Cyclopropane Cleavage Research Articles

Ni-Catalyzed ZnCl2–Assisted Domino Coupling of Enones and Alkyne-Tethered Vinylcyclopropanes via C–C Bond Cleavage of Cyclopropane

Ni-Catalyzed ZnCl₂–Assisted Domino Coupling of Enones and Alkyne-Tethered Vinylcyclopropanes via C–C Bond Cleavage of Cyclopropane

Electrochemical Formation of Oxazolines by 1,3-Oxyfluorination of Non-activated Cyclopropanes.

The C-C bond in non-activated cyclopropanes can be intramolecularly cleaved with an electrochemically generated amidyl radical forming oxazolines. In the presence of TBABF4, this provides 1,3-oxyfluorination products. C-C bond cleavage of cyclopropane proceeds with inversion of the configuration, suggesting an intramolecular homolytic substitution (SHi) mechanism. The performance of TBABF4 as an efficient fluoride source was explained by accumulation of the BF4- anion at the anode surface, at which a carbocation is formed by the oxidation of the C-centered radical.

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 β-carbon elimination of a stable 6-membered chelate palladium complex occurs, generating a conjugated azine as a reaction intermediate for the following cycloisomerization.

Computational Study of Mechanisms and Tether Length Effects of Rh-Catalyzed [3+2] and [3+2+1] Reactions of Ene/Yne-Vinylcyclopropanes.

DFT calculations have been applied to study the mechanisms of [3+2] and [3+2+1] reactions of ene/yne-vinylcyclopropanes (shorted as ene/yne-VCPs). The [3+2] reactions of ene/yne-VCPs start from C-C cleavage of cyclopropane (CP cleavage) to form six-membered rhodacycle, followed by alkene/alkyne insertion and reductive elimination. The [3+2+1] reactions have two competing pathways, one is the [3+2+1] pathway (CP cleavage, ene/yne insertion, CO insertion and reductive elimination) and the other is the [3+1+2] pathway (CP cleavage, CO insertion, ene/yne insertion and reductive elimination). The length of tether in substrates affects the ene/yne insertion steps in these cycloadditions, making some reactions fail or changing the reaction pathways. The reasons for these tether length effects are discussed.

Photoredox-catalyzed C–C bond cleavage of cyclopropanes for the formation of C(sp3)–heteroatom bonds

Sterically congested C–O and C–N bonds are ubiquitous in natural products, pharmaceuticals, and bioactive compounds. However, the development of a general method for the efficient construction of those sterically demanding covalent bonds still remains a formidable challenge. Herein, a photoredox-driven ring-opening C(sp3)–heteroatom bond formation of arylcyclopropanes is presented, which enables the construction of structurally diversified while sterically congested dialkyl ether, alkyl ester, alcohol, amine, chloride/fluoride, azide and also thiocyanate derivatives. The selective single electron oxidation of aryl motif associated with the thermodynamic driving force from ring strain-release is the key for this transformation. By this synergistic activation mode, C–C bond cleavage of otherwise inert cyclopropane framework is successfully unlocked. Further mechanistic and computational studies disclose a complete stereoinversion upon nucleophilic attack, thus proving a concerted SN2-type ring-opening functionalization manifold, while the regioselectivity is subjected to an orbital control scenario.

Mechanism and Stereochemistry of Rhodium-Catalyzed [5 + 2 + 1] Cycloaddition of Ene-Vinylcyclopropanes and Carbon Monoxide Revealed by Visual Kinetic Analysis and Quantum Chemical Calculations.

Previously, we developed a rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and carbon monoxide to synthesize eight-membered carbocycles. The efficiency of this reaction can be appreciated from its application in the synthesis of several natural products. Herein we report the results of a 15-year investigation into the mechanism of the [5 + 2 + 1] cycloaddition by applying visual kinetic analysis and high-level quantum chemical calculations at the DLPNO-CCSD(T)//BMK level. According to the kinetic measurements, the resting state of the catalyst possesses a dimeric structure (with two rhodium centers) whereas the active catalytic species is monomeric (with one rhodium center). The catalytic cycle consists of cyclopropane cleavage (the turnover-limiting step), alkene insertion, CO insertion, reductive elimination, and catalyst transfer steps. Other reaction pathways have also been considered but then have been ruled out. The steric origin of the diastereoselectivity (cis versus trans) was revealed by comparing the alkene insertion transition states. In addition, how the double-bond configuration of the VCPs (Z versus E) affects the substrate reactivity and the origins of chemoselectivity ([5 + 2 + 1] versus [5 + 2]) were also investigated. The present study will provide assistance in understanding other carbonylative annulations catalyzed by transition metals.

Electrochemical C\u2212C bond cleavage of cyclopropanes towards the synthesis of 1,3-difunctionalized molecules

Electrochemistry has a lot of inherent advantages in organic synthesis and many redox reactions have been achieved under electrochemical condition. However, the electrochemical C−C bond cleavage and functionalization reactions are less studied. Here we develop electrochemical C−C bond cleavage and 1,3-difuntionalization of arylcyclopropanes under catalyst-free and external-oxidant-free conditions. 1,3-difluorination, 1,3-oxyfluorination and 1,3-dioxygenation of arylcyclopropanes are achieved with a high chemo- and regioselectivity by the strategic choice of nucleophiles. This protocol has good functional groups tolerance and can be scaled up. Mechanistic studies demonstrate that arylcyclopropane radical cation obtained from the anode oxidation and the subsequently generated benzyl carbonium are the key intermediates in this transformation. This development provides a scenario for constructing 1,3-difunctionalized molecules.

Creating Stereocenters within Acyclic Systems by C-C Bond Cleavage of Cyclopropanes.

Recent developments in the stereoselective synthesis of polysubstituted cyclopropanes nowadays allow chemists to easily access these strained rings with high diastereo- and enantiomeric ratios. In turn, this development has created a paradigm shift for the synthesis of stereodefined acyclic molecules though selective carbon-carbon bond cleavage. Through chosen illustrative examples, we aim to show in this review that the cleavage of cyclopropane is a powerful approach to reveal sp3 stereocenters in acyclic systems. The application of these concepts was illustrated by the total syntheses of several natural products and other important molecules, further showing the power of these strategies as a powerful tool in organic synthesis.

Cobalt-Catalyzed Intramolecular Hydroacylation Involving Cyclopropane Cleavage.

A simple cobalt-diphosphine catalyst has been found to efficiently promote intramolecular cyclization of ortho-cyclopropylvinyl- and cyclopropylidenemethyl-substituted benzaldehydes into benzocyclooctadienone and benzocycloheptadienone derivatives, respectively. This ring-opening hydroacylation likely involves aldehyde C-H oxidative addition, olefin insertion, cyclopropane cleavage by β-carbon elimination, and C-C bond-forming reductive elimination, as was supported by mechanistic experiments and DFT calculations.

Amination of Carbenium Ions Generated by Directed Protonolysis of Cyclopropane

Directed intramolecular protonolyis of the cyclopropane C-C bond is demonstrated as a strategy to generate carbenium ions. This intermediate can be subjected to amination with nitriles under Ritter reaction conditions. Directing groups such as carbamate, carboxamide, urea, ester, and ketone were found to be efficient for regioselective anti-Markovnikov cleavage of cyclopropane. Depending on the directing group, the amination provided orthogonally protected 1,4-diamine, ε-amino carboxylic, and ε-amino ketone derivatives.

Synthetic Studies on the Marine-Derived Sesquiterpene (+)-Viridianol: Divergent Behaviour of Two Structurally Related, Ring-Fused Cyclopropanes Under the Same Hydrogenolytic Conditions

Hydrogenolytic cleavage of the ring-fused cyclopropane 11 using hydrogen in the presence of platinum oxide afforded the gem-dimethylated cyclohexane 12 in 99% yield. In contrast, analogous treatment of congener 13 afforded only trace amounts of the targeted and gem-dimethylated sesquiterpene (+)-viridianol (1), the major products of reaction now being the vic-dimethylated compound 14 and the 2-fold ring-cleavage product 15.

Mechanistic understanding of [Rh(NHC)]-catalyzed intramolecular [5 + 2] cycloadditions of vinyloxiranes and vinylcyclopropanes with alkynes.

Zhang and co-workers have recently advanced the carbon [5 + 2] cycloaddition of vinylcyclopropane and alkyne (VCP-alkyne) to the hetero-[5 + 2] cycloaddition of vinyloxirane with alkyne (VOR-alkyne). Herein, we present a systematic computational study to gain insights into the detailed reaction mechanisms and origins of mechanistic differences of the two types of cycloadditions (all-carbon [5 + 2] cycloaddition vs. hetero-[5 + 2] cycloaddition). Instead of the general mechanism of rhodium-catalyzed VCP-alkyne cycloaddition that involves cyclopropane cleavage, alkyne insertion and reductive elimination, the rhodium-catalyzed VOR-alkyne cycloaddition occurs via oxidative alkyne-alkene cyclization, oxirane cleavage and reductive elimination. The cycloaddition of VOR-alkyne represents the first example of preferring the oxidative alkyne-alkene cyclization mechanism within rhodium-catalyzed [5 + 2] cycloadditions. The origins of the mechanistic difference are derived from the stabilizing effects due to the favorable ligand-substrate C-H/π dispersion interaction and the substrate-substrate C-HO hydrogen-bond interaction in the oxidative alkyne-alkene cyclization step of the hetero-[5 + 2] cycloaddition. The VOR-alkyne cycloaddition gives a bicyclo[5.3.0] product featuring a 2,5-dihydrooxepin moiety, which can further undergo a [3,3]-sigmatropic rearrangement giving the final bicyclo[3.1.0] product, because a carbonyl structure is more favorable than an enolate structure.

Ni-Al Bimetallic Catalyzed Enantioselective Cycloaddition of Cyclopropyl Carboxamide with Alkyne.

A Ni-Al bimetallic catalyzed enantioselective cycloaddition reaction of cyclopropyl carboxamides with alkynes has been developed. A series of cyclopentenyl carboxamides were obtained in up to 99% yield and 94% ee. The bifunctional-ligand-enabled bimetallic catalysis proved to be an efficient strategy for the C-C bond cleavage of unreactive cyclopropanes.

Amide-Group-Directed Protonolysis of Cyclopropane: An Approach to 2,2-Disubstituted Pyrrolidines.

Regioselective protonolytic C-C bond cleavage of acylated aminomethyl cyclopropanes can be achieved using trifluoroacetic acid. The intermediate tertiary carbenium ion undergoes an intramolecular amination to give 2,2-substituted pyrrolidines. The strength of the acid and the amine substituent are important factors to achieve high regioselectivity, suggesting intramolecular proton transfer from the protonated amide function. Preliminary mechanistic studies revealed that cyclopropane cleavage proceeds with retention of configuration at the carbon to which the proton is attached. This observation is consistent with the "edge" protonation trajectory of the C-C bond.

Olefin‐Migrative Cleavage of Cyclopropane Rings through the Nickel‐Catalyzed Hydrocyanation of Allenes and Alkenes

AbstractA nickel‐catalyzed hydrocyanation triggered by hydronickelation of the carbon‐carbon double bonds of allenes followed by cyclopropane cleavage is described. The observed regio‐ and stereochemistries in the products are strongly influenced by the initial hydronickelation step, and allenyl‐ and methylenecyclopropanes reacted smoothly to promote the cleavage of cyclopropane. In contrast, this cleavage was not observed with vinylidenecyclopropanes, because the initial hydronickelation does not give a suitable intermediate for cleavage of the cyclopropanes.magnified image

ChemInform Abstract: Rhodium‐Catalyzed [5 + 2 + 1] Cycloaddition of Ene‐Vinylcyclopropanes and CO: Reaction Design, Development, Application in Natural Product Synthesis, and Inspiration for Developing New Reactions for Synthesis of Eight‐Membered Carbocycles

AbstractReview: 66 refs.

Catalytic [3 + 2] Cycloaddition through Ring Cleavage of Simple Cyclopropanes with Isocyanates.

The catalytic synthesis of γ-butyrolactams was established via [3 + 2]-cycloaddition of cyclopropanes with isocyanates. An organotin iodide ate complex, MgBr(+)[Bu2SnBrI2](-), was employed as an effective catalyst. Simple cyclopropanes that lack aryl or vinyl substituents were useful precursors. Even acyl cyclopropanes were applicable. The hybrid characteristics of a tin complex, acidic MgBr(+) with nucleophilic tin iodide, was responsible for the catalytic reaction.

Rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes and CO: reaction design, development, application in natural product synthesis, and inspiration for developing new reactions for synthesis of eight-membered carbocycles.

Practical syntheses of natural products and their analogues with eight-membered carbocyclic skeletons are important for medicinal and biological investigations. However, methods and strategies to construct the eight-membered carbocycles are limited. Therefore, developing new methods to synthesize the eight-membered carbocycles is highly desired. In this Account, we describe our development of three rhodium-catalyzed cycloadditions for the construction of the eight-membered carbocycles, which have great potential in addressing the challenges in the synthesis of medium-sized ring systems. The first reaction described in this Account is our computationally designed rhodium-catalyzed two-component [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and CO for the diastereoselective construction of bi- and tricyclic cyclooctenones. The design of this reaction is based on the hypothesis that the C(sp(3))-C(sp(3)) reductive elimination of the eight-membered rhodacycle intermediate generated from the rhodium-catalyzed cyclopropane cleavage and alkene insertion, giving Wender's [5 + 2] cycloadduct, is not easy. Under CO atmosphere, CO insertion may occur rapidly, converting the eight-membered rhodacycle into a nine-membered rhodacycle, which then undergoes an easy C(sp(2))-C(sp(3)) reductive elimination process and furnishes the [5 + 2 + 1] product. This hypothesis was supported by our preliminary DFT studies and also served as inspiration for the development of two [7 + 1] cycloadditions: the [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes (BDCPs) and CO for the construction of cyclooctadienones, and the benzo/[7 + 1] cycloaddition of cyclopropyl-benzocyclobutenes (CP-BCBs) and CO to synthesize the benzocyclooctenones. The efficiency of these rhodium-catalyzed cycloadditions can be revealed by the application in natural product synthesis. Two eight-membered ring-containing natural products, (±)-asterisca-3(15),6-diene and (+)-asteriscanolide, have been synthesized using the [5 + 2 + 1] cycloaddition as the key step. In the latter case, excellent asymmetric induction was obtained using a chiral substrate. The efficiency of the [5 + 2 + 1] reaction was further demonstrated by the synthesis of four sesquiterpene natural products, (±)-pentalenene, (+)-hirsutene, (±)-1-desoxyhypnophilin, and (±)-hirsutic acid C, containing linear or branched triquinane skeletons utilizing the tandem or stepwise [5 + 2 + 1] cycloaddition/aldol reaction strategy. With the success of [5 + 2 + 1] cycloaddition in natural product synthesis, application of the [7 + 1] and benzo/[7 + 1] cycloadditions in target- and function-oriented syntheses can be envisioned.

Au-catalyzed ring-opening reactions of 2-(1-alkynyl-cyclopropyl)pyridines with nucleophiles.

A novel method for the C-C bond cleavage of cyclopropanes was developed by gold-catalyzed cycloisomerization of 2-(1-alkynyl-cyclopropyl)pyridine with nucleophiles, which provides efficient access to structurally diverse indolizines under mild conditions. A series of N-, C- and O-based nucleophiles were involved in this reaction to afford the corresponding indolizines in modest to excellent yields.

Mechanistic Insight into the Spirocyclopropane Isoxazolidine Ring Contraction

A mechanistic study of the ring contraction of spirocyclopropane isoxazolidines to form β-lactams is reported. Based on experimental and computational investigations, we propose a concerted mechanism that proceeds with retention of configuration during cyclopropane cleavage.