Cyclopropanation Reactions Research Articles

Mechanistic differences between aryl iodide electrophiles and pronucleophiles in Pd-catalyzed coupling with cyclopropenes: a DFT study

Computational studies were carried out to investigate the mechanisms of Pd-catalyzed ring-opening reactions of cyclopropenes with pronucleophiles (H-Nu) and aryl iodide electrophiles, respectively.

Catalytic cyclopropanation reactions with α-silyl-, germanyl- and stannyl carbenes generated from cyclopropenes.

Silylcyclopropenes are employed as precursors of α-silyl vinyl carbenes and trapped with alkenes. Cyclopropylsilanes were obtained in good yields with ample scope and complete regio- and diastereoselectivity. Stereoretentive protodesilylations enabled access to cis-1,2-disubstituted cyclopropanes. Cyclopropylstannanes and -germanes can also be prepared from the corresponding cyclopropenes.

Highly enantioselective synthesis of norcaradiene derivatives from naphthyl diazoacetamides using a Ru(II)-Pheox complex.

The highly regio- and enantioselective intramolecular cyclopropanation reactions of naphthyl diazoacetamides have been reported herein. In the presence of a Ru(II)-Pheox catalyst, chiral and stable norcaradiene derivatives were obtained from the corresponding diazoacetamides via carbene transfer reactions in high yields (up to 99%) and with high enantioselectivities (up to 99% ee).

Phosphine-catalysed intermolecular cyclopropanation reaction between benzyl bromides and activated alkenes

An intermolecular cyclopropanation reaction between benzyl bromides and activated alkenes was reported catalysed by a bifunctional phosphine.

Visible‐Light‐Mediated Ring‐Opening Reactions of Cyclopropanes

AbstractDue to the high reactivity of cyclopropanes, different methods have been developed for their stereo‐ and regio‐controlled ring‐opening reactions to achieve a variety of synthetically useful targets. The traditional methods for the ring‐opening include thermolysis, use of oxidants, transition metals or radical precursors in which many of them encounter various difficulties. In the past several years, visible‐light‐mediated photoredox reactions received considerable attention for various organic transformations. Several methodologies have been developed in recent times for the visible‐light‐mediated ring‐opening reactions of cyclopropanes. Considering the synthetic potential of this class of reactions, we provide a summary of various methodologies developed for the cyclopropane ring‐opening reactions under visible‐light photoredox catalysis.

Recent progress in radical SAM enzymes: New reactions and mechanisms

<p indent="0mm"><italic>S</italic>-adenosyl-<italic>L</italic>-methionine (SAM) is the second largest cofactor in the human body, and its metabolism is closely related to various physiological activities. In addition to a methyl donor, SAM is also used by radical SAM enzymes with a [4Fe-4S] cluster to catalyze a series of radical reactions. Since the discovery of this enzyme family, it has been found to play important physiological functions in all kingdoms of life. According to bioinformatics prediction, over 220000 radical SAM enzymes are involved in more than 85 biochemical transformations. Almost all radical SAM enzymes have a conserved CxxxCxxC motif, which coordinates the [4Fe-4S] cluster. The reduced [4Fe-4S] cluster provides an electron to SAM to cleave the C_{5′,adenosine}−S bond of SAM and generates a 5′-deoxyadenosine radical (5′-dA·). This radical then grabs a hydrogen atom from the substrate to generate the substrate radical and initiates many different types of reactions. These include thioether crosslinking reactions, radical addition reactions that generate C–C bonds, aliphatic etherification that generates C−O bonds, oxidation reactions, complex rearrangement reactions, methylation, methylthiolation, cyclopropanation reactions and so on. The nonclassical radical SAM enzyme Dph2 cleaves the C_γ,Met–S bond of SAM to generate a 3-amino-3-carboxylpropyl radical (ACP radical), which is added to a histidine residue of the substrate protein elongation factor EF2 for diphthamide biosynthesis. Radical SAM enzymes have a very rich substrate scope, including ribosomally synthesized and posttranslationally modified peptides (RiPPs), proteins, nucleosides and all kinds of small molecules. Classifying by the type of substrate, this review summarizes some of the newly discovered radical SAM enzymes since 2015 and introduces the catalytic mechanism. In addition to new enzymes and reactions, strides have been made in mechanistic studies of radical SAM enzymes in the past several years. Using rapid freeze-quench (RFQ) combined with electron spin resonance spectroscopy (EPR) and electron-nucleus double resonance spectroscopy (ENDOR), researchers have captured and characterized two types of novel intermediates in radical SAM enzymes. These two intermediates are organometallic species with Fe–C bonds formed by the iron-sulfur cluster with the 5′-dA radical and ACP radical, respectively. These findings answer the long-standing question of how enzymes control active organic radical species in radical SAM enzymes and the regioselectivity of SAM cleavage. Finally, we look forward to the future directions of radical SAM enzymes. As discussed above, radical SAM enzymes catalyze numerous difficult reactions, such as C−H activation and C−C bond formation. New enzymatic reactions with unnatural substrates could be developed with protein engineering. Therefore, natural product analogs could be easily made for drug development. Furthermore, in the radical SAM chemistry, only Dph2 can cleave SAM unconventionally to generate the ACP radical, other than the 5′-dA radical from all the other radical SAM enzymes. Whether there are more enzymes using this mechanism to catalyze the reaction remains unexplored. We expect that more Dph2-like enzymes that can generate ACP radicals will be discovered in the future. Finally, the drawback for almost all the reported radical SAM enzymes thus far is their low efficiency. Protein engineering or other strategies that could increase the stability and efficiency of radical SAM enzymes are in high demand. Only by this means would we expect more widespread use of radical SAM enzymes as biocatalysts in synthetic biology.

The copper-catalyzed ring-opening reactions of cyclopropanes by N-fluorobenzenesulfonimide toward N-allylsulfonamides

In this paper, we reported a copper-catalyzed ring-opening reaction of arylcyclopropanes by N-fluorobenzenesulfonimide, leading to N-allylsulfonamides in moderate to good yields. This procedure tolerated bromo, fluoro, trifluoromethyl, phenyl and alkyl groups in the phenyl, proceeding with a sequential ring-opening of arylcyclopropanes, and copper-mediated β-H elimination of alkyl radical.

Catalytic Deoxygenative Cyclopropanation of 1,2-Dicarbonyl or Monocarbonyl Compounds via Molybdenum Catalysis

AbstractThe cyclopropanation of alkenes through the transition-metal-catalyzed decomposition of diazo compounds is a powerful and straightforward strategy to produce cyclopropanes. Nevertheless, the appeal of further application of this strategy is tempered by the potentially explosive nature of the diazo substrates. Therefore, it is highly desirable to develop sustainable and operationally safe surrogates for diazo compounds. In this Synpacts article, we discuss recent advances on the cyclopropane syntheses through the catalytic cyclopropanation of alkenes and metal carbenes generated in situ from nondiazo precursors as well as highlight our recent progress on the unprecedented molybdenum-catalyzed deoxygenative cyclopropanation reaction of 1,2-dicarbonyl or monocarbonyl compounds.

A comparative study on the autoignition characteristics of cyclopropane and propane at high temperatures

An understanding of the autoignition characteristics of cyclopropane, the smallest cycloalkane, would have potential implications for constructing combustion and pyrolysis models for polycyoalkane fuels. However, there are limited studies on the combustion chemistry of cyclopropane in the literature, and the ignition difference between cyclopropane and propane is also unclear. In this work, we explored the reaction pathways of cyclopropane and propane at high temperatures by quantum-chemical calculation and kinetic modeling, and a combustion mechanism for cyclopropane was constructed based on the public core mechanism, UCSD. The computed results show that cyclopropane has a ring-opening reaction, H-abstraction and addition-ring-opening reactions with active radicals and oxygen molecules in the chain initiation process, while propane only has the usual H-abstraction and bond dissociation reactions. Moreover, the kinetic modeling results show that cyclopropane (air mixture) has a shorter ignition delay time (IDT) than propane at a high equivalence ratio (ϕ = 3, p = 5.5 atm), but a longer IDT than that of propane when the equivalence ratio decreases to 0.333, in accordance with available experimental data. Sensitivity analyses demonstrate that reactions of H and CH3 radicals with oxygen molecules accelerate both the ignition of cyclopropane and propane under the conditions considered in this study. Reaction pathway analyses indicate that cyclopropane is consumed through conversion to propylene at high temperatures, whereas oxidation of propane is mainly initiated by H-abstraction reactions. In contrast with propane, the IDTs of cyclopropane increase with decreasing equivalence ratio. The reason is that ring strain favors the ring-opening reaction of cyclopropane to propylene both kinetically and thermodynamically. At high equivalence ratios, more energy is released, leading to an increase in the system temperature which promotes the ignition of cyclopropane.

Synthesis, Reactivity and Electronic Properties of Quinazolin‐2‐one‐Based N‐Heterocyclic Carbenes

AbstractThe electronic properties of a new member F of the family of cyclic (aryl)(amido)carbenes (CArAmC) have been determined. Suitable precursors can easily be obtained by a straightforward synthesis starting from 2‐nitrobenzaldehyde (5). Metal complexes (14, 15) and chalcogen adducts (12, 13) were prepared and their spectroscopic data were evaluated and compared with those reported for CArAmCs (C, D) and the mixed (amino)(amido)carbene E which is a constitutional isomer of the newly reported carbene F. The IR spectroscopic determination indicates an unexceptional TEP value of 2055 cm−1, whereas the strong π‐accepting character is reflected by a chemical shift of δ(77Se) 936 ppm for the Se‐adduct 12 a. However, a significant degree of electrophilic reactivity of the in situ‐generated carbene F was not observed, as, for example, no cyclopropanation reactions with olefins could be detected. DFT calculations provide a rationale for these experimental observations.

Asymmetric synthesis of a cyclopropanecarboxylic acid derivative – the potential agonist/antagonist of GABA receptors

The synthesis of enantiomerically pure (1S,2S,S P)-1-[hydroxy(methyl)phosphonyl]-2-aminocyclopropanecarboxylic acid (1) (a potential agonist/antagonist of GABA receptors) was accomplished in six steps based on optically inactive methyl 2-[methoxy(methyl)phosphonyl]acrylate (2). The key steps of this synthesis included the cyclopropane ring formation by the asymmetric cyclopropanation reaction of 2 with (S)-dimethylsulfonium(p-tolylsulfinyl)methylide (3), regio and stereoselective installation of ethoxycarbonyl group in the cyclopropane ring, and the chemoselective desulfinylation reaction conducted with phenylsilane under the basic conditions.

Organoselenium-Catalyzed Asymmetric Cyclopropanations of (E)-Chalcones.

We report a new class of chiral tetrahydroselenophene based on (S)-diphenyl(tetrahydroselenophen-2-yl)methanol, which was prepared from (R)-3-(3-bromopropyl)-2,2-diphenyloxirane and sodium selenide. These chiral tetrahydroselenophene-based compounds were used to catalyze asymmetric cyclopropanation reactions; the selenonium ylide intermediates formed from these selenium-containing catalysts and benzyl bromide efficiently react with (E)-chalcones to give various cyclopropanes (27 examples) with excellent enantioselectivities of ≤99% ee and are the first examples of organoselenium-catalyzed asymmetric cyclopropanations.

Synthesis of Carbazoles and Dihydrocarbazoles by a Divergent Cascade Reaction of Donor-Acceptor Cyclopropanes.

An alkylation/olefination cascade of indolecarboxaldehydes and phosphonate-functionalized donor–acceptor cyclopropanes affords functionalized dihydrocarbazoles and cyclohepta[cd]indoles in formal (3 + 3) and (4 + 3) cycloadditions. A minor modification to the reaction conditions also allows access to the fully aromatic heterocyclic scaffolds by thermal loss of an electron-rich aryl moiety.

Combined Experimental and Computational Study of Ruthenium N-Hydroxyphthalimidoyl Carbenes in Alkene Cyclopropanation Reactions.

A combined experimental–computational approach has been used to study the cyclopropanation reaction of N-hydroxyphthalimide diazoacetate (NHPI-DA) with various olefins, catalyzed by a ruthenium-phenyloxazoline (Ru-Pheox) complex. Kinetic studies show that the better selectivity of the employed redox-active NHPI diazoacetate is a result of a much slower dimerization reaction compared to aliphatic diazoacetates. Density functional theory calculations reveal that several reactions can take place with similar energy barriers, namely, dimerization of the NHPI diazoacetate, cyclopropanation (inner-sphere and outer-sphere), and a previously unrecognized migratory insertion of the carbene into the phenyloxazoline ligand. The calculations show that the migratory insertion reaction yields an unconsidered ruthenium complex that is catalytically competent for both the dimerization and cyclopropanation, and its relevance is assessed experimentally. The stereoselectivity of the reaction is argued to stem from an intricate balance between the various mechanistic scenarios.

Efficient Asymmetric Simmons-Smith Cyclopropanation and Diethylzinc Addition to Aldehydes Promoted by Enantiomeric Aziridine-Phosphines

During an implementation of current research, a set of optically pure chiral aziridines and aziridine imines bearing a phosphine moiety was prepared with high values of chemical yield. The above chiral heteroorganic derivatives were tested for catalytic utility as chiral ligands in asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to various aldehydes. Most of the desired products were formed in high chemical yields, with satisfactory values of enantiomeric excess (sometimes more than 90%) and diastereomeric ratios (in case of cyclopropanation reaction).

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.

Mechanism and Selectivity of Cyclopropanation of 3-Alkenyl-oxindoles with Sulfoxonium Ylides Catalyzed by a Chiral N,N'-Dioxide-Mg(II) Complex.

The mechanism and stereoselectivity of an asymmetric cyclopropanation reaction between 3-alkenyl-oxindole and sulfoxonium ylide catalyzed by a chiral N,N'-dioxide-Mg(II) complex were explored using the B3LYP-D3(BJ) functional and the def2-TZVP basis set. The noncatalytic reaction occurred via a stepwise mechanism, with activation barriers of 21.6-23.5 kcal mol-1. The C2-Cα bond formed followed by the carbanion SN2 substitution, constructing a three-membered ring in spiro-cyclopropyl oxindoles, accompanied by the release of dimethylsulfoxide. The electron-withdrawing N-protecting t-butyloxy carbonyl (Boc) and acetyl (Ac) groups in isatin enhanced the local electrophilicity of the C2 atom and the repulsion between the two COPh groups in the reactants, contributing to high reactivity as well as good diastereoselectivity results. The N-Boc-3-phenacylideneoxindole coordinated to the chiral ligand (L-PiPr2) in a bidentate fashion, forming a hexacoordinate-Mg(II) complex as the reactive species. The origin of enantioselectivity was from the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the si-face of oxindole. The repulsion between the SO(CH3)2 and COPh groups in 3-alkenyl-oxindole and the neighboring ortho-iPr group in the ligand directed the re-face of ylide to attack the re-face of oxindole preferably, contributing to the high diastereoselectivity of the product. A metal-ion-ligand matching relationship was important for a good asymmetric induction effect of the chiral N,N'-dioxide-metal catalyst. A large chiral cavity in the Zn(II) catalyst weakened the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the prochiral face of oxindole, leading to inferior enantioselectivity observed in the experiment.

Synthesis and Reactions of 1,3,5-Tri- and 1,3,5,7-Tetracarbonyl Compounds

AbstractThe reaction of 1,3-bis(silyloxy)-1,3-butadienes with functionalized and nonfunctionalized acid chlorides and bis(acid chlorides) gives rise to the formation of a great variety of 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds and cyclic products derived from them. Examples include functionalized and nonfunctionalized 3,5-dioxopentanoates, 3,5-dioxopimelates, 3-alkylidene-3H-isobenzofuran-1-ones, salicylates, 3(2H)furanones, and 3-oxo-4-sulfonylesters. Methylation and cyclopropanation reactions of 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds do not provide access to the expected permethylated and cyclopropanated polycarbonyl compounds. However, the latter could be prepared by stepwise protocols. The reaction of 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds with dinucleophiles resulted in cyclization reactions to give a variety of heterocyclic structures.1 Introduction2 Reactions of 1,3-Bis(silyloxy)-1,3-butadienes with Acid Chlorides3 Reactions of 1,3,5-Tri- and 1,3,5,7-Tetracarbonyl Compounds4 Conclusion

Stereoselective synthesis of novel carbocyclic and heterocyclic scaffolds of medicinal importance from biocatalytically derived enantiopure α-substituted-β-hydroxy esters

Biocatalytically derived enantiopure α-substituted-β-hydroxy esters can act as a potential precursor for the stereoselective synthesis of a diverse set of small organic molecules of medicinal importance. Chiral γ-Z-butenolides can be constructed through a “Pd–Cu” bimetallic cascade cyclization. Synthetic anti-viral compound 5′-methylaristeromycin was accessed through RCM (ring closing metathesis) and nucleophilic opening of epoxide with nucleobase adenine. Structurally novel enantiopure cyclitol analogs were synthesized efficiently through RCM reaction, enzymatic desymmetrization, and cyclopropanation reaction starting from the same precursor. Chiral cyclic γ-keto-ester was accessed by exploration of asymmetric Stetter reaction from the same starting material. Finally, novel bicyclic enones can also be synthesized through RCM/Robinson annulation sequence. All the synthesized compounds can be potentially useful in medicinal chemistry research.

Importance of Thermal Stability Data to Avoid Dangerous Reagents: Temozolomide Case Study

First disclosed in the 1970s, Temozolomide (TMZ) was recently reported to be a nonexplosive surrogate for methyl diazonium. As part of a program to explore an esterification reaction of a hindered carboxylic acid, TMZ was considered as a possible reagent to perform this challenging transformation. After preliminary DSC screening resulted in an alarming difference from what was previously reported, the decision was made to further investigate TMZ from a thermal stability perspective. DSC, impact testing, accelerating rate calorimetry, U.N. Test Series 2, and U.N. Test Series 3 testing were performed on TMZ. The results showed that TMZ is tentatively considered a Class 1 explosive. Extreme caution should be used if TMZ is to be produced or used to perform esterification or cyclopropanation reactions.