Simmons–Smith reaction

It uses a methylene free radical intermediate that is delivered to both carbons of the alkene simultaneously, therefore the configuration of the double bond is preserved in the product and the reaction is stereospecific.

[5][6] The Simmons–Smith reaction is generally preferred over other methods of cyclopropanation,[7] however it can be expensive due to the high cost of diiodomethane.

[11][12] However, when a hydroxy substituent is present in the substrate in proximity to the double bond, the zinc coordinates with the hydroxy substituent, directing cyclopropanation cis to the hydroxyl group (which may not correspond to cyclopropanation of the sterically most accessible face of the double bond):[13] An interactive 3D model of this reaction can be seen at ChemTube3D.

Although asymmetric cyclopropanation methods based on diazo compounds (the Metal-catalyzed cyclopropanations) exist since 1966, the asymmetric Simmons–Smith reaction was introduced in 1992 [14] with a reaction of cinnamyl alcohol with diethylzinc, diiodomethane and a chiral disulfonamide in dichloromethane: The hydroxyl group is a prerequisite serving as an anchor for zinc.

[25] Furthermore, Et2Zn and CH2I2 react with allylic thioethers to generate sulfur ylides, which can subsequently undergo a 2,3-sigmatropic rearrangement, and will not cyclopropanate an alkene in the same molecule unless excess Simmons–Smith reagent is used.

[26]The Simmons–Smith reaction is rarely used in it original form and a number of modifications to both the zinc reagent and carbenoid precursor have been developed and are more commonly employed.

[30] Upon treatment with stoichiometric amounts of zinc halide, an organozinc compound similar to the carbenoid discussed above is produced.

Additionally, the intermediate can react with alcohols to produce iodophenylmethane, which can further undergo an SN2 reaction to produce ROCHPh, as in Pathway C. The highly electrophilic nature of the zinc carbenoid reduces the useful scope of the Simmons-Smith cyclopropanation to electron-rich alkenes and those bearing pendant coordinating groups, most commonly alcohols.

Although not commonly used, Simmons-Smith reagents that display similar reactive properties to those of zinc have been prepared from aluminum and samarium compounds in the presence of CH2IX.

Iodo- or chloro- methylsamarium iodide in THF is an excellent reagent to selectively cyclopropanate the allylic alcohol, presumably directed by chelation to the hydroxyl group.

However, both reactions require near stoichiometric amounts of the starting metal compound, and Sm/Hg must be activated with the highly toxic HgCl2.

The Simmons-Smith reagent binds first to the carbonyl group and subsequently to the α-carbon of the pseudo-enol that the first reaction forms.

[37][38] A Furukawa-modified Simmons–Smith reaction cyclopropanates both double bonds in an allenamide to form amido-spiro [2.2] cyclopentanes, featuring two cyclopropyl rings which share one carbon.

An allyl substituent on the starting material is Simmons-Smith cyclopropanated, and the carboxylic acid is subsequently deprotected via ozonolysis to form the precursor.