Simmons-Smith reaction, use

A modified version of the Simmons-Smith reaction uses dibromomethane and in situ generation of the Cu-Zn couple.171 Sonication is used in this procedure to promote reaction at the metal surface. 

The methods for stereocontrolled synthesis of cyclopropylboronic esters have been studied (Scheme 29). The palladium-catalyzed reaction of diazoalkanes (method A), Simmons-Smith reaction (method B), or asymmetric Simmons-Smith reaction using chiral diamines such as 270 (method C) for chiral or achiral 1-alkenylboronic esters... 

Table 7. Examples of improved Simmons-Smith reactions using zinc-silver couple and pyridine work-up... 

Small ring synthesis. Simmons-Smith reactions using CH2l2-Et2Zn as reagent are enantioselective in the presence of chiral rrans-I,2-cyclohexanedisulfonamides... 

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). 

Charette and co-workers reported a chiral Lewis acid-catalysed Simmons-Smith reaction, using a titanium TADDOL complex, although in general this system shows limited substrate scope compared to the Kobayashi system. ... 

Although methylene prepared from diazomethane itself is not synthetically useful, addition of methylene to an alkene can be accomplished using a reaction first reported by the American chemists Howard Simmons and Ronald Smith. The Simmons-Smith reaction uses diiodomethane and zinc dust activated by a small amount of copper (a so-called "zinc-copper couple") to produce iodomethylzinc iodide, in a reaction reminiscent of a Grignard reaction. Even though we show the Sinunons-Smith reagent here as ICH2ZnI, its structure is considerably more complex and not fully imderstocxl. 

The Simmons-Smith reaction has been used to great advantage in the conversion of 19-nor steroids to the naturally occurring 10)5-methyl steroids as well as the unnatural lOa-methyl steroids. Thus methylenation of androst-5(10)-ene-3a,17 -diol (9) proceeds in an autoclave at elevated temperatures with stereospecific a-face addition to give the 5a,10a-methylene compound (10) in 85% yield. 

The Simmons-Smith reaction has been used as the basis of a method for the indirect a methylation of a ketone. The ketone (illustrated for cyclohexanone) is first converted to an enol ether, an enamine (16-12) or silyl enol ether (12-22) and cyclopropanation via the Simmons-Smith reaction is followed by hydrolysis to give a methylated ketone. A related procedure using diethylzinc and diiodomethane allows ketones to be chain extended by one carbon. In another variation, phenols can be ortho methylated in one laboratory step, by treatment with Et2Zn and... 

The cyclopropanation of 1-trimethylsilyloxycyclohexene in the present procedure is accomplished by reaction with diiodomethane and diethylzinc in ethyl ether." This modification of the usual Simmons-Smith reaction in which diiodomethane and activated zinc are used has the advantage of being homogeneous and is often more effective for the cyclopropanation of olefins such as enol ethers which polymerize readily. However, in the case of trimethylsilyl enol ethers, the heterogeneous procedures with either zinc-copper couple or zinc-silver couple are also successful. Attempts by the checkers to carry out Part B in benzene or toluene at reflux instead of ethyl ether afforded the trimethylsilyl ether of 2-methylenecyclohexanol, evidently owing to zinc iodide-catalyzed isomerization of the initially formed cyclopropyl ether. The preparation of l-trimethylsilyloxybicyclo[4.1.0]heptane by cyclopropanation with diethylzinc and chloroiodomethane in the presence of oxygen has been reported. "... 

Owing to the widespread use of ultrasonic cleaning baths, it is not surprising that many early sonochemical experiments were directed at reactions where dirty metal surfaces were thought to be the cause of inefficiencies. Reactions typified by Grignard and Simmons Smith reactions (Scheme 7.11) are often not predictable, sometimes having long induction periods followed by violent exotherms. Frequently, small... 

Several modifications of the Simmons-Smith procedure have been developed in which an electrophile or Lewis acid is included. Inclusion of acetyl chloride accelerates the reaction and permits the use of dibromomethane.174 Titanium tetrachloride has similar effects in the reactions of unfunctionalized alkenes.175 Reactivity can be enhanced by inclusion of a small amount of trimethylsilyl chloride.176 The Simmons-Smith reaction has also been found to be sensitive to the purity of the zinc used. Electrolytically prepared zinc is much more reactive than zinc prepared by metallurgic smelting, and this has been traced to small amounts of lead in the latter material. 

An unusual combination, namely a Michael addition and a Simmons-Smith reaction, has been elaborated by the group of Alexakis [112]. Using their protocol, 3/5-as well as 3/6-annulated systems can easily be obtained, which might be useful as precursors for the total syntheses of (-)-(S,S)-clavukerin A and (+)-(R,S)-iso-clavukerin, both isolated from Clavularia koellikeri [113]. 

Zinc promoted reactions are responsive to ultrasonic waves. The classic Simmons-Smith reaction was among our first successes(21). Using zinc powder and diiodomethane we obtained good yields of cyclopropanes from styrene and acenaphthene. However, we could not... 

The direct reaction of zinc metal with organic iodides dates back to the work of Frankland(67). Several modifications have been suggested since that time to increase the reactivity of the metal. The majority of these modifications have employed zinc-copper couples(68-72), sodium-zinc alloys(73), or zinc-silver couples(77). Some recent work has indicated that certain zinc-copper couples will react with alkyl bromides to give modest yields of dialkylzinc compounds(74,73). However, all attempts to react zinc with aryl iodides or bromides have met with failure. The primary use of zinc couples has been in the Simmons-Smith reaction. This reaction has been primarily used with diiodomethane as 1,1-dibromides or longer chain diiodides have proven to be too unneactive even with the most reactive zinc couples. 

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 seemingly straightforward protonolysis of ZnMe2 with 2-(methylthio)ethanol in CH2C12 (Scheme 95) afforded [MeZn(/i3-OCH2CH2SMe)Zn(/i-Cl)Me]2 149.215 The presence of both methyl and chloride substituents on zinc suggests that the solvent (CH2C12) is involved in the reaction, which should call into question the use of dichloro-methane as solvent in the Simmons-Smith reaction. 

Furthermore, cyclopropane structures have often served as intermediates in organic synthesis. For these reasons, olefin cyclopropanation has proved to be a useful tool for synthetic organic chemists. This has led to the development of several methods for cyclopropanation reactions,91 including the metal-catalyzed reactions of diazo compounds with olefins, as well as the Simmons-Smith reaction. 

The Simmons-Smith reaction " and its variants are widely used for the stereospecific synthesis of cyclopropane compounds. The methodology involves the use of copper-treated zinc metal (the zinc-copper couple) with diiodomethane to add methylene to a carbon-carbon double bond. Alternative use of diazomethane in catalytic reactions does not offer the same synthetic advantages and is usually avoided because of safety considerations. As significant as is the Simmons-Smith reaction for cyclopropane formation, its employment for organic synthesis was markedly advanced by the discovery that allylic and homoallylic hydroxyl groups accelerate and exert stereochemical control over cyclopropanation of alkenes (e.g, Eq. 21), and this acceleration has been explained by a transition state model... 

Catalytic processes using diazo chemistry and stoichiometric methods with Fischer carbenes are complimentary for the introduction of a substituted carbene into a molecule. For methylene addition, however, there is no viable alternative to the modified Simmons-Smith reaction. Ring-closing metathesis, and its ROMP counterpart, have matured so fast that even now they rank among the most useful synthetic methodologies in organic chemistry. 

Preparation of spiro[2.3]hexanes is possible by the addition of methylene or a methylene equivalent to an exocyclic C —C double bond. Generally, the Simmons Smith reaction is used (see Section l.A.1.2.1.), but formation of carbenes from nitroso compounds can also be used.73-75,333 The 1,1-dihalo derivative can be prepared by phase-transfer-catalyzed reactions.48 For example, reaction of a mixture of cis- and trans-1,2-dimethyl-3-methylenecyclobutane with dibromo-carbene gave a mixture of cis- and lrans-1,1-dibromo-4,5-dimcthylspiro[2.3]hexanc (2).48... 

The presence of an excellent recent review in this area [7] will curtail discussion to three papers. Taguchi et al. [360] showed that protected /Lfluoroallylic alcohols underwent Simmons-Smith reactions more slowly than the non-fluori-nated congeners, but still afforded useful yields of cyclopropane products (Eq. 140) with an excess of the methylene transfer reagent. 

The synthesis of substituted glutamic acid analogues has been pursued by many routest94-106 using asymmetric alkylation, Simmons-Smith reactions, Diels-Alder reactions, and nickel complexes of glycine or alanine equivalents. 

A study of the scope of the reaction has shown that mono- and disubstituted alkenes and, particularly, aryl-substituted alkenes are the best substrates. Various limitations have been noted, some not unexpected (sensitivity to steric effects), others quite surprising (complex reactivity of cyclohexenes). Nevertheless, the exceptionally high stability of the reagent should make it available from the shelf, and in appropriate cases its use is to be considered as an alternative to the Simmons-Smith reaction. 

The Simmons-Smith reaction, which involves cyclopropanation by the Zn CH2I2 system (equation 6), is a very popular variant of this method22. However, an application of the Simmons-Smith reaction to methylenecycloalkanes often requires the use of high excess (up to ten equivalents) of the reagent, which complicates the workup and lowers the yields. 

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