Cyclopropanation Of Alkenes Research Articles

Highly Diastereoselective Radical Cyclopropanation of Olefins via Cobaloxime‐Based Metalloradical Catalysis

Highly Diastereoselective Radical Cyclopropanation of Olefins via Cobaloxime‐Based Metalloradical Catalysis

“Boron Ylide” Enables Stereoselective Construction of gem‐Diborylcyclopropanes

AbstractThe stereoselective cyclopropanation of olefins with “boron ylide” is disclosed for the first time, providing a modular strategy for the synthesis of stereospecific diboryl‐functionalized cyclopropanes. The chiral gem‐diborylcyclopropanes are synthesized with excellent enantioselectivity with the aid of a chiral auxiliary. Based on the powerful transformable ability of boryl group, those challenging multi‐quaternary carbon centers in cyclopropane units have been facilely constructed with excellent stereoselectivity. Control experiments indicate that the boryl groups are necessary for both chemoselectivity and stereoselectivity control.

"Boron Ylide" Enables Stereoselective Construction of gem-Diborylcyclopropanes.

The stereoselective cyclopropanation of olefins with "boron ylide" is disclosed for the first time, providing a modular strategy for the synthesis of stereospecific diboryl-functionalized cyclopropanes. The chiral gem-diborylcyclopropanes are synthesized with excellent enantioselectivity with the aid of a chiral auxiliary. Based on the powerful transformable ability of boryl group, those challenging multi-quaternary carbon centers in cyclopropane units have been facilely constructed with excellent stereoselectivity. Control experiments indicate that the boryl groups are necessary for both chemoselectivity and stereoselectivity control.

C-H Insertion from Isolable Copper Benzylidenes.

Despite the utility of copper catalysts for the insertion of carbene moieties into C-H bonds, the copper carbene intermediate often invoked in these transformations has not been isolated. Herein, we describe the synthesis and structural characterization of a series of copper benzylidenes utilizing the sterically encumbered dipyrrin ligand (EmL)H. These isolated copper carbenes demonstrate intramolecular insertion into the primary C(sp3)-H bond of the ligand (EmL)H and intermolecular insertion into ethereal and allylic C-H bonds. The copper carbenes isolated are best described as Cu(I) carbene adducts akin to canonical Fischer carbenes, given their diamagnetic ground state and electrophilic carbene reactivity. Furthermore, the insertion chemistry can be rendered catalytic utilizing a more sterically exposed dipyrrin ligand (ArFL)H. The ability to isolate and observe stoichiometric C-H insertion and olefin cyclopropanation from well-characterized copper benzylidenes illuminates their viability as catalytic intermediates and their participation in potential catalyst deactivation pathways.

Anti-selective Cyclopropanation of Nonconjugated Alkenes with Diverse Pronucleophiles via Directed Nucleopalladation.

A facile approach to obtaining densely functionalized cyclopropanes is described. The reaction proceeds under mild conditions via the directed nucleopalladation of nonconjugated alkenes with readily available pronucleophiles and gives excellent yields and good anti-selectivity using I2 and TBHP as oxidants. Pronucleophiles bearing a diverse collection of electron-withdrawing groups, including -CN, -CO2R, -COR, -SO2Ph, -CONHR, and -NO2, are well tolerated. Internal alkenes, which are generally challenging substrates in other cyclopropanation methods, provide excellent yields and good diastereoselectivity in this methodology, allowing for controlled access to cyclopropanes substituted at all three C atoms. DFT calculations and mechanistic experiments reveal that the major mechanistic pathway involves the initial α-iodination of the nucleophile, followed by anti-carbopalladation and intramolecular C(sp3)-I oxidative addition. Strain-release-promoted C(sp3)-C(sp3) reductive elimination then furnishes the cyclopropanated product.

(XantPhos)AgBr as a cheap and readily available catalyst for the bromofluorocyclopropanation of electron-rich alkenes

A silver phosphine complex (XantPhos)AgBr proved to be a cheap and readily accessible catalyst for bromofluoro- cyclopropanation of electron-rich alkenes with CFBr2CO2Na. Ozonolysis followed by treatment with NaHSO3 was shown to be an effective protocol to purify gem-bromofluoro- cyclopropanes from unreacted alkene precursors.

Synthesis, Reactivity, and Bonding Analysis of a Tetracoordinated Nickel Carbene.

Nickel carbenes are key reactive intermediates in the catalytic cyclopropanation of olefins and other reactions, but isolated examples are scarce and generally rely on low coordination numbers (≤ 3) to stabilize the metal-ligand multiple bond. Here we report the isolation and characterization of a stable tetracoordinated nickel carbene bearing a triphosphine pincer ligand. Its nucleophilic character is evidenced by reaction with acids, and it can transfer the carbene fragment to CO to form a ketene. A computational study of the Ni=C chemical bond sheds light on the role of the third phosphine in the pincer framework to the stabilization of the nickel carbene fragment.

Alkene Cyclopropanation with gem-Dichloroalkanes Catalyzed by (PNN)Co Complexes: Scope and Mechanism

Alkene Cyclopropanation with <i>gem</i>-Dichloroalkanes Catalyzed by (PNN)Co Complexes: Scope and Mechanism

Dichloromethane as C1 Synthon for the Photoredox Catalytic Cyclopropanation of Aromatic Olefins

AbstractDichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible‐light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3−Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non‐cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium‐labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development.

Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

Dichloromethane as C1 Synthon for the Photoredox Catalytic Cyclopropanation of Aromatic Olefins.

Dichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible-light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3-Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non-cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium-labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development.

Heterogeneous Fe-N-C Catalyst for Aerobic Dehydrogenation of Hydrazones to Diazo Compounds Used for Carbene Transfer.

Organic diazo compounds are versatile reagents in chemical synthesis and would benefit from improved synthetic accessibility, especially for larger scale applications. Here, we report a mild method for the synthesis of diazo compounds from hydrazones using a heterogeneous Fe-N-C catalyst, which has Fe ions dispersed within a graphitic nitrogen-doped carbon support. The reactions proceed readily at room temperature using O2 (1 atm) as the oxidant. Aryl diazoesters, ketones, and amides are accessible, in addition to less stable diaryl diazo compounds. Initial-rate data show that the Fe-N-C catalyst achieves faster rates than a heterogeneous Pt/C catalyst. The oxidative dehydrogenation of hydrazones may be performed in tandem with Rh-catalyzed enantioselective C-H insertion and cyclopropanation of alkenes, without requiring isolation of the diazo intermediate. This sequence is showcased by using a flow reactor for continuous synthesis of diazo compounds.

Zeolite Catalytic Simmons–Smith Cyclopropanation of Alkenes for the Synthesis of High-Energy-Density Fuels

Zeolite Catalytic Simmons–Smith Cyclopropanation of Alkenes for the Synthesis of High-Energy-Density Fuels

Cyclopropanation of Alkenes with Halodiazirines as Halocarbene Precursors in Continuous Flow.

The cyclopropanation reaction of alkenes with photolytically-generated chlorocarbenes from chlorodiazirines is reported as an effective way to prepare substituted 3-chloro-3-aryl-cyclopropanes. This practical and efficient approach allows the synthesis of various 3-chloro-3-aryl-cyclopropanes (32 examples) in continuous flow in 5-minute residence time under light-emitting diode (LED) irradiation. The conditions using 380 nm LED irradiation were successfully extended to the synthesis of substituted 3-bromo-3-aryl-cyclopropanes (3 examples).

Cyclopropanation Using Electrons Derived from Hydrogen: Reaction of Alkenes and Hydrogen without Hydrogenation.

Have you ever imagined reactions of alkenes with hydrogen that result in anything other than hydrogenation or hydrogenative C-C coupling? We have long sought to develop not only hydrogenation catalysts that activate H2 as hydride ions but also electron transfer catalysts that activate H2 as a direct electron donor. Here, we report the reductive cyclopropanation of alkenes using an iridium electron storage catalyst with H2 as the electron source without releasing metal waste from the reductant. We discuss the catalytic mechanism with selectivity to give the trans-isomer. These findings are based on the isolation of three complexes and density functional theory calculations.

Cyclopropanation of unactivated alkenes with non-stabilized iron carbenes

Cyclopropanes are ubiquitous in medicines, yet robust synthetic access to a wide range of sterically and electronically diverse analogs remains a challenge. To address the synthetic limitations of the most direct strategy, (2+1) cycloaddition, we sought to develop a variant that employs non-stabilized carbenes. We present herein an FeCl2-catalyzed cyclopropanation that uniquely employs aliphatic (enolizable) aldehydes as carbene precursors. A remarkably broad range of alkenes may be coupled with these non-stabilized, alkyl carbenes. This extensive scope enables the synthesis of novel classes of cyclopropanes bearing alkyl, benzyl, allyl, halide, and heteroatom substituents, as well as spirocyclic and fused bicycles. Over 40 examples illustrate the broad generality, efficiency, selectivity, functional group tolerance, and practical utility of this approach. Mechanistic insights, gathered from stereochemical probes and competition experiments, are included to reveal the applicability of this non-stabilized carbene route for novel cyclopropane synthesis.

Chiral 4-MeO-Pyridine (MOPY) Catalyst for Enantioselective Cyclopropanation: Attenuation of Lewis Basicity Leads to Improved Catalytic Efficiency.

The design of pyridine-derived organocatalysts aims at the increase of their Lewis basicity, however such an approach is not always efficient. For example, strongly Lewis basic DMAP is completely inefficient as catalyst in the cyclopropanation reaction. Herein we disclose an alternative approach that relies on attenuation of DMAP Lewis basicity. Specifically, the replacement of 4-dimethylamino substituent in DMAP for 4-MeO group delivered a highly efficient catalyst for cyclopropanation of electron-deficient olefins with α-bromoketones. Kinetic studies provide compelling evidence that the superior catalytic efficiency of 4-MeO pyridine (MOPY) is to be attributed to the favorable balance between Lewis basicity and leaving group ability. The use of chiral, enantiomerically pure MOPY catalyst has helped to achieve high enantioselectivities (up to 91 : 9 er) in the previously unreported pyridine-catalyzed cyclopropanation reaction.

Synthesis, structural analysis, DFT study, and catalytic performance of a glycine-Schiff base binuclear copper(ii) complex

We report the synthesis of a binuclear copper(ii) complex with a Schiff base ligand from glycine, showing excellent catalytic performance in olefin cyclopropanation and C–S cross-coupling, with high yields, selectivity, and versatility.

Vitamin B12 -Photocatalyzed Cyclopropanation of Electron-Deficient Alkenes Using Dichloromethane as the Methylene Source.

The cyclopropyl group is of great importance in medicinal chemistry, as it can be leveraged to influence a range of pharmaceutical properties in drug molecules. This report describes a Vitamin B12 -photocatalyzed approach for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH2 Cl2 ) as the methylene source. The reaction proceeds in good to excellent yields under mild conditions, has excellent functional group compatibility, and is highly chemoselective. The scope could also be extended to the preparation of D2 -cyclopropyl and methyl-substituted cyclopropyl adducts starting from CD2 Cl2 and 1,1-dichloroethane, respectively.

Enantio- and Diastereoselective Cyclopropanation of Alkenes by Iron(III)-Based Metalloradical Catalysis

Enantio- and Diastereoselective Cyclopropanation of Alkenes by Iron(III)-Based Metalloradical Catalysis