Cyclopropyl Research Articles

Metal-catalysed C-C bond formation at cyclopropanes.

Cyclopropanes are important substructures in natural products and pharmaceuticals. Although traditional methods for their incorporation rely on cyclopropanation of an existing scaffold, the advent of transition-metal catalysis has enabled installation of functionalized cyclopropanes using cross-coupling reactions. The unique bonding and structural properties of cyclopropane render it more easily functionalized in transition-metal-catalysed cross-couplings than other C(sp3) substrates. The cyclopropane coupling partner can participate in polar cross-coupling reactions either as a nucleophile (organometallic reagents) or as an electrophile (cyclopropyl halides). More recently, single-electron transformations featuring cyclopropyl radicals have emerged. This Review will provide an overview of transition-metal-catalysed C-Cbond formation reactions at cyclopropane, covering both traditional and current strategies, and the benefits and limitations of each.

N‐Heterocyclic Carbene‐Catalyzed Activation of 3‐Membered Rings: Cyclopropanes, Epoxides, Azirines and Aziridines

AbstractThe activations of carbonyl compounds bearing cyclopropyl, epoxyl, azirine and aziridinyl groups by N‐heterocyclic carbene (NHC) organic catalysts are reviewed. The reactions are introduced and discussed from 3 aspects according to the activation modes involved in these transformations. A brief summary on the achievements and the remaining challenges in NHC‐catalyzed activation of cyclopropanes and their analogues is given at the end of this minireview. Our own perspectives on the future development within this highly active research field are also provided.

Sulfenate Anion Catalyzed Diastereoselective Synthesis of Aziridines.

Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans-aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO- ) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron-rich and electron-poor aryl groups were shown to be compatible with this method (33 examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring-opening reactions, with a cyclobutyl-substituted norephedrine derivative obtained through a four-step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans-diastereoselectivity.

Sulfenate Anion Catalyzed Diastereoselective Synthesis of Aziridines

AbstractAziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans‐aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO–) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron‐rich and electron‐poor aryl groups were shown to be compatible with this method (33 examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring‐opening reactions, with a cyclobutyl‐substituted norephedrine derivative obtained through a four‐step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans‐diastereoselectivity.

Carbene transfer in a cell

Synthetic chemists have long used carbenes to create cyclopropyl groups and to strategically insert carbon into certain bonds. But these highly reactive intermediates haven’t been available in the realm of synthetic biology—until now. Scientists have created Streptomyces albus cells that can biosynthesize azaserine, a natural product and carbene precursor, and they got it to react with styrene also made by the same cellular system. An engineered P450 enzyme catalyzed the cyclopropanation reaction (shown). “The whole process end to end is happening in the cell. You basically are adding glucose on one side and getting a cyclopropanated bioactive compound on the other side,” says Aindrila Mukhopadhyay, an expert in microbial processes at Lawrence Berkeley National Laboratory, and a leader on the project. The synthetic biology system could help researchers create cyclopropanated versions of natural products, says John F. Hartwig, a chemist at the University of California, Berkeley, who also co-led the

Antibacterial and antibiofilm activity of permanently ionized quaternary ammonium fluoroquinolones

A series of quaternary ammonium fluoroquinolones was obtained by exhaustive methylation of the amine groups present at the 7-position of fluoroquinolones, including ciprofloxacin, enoxacin, gatifloxacin, lomefloxacin, and norfloxacin. The synthesized molecules were tested for their antibacterial and antibiofilm activities against Gram-positive and Gram-negative human pathogens, i.e. Staphylococcus aureus and Pseudomonas aeruginosa. The study showed that the synthesized compounds are potent antibacterial agents (MIC values at the lowest 6.25 μM) with low cytotoxicity in vitro as assessed on the BALB 3T3 mouse embryo cell line. Further experiments proved that the tested derivatives are able to bind to the DNA gyrase and topoisomerase IV active sites in a fluoroquinolone-characteristic manner. The most active quaternary ammonium fluoroquinolones, in contrast to ciprofloxacin, reduce the total biomass of P. aeruginosa ATCC 15442 biofilm in post-exposure experiments. The latter effect may be due to the dual mechanism of action of the quaternary fluoroquinolones, which also involves disruption of bacterial cell membranes. IAM-HPLC chromatographic experiments with immobilized artificial membranes (phospholipids) showed that the most active compounds were those with moderate lipophilicity and containing a cyclopropyl group at the N1 nitrogen atom in the fluoroquinolone core.

Carbon-Centered Radical with Leaving Group-Mediated Ring Opening of Cyclopropenes via the Rearrangement of Cyclopropyl to the Allyl Radical: A General Access to Multisubstituted 1,3-Dienes

We design and develop a general strategy for the assembly of multisubstituted 1,3-diene derivatives. This methodology proceeds through the cleavage of cyclopropenes via the rearrangement of the cyclopropyl radical to the allyl radical after the addition of a carbon-centered radical with a leaving group onto the strained double bond, leading to 1,3-diene products with the release of the leaving group. This approach represents a reaction mode for carbon-centered radical-mediated functionalization of cyclopropenes with ring cleavage. The transformation occurs under mild reaction conditions and shows high functional group tolerance. These highly valuable and modifiable 1,3-diene products show good antitumor activity against HCT116 cells.

Localization of cyclopropyl groups and alkenes within glycerophospholipids using gas-phase ion/ion chemistry.

Shotgun lipid analysis using electrospray ionization tandem mass spectrometry (ESI-MS/MS) is a common approach for the identification and characterization of glycerophohspholipids GPs. ESI-MS/MS, with the aid of collision-induced dissociation (CID), enables the characterization of GP species at the headgroup and fatty acyl sum compositional levels. However, important structural features that are often present, such as carbon-carbon double bond(s) and cyclopropane ring(s), can be difficult to determine. Here, we report the use of gas-phase charge inversion reactions that, in combination with CID, allow for more detailed structural elucidation of GPs. CID of a singly deprotonated GP, [GP - H]- , generates FA anions, [FA - H]- . The fatty acid anions can then react with doubly charged cationic magnesium tris-phenanthroline complex, [Mg(Phen)3 ]2+ , to form charge inverted complex cations of the form [FA - H + MgPhen2 ]+ . CID of the complex generates product ion spectral patterns that allow for the identification of carbon-carbon double bond position(s) as well as the sites of cyclopropyl position(s) in unsaturated lipids. This approach to determining both double bond and cyclopropane positions is demonstrated with GPs for the first time using standards and is applied to lipids extracted from Escherichia coli.

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres.

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)-C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

Strain-Release-Controlled [4 + 2 + 1] Reaction of Cyclopropyl-Capped Diene-ynes/Diene-enes and Carbon Monoxide Catalyzed by Rhodium.

Achieving transition-metal-catalyzed reactions of diene-ynes/diene-enes and carbon monoxide (CO) to deliver [4 + 2 + 1] cycloadducts, rather than the kinetically favored [2 + 2 + 1] products, is challenging. Here, we report that this can be solved by adding a cyclopropyl (CP) cap to the diene moiety of the original substrates. The resulting CP-capped diene-ynes/diene-enes can react with CO under Rh catalysis to give [4 + 2 + 1] cycloadducts exclusively without forming [2 + 2 + 1] products. This reaction has a broad scope and can be used to synthesize useful 5/7 bicycles with a CP moiety. Of the same importance, the CP moiety in the [4 + 2 + 1] cycloadducts can act as an intermediate group for further transformations so that other challenging bicyclic 5/7 and tricyclic 5/7/5, 5/7/6, and 5/7/7 skeletons, some of which are widely found in natural products, can be accessed. The mechanism of this [4 + 2 + 1] reaction has been investigated by quantum chemical calculations, and the role of the CP group in avoiding the possible side [2 + 2 + 1] reaction has been identified, showing that the [4 + 2 + 1] is controlled by releasing the ring strain in the methylenecyclopropyl (MCP) group (about 7 kcal/mol) in the CP-capped dienes.

Synthesis of cyclopropanes through gold-catalyzed [2 + 1] cycloaddition of allenamides with sulfoxonium ylides.

Cyclopropyl groups are widely found in pharmaceutical products and their application as precursors or key reaction intermediates benefits the development of a wide range of reactions. Herein, we report a facile protocol for the synthesis of this compound through gold-catalyzed [2 + 1] cycloaddition of allenamides with sulfoxonium ylides. The reaction exhibited good functional group tolerance and high efficiency, affording the products in good to excellent yields with good diastereoisomerism. The steric hindrance between the sulfonamide group and the gold catalyst determined the major configuration of the formed cis-cyclopropane product. Moreover, the aldehyde could be converted to amide under Schmidt reaction conditions and alcohol under reduction conditions.

Quantitative analysis of steric effects on the regioselectivity of the Larock heteroannulation reaction.

Alkylphenylacetylene derivatives were synthesized and used as reactants in the Larock heteroannulation reaction to investigate the steric influence on regioselectivity. Large alkyl groups preferentially yielded 2-alkyl-3-phenylindole products, while smaller alkyl groups provided 3-alkyl-2-phenylindole as major products. The logarithm of regioisomeric product ratios exhibited good correlations with various steric parameters. Notably, the Charton values provided the best correlation when excluding the cyclopropyl group. In addition, the Boltzmann-weighted Sterimol parameter (wSterimol) was utilized to generate a good predictive model, indicating the B1 wSterimol as the significant regiochemical determining parameter with no obvious deviation for the cyclopropyl group. Relative atomic distances within the DFT-optimized transition state structures revealed good correlations with the logarithm of regioisomeric ratios. Furthermore, the cyclopropyl adsorption complex indicated electronic contribution, explaining the peculiar behavior of this substituent in the experimental observation.

Front Cover: A Remarkable Ring Opening Observed in the Reaction of Cyclopropyl Ferrocenyl Thioketone with Triiron Dodecacarbonyl Fe3(CO)12 (Eur. J. Inorg. Chem. 36/2022)

The Front Cover shows the radical-mediated ring opening process of a cyclopropyl group resulting in a homoallyl radical, which is illustrated by the blossoming of the flowering plant Cirsium arvense, typical at this time of year in some regions of Europe. Based on a proposed reaction mechanism, this is the crucial and initial step in the reaction of cyclopropyl ferrocenyl thioketone with triiron dodecacarbonyl (Fe3(CO)12) as Fe0 precursor, accompanied by oxidation of a [Fe0] unit to [FeI]. In a follow-up bifurcating cascade, the reaction leads to two different iron carbonyl complexes with ring-opened fragments, a mononuclear η4-1-thia-1,3-diene-type species and a dinuclear η2-acyl-type compound. Cover designed by P. Buday. More information can be found in the Research Article by G. Mlostoń, W. Weigand and co-workers.

How mono- and diphosphine ligands alter regioselectivity of the Rh-catalyzed annulative cleavage of bicyclo[1.1.0]butanes

Rh(I)-catalyzed cycloisomerizations of bicyclo[1.1.0]butanes provide a fruitful approach to cyclopropane-fused heterocycles. Products and stereochemical outcome are highly dependent on catalyst. The triphenylphosphine (PPh3) ligand provides pyrrolidines, placing substituents anti to the cyclopropyl group. The 1,2-bis(diphenylphosphino)ethane (dppe) ligand yields azepanes with substituents syn to the cyclopropyl group. In this work, quantum mechanical DFT calculations pinpoint a reversal of regio- and diastereoselectivity, suggesting a concerted (double) C−C bond cleavage and rhodium carbenoid formation, driven by strain-release. The ligand-influenced cleavage step determines the regioselectivity of carbometalation and product formation, and suggests new applications of bicyclobutanes.

Laminar burning velocities of cyclopropane flames

Cyclopropane, c-C3H6, the simplest cycloalkane, is seldom included in detailed kinetic mechanisms for hydrocarbons, though it may exhibit unusual kinetic features yet to be analysed due to a lack of studies of its combustion characteristics. In this work, laminar burning velocities of cyclopropane flames have been determined using the heat flux method at atmospheric pressure and an initial gas mixture temperature of 298 K. The fuel consisting of 50% c-C3H6 + 50% N2 was burnt with air covering the range of equivalence ratios 0.6 – 1.5. The detailed kinetic model of the authors was extended by the reactions of cyclopropane and cyclopropyl radical, c-C3H5, with the rate constants selected from the literature. This mechanism, as well as the most recent mechanisms for c-C3H6 of Wang et al. (2022) and of Lei et al. (2022), have been compared with the burning velocities of propylene + air flames and with the new experimental results for cyclopropane flames. The model of Lei et al. (2022) significantly underpredicts the burning velocities for both fuels, on the other hand, good agreement with predictions of the present model and of Wang et al. (2022) was observed at 1 atm. However, further sensitivity and rate-of-production analyses revealed important differences in the pathways of c-C3H6 oxidation predicted by the two mechanisms. The present kinetic model was also tested using all available measurements of cyclopropane ignition delays in shock tubes, which combined cover the range of equivalence ratios from 0.33 to 3, at pressures 1 - 10 atm, and temperatures 1100 – 2100 K. Overall good performance of the model was demonstrated across these ranges of conditions and compositions of the mixture. A direct comparison of the experimental data shows that ignition delays of propylene are slightly longer than those of cyclopropane, yet in most cases within the overlapping uncertainties or scattering between different experimental facilities. The laminar burning velocities of c-C3H6 + air are slightly higher than those of C3H6 + air at least according to the predictions of the present mechanism and the model of Wang et al. (2022).

MOF-derived N-Co/Fe-PC composite as heterogeneous electro-Fenton catalysis combined with electrocoagulation process for enhanced degradation of Cu-CIP complexes from wastewater

Recently, heavy metal-antibiotic complexes have been frequently detected in wastewater, posing a serious threat to the human health. In this study, a novel combination of heterogeneous electro-Fenton (hetero-EF) and electrocoagulation process was developed for efficient removal of Cu-ciprofloxacin complexes (Cu-CIP). As hetero-EF cathode catalyst, N doped porous carbon loaded with Co/Fe sites (N-Co/Fe-PC) was innovatively synthesized, and Fe/CoNC structure was formed. The homogeneous mixing of Fe3C and Co3Fe7 resulted in the electron transfer and accumulation on Fe3C, which optimized the active substance and facilitated the oxygen reduction reaction. The effects of current, electrolyte type, pH, and concentration were comprehensively investigated, and the optimum removal efficiency of Cu, CIP, and TOC were 99.69 %, 96.40 %, and 83.62 %, respectively. Besides, it revealed that ·O2– was the dominant contributor to the Cu-CIP degradation. As a result, Cu-CIP complexes were degraded into small molecules and released Cu2+ with the ring-opening demethylation of the piperazine ring, cleavage and demethylation of carboxyl group, hydroxylation of the piperazine ring, and β-cleavage reactions of cyclopropyl group. Meanwhile, they were also adsorbed by aluminum hydroxide/hydroxyl oxides especially γ-AlOOH generated from the anode and finally coprecipitated. This study will provide a novel technology and theoretical basis for enhanced degradation of heavy metal-antibiotic complexes from wastewater.

Discovery of a potent EGFR and ALK dual mutation inhibitor containing N-(3-((4-((2-(cyclopropylsulfinyl)phenyl)amino)pyrimidin-2-yl)amino) phenyl)acrylamide scaffold

A series of EGFR and ALK dual inhibitors containing sulfoxide and cyclopropyl groups were designed and synthesized. The lead compound 8a showed a significant activity against EGFR and ALK in both the enzymatic and cellular assays. The study of anti-tumor mechanism indicated that 8a could effectively block the phosphorylation of EGFR and ALK proteins, so as to effectively inhibiting the proliferation and inducing apoptosis of H1975 tumor cells, blocking the cell cycle and reducing the mitochondrial membrane potential inhibited the migration of H1975 cells. In vivo studies, compounds 8a and 8d can significantly subside the tumor tissue of nude mice without obvious toxicity.

Ring-Opening Dynamics of the Cyclopropyl Radical and Cation: the Transition State Nature of the Cyclopropyl Cation.

We provide compelling experimental and theoretical evidence for the transition state nature of the cyclopropyl cation. Synchrotron photoionization spectroscopy employing coincidence techniques together with a novel simulation based on high-accuracy ab initio calculations reveal that the cation is unstable via its allowed disrotatory ring-opening path. The ring strains of the cation and the radical are similar, but both ring opening paths for the radical are forbidden when the full electronic symmetries are considered. These findings are discussed in light of the early predictions by Longuet-Higgins alongside Woodward and Hoffman; we also propose a simple phase space explanation for the appearance of the cyclopropyl photoionization spectrum. The results of this work allow the refinement of the cyclopropane C-H bond dissociation energy, in addition to the cyclopropyl radical and cation cyclization energies, via the Active Thermochemical Tables approach.

Visible-Light-Induced [4+1] Cyclization-Aromatization of Acylsilanes and α,β-Unsaturated Ketones

Visible-Light-Induced [4+1] Cyclization-Aromatization of Acylsilanes and α,β-Unsaturated Ketones

Hybridization of laccase with dendrimer-grafted silica-coated hercynite-copper phosphate magnetic hybrid nanoflowers and its application in bioremoval of gemifloxacin.

Laccase was successfully hybridized with polyamidoamine (PAMAM) dendrimer-grafted silica-coated hercynite-copper phosphate magnetic hybrid nanoflowers (MHNFs) to increase the catalytic performance of the enzyme and apply in an effective bioremoval of gemifloxacin. For this purpose, the magnetic nanoparticles (MNPs) of hercynite were covered with a silica layer, and the core-shell SiO2@hercynite was then modified with PAMAM dendrimer to increase the surface area of the carrier for the enzyme attachment. Subsequently, the whole complex was hybridized with laccase and copper phosphate to attain a large surface area (104.3 m2g-1). The fabricated MHNFs acquired the entrapment yield and efficiency of 90 ± 3% and 66 ± 5%, respectively. The catalytic activity of the fabricated biocatalyst was remained up to 50% after 13 reusability cycles. Approximately 90% of gemifloxacin was removed by the constructed MHNFs after 3h incubation by adsorption and degradation mechanisms. The biotransformation products were then identified, and degradation pathways were proposed as defluorination, decarboxylation, elimination of a cyclopropyl group, and cleavage of the pyrrolidine moiety. Furthermore, the toxicity of gemifloxacin was effectively diminished against some bacterial strains.