Theoretical (DFT) insights into the mechanism of copper-catalyzed cyclopropanation reactions. Implications for enantioselective catalysis

The mechanism of the copper(I)-catalyzed cyclopropanation reaction has been extensively investigated for a medium-size reaction model by means of B3LYP/6-31G(d) calculations. The starting ethylene complex of the N,N'-dimethylmalonaldiimine--copper (I) catalyst undergoes a ligand exchange with methyl diazoacetate to yield a reaction intermediate, which subsequently undergoes nitrogen extrusion to generate a copper--carbene complex. The cyclopropanation step takes place through a direct carbene insertion of the metal--carbene species to yield a catalyst--product complex, which can finally regenerate the starting complex. The stereochemical predictions of a more realistic model (by considering a chiral bis(oxazoline)--copper (I) catalyst) have been rationalized in terms of steric repulsions, showing good agreement with experimental data.     

On the mechanism of the Rh(II)-catalysed cyclopropanation of alkenes

The mechanism of Rh(ii)-catalysed cyclopropanation has been investigated computationally using Rh(2)(formate)(4) as a model precatalyst, with the model organic substrates CH(2)N(2) and C(2)H(4) and MeCl as a model for coordinating solvent. Three potential carriers of catalysis have been identified, one retaining the Rh(2)(formate)(4) framework and two others resulting from ligand insertion of Rh-CH(2) into an Rh-O bond. Both 2 + 1 and 2 + 2 pathways have been identified for the cyclopropanation step depending on the catalytic carrier involved. Complexes resulting from CH(2) insertion into the Rh-O bond are more efficient at lowering the activation enthalpy for CH(2)-N(2) scission in the rate determining step.     

Divergent reactivity of allene-containing α-diazoesters using Cu and Rh catalysis

A versatile intramolecular reaction of allene-containing diazomalonates that exhibits excellent chemoselectivity for either allenic C–H insertion or cyclopropanation is demonstrated. The identity of the product depends on the transition metal catalyst that is employed for the reaction. Rh catalysts promote exclusive C–H insertion with good diastereoselectivity for the trans product, while Cu catalysis enables intramolecular cyclopropanation to yield methylenecyclopropanes with moderate to good E:Z ratios.     

Towards a rational design of ruthenium CO2 hydrogenation catalysts by Ab initio metadynamics

Complete reaction pathways relevant to CO2 hydrogenation by using a homogeneous ruthenium dihydride catalyst ([Ru(dmpe)2H2], dmpe=Me2PCH2CH2PMe2) have been investigated by ab initio metadynamics. This approach has allowed reaction intermediates to be identified and free-energy profiles to be calculated, which provide new insights into the experimentally observed reaction pathway. Our simulations indicate that CO2 insertion, which leads to the formation of formate complexes, proceeds by a concerted insertion mechanism. It is a rapid and direct process with a relatively low activation barrier, which is in agreement with experimental observations. Subsequent H2 insertion into the formate--Ru complex, which leads to the formation of formic acid, instead occurs via an intermediate [Ru(eta2-H2)] complex in which the molecular hydrogen coordinates to the ruthenium center and interacts weakly with the formate group. This step has been identified as the rate-limiting step. The reaction completes by hydrogen transfer from the [Ru(eta2-H2)] complex to the formate oxygen atom, which forms a dihydrogen-bonded Ru--HHO(CHO) complex. The activation energy for the H2 insertion step is lower for the trans isomer than for the cis isomer. A simple measure of the catalytic activity was proposed based on the structure of the transition state of the identified rate-limiting step. From this measure, the relationship between catalysts with different ligands and their experimental catalytic activities can be explained.     

Deactivation of Ru-benzylidene Grubbs catalysts active in olefin metathesis

In this work, we explore the reactivity induced by coordination of a CO molecule trans to the Ru-benzylidene bond of a prototype Ru-olefin metathesis catalyst bearing a N-heterocyclic carbene (NHC) ligand. DFT calculations indicate that CO binding to the Ru center promotes a cascade of reactions with very low-energy barriers that lead to the final crystallographically characterized product, in which the original benzylidene group has attacked the proximal aromatic ring of the ligand leading to a cycloheptatriene ring through a Buchner ring expansion. In conclusion, the overall mechanism is best described as a carbene insertion into a C–C bond of the aromatic N-substituent of the NHC ligand, forming a cyclopropane ring. This cyclopropanation step is followed by a Buchner ring expansion reaction, leading to the experimentally observed product presenting a cycloheptatriene ring.     

A New Approach in Enantioselective Catalytic with Bis(oxazoline) Ligand-Metal Complexes

In recent years, the research of enantioselective-catalyzed reaction and the catalyst has got great development. Of the various chiral catalysts, great attention was given to the C₂-symmetry chiral bis(oxazoline)ligand-metal complexes for they could be easily synthesized and have shown good enantioselection in various catalytic processes, including cyclopropanation from dihalogenmethane^[1] and diazoacetate^[2].But no report has been found of enantioselective-catalyzed cyclopropanation from sulfonyl-carbanions and alkenes. The test of chiral cyclopropanation from sulfonylcarbanions with nickel bis(oxazolinyl)pyridine catalyst has been made in our lab, and alkylation of aldehydes with diethyl zinc in the presence of nickel or iron bis(oxazolinyl)pyridine was also tested (scheme 1). Some asymmetric effects were observed in these reactions.     

Rhodium chemzymes: Michaelis-Menten kinetics in dirhodium(II) carboxylate-catalyzed carbenoid reactions

Rhodium carboxylate-mediated reactions of diazoketones involving cyclopropanation, C-H insertion, and aromatic C-C double bond addition/electrocyclic ring opening obey saturation (Michaelis-Menten) kinetics. Axial ligands for rhodium, including aromatic hydrocarbons and Lewis bases such as nitriles, ethers, and ketones, inhibit these reactions by a mixed kinetic inhibition mechanism, meaning that they can bind both to the free catalyst and to the catalyst-substrate complex. Substrate inhibition can also be exhibited by diazocompounds bearing these groupings in addition to the diazo group. The analysis of inhibition shows that the active catalyst uses only one of its two coordination sites at a time for catalysis. Some ketones exhibit the interesting property that they selectively bind to the catalyst-substrate complex. The similarity of the kinetic constants from different types of reactions with similar diazoketones, regardless of the linking unit or the environment of the reacting alkene, suggests that the rate-determining step is the generation of the rhodium carbenoid. A very useful rhodium carboxylate catalyst for asymmetric synthesis, Rh(2)(DOSP)(4), shows slightly slower kinetic parameters than the achiral catalysts, implying that enantioselectivity of this catalyst is based on slowing reactions from one of the enantiotopic faces of the reactant, rather than any type of ligand-accelerated catalysis. A series of rhodium catalysts derived from acids with pK(a)s spanning 4 orders of magnitude give very similar kinetic constants.     

Imine hydrosilylation using an iron complex catalyst: A computational study

The reaction mechanism for imine hydrosilylation in the presence of an iron methyl complex and hydrosilane was studied using density functional theory at the M06/6-311G(d,p) level of theory. Benzylidenemethylamine (PhCH = NMe) and trimethylhydrosilane (HSiMe₃) were employed as the model imine and hydrosilane, respectively. Hydrosilylation has been experimentally proposed to occur in two stages. In the first stage, the active catalyst (CpFe(CO)SiMe₃, 1 ) is formed from the reaction of pre-catalyst, CpFe(CO)₂Me, and hydrosilane through CO migratory insertion into the Fe Me bond and the reaction of the resulting acetyl complex intermediate with hydrosilane. In the second stage, 1 catalyzes the reaction of imine with hydrosilane. Calculations for the first stage showed that the most favorable pathway for CO insertion involved a spin state change, that is, two-state reactivity mechanism through a triplet state intermediate, and the acetyl complex reaction with HSiMe₃ follows a σ-bond metathesis pathway. The calculations also showed that, in the catalytic cycle, the imine coordinates to 1 to form an Fe C N three-membered ring intermediate accompanied by silyl group migration. This intermediate then reacts with HSiMe₃ to yield the hydrosilylated product through a σ-bond metathesis and regenerate 1 . The rate-determining step in the catalytic cycle was the coordination of HSiMe₃ to the three-membered ring intermediate, with an activation energy of 23.1 kcal/mol. Imine hydrosilylation in the absence of an iron complex through a [2 + 2] cycloaddition mechanism requires much higher activation energies. © 2018 Wiley Periodicals, Inc.     

Highly Diastereoselective and Enantioselective Olefin Cyclopropanation Using Engineered Myoglobin‐Based Catalysts

Using rational design, an engineered myoglobin‐based catalyst capable of catalyzing the cyclopropanation of aryl‐substituted olefins with catalytic proficiency (up to 46 800 turnovers) and excellent diastereo‐ and enantioselectivity (98–99.9 %) was developed. This transformation could be carried out in the presence of up to 20 g L^?1 olefin substrate with no loss in diastereo‐ and/or enantioselectivity. Mutagenesis and mechanistic studies support a cyclopropanation mechanism mediated by an electrophilic, heme‐bound carbene species and a model is provided to rationalize the stereopreference of the protein catalyst. This work shows that myoglobin constitutes a promising and robust scaffold for the development of biocatalysts with carbene‐transfer reactivity.     

Rh-mediated polymerization of carbenes: mechanism and stereoregulation

Ligand variation, kinetic investigations, and computational studies have been used to elucidate the mechanism of rhodium-catalyzed diazoalkane polymerization. Variations in the "N,O" donor part of the catalyst precursors (diene)Rh(I)(N,O) result in different activities but virtually identical molecular weights, indicating that this part of the precursor is lost on forming the active species. In contrast, variation of the diene has a major effect on the nature of the polymer produced, indicating that the diene remains bound during polymerization. Kinetic studies indicate that only a small fraction of the Rh (1-5%) is involved in polymerization catalysis; the linear relation between polymer yield and M(w) suggests that the chains terminate slowly and chain transfer is not observed (near living character). Oligomers and fumarate/maleate byproducts are most likely formed from other "active" species. Calculations support a chain propagation mechanism involving diazoalkane coordination at the carbon atom, N(2) elimination to form a carbene complex, and carbene migratory insertion into the growing alkyl chain. N(2) elimination is calculated to be the rate-limiting step. On the basis of a comparison of NMR data with those of known oligomer fragments, the stereochemistry of the new polymer is tentatively assigned as syndiotactic. The observed syndiospecificity is attributed to chain-end control on the rate of N(2) elimination from diastereomeric diazoalkane complexes and/or on the migratory insertion step itself.     

Highly Chemo‐ and Stereoselective Catalyst‐Controlled Allylic C−H Insertion and Cyclopropanation Using Donor/Donor Carbenes

The highly chemo‐, enantio‐, and diastereoselective catalyst‐controlled intramolecular allylic C−H insertion and cyclopropanation of donor/donor carbenes are reported. The Ru^II/Pybox complex selectively catalyzed the intramolecular allylic C−H insertion, providing vinyl‐substituted dihydroindoles with greater than 20:1 chemoselectivity and up to greater than 99 % ee. Chiral dirhodium(II) tetracarboxylates, however, selectively promoted the intramolecular cyclopropanation, giving rise to cyclopropane‐fused tetrahydroquinoline derivatives in excellent yields with greater than 99:1 chemoselectivity and up to 97 % ee.     

trans-Cyclopropyl beta-amino acid derivatives via asymmetric cyclopropanation using a (Salen)Ru(II) catalyst

trans-Cyclopropyl beta-amino acid derivatives can be synthesized in five steps with excellent enantioselectivities using a chiral (Salen)Ru(II) cyclopropanation catalyst in the key asymmetry-induction step. This facile synthesis proceeds with high overall yield and can be used to prepare a number of carbamate-protected (Cbz and Boc are demonstrated) beta-amino acid derivatives.     

Computational Insights into Different Mechanisms for Ag-, Cu-, and Pd-Catalyzed Cyclopropanation of Alkenes and Sulfonyl Hydrazones

The [2+1] cycloaddition reaction of a metal carbene with an alkene can produce important cyclopropane products for synthetic intermediates, materials, and pharmaceutical applications. However, this reaction is often accompanied by side reactions, such as coupling and self-coupling, so that the yield of the cyclopropanation product of non-silver transition-metal carbenes and hindered alkenes is generally lower than 50 %. To solve this problem, the addition of a low concentration of diazo compound (decomposition of sulfonyl hydrazones) to alkenes catalyzed by either CuOAc or PdCl₂ was studied, but side reactions could still not be avoided. Interestingly, however, the yield of cyclopropanation products for such hindered alkenes were as high as 99 % with AgOTf as a catalyst. To explain this unexpected phenomenon, reaction pathways have been computed for four different catalysts by using DFT. By combining the results of these calculations with those obtained experimentally, it can be concluded that the efficiency of the silver catalyst is due to the barrierless concerted cycloaddition step and the kinetic inhibition of side reactions by a high concentration of alkene.     

Stereochemical control mechanisms in propylene polymerization mediated by C1-symmetric CGC titanium catalyst centers

This work analyzes stereochemical aspects of olefin polymerization processes mediated by the C1-symmetric constrained geometry catalyst H2Si(ind)(tBuN)TiCH3+ (ind = indenyl), including the role of the cocatalyst/counteranion. The energetics of catalyst activation are first analyzed and shown to compare favorably with experiment. The energetics of heterolytic ion pair separation are next scrutinized, and the effects of solvation environment are assessed. Computed thermodynamic profiles for ethylene insertion at H2Si(ind)(tBuN)TiCH3+ indicate that the kinetics of insertion processes at the H2Si(ind)(tBuN)TiR+ cation can be analyzed in terms of SCF potential energies. We next compare the energetic profile for ethylene insertion at the naked H2Si(ind)(tBuN)TiCH3+ cation with that at the related H2Si(ind)(tBuN)TiCH3+H3CB(C6F5)3- ion pair to understand counterion effects. It is seen that the counterion, although affecting overall catalytic activity, does not significantly influence enchainment stereochemistry or polymer microtacticity. Next, the second ethylene insertion at H2Si(ind)(tBuN)Ti(nC3H7)+H3CB(C6F5)3- is analyzed to evaluate counteranion influence on the propagation barrier. It is found that the ethylene uptake transition state is energetically comparable to the first insertion transition state and that solvation has negligible effects on the energetic profile. These findings justify analysis of the propylene insertion process within the less computationally demanding "naked cation" model. Thus, monomer enchainment at H2Si(ind)(tBuN)TiR+ is analyzed for H2Si(ind)(tBuN)TiCH3+ + propylene (first insertion) and for H2Si(ind)(tBuN)Ti(iC4H6)+ + propylene (second insertion). Data describing the first insertion highlight the sterically dominated regioselection properties of the system with activation energies indicating that olefin insertion regiochemistry is predominantly 1,2 (primary), while the second insertion similarly reflects the catalyst stereoinduction properties, with steric effects introduced by the growing chain (mimicked by an isobutyl group) preferentially favoring insertion pathways that afford isotactic enrichment, in agreement with experiment.     

Gold‐Catalyzed Formal C−C Bond Insertion Reaction of 2‐Aryl‐2‐diazoesters with 1,3‐Diketones

The transition‐metal‐catalyzed formal C−C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3‐diketones instead gives C−H bond insertion products. Herein, we report a protocol for a gold‐catalyzed formal C−C bond insertion reaction of 2‐aryl‐2‐diazoesters with 1,3‐diketones, which provides efficient access to polycarbonyl compounds with an all‐carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C−C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring‐opening of the resulting donor–acceptor‐type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis‐acid‐catalyzed C−C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step.     

Highly asymmetric intramolecular cyclopropanation of acceptor-substituted diazoacetates by Co(II)-based metalloradical catalysis: iterative approach for development of new-generation catalysts

3,5-Di(t)Bu-QingPhyrin, a new D(2)-symmetric chiral porphyrin derived from a chiral cyclopropanecarboxamide containing two contiguous stereocenters, has been developed using an iterative approach based on Co(II)-catalyzed asymmetric cyclopropanation of alkenes. The Co(II) complex of 3,5-Di(t)Bu-QingPhyrin, [Co(P2)], has proved to be a general and effective catalyst for asymmetric intramolecular cyclopropanation of various allylic diazoacetates (especially including those with α-acceptor substituents) in high yields with excellent stereoselectivities. The [Co(P2)]-based intramolecular metalloradical cyclopropanation provides convenient access to densely functionalized 3-oxabicyclo[3.1.0]hexan-2-one derivatives bearing three contiguous quaternary and tertiary chiral centers with high enantiomeric purity.     

A non-fluorous copper catalyst for the styrene cyclopropanation reaction in a fluorous medium

The complex Tp(Br3)Cu(NCMe) (1), containing no fluorine atoms, can be dissolved in the perfluoropolyether FOMBLIN and employed as a catalyst for the styrene cyclopropanation reaction with ethyl diazoacetate, with activities and diastereo-selectivities identical to those observed under homogeneous conditions with the advantage of being able to use a fluorous separation technique for catalyst recycling.     

Intermolecular C-H functionalization versus cyclopropanation of electron rich 1,1-disubstituted and trisubstituted alkenes

Rhodium(II)-catalyzed reactions of aryldiazoacetates with electron rich 1,1-disubstituted and trisubstituted alkenes were systematically studied. The regio-, diastereo- and enantioselectivity of the chemistry was profoundly influenced by the nature of the substrates and the catalyst. Conditions were developed for either selective cyclopropanation or C-H insertion. Both reactions can be achieved with high diastereo- and enantioselectivity (for C-H insertion: >90% de, up to 96% ee, for cyclopropanation: >94% de, up to 95% ee). For the 1,1-disubstituted vinyl ethers, cyclopropanation occurs with variable diastereoselectivity but in optimized systems the cyclopropane is formed in >94% de and up to 98% ee.     

Carbenoid transfer in competing reactions catalyzed by ruthenium complexes

Aiming at improving catalyst activity, ten ruthenium promoters have been investigated in carbenoid transfer from ethyl diazoacetate to styrene as a model substrate. Optimal selectivity in cyclopropanation has been attained with the new NHC–Ru complex 10 , as well as with the Fischer carbene 7 . The surprising non‐metathetical behavior of the Grubbs’ first‐generation catalyst in this multifaceted process is highlighted. Copyright © 2014 John Wiley & Sons, Ltd.     

A fluorous chiral dirhodium(II) complex as a recyclable asymmetric catalyst

[reaction: see text] The chiral fluorous complex tetrakis-dirhodium(II)-(S)-N-(n-perfluorooctylsulfonyl)prolinate has been prepared and used as a catalyst in homogeneous or fluorous biphasic fashion. The catalyst displays good chemo- and enantioselectivity in intermolecular cyclopropanation and C-H bond activation reactions. The catalyst can be simply and thoroughly separated from the reaction mixture and is recyclable.