Simmons-Smith reagent cyclopropanation with

Simmons-Smith reagent Named after the duPont chemists who discovered that diiodo-mechane would react with an active zinc-copper couple in ether to give a reagent with molecular formula ICHiZnl. The reagent adds stereospecifically cis- to alkenes to give cyclopropanes in high yields. 

Cyclopropanation with Halomethylzinc Reagents. A very effective means for conversion of alkenes to cyclopropanes by transfer of a CH2 unit involves reaction with methylene iodide and a zinc-copper couple, referred to as the Simmons-Smith reagent.169 The reactive species is iodomethylzinc iodide.170 The transfer of methylene occurs stereospecifically. Free CH2 is not an intermediate. Entries 1 to 3 in Scheme 10.9 are typical examples. 

The carbenoid from Et2Zn/CH2I2 [17], particularly when generated in the presence of oxygen [18], is more reactive than the conventional Simmons-Smith reagents. The milder conditions required are suitable for the preparation of 1-[16, 19] or 2-alkoxy-l-siloxycyclopropanes [20], which are generally more sensitive than the parent alkyl substituted siloxycyclopropanes (Table 2). Cyclopropanation of silyl ketene acetals is not completely stereospecific, since isomerization of the double bond in the starting material competes with the cyclopropanation [19]. 

Although many recent improvements in the preparation of the Simmons Smith reagent might be helpful23 24, the authors of this chapter would recommend one to consider an alternative two-step cyclopropanation procedure, which includes cycloaddition of dichloro- or dibromocarbene to methylenecycloalkane25 followed by reductive dehalo-genation (equation l)26. The first reaction is usually carried under phase transfer conditions and presents a very simple and efficient procedure. Reduction of gem-dihalocyclopropanes with lithium in tert-butanol or with sodium in liquid ammonia usually proceeds without complications and with high yield. 

Diastereoselective cyclopropanation of enones.1 The homochiral ketals of cyclic a,p-enones obtained by reaction with 1,4-di-O-benzyl-L- or D-threitol2 undergo diastereoselective cyclopropanation on reaction with the Simmons-Smith reagent (8-20 1). The diastereoselectivity is less in the case of ketals of cyclic p, 7-enones (2 1). 

Fig. 3.16. Two reactions that demonstrate the stereospecificity of n s-cycLopropanations with the Simmons-Smith reagent. In the first reaction the zinc carbenoid is produced according to the original method, and in the second it is produced by the Furukawa variant.

The selective cyclopropanation of the a-enone silyl enol ether 75, by methylene iodide and the zinc-silver couple 2), is remarkable. Only the double bond bearing the tri-methylsiloxy group reacted to yield the 1-trimethylsiloxy vinylcyclopropane 76 when not more than 1.1 equivalent of the Simmons-Smith reagent was used, but the bis-cyclopropanation product 77 was obtained in good yield with an excess (3 equivalents) of the cyclopropanating reagent, Eq. (24) 42). 

Fig. 3.12. Two reactions that demonstrate the stereospecificity of cis cyclopropanations with the Simmons-Smith reagent.

The methylene generated from diazomethane reacts with alkenes to form cyclopropanes, but diazomethane is very toxic and explosive, and the methylene generated is so reactive that it forms many side products. A safer and more reliable way to make cyclopropanes is with the Simmons-Smith reagent. 

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. 

This type of coordination is useful for highly stereoselective syntheses of cyclopropane derivatives. Reaction of A -cyclohexenyl methyl ether with the Simmons-Smith reagent gives CM-2-bicyclo[4.1.0]heptyl methyl ether without the trans isomer 103). The Simmons-Smith reaction with 7-tCT f-hutoxynorbornadiene gives syn-exo- IV) and syn-endo isomer (V) without the anti isomers 260). 

Solutions of (I), (VIII), and (IX) in ether react with olefins to give the corresponding cyclopropane derivatives 200, 427a, 542-546). Burger and Huisgen 64) concluded that the Simmons-Smith reagent [CH2I2 +... 

Z)-Disubstituted cyclopropanes. The (Z)-vinylstannane 2 (above) reacts with the Simmons-Smith reagent to give the c/i-l,2-disubstituted cyclopropane 3 in 70% yield. The product is useful for pteparation of optically active cyclopropanes. 

Cyclopropanation. Irradiation (350 nm.) of CH2I2 in the presence of alkenes yields the corresponding cyclopropane adducts with complete retention of stereochemistry. The reaction is facilitated by increasing alkyl substitution in contrast to the Simmons-Smith reagent, this reaction is not sensitive to steric factors. Presumably methylene ( CH2) is the reactive species. ... 

Cyclopropanation of an altylic alcohol. The reaction of the aliylic alcohol (1) with the Simmons-Smith reagent is extremely sensitive to dehydration to the diene (3). The best yields of (2) are obtained by careful control of the temperature (31-38°). 

Steric course. Cyclopropane formation with the Simmons-Smith reagent is a stereospecific cis- addition for example cis- and tran.s-hexene-3 give pure cis- and fran5--l, 2-diethylcyclopropane. 

In the presence of CuCl, exo-3-tricyclo[3.2.1.02 4]octene-6-yl-3-hexene-2-oic acid methyl ester (72) is isolated after TLC in 60% yield (Z E = 1.5 1) 67c). This is comparable to the course of the cyclopropanation of norbornadiene with both the Simmons-Smith reagent and diazomethane-CuCl. In both cases the exo-anti route is favored over the exo-syn 63). It is important to notice, that in the above mentioned nickel(O) catalyzed reactions (Eq. 11) hexatriene derivatives have never been observed. 

The classical Simmons-Smith reagent was used to cyclopropanate a double bond in the presence of a triple bond in the synthesis of racemic 11,12-cyclopropyl analogs of hepoxilins Aj and ( )-Undec-2-en-5-ynol (4) was treated with diiodomethane/zinc-copper couple in anhydrous diethyl ether to afford the intermediate racemic (lS, 2S )-l-hydroxymethyl-2-... 

This sequence has been used for the synthesis of the sesquiterpenes ( —)- and ( + )-thujop-sene. The allylic /1-hydroxysulfoximines 47 and 49 were separated by column chromatography on silica gel and treated separately with excess of Simmons Smith reagent prepared from zinc/ silver amalgam and diiodomethane in diethyl ether giving 48 and 50, respectively. The Simmons-Smith reaction took place stereospecifically cis to the hydroxy group of the allylic ff-hydroxysulfoximines. Cyclopropanes 48 and 50 were converted to ( —)- and (- -)-thujopsene. 

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