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 vigabatrin, 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 ß-Dialkylamino Chalcones with Dimethylsulfonium Methylide.

We describe the synthesis of functionalized furans using the concept of the extended Corey-Chaykovsky reaction. Namely, ß,ß-disubstituted α,ß-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. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives.

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 via 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 N-alkylation or C(4)-alkylation, or a mixture of both were formed. The products of the C(4) alkylation were transformed in one step into tetrahydropyrazolo[3,4-b]azepines that are attractive for medicinal chemistry and pharmacology.

Donor-Acceptor Cyclopropane Ring Opening with 6-Amino-1,3-dimethyluracil and Its Use in Pyrimido[4,5-b]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-1H-pyrimido[4,5-b]azepine-2,4,8-triones, an interesting subclass of nucleobase analogues.

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

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet 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 endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.

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 one-pot 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. The ability of 1-methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane, epoxide ring-opening and other organic transformations.

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

A simple general method for the synthesis of 1-acyl-2-(ortho-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(C6F5)3 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 SN2 conditions led to the formation of 2-arylsuccinonitriles.

A Route to (Het)arene-Annulated Pyrrolo[1,2-d][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[x,y-b]pyrrolo[1,2-d][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 N-(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.

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.

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

A simple method has been developed for the synthesis of cyclopropa[c]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.

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 ß-amino acids and pyrrolo[1,2- d][1,4]diazepin-4(5 H)-ones from 2-(2-furyl)ethylamines and α-amino acids. The cytotoxicity of the synthesized pyrrolodiazepinones was studied.

(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. We have shown that the reactivity of the donor-acceptor cyclopropane increases with the increase of the electron-donating character of (hetero)aromatic group attached to the alkenyl moiety. The synthetic utility of the developed methodology was also demonstrated through the synthesis of polysubstituted cyclopentane and piperidine derivatives.

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.