Addition Simmons-Smith reactions

Yields m Simmons-Smith reactions are sometimes low Nevertheless because it often provides the only feasible route to a particular cyclopropane derivative it is a valu able addition to the organic chemist s store of synthetic methods... 

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 (Section 14.12) Methylene transfer from iodo-methylzinc iodide converts alkenes to cyclopropanes. The reaction is a stereospecific syn addition of a CH2 group to the double bond. 

By application of the Simmons-Smith reaction it is possible to synthesize a cyclopropane from an alkene by formal addition of carbene to the carbon-carbon double bond, without a free carbene being present in the reaction mixture the... 

The addition of carbene to a 3-(halopropyl)-5//-dibenz[7>./]azepine 5 (X = Cl, Br) in a Simmons—Smith reaction is more complex and results in a mixture of the tetracycle 6 (6%), its cyclopropano derivative 7 (48 %), the 5-allyl derivative 8 and the (cyclopropyl)methyl compound 9, the latter two products in a combined yield of 12%.31... 

Addition of TCS 14 to CH2l2/Zn, which contains up to 0.04 mol% of lead impurity, improves the Simmons-Smith reaction of olefins such as cyclooctene to give up to 96% of the cyclopropane 2103 [36] (Scheme 13.12). 

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]. 

The preparation of [5]rotane 81 (pentaspiro[2.0,2.0.2.0.2.0.2.0]pentadeeane), again includes one step of carbene addition, by the Simmons-Smith reaction, to 13-methyle-ne-tetraspiro[2.0.2.0,2.0.2.1]tridecane 8026). A full paper on the subject appeared later 27 >. 

The rhodium acetate catalyzed addition of ethyl diazoacetate to MCP (1) gave spiropentane 619 in high yield (Scheme 89) [6e]. The same compound 619 was obtained in lower yield by a Simmons-Smith reaction to methylenecyclo-propane 217 [164],... 

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. 

Taking 1,2-disubstituted cyclopropane as an example, retro synthesis analysis shows that there are three possible ways to disconnect the three-membered ring—a, b, and c as shown in Figure 5-11. Route a involves the addition of methylene across a double bond, and this is often a stereospecific conversion or Simmons-Smith reaction.92 One can clearly see that route b or c will encounter the issue of cis/trans-product formation. 

Finally, it should be mentioned that from a purely synthetic point of view the reactions involving "transfer" of methylene groups -like the Simmons-Smith reaction [27] or Seyferth s reagents [28]- may be considered formally as cheletropic additions of a [2 + 1] type. 

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... 

Examples of the Simmons-Smith reaction are presented in Table 5, with emphasis on more recent work. For additional examples, the reader is referred to extensive tabulations in earlier, comprehensive reviews. 1 e>57... 

Cyclopropanes are commonly synthesized with Zn(CH2I)2 (37) using the Simmons-Smith-reactum.16 This reaction proceeds via one-step addition of one of the methylene groups of the zinc reagent to olefins. As an advantage of the Simmons-Smith-reaction no free carbene is involved. 

CHX3/UH ) (CH I2, Zn/Cu) (Section 11.8) R—CH—CH2 tives.These are syn additions.The Simmons-Smith reaction generates a carbenoid that reacts like methylene. 

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