Simmons-Smith reactions

In this reaction, sonochemically activated zinc and methylene iodide are used. The generated carbene adds on to an olefinic bond to give 91% yield 

The above method can be scaled and has several advantages. The reagent used, ZnlCR is known as Simmons-Smith reagent. 

Simmons-Smith reagent 2ICH2Znl (ICH2)2Zn + Znl2 

In 1958 Simmons and Smith described a new and general synthesis of cyclopropanes by treatment of olefins with a reagent prepared from methylene iodide and a zinc-copper couple in ether solution. 

Blanchard and Simmons suggested that the stable organozinc intermediate obtained in this reaction is probably bis-(iodomethyl) zinc zinc iodide (1). 

In a further extension of this reaction Winstein and Dauben showed that the action of the methylene-transfer reagent (1) on A -cycloal-kenols, e.g., (2), proceeds by stereospecific cis addition to give the cw-cyclo-propyl carbinol (5). It was also observed that both the rate and yield of the hydroxyl-assisted reaction are increased substantially. It has been suggested that the high stereoselectivity observed in these instances is best explained by complex formation or reaction of the reagent (1) with the hydroxyl group of (2) followed by intromolecular transfer of methylene. 

For his work on chirally catalyzed oxidation reactions, representing a major contribution to the development of catalytic asymmetric synthesis, K. B. Sharpless was awarded the Nobel Prize for chemistry in 2001.  

Schinzer in Organic Synthesis Highlights 11 (Ed. H. Waldmann), VCH, Wein- 

Guzman-Perez, Angew. Chem. 1998, 110, 402-415, Angew. Chem. Int. Ed. Engl. 1998, 37, 388. 

Aldrich, Handbook of Eine Chemicals and Laboratory Equipment, 2003-2004. 

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 

By reaction of zinc-copper couple with diiodomethane 2 an organozinc species 4 is formed, similar to a Grignard reagent. Its structure cannot be fully described by a single structural formula. The actual structure depends on the reaction conditions—e.g. the solvent used this corresponds to the Schlenk equilibrium as it is observed with the Grignard reaction  

Example 3, Diastereoselective Simmons-Smith cyclopropanations of allylic amines and carbamates  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 236, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 253, Springer International PubUshing Switzerland 2014 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

All ring chemistry tables are organized into what is called binary search trees. Queries are posed about the existence of certain structural features. Each of these questions is answerable with a yes or a no. Based on the answer one of two different followup questions is selected. Embedded within the table may be requests for subgoals, either those already in the PGI or PGA table or for special reactions which are needed only for these transforms and are not of general synthetic interest. 

The example below shows some of the synthetic routes generated by the Diels Alder transform for the indicated precursor. It is important to note that while some of the chemistry may look somewhat naive, it can be quite thought provoking. 

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. 

Equation (17), derived from the kinetic scheme (16), relates the intramolecular ( hMd) ind intermolecular (kajk t) kinetic isotope effects. 

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This reaction is called the Smmons-Smith reaction and is one of the few methods avail able for the synthesis of cyclopropanes Mechanistically the Simmons-Smith reaction seems to proceed by a single step cycloaddition of a methylene (CH2) unit from lodomethylzmc iodide to the alkene... 

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... 

It IS clear that free CH2 is not involved m the Simmons-Smith reaction but there... 

Simmons-Smith reaction (Section 14 12) Reaction of an alkene with lodomethylzmc iodide to form a cyclopropane denvative... 

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 synthesis of 11 jS-hydroxy-A -3-ketones (17) from A ° -compounds (16) has been carried out by the homoallylic hydroxyl-assisted Simmons-Smith reaction. 

Serini reaction, 167 Simmons-Smith reaction, 107 Sodium acetylide, 138 Sodium bismuthate, 147, 149 Sodium bistrimethylsilylamide, 90 Sodium chloroacetylide, 68 Solvolytic cleavage of cyclic ethers, 267 3- (5 -Spiro-2, 2 -dimethyloxazolidi nyl) -cholestane, 360... 

It is clear that free CH2 is not involved in the Simmons-Smith reaction, but there is substantial evidence to indicate that caibenes aie formed as intermediates in certain other reactions that convert alkenes to cyclopropanes. The most studied exanples of these reactions involve dichlorocaibene and dibromocaibene. 

Without question, the most powerful method for cyclopropane formation by methylene transfer is the well-known Simmons-Smith reaction [6]. In 1958, Simmons and Smith reported that the action of a zinc-copper couple on diiodomethane generates a species that can transform a wide variety of alkenes into the corresponding cyclopropanes (Scheme 3.3) [7]. 

These initial reports demonstrated that a catalytic asymmetric variant of the Simmons-Smith reaction could be developed. Although good yields and selectivities were obtained, the lack of a clear understanding of the origin of activation, the limited structural information on the active species and the absence of a stereochemical model made rational improvements difficult at best. The next... 

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. 

Schlenk equilibrium 93 s-cis 7, 9, 26, 31, 35 sdyl-substituted 16 Simmons-Smith reaction 87 SnClj 309 SnCU 309 solid-phase 198 square bipyramidal 255 rr-stacking 8 stannyl-substituted 16 s-trans 7, 26 - acrolein 307 succinimide 227 sulfonamides 122 synchronicity 306... 

The Simmons-Smith reaction is well suited for the synthesis of spirocyclic compounds. It has for example been applied for the construction of the fifth cyclopropane ring in the last step of a synthesis of the rotane 8 ... 

The zinc iodide formed in a Simmons-Smith reaction can act as Lewis acid, and thereby may catalyze rearrangement reactions however interfering side-reactions are generally rare. 

A carbene, R2C , is a neutral molecule containing a divalent carbon with only six valence electrons. Carbenes are highly reactive toward alkenes, adding to give cyclopropanes. Nonlialogenated cyclopropanes are best prepared by treatment of the alkene with CH212 and zinc-copper, a process called the Simmons-Smith reaction. 

Simmons-Smith reaction of cyclohexene with diiodomethane gives a single cyclopropane product, but the analogous reaction of cyclohexene with 1,1-diiodoethane gives (in low yield) a mixture of two isomeric methyl-cyclopropane products. What are the two products, and how do they differ ... 

Simmons-Smith reaction (Section 7.6) The reaction of an alkene with CH2l2 and Zn—Cu to yield a cyclopropane. 

Digitoxigenin, structure of, 1097 Digitoxin, structure of, 989 Dihalide, alkynes from, 261 Dihedral angle, 94 Diiodomelhane. Simmons-Smith reaction with, 228-229 Diisobutylaluminum hydride, reaction with esters, 812 structure of, 699 Diisopropylamine, pK.d of, 923 1,3-Diketone, pfCa of, 852 Dimethyl disulfide, bond angles in, 20 structure of, 20 Dimethyl ether, electrostatic... 

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