Cyclopropanation Simmons-Smith reagent

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. 

Iodomethylzinc iodide is known as the Simmons-Smith reagent, after Howard E. Simmons and Ronald D. Smith of Du Pont who first described its use in the preparation of cyclopropanes. 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

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. 

A simpler example of this kind of stereochemical control is the cyclopropanation of cyclopenten-2-ol (5) by the Simmons-Smith reagent in which the cij-biciclo[3.1.0]hexan-2-ol (7) is the diastereomer exclusively formed. As in the case of the hydrogen in strychnine, the methylene enters stereoselectively by intramolecular transference from an intermediate complex ( . 

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]. 

SAMPLE SOLUTION (a) In a cyclopropane synthesis using the Simmons-Smith reagent, you should remember that a CH2 unit is transferred. Therefore, retro-synthetically disconnect the bonds to a CH2 group of a three-membered ring to identify the starting alkene. 

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). 

Camphor- 10-sulfonic acid, 62 (S)-2-(l-Hydroxy-1-methylethyl)-pyrrolidine, 146 a-Methylbenzylamine, 185 Quina alkaloids, 264 Cycloaddition reactions 2-Oxazolidones, chiral, 225 Cyclopropanation Diiodomethane-Diethylzinc, 276 Simmons-Smith reagent, 275 Deprotonation Lithium amides, chiral, 159... 

Simmons-Smith reagent, 275 Unsubstituted cyclopropanes by cycli-zation reactions Menthol, 172... 

CYCLOPROPANATION Palladium(II) acetate. Rhodium(III) porphyrins. Simmons-Smith reagent. Zinc. 

Conversion of an alkene to a cyclopropane can be accomplished to using the Simmons-Smith reagent (iodomethylzinc iodide). 

The esters, 7-ethoxycyclopropyl acetate (7 a) and benzoate (7b) have been synthesized by the addition of the Simmons-Smith reagent 22> to 1-ethoxy vinyl acetate and benzoate, respectively.4) A potential difficulty in this reaction lies in the fact that zinc iodide, a Lewis acid, is generated in the process and may induce cyclopropane ring opening (Section 4.3.3). However, when glyme is used as a solvent, the acid-labile bonds remain intact since the zinc salt is insoluble in this medium.23)... 

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.

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