Methylene transfer or carbometalation? A theoretical study to determine the mechanism of lithium carbenoid-promoted cyclopropanation reactions in aggregation and solvation States

Density functional theory calculations for the lithium carbenoid-promoted cyclopropanations in aggregation and solvation states are presented in order to investigate the controversy of the mechanistic dichotomy, that is, the methylene-transfer mechanism and the carbometalation mechanism. The methylene-transfer mechanism represents the reaction reality, whereas the carbometalation pathway does not appear to compete significantly with the methylene-transfer pathway and should be ruled out as a major factor. A simple model calculation for monomeric lithium carbenoid-promoted cyclopropanations with ethylene in the gas phase is not sufficient to reflect the reaction conditions accurately or to determine the reaction mechanism since its result is inconsistent with the experimental facts. The aggregated lithium carbenoids are the most probable reactive species in the reaction system. The calculated reaction barriers of the methylene-transfer pathways are 10.1 and 8.0 kcal/mol for the dimeric (LiCH2F)2 and tetrameric (LiCH2F)4 species, respectively, compared with the reaction barrier of 16.0 kcal/mol for the monomeric LiCH2F species. In contrast, the reaction barriers of the carbometalation pathways are 26.8 kcal/mol for the dimeric (LiCH2F)2 and 33.9 kcal/mol for the tetrameric (LiCH2F)4 species, compared with the reaction barrier of 12.5 kcal/mol for the monomeric LiCH2F species. The effects of solvation were investigated by explicit coordination of the solvent molecules to the lithium centers. This solvation effect is found to enhance the methylene-transfer pathway, while it is found to impede the carbometalation pathway instead. The combined effects of the aggregation and solvation lead to barriers to reaction in the range of 7.2-9.0 kcal/mol for lithium carbenoid-promoted cyclopropanation reactions along the methylene-transfer pathway. Our computational results are in good agreement with the experimental observations.     

Theoretical studies of samarium carbenoid promoted cyclopropanation reaction with allylic alcohol on the reaction pathways

The density functional theory was employed to investigate the mechanism for the cyclopropanation reactions of samarium carbenoid with an allylic alcohol. Seven competitive reaction pathways were investigated. Analysis of the calculated results shows that the models 4 and 6 have relatively low reaction barriers which suggested that the deprotonation of allylic alcohol promoted by CH₃SmCH₂I plays a significant important role in the cyclopropanation reaction via a samarium carbenoid. The methylene transfer and carbometalation pathways are involved in both intermolecular and intramolecular reaction pathways. On the basis of the energetics of the reaction pathways, the methylene transfer pathway is favored over the carbometalation pathway in the whole reactions. Our computational results are in good agreement with the experimental results performed by G.A. Molander and L.S. Harring.     

钐(II)类卡宾CH_3SmCH_2I与乙烯环丙烷化反应及溶剂化效应(THF)对反应途径影响的理论研究

用密度泛函B3LYP方法研究了过渡金属钐类卡宾与乙烯的环丙烷化反应的机理.对钐类卡宾试剂CH3SmCH2I和CH2CH2反应的反应物、中间体、过渡态和产物构型的全部结构几何参数进行了优化,并计算了THF溶液的溶剂化效应,用内禀反应坐标(IRC)计算和频率分析方法,对过渡态进行了验证.结果表明:CH3SmCH2I与CH2CH2环丙烷化反应按亚甲基转移机理(通道A)和卡宾金属化机理(通道B)都可以进行,与锂类卡宾的反应机理相同,通道A比通道B反应的势垒降低了14.65kJ/mol.溶剂化效应使通道B比通道A的反应势垒大幅度提高,更有利于反应沿通道A进行,而不利于通道B.     

Samarium(III) carbenoid as a competing reactive species in samarium-promoted cyclopropanation reactions

The trivalent samarium carbenoid I2SmCH2I-promoted cyclopropanation reactions with ethylene have been investigated and are predicted to be highly reactive, similarly to the divalent samarium carbenoid ISmCH2I. The methylene transfer and carbometalation pathways were explored and compared with and without coordination of THF solvent molecules to the carbenoid. The methylene transfer was found to be favored, with the barrier to reaction going from 12.9 to 9.2 kcal/mol compared to barriers of 15.4-17.5 kcal/mol for the carbometalation pathway upon the addition of one THF molecule.     

钐(II)类卡宾CH3SmCH2I与乙烯环丙烷化反应及溶剂化效应的理论研究

用密度泛函B3LYP方法研究了过渡金属钐类卡宾与乙烯的环丙烷化反应的机理. 对钐类卡宾试剂CH₃SmCH₂I和CH₂CH₂反应的反应物、中间体、过渡态和产物构型的全部结构几何参数进行了优化, 并计算了THF溶液的溶剂化效应, 用内禀反应坐标(IRC)计算和频率分析方法, 对过渡态进行了验证. 结果表明: CH₃SmCH₂I与CH₂CH₂环丙烷化反应按亚甲基转移机理(通道A)和卡宾金属化机理(通道B)都可以进行, 与锂类卡宾的反应机理相同, 通道A比通道B反应的势垒降低了14.65 kJ/mol. 溶剂化效应使通道B比通道A的反应势垒大幅度提高, 更有利于反应沿通道A进行, 而不利于通道B.     

Theoretical study of samarium (II) carbenoid (ISmCH2I) promoted cyclopropanation reactions with ethylene and the effect of THF solvent on the reaction pathways

A computational study of the cyclopropanation reactions of divalent samarium carbenoid ISmCH(2)I with ethylene is presented. The reaction proceeds through two competing pathways: methylene transfer and carbometalation. The ISmCH(2)I species was found to have a "samarium carbene complex" character with properties similar to previously investigated lithium carbenoids (LiCH(2)X where X = Cl, Br, I). The ISmCH(2)I carbenoid was found to be noticeably different in structure with more electrophilic character and higher chemical reactivity than the closely related classical Simmons-Smith (IZnCH(2)I) carbenoid. The effect of THF solvent was investigated by explicit coordination of the solvent THF molecules to the Sm (II) center in the carbenoid. The ISmCH(2)I/(THF)(n)() (where n = 0, 1, 2) carbenoid methylene transfer pathway barriers to reaction become systematically lower as more THF solvent is added (from 12.9 to 14.5 kcal/mol for no THF molecules to 8.8 to 10.7 kcal/mol for two THF molecules). In contrast, the reaction barriers for cyclopropanation via the carbometalation pathway remain high (>15 kcal/mol). The computational results are briefly compared to other carbenoid reactions and related species.     

A density functional theory investigation of the Simmons-Smith cyclopropanation reaction: examination of the insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions.

The insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions with CH(2)CH(2) have been investigated using B3LYP level density functional theory calculations. The Simmons-Smith cyclopropanation reaction of olefins does not proceed easily due to the relatively large barriers on the insertion and cyclopropanation pathways. The computed results indicate that the IZnCH(2)I molecule is the active reagent in the Simmons-Smith reaction. This is consistent with the IZnCH(2)I reactive species being generated from diiodomethane and a Zn-Cu couple as proposed by several other research groups. The Simmons-Smith IZnCH(2)I carbenoid and CH(2)I-I carbenoid cyclopropanation reactions with olefins are compared. The reactions of olefins with the radicals from the decomposition of the IZnCH(2)I and CH(2)I-I species were also compared. We found that the chemical reactivity of the carbenoid species is dependent on its electrophilic behavior, steric effects, the leaving group character and the mechanism of the cyclopropanation reactions.     

Enantioselective Iron‐Catalyzed Intramolecular Cyclopropanation Reactions

An iron‐catalyzed asymmetric intramolecular cyclopropanation was realized in high yields and excellent enantioselectivity (up to 97 % ee) by using the iron complexes of chiral spiro‐bisoxazoline ligands as catalysts. The superiority of iron catalysts exhibited in this reaction demonstrated the potential abilities of this sustainable metal in asymmetric carbenoid transformation reactions.     

钐(Ⅱ)类卡宾CH3SmCH2X(X=Cl、Br和I)促进乙烯环丙烷化反应途径的理论研究

In order to have efficient and highly stereoselective cyclopropanating reagents, the cyclopropanation reaction of ethylene promoted with Samarium(Ⅱ) carbenoid Simmons-Smith(SS)reagent were studied by means of B3LYP hybrid density functional method. The geometries for reactants, transition states and products are completely optimized. All transition states were verified by the vibrational analysis and the intrinsic reaction coordinate (IRC) calculations. The results showed that, identical with the lithium carbenoid,CH3SmCH2X(X=Cl, Br and I) can fairly react with ethylene via both methylene transfer pathway (pathway A) and carbometalation pathway (pathway B). And the cyclopropanation reaction via methylene transfer pathway proceeds with a lower barrier and at lower temperatures.     

Dirhodium tetracarboxylate derived from adamantylglycine as a chiral catalyst for carbenoid reactions

[reaction: see text] The dirhodium tetracarboxylate, Rh2(S-PTAD)4, derived from adamantylglycine, is a very effective chiral catalyst for carbenoid reactions. High asymmetric induction was obtained in Rh2(S-PTAD)4-catalyzed intramolecular C-H insertion (94% ee), intermolecular cyclopropanation (99% ee), and intermolecular C-H insertion (92% ee).     

Quantum chemistry study on the reactivity of PhOTiCl2CH2Cl and Cl3TiCH2Cl cyclopropanation reagents with olefins

In order to explore the new and efficient cyclopropanation reagents, a theoretical investigation of the cyclopropanation reactions of titanium carbenoid PhOTiCl₂CH₂Cl and Cl₃TiCH₂Cl with olefins was given at the B3LYP level of theory. All of the reactions examined displayed similar concerted mechanisms for the cyclopropanation of these reagents. The reactions are predicted to be highly chemical reactivity with low barriers and could be favored in experiment, and the cyclopropanation reaction proceed easily at lower temperature. The computational results are briefly compared to other carbenoid reactions and related species.     

Ruthenium-catalyzed intramolecular cyclization of diazo-β-ketoanilides for the synthesis of 3-alkylideneoxindoles

With [Ru(p-cymene)Cl(2)](2) as catalyst, diazo-β-ketoanilides would undergo intramolecular carbenoid arene C-H bond functionalization to afford 3-alkylideneoxindoles in up to 92% yields. The reaction occurs under mild conditions and exhibits excellent chemoselectivity. The lack of primary KIE (k(H)/k(D) ~ 1) suggests that the reaction should not proceed by rate-limiting C-H bond cleavage; a mechanism involving cyclopropanation of the arene is proposed.     

Ruthenium-catalyzed stereoselective intramolecular carbenoid C-H insertion for beta- and gamma-lactam formations by decomposition of alpha-diazoacetamides

[reaction: see text] An operationally simple catalytic system based on [RuCl(2)(p-cymene)(2)] was developed for stereoselective cyclization of alpha-diazoacetamides by intramolecular carbenoid C-H insertion, and beta-lactams were produced in excellent yields and >99% cis-stereoselectivity. The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With alpha-diazoanilides as substrate, the carbenoid insertion was directed selectively to aromatic C-H bond leading to gamma-lactam formation (>95% yield).     

Reaction pathways of the Simmons-Smith reaction

The cyclopropanation reaction of an alkene with a metal carbenoid has been studied by means of the B3LYP hybrid density functional method. The cyclopropanation of ethylene with a lithium carbenoid or a zinc carbenoid [Simmons-Smith (SS) reagent] goes through two competing pathways, methylene transfer and carbometalation. Both processes are fast for the lithium carbenoid, while, for the zinc carbenoid, only the former is fast enough to be experimentally feasible. The reaction of an SS reagent (ClZnCH(2)Cl) with ethylene and an allyl alcohol in the presence of ZnCl(2) was also studied. The allyl alcohol reaction was modeled with an SS reagent/alkoxide complex (ClCH(2)ZnOCH(2)CH=CH(2)) formed from the SS reagent and allyl alcohol. Two modes of acceleration were found. The first involves the well-accepted mechanism of 1,2-chlorine migration, and the second involves a five-centered bond alternation. The latter was found to be more facile than the former and to operate equally well both with ethylene and with aggregates of SS reagent/alkoxide complexes. Calculations on the SS reaction with 2-cyclohexen-1-ol offer a reasonable model for the hydroxy-directed diastereoselective SS reaction, which has been used for a long time in organic synthesis.     

Carbenoid Pathways in Copper‐Catalyzed Intramolecular Cyclopropanations of Phenyliodonium Ylides

The enantioselectivity of the copper‐catalyzed intramolecular cyclopropanation of allyl diazomalonates and the corresponding phenyliodonium ylides was investigated with a series of chiral, non‐racemic ligands. The reaction of 6b in the presence of the bis[dihydrooxazole] ligand Xa in refluxing 1,2‐dichloroethane proceeded to 8b with an enantiomer excess (ee) of up to 72% under optimized conditions. In contrast, 8b resulting from reaction of ylide 7b with the same ligand, but in CH₂Cl₂ at 0°, had an ee of only 30%. With other ligands, diazomalonate 6b reacted with a lower enantioselectivity than ylide 7b , however. The intramolecular cyclopropanation of the acetoacetate‐derived phenyliodonium ylide 15b afforded 16b with 68% ee with ligand Xa , but the corresponding diazo compound was unreactive when exposed to chiral copper catalysts. The observation of asymmetric induction in the Cu‐catalyzed reactions of the ylides 7 and 15 is consistent with a carbenoid mechanism; however, the discrepancy of the enantioselectivities observed between diazomalonate 6b and ylide 7b suggests a competing unselective pathway for cyclopropanation outside of the coordination sphere of copper.     

Amino-zinc-enolate carbometalation reactions: application to ring closure of terminally substituted olefin for the asymmetric synthesis of cis- and trans-3-prolinoleucine

The amino-zinc-enolate cyclization reaction is a straightforward route for the synthesis of 3-substituted prolines. As classical intramolecular carbometalation reactions, the applicability of the addition of zinc to a double bond was limited to a substrate in which the terminal alkene carbon was unsubstituted. Being interested in the synthesis of cis- and trans-3-prolinoleucine derivatives for our structure-activity relation (SAR) studies, we focused our effort on the preparation of these compounds by amino-zinc-enolate cyclization of terminally substituted double bonds. Herein we report that the attachment of an activating group such as cyclopropyl to the terminal olefin carbon allows the amino-zinc-enolate cyclization of a terminally substituted alkene. The reaction is stereospecific, leading to a trans-3-substituted proline derivative, whereas a cis stereochemistry was observed with the amino-zinc-enolate cyclization of terminally nonsubstituted olefins. Absolute configurations obtained for the 3-prolinoleucine were established by X-ray analysis, NMR, and optical activity comparison of the cis and trans derivatives obtained by an unambiguous pathway.     

Synthesis and chemistry of bridgehead allylsilanes. Stereoselective reactions with aldehydes

A type II intramolecular Diels-Alder reaction provides access to bicyclo[5.3.1] ring systems with an imbedded bridgehead allylsilane. The Lewis acid catalyzed reactions of these compounds with aldehydes proceed efficiently and with control of stereochemistry. [reaction: see text]     

Asymmetric synthesis of cis-5-tert-butylproline with metal carbenoid NH insertion

The highly stereoselective intramolecular metal carbenoid insertion reaction of sulfinimine-derived delta-amino alpha-diazoesters is used to prepare cis-5-tert-butylproline. A concerted or nearly concerted metal carbenoid N-H insertion reaction mechanism is proposed.     

Rhodium(II)-catalyzed carbocyclization reaction of alpha-diazo carbonyls with tethered unsaturation

o-Alkynyl-substituted alpha-diazoketones undergo internal cyclization to produce indenone derivatives upon treatment with catalytic quantities of Rh(II)-carboxylates. A variety of structural influences were encountered by varying the nature of the substituent group attached to the diazo center. The cyclization reaction involves addition of a rhodium-stabilized carbenoid onto the acetylenic pi-bond to generate a cycloalkenone carbenoid. The cyclized carbenoid was found to undergo both aromatic and aliphatic C-H insertion as well as cyclopropanation across a tethered pi-bond. Subjection of diazo phenyl acetic acid 3-phenylprop-2-ynyl ester to Rh(II) catalysis furnished 8-phenyl-1, 8-dihydro-2-oxacyclopenta[a]indenone in high yield. The formation of this compound involves cyclization of the initially formed carbenoid onto the alkyne to produce a butenolide which then undergoes C-H insertion into the neighboring aromatic system. When a vinyl ether is added, the initially formed rhodium carbenoid intermediate can be intercepted by the electron-rich pi-bond prior to cyclization. Different rhodium catalysts were shown to result in significant variation in the product ratios. The competition between bimolecular cyclopropanation, 1,2-hydrogen migration, and internal cyclization was probed using several enol ethers as well as diazoesters which possess different substituent groups on the ester backbone. The specific path followed was found to depend on electronic, steric, and conformational factors.     

Electrophilic cyclizations of vinylcyclopropanols to tethered aldehydes

[reaction: see text]. The intramolecular, stereoselective addition of 1-vinylcyclopropanols to tethered aldehydes has been achieved under mild conditions. Thus, sequential application of the titanium-mediated cyclopropanation of alpha,beta-unsaturated esters and the electrophilic cyclization of the aldehyde-tethered cyclopropanol products provides the facile formation of carbocyclic rings.