-acceptor cyclopropanes and ammonia or methylamine. This protocol includes a facile synthesis of 2-oxopyrrolidine-3-carboxamides and their acid hydrolysis to γ-aryl- or γ-alkenyl-substituted GABAs, which can serve as perspective building blocks for the synthesis of various GABA-based N-heterocycles and bioactive compounds.

Donor-Acceptor Cyclopropane Ring Expansion to 1,2-Dihydronaphthalenes. Access to Bridged Seven-Membered Lactones.

A Lewis-acid-promoted domino ring-opening cyclization of readily available donor-acceptor cyclopropanes with a preinstalled electrophilic center, embedded in a donor group, to functionalized 1,2-dihydronaphthalenes is reported herein. The obtained compounds are transformed to pharmacologically attractive bridged tricyclic esters in a diastereospecific manner.

Extended Version of the Corey-Chaykovsky Reaction: Synthesis of 2,4-Substituted Furans by the Treatment of β-Dialkylamino Chalcones with Dimethylsulfonium Methylide.

We describe the synthesis of functionalized furans using the concept of the extended Corey-Chaykovsky reaction. Namely, β,β-disubstituted α,β-unsaturated ketones were treated with dimethylsulfonium methylide to give vinyloxiranes, which immediately rearranged into the corresponding furans. The developed approach allows for synthesizing a broad range of unsymmetrically di- and trisubstituted furans containing various functionalities in the core.

Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor-Acceptor Cyclopropanes and Anilines/Benzylamines.

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation.

Ambident reactivity of 5-aminopyrazoles towards donor-acceptor cyclopropanes.

Lewis acid-catalysed reactions of donor-acceptor cyclopropanes with 1,3-disubstituted 5-aminopyrazoles were investigated. Under catalysis with gallium(III) chloride, products of the three-membered ring opening a nucleophilic attack of the exocyclic amino group were obtained in a chemoselective manner. Oppositely, in the presence of scandium(III) triflate, products of either -alkylation or (4)-alkylation, or a mixture of both were formed.

Expanding Stereoelectronic Limits of - Cyclizations: Synthesis of Benz[]azepines from Donor-Acceptor Cyclopropanes.

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in -- cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of - cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-- process. Substrates containing a -alkyl--arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[]azepin-2-ones in high yields.

Donor-Acceptor Cyclopropane Ring Opening with 6-Amino-1,3-dimethyluracil and Its Use in Pyrimido[4,5-]azepines Synthesis.

A scandium trifluoromethanesulfonate-catalyzed reaction of donor-acceptor cyclopropanes with 6-amino-1,3-dimethyluracil was found to proceed as three-membered ring opening via nucleophilic attack of the C(5) atom of an ambident nucleophile serving as an enamine equivalent. It was shown that, under basic conditions, the obtained products underwent cyclization to 6,7-dihydro-1-pyrimido[4,5-]azepine-2,4,8-triones, an interesting subclass of nucleobase analogues.

One-Step Synthesis of Triphenylphosphonium Salts from (Het)arylmethyl Alcohols.

Two approaches for the synthesis of substituted phosphonium salts from easily available benzyl alcohols and their heterocyclic analogs have been developed. The developed protocols are complementary: the direct mixing of alcohol, trimethylsilyl bromide, and triphenylphosphine in 1,4-dioxane followed by heating at 80 °C was found to be more efficient for acid-sensitive substrates, such as salicyl or furfuryl alcohols as well as secondary benzyl alcohols, while a procedure including sequential addition of trimethylsilyl bromide and triphenylphosphine gave higher yields for benzyl alcohols bearing electroneutral or electron-withdrawing substituents.

Transformation of 3-(Furan-2-yl)-1,3-di(het)arylpropan-1-ones to Prop-2-en-1-ones via Oxidative Furan Dearomatization/2-Ene-1,4,7-triones Cyclization.

The approach to 3-(furan-2-yl)-1,3-di(het)arylprop-2-en-1-ones based on the oxidative dearomatization of 3-(furan-2-yl)-1,3-di(het)arylpropan-1-ones followed by an unusual cyclization of the formed di(het)aryl-substituted 2-ene-1,4,7-triones has been developed. The cyclization step is related to the Paal-Knorr synthesis, but the furan ring formation is accompanied in this case by a formal shift of the double bond through the formation of a fully conjugated 4,7-hydroxy-2,4,6-trien-1-one system or its surrogate.

Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1-Methylimidazolium Thiocyanate.

We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Brønsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate-based protic ionic liquids for the ring-opening of donor-acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time-efficient step.

Synthesis of (Het)aryl 2-(2-hydroxyaryl)cyclopropyl Ketones.

A simple general method for the synthesis of 1-acyl-2-(-hydroxyaryl)cyclopropanes, which belong to the donor-acceptor cyclopropane family, has been developed. This method, based on the Corey-Chaykovsky cyclopropanation of 2-hydroxychalcones, allows for the preparation of a large diversity of hydroxy-substituted cyclopropanes, which can serve as promising building blocks for the synthesis of various bioactive compounds.

Ring Opening of Donor-Acceptor Cyclopropanes with Cyanide Ion and Its Surrogates.

A straightforward method for ring opening of donor-acceptor cyclopropanes with trimethylsilyl cyanide as a surrogate of cyanide ion in the presence of B(CF) or trifluoromethanesulfonic acid as a catalyst has been developed. The methodology provides a short route to γ-cyanoesters that can be useful synthetic intermediates for the synthesis of diverse bioactive molecules such as glutaric and δ-aminovaleric acid derivatives, 3-arylpiperidines, or other substituted phenethylamines. Oppositely, the attempts to synthesize these γ-cyanoesters by direct reaction of cyclopropanes with sodium cyanide under typical S2 conditions led to the formation of 2-arylsuccinonitriles.

A Route to (Het)arene-Annulated Pyrrolo[1,2-][1,4]diazepines via the Expanded Intramolecular Paal-Knorr Reaction: Nitro Group and Furan Ring as Equivalents of Amino Group and 1,4-Diketone.

A straightforward protocol toward pharmacologically relevant (het)areno[,-]pyrrolo[1,2-][1,4]diazepines in good to high yields has been described. The designed approach consists of an acid-promoted furan ring opening in easily accessible -(2-furylethyl)-2-nitroanilines or their heterocyclic analogues followed by the reductive cyclization of the corresponding nitro-1,4-diketones.

Donor-Acceptor Cyclopropanes in the Synthesis of Carbocycles.

Donor-acceptor cyclopropanes not only participate in a broad range of ring openings with nucleophiles, electrophiles, radical and red-ox agents, but also are excellent substrates for various (3+n)-cycloaddition and (3+n)-annulation processes. Moreover, under treatment with Lewis acid donor-acceptor cyclopropanes can produce new ring systems via isomerization or cyclodimerization. Authors' contribution to the synthesis of diverse carbocycles from donor-acceptor cyclopropanes is summarized in this account.

Convenient Synthesis of Functionalized Cyclopropa[]coumarin-1a-carboxylates.

A simple method has been developed for the synthesis of cyclopropa[]coumarins, which belong to the donor-acceptor cyclopropane family and, therefore, are promising substrates for the preparation of chromene-based fine chemicals. The method, based on the acetic acid-induced intramolecular transesterification of 2-arylcyclopropane-1,1-dicarboxylates, was found to be efficient for substrates containing hydroxy group directly attached to the aromatic ring.

Expanding the Reactivity of Donor-Acceptor Cyclopropanes: Synthesis of Benzannulated Five-Membered Heterocycles via Intramolecular Attack of a Pendant Nucleophilic Group.

Lewis-acid-induced domino transformations of donor-acceptor cyclopropanes, possessing a nucleophilic center embedded in a donor group, into functionalized 2,3-dihydrobenzo[ b]furans and 2,3-dihydrobenzo[ b]thiophenes are reported herein. An unusual switch of the electrophilic center in the three-membered ring, from the atom bearing a donor substituent to an unsubstituted carbon atom, was achieved by a judicious choice of Lewis acid, which induces the isomerization of a cyclopropane to an electrophilic alkene, and the length of linker, connecting a nucleophilic moiety and the small ring.

A General Synthetic Route to Isomeric Pyrrolo[1,2- x][1,4]diazepinones.

A simple one-pot method for the synthesis of isomeric pyrrolo[1,2- x][1,4]diazepinones in reasonable yields was developed. The method is based on the condensation of readily available N-Boc amino acids with biomass-derived furans containing aminoalkyl groups followed by deprotection, furan ring opening, and Paal-Knorr cyclization. Using this approach, we synthesized pyrrolo[1,2- a][1,4]diazepin-3(2 H)-ones from furfurylamines and β-amino acids and pyrrolo[1,2- d][1,4]diazepin-4(5 H)-ones from 2-(2-furyl)ethylamines and α-amino acids.

(3+3)-Annulation of Donor-Acceptor Cyclopropanes with Diaziridines.

The first example of (3+3)-annulation of two different three-membered rings is reported herein. Donor-acceptor cyclopropanes in reaction with diaziridines were found to afford perhydropyridazine derivatives in high yields and diastereoselectivity under mild Lewis acid catalysis. The disclosed reaction is applicable for the broad substrate scope and exhibits an excellent functional group tolerance.

Lewis Acid Triggered Vinylcyclopropane-Cyclopentene Rearrangement.

We report a mild Lewis acid induced isomerization of donor-acceptor cyclopropanes, containing an alkenyl moiety and diverse electron-withdrawing group(s) at the adjacent positions, into substituted cyclopentenes. We have found that 1,1,2-trisubstituted cyclopent-3-enes were exclusively obtained in yield of 51-99% when cyclopropanes with a 2-substituted alkenyl group as a donor underwent isomerization. For cyclopropanes bearing a trisubstituted alkenyl group either the corresponding cyclopent-3-enes or isomeric cyclopent-2-enes having two acceptor groups at the C(1) atom were formed, with the reaction selectivity being determined by the applied Lewis acid.

Domino Staudinger/aza-Wittig/Mannich Reaction: An Approach to Diversity of Di- and Tetrahydropyrrole Scaffolds.

A highly efficient and selective domino reaction producing valuable di- and tetrahydropyrrole-based skeletons from azidoethyl-substituted CH-acids and (thio)carbonyl compounds has been developed. By involving the additional functional groups in starting compounds into the domino reaction or postmodification of the primary reaction products, the simple construction of the pharmaceutically relevant three- and polycyclic azaheterocyclic scaffolds was demonstrated.

Oxidative Furan-to-Indole Rearrangement. Synthesis of 2-(2-Acylvinyl)indoles and Flinderole C Analogues.

Oxidative rearrangement of 2-(2-aminobenzyl)furans affording 2-(2-acylvinyl)indoles in a stereocontrolled manner in good-to-excellent yields has been developed. Thus, (2-aminobenzyl)furans with electron-releasing alkoxy substituents in the phenyl group form only E-isomers of 2-(2-acylvinyl)indoles. Conversely, substrates without such substituents produce target products as Z-isomers exclusively.

From Umpolung to Alternation: Modified Reactivity of Donor-Acceptor Cyclopropanes Towards Nucleophiles in Reaction with Nitroalkanes.

A conceptually new type of donor-acceptor cyclopropane reactivity towards nucleophiles has been disclosed. An essential characteristic of the process is an unusual nucleophilic attack on the C(3)-position of a cyclopropane, combined with typical small ring-opening by cleavage of the C(1)-C(2) bond between the acceptor and the donor. Based on this new reaction between cyclopropane-1,1-diesters and nitroalkanes, we developed a convenient approach to γ-nitroesters that can be efficiently transformed to the substituted pyrrolidones, structural analogues of racetame family drugs (rolipram, phenylpiracetam, etc.