Annulation of a Methylenecyclopropane with Cyanoalkenes Catalyzed by Lewis Bases.

The annulation of a methylenecyclopropane with acyl cyanoalkenes by using DABCO or quinuclidine as a catalyst to give 2,3-dihydofurans has been developed. A stoichiometric amount of the Lewis bases promoted the isomerization of 2,3-dihydrofurans to furans. 1 H NMR spectra of the reaction in situ revealed that the methylenecyclopropane is opened by the Lewis base to form a reaction intermediate that is added to the cyanoalkenes.

Lewis Acid Catalyzed Cyclopropane Ring-Opening-Cyclization Cascade Using Thioureas as a N,N-bisnucleophile: Synthesis of Bicyclic Furo-, Pyrano-, and Pyrrololactams via a Formal [4+1]-Addition.

Fused bicyclic cyclopropanes were converted by Lewis acid-catalysis with thioureas to furo-, pyrano, and pyrrolo-lactams with yields of up to 99% and high diastere-oselectivity. The formation of the title compounds, repre-senting a formal [4+1]-cycloaddition to a donor-acceptor substituted cyclopropane, follows a cascade reaction involving SN1-type ring-opening addition and cyclization. Thiourea, being a cost-effective and odorless reagent, acts as an N,N-bis-nucleophile to generate bicyclic compounds containing an N­substituted γ-lactam moiety.

The TaCl5-Mediated Reaction of Dimethyl 2-Phenylcyclopropane-1,1-dicarboxylate with Aromatic Aldehydes as a Route to Substituted Tetrahydronaphthalenes.

It is found that the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 2 equivalents each of aromatic aldehydes and TaCl5 in 1,2-dichloroethane at 23 °C for 24 h after hydrolysis gives substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H)-dicarboxylates in good yield. This represents a new type of reactions between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes, yielding chlorinated tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety. A plausible reaction mechanism is proposed.

Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Formal High-Order Cycloadditions of Donor-Acceptor Cyclopropanes with Cycloheptatrienes.

Design of various cycloaddition / annulation processes is one of the most intriguing challenges during all time in the development of the donor-acceptor (D-A) cyclopropanes chemistry. In this work, a new missing class of formal high-order [6+n]-cycloaddition and annulation processes of D-A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D-A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was study in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates from starting D-A cyclopropanes, when other Lewis acids are ineffective and non-selective. New important examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]- cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself also can successfully act as a hydride anion donor which allows ionic hydrogenation of D-A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered-based carbocycles has been developed.

Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic ß-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Donor-Acceptor Cyclopropanes: Activation Enabled by a Single, Vinylogous Acceptor.

A novel class of highly activated donor-acceptor cyclopropanes bearing only a single, vinylogous acceptor is presented. These strained moieties readily undergo cycloadditions with aldehydes, ketones, thioketones, nitriles, naphth-2-ols and various other substrates to yield the corresponding carbo- and heterocycles. Diastereocontrol can be achieved through the choice of catalyst (Brønsted or Lewis acid). The formation of tetrahydrofurans was shown to be highly enantiospecific when chiral cyclopropanes are employed. A series of mechanistic and kinetic experiments was conducted to elucidate a plausible catalytic cycle and to rationalize the stereochemical outcome.

Intramolecular, Interrupted Homo-Nazarov Cascade Biscyclizations to Angular (Hetero)Aryl-Fused Polycycles.

Herein, a SnCl4 -catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization to access angular (hetero)aryl-fused polycycles is reported. Subsequent decarboxylation of the readily enolizable products afforded the angular products in up to 71 % yield over two steps, with the trans-diastereomers as the major products. The cyclopropyl homo-Nazarov cyclization precursors were formed using a scalable and modular synthetic route that, ultimately, offers access to 6,6,6-, 6,6,5-, 6,5,6-, 6,6,5,6-, and 6,6,6,5-fused angular polycyclic products. To showcase the rigor and utility of the method, an 8-step total synthesis of (±)-1-oxoferruginol, an antibacterial aromatic abietane diterpenoid, was disclosed.

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.

"Cyclopropanation of Cyclopropanes": GaCl3-Mediated Ionic Cyclopropanation of Donor-Acceptor Cyclopropanes with Diazo Esters as a Route to Tetrasubstituted Activated Cyclopropanes.

A new ionic cyclopropanation process involving the addition of diazo esters to donor-acceptor cyclopropanes (DAC) activated by GaCl3 has been developed. The reactions occur via 1,2-zwitterionic gallium complexes with elimination of nitrogen in all cases to give 1,1,2,3-tetrasubstituted cyclopropanes as the main products. Also, a number of related processes with the formation of various polysubstituted cyclopropanes, alkenes, and cyclobutanes, including products of multiple diazo ester addition, have been developed. Obtained by the developed method tetrasubstituted cyclopropanes are activated cyclopropanes such as DAC and can be used for further synthesis in this capacity. Their new reaction with benzaldehyde promoted by TiCl4 and involving one of the additional functional groups has been demonstrated, which leads to five-membered lactones. The mechanisms of the occurring processes, as well as the structures and stereochemistry of a rich range of products formed, are discussed in detail.

Synthesis of Polymers Bearing a Chiral Backbone via Stereospecific Ionic Ring-Opening Polymerization of Chiral Donor-Acceptor Cyclopropanes.

The stereospecific ionic ring-opening polymerization of various donor-acceptor cyclopropanes is reported. The chiral cyclopropane monomers are readily prepared with established methodology and stereospecific polymerization is best conducted with a catalytic amount of MgBr2 serving as a Lewis acid and as an initiator. Polymers with molecular masses of up to 7800 g mol-1 containing a stereocenter in every repeating unit are obtained and the substituents of the monomers can be readily varied to access a novel class of chiral polymers.

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.

Asymmetric Catalytic Reactions of Donor-Acceptor Cyclopropanes.

Due to the synergistic "push-pull" effect of vicinal electron-donating and electron-withdrawing groups, donor-acceptor (D-A) cyclopropanes have been recognized as one of the most powerful building blocks to generate polyfunctional reactive intermediates after a strain-driven ring cleavage. Enantioselective reactions of D-A cyclopropanes provide an efficient approach to enantioenriched acyclic and cyclic compounds. A number of chiral Lewis/Brønsted acids, transition metals, and organocatalysts have been designed for such transformations, including ring-openings, annulations, and rearrangements. This minireview highlights the developments and new advances in this field and describes new synthetic opportunities offered by these interesting methodologies.

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.

Ferrocenyl-substituted tetrahydrothiophenes via formal [3 + 2]-cycloaddition reactions of ferrocenyl thioketones with donor-acceptor cyclopropanes.

Ferrocenyl thioketones reacted with donor-acceptor cyclopropanes in dichloromethane at room temperature in the presence of catalytic amounts of Sc(OTf)3 yielding tetrahydrothiophene derivatives, products of formal [3 + 2]-cycloaddition reactions, in moderate to high yields. In all studied cases, dimethyl 2-arylcyclopropane dicarboxylates reacted with the corresponding aryl ferrocenyl thioketones in a completely diastereoselective manner to form single products in which (C-2)-Ar and (C-5)-ferrocenyl groups were oriented in a cis-fashion. In contrast, the same cyclopropanes underwent reaction with alkyl ferrocenyl thioketones to form nearly equal amounts of both diastereoisomeric tetrahydrothiophenes. A low selectivity was also observed in the reaction of a 2-phthalimide-derived cyclopropane with ferrocenyl phenyl thioketone.

New Dyes Based on Extended Fulvene Motifs: Synthesis through Redox Reactions of Naphthoquinones with Donor-Acceptor Cyclopropanes and Their Spectroelectrochemical Behavior.

Novel dyes based on extended fulvene motifs are reported. The carbon skeleton was generated by a catalyzed addition of donor-acceptor cyclopropanes to naphthoquinone. The hydroxy group at the central ring of the tricyclic fulvene motif was converted into the triflate, which reacted efficiently with a wide range of nucleophiles, resulting in substitution and thereby providing new derivatives. The synthetic versatility allowed us to investigate the absorption, electrochemical, and UV/Vis-NIR spectroelectrochemical properties of these dyes as a function of the substituents. The dyes were shown to participate in reductive electrochemistry, the reversibility of which can be improved by appropriate selection of the substituents. Additionally, first signs of NIR electrochromism are presented, opening new avenues for the future investigations of such dyes.

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.

Regio- and Stereoselective Synthesis of Functionalized Dihydropyridines, Pyridines, and 2H-Pyrans: Heck Coupling of Monocyclopropanated Heterocycles.

A palladium-catalyzed coupling between aryl halides and monocyclopropanated pyrroles or furans has been developed, leading to valuable six-membered N- and O-heterocycles. As the key step, a selective cleavage of the non-activated endocyclic C-C bond of the 2-heterobicyclo-[3.1.0]hexane framework is achieved. The developed method offers access to highly functionalized piperidines, pyridines, and pyrans that are challenging to access by traditional methods.

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.

Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor-Acceptor meso-Diaminocyclopropanes.

The first Lewis acid catalyzed enantioselective ring-opening desymmetrization of a donor-acceptor meso-diaminocyclopropane is reported. The copper(II)-catalyzed Friedel-Crafts alkylation of indoles and one pyrrole with an unprecedented meso-diaminocyclopropane delivered enantioenriched, diastereomerically pure urea products, which are structurally related to natural and synthetic bioactive compounds. The development of a new ligand through the investigation of an underexplored subclass of bis(oxazoline) ligands was essential for achieving high enantioselectivities.