Mechanism of the Simmons-Smith reaction

Because of the complexity of the pathway, the sensitivity of the reagents involved, the heterogeneous nature of the reaction, and the limitations of modern experimental techniques and instrumentation, it is not surprising that a compelling picture of the mechanism of the Simmons-Smith reaction has yet to emerge. In recent years, the application of computational techniques to the study of the mechanism has become important. Enabling theoretical advances, namely the implementation of density functional theory, have finally made this complex system amenable to calculation. These studies not only provide support for earlier conclusions regarding the reaction mechanism, but they have also opened new mechanistic possibilities to view. 

Bernardi and co-workers investigated the mechanism of the Simmons-Smith reaction theoretically at the DFT (B3LYP) level of theory, using ClCH2ZnCl as a model system.95 Of the two available reaction channels (addition and insertion), the former process was found to have the lower activation energy (107.7 vs. 150.7 kj moP1), and this result correlates well with the exclusive cyclopropanation over the competing insertion reaction. 

The mechanism of the Simmons-Smith reaction appears to be a carbene transfer from the metal to the aikene without any free carbene being released. It may look something like this. 

A modified version of the Simmons-Smith reaction uses dibromomethane and in situ generation of the Cu-Zn couple. Sonication is used in this procedure to promote reaction at the metal surface. Cyclopropanation can also be affected with a combination of CH2I2 and an alkylzinc reagent. The reaction is stereospecific and strongly regioselective. Thus, it has been found that cyclopentenol gives only the mdo-bicyclic alcohol (Scheme 5.34). The mechanism of the Simmons-Smith reaction appears to be carbene transfer from the metal to the alkene without any free carbene being released (Scheme 5.35). 

Starting olefins. No insertion of methylene group into the C—H bond linked to the olefinic double bond is observed. Thus the mechanism of reaction (8) is closely related to that of the Simmons-Smith reaction. However, reaction (8) is much more rapid than the corresponding Simmons-Smith reaction, and methylene iodide must be added slowly to moderate the reaction. The first step of reaction (8) was shown to be the formation of ethyl iodide and iodomethylethylzinc (XIII), which undergoes methylene transfer reaction with olefins. Since two ethyl-zinc... 

It should be noted that CH2 transfer to olefins using monohalomethylmer-cury compounds proceeds by a concerted mechanism similar to that of the Simmons-Smith reaction . Bis(bromomethyl)mercury is stable in refluxing benzene only in the presence of a CH2 acceptor does CH2 extrusion from the mercurial take place.-The nature of the olefin has a large effect on the rate of the reaction (2,3-dimethyl-2-pentene, 26 3-ethyl-2-pentene. 4.2 cyclohexene, 1.0 l-heptene, 0.225). 

The mechanism for the formation of this carbenoid and for its reaction with alkenes need not concern us here. Just remember that it reacts as though it is methylene. The Simmons-Smith reaction is an excellent way to prepare cyclopropane derivatives from alkenes, as shown in the following examples. Note the stereochemistry in the second equation. 

A cis addition mechanism is generally accepted for the reaction, because cis addition to an olefinic bond generally occurs with predominant attack at trans bonds, and the Simmons-Smith reagent attacks preferentially one of the trans olefinic bonds of trans,trans,cis-1,5,9-cyclodode-catriene and then the cis double bond of the monoadduct (378). The close correspondence in relative rates of olefins for the cyclopropane formation by the Simmons-Smith reaction with those for diimide reduction and peroxide epoxidation supports the concept 409). The latter two reactions are generally considered to proceed via cis addition. 

The Simmons-Smith reaction with cyclopenten-4-ol gives exclusively the cis isomer of bicyclo[3.1.0]hexan-3-ol (94, 540, 541). Cleavage of the Simmons-Smith reagent by the hydroxyl group would give a salt (VI), and intramolecular methylene transfer would then yield m-bicyclo-[3.1.0]hexan-3-ol after hydrolysis (42). An alternative mechanism was... 

The Simmons-Smith reaction does not involve a free carbene. Rather, the reaction of CH2I2 with Zn(Cu) forms (iodomethyl)zinc iodide, which transfers a CH2 group to an alkene, as shown in Mechanism 26.5. 

Methylene iodide and a zinc-copper couple react in ether solution to give bis-(iodomethyl)zinc zinc iodide . Closely related reagents are accessible by the reaction of zinc halides with diazomethane . These reagents have been widely used in the synthesis of cyclopropanes from olefins. Norcarane formation from cyclohexene and bis(iodomethyl)zinc was found to be second order, k = (6.3 0.5) x 10 l.mole . sec " at 0°C These findings cannot be reconciled with the intermediacy of free methylene. A one-step methylene transfer mechanism has therefore been proposed for the Simmons-Smith reaction, viz. 

When the thioacetal (128) was treated with allylmagnesium bromide and subsequently with BFs etherate, nucleophilic addition on the carbonyl carbon and a subsequent cationic cyclization took place the product (129) was obtained by aromatization with loss of methanethiol (Scheme 18) <84TL5095>. The reaction of (128) under the Simmons-Smith reaction conditions gave the thienothiepine derivative (130). The proposed mechanism for the formation of (130) involves a nucleophilic attack of the initially formed sulfonium ylide intermediate, intramolecular aldol type condensation, aromatization and demethylation (Scheme 19) <89TL3093>. 

This study suggests a radically new explanation for the nature of Lewis acid activation in the Simmons-Smith cyclopropanation. The five-centered migration of the halide ion from the chloromethylzinc group to zinc chloride as shown in TS2 and TS4 has never been considered in the discussion of a mechanism for this reaction. It remains to be seen if some experimental support can be found for this unconventional hypothesis. The small energy differences between all these competing transition states demand caution in declaring any concrete conclusions. 

Cyclopropanation of alkenes with the Simmons-Smith reagent bears some similarity to epoxidation. Both reactions are stereospecific cycloadditions, and iodomethylzinc iodide behaves, like peroxy acids, as a weak electrophile. Both cycloadditions take place faster with more highly substituted double bonds than less substituted ones, but are sensitive to steric hindrance in the alkene. These similarities are reflected in the mechanisms proposed for the two reactions shown in Mechanism 14.2. Both are believed to be concerted. 

Simmons-Smith reaction Areactionin which a cyclopropane ring is produced from an alkene. It uses the Simmons-Smlth recent, which was originally diiodo-methane (CH2I2) with aZn/Cu couple. Usually, diethyl zinc is used rather than Zn/Cu. The mechanism involves the formation of H2C(I) (Znl) and carbene transfer from the zinc to the double bond of the alkene. 

Perhaps the earliest example was published in 1969 by Whitlock and Overman, who described angular methylation of a cyclic lithium enolate with Simmons-Smith reagent. H. W. Whitlock, Jr. and L. E. Overman, J. Org. Chem., 34, 1962 (1969). However, since the mechanism of this reaction is not clear, it is not included in this review. 

Some of the evidence for this comes from a reaction that not only throws light on to the mechanism of Simmons-Smith cyclopropanations, but makes them of even greater value in synthesis. When an allylic alcohol is cyclopropanated, the new methylene group adds stereoselectively to the same face of the double bond as the alcohol group. 

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