The Simmons–Smith reaction converts alkenes stereospecifically into cyclopropanes using an organozinc carbenoid reagent. First reported in 1958 by Howard E. Simmons and Ronald D. Smith, the reaction is named after them.

The reaction constructs cyclopropane rings under relatively mild conditions, without the need to introduce additional functional groups beforehand. A key feature is its stereospecificity: the cis or trans configuration of the starting alkene is generally retained in the cyclopropane product. The reaction is widely used in the synthesis of complex organic molecules, particularly for building cyclopropane motifs in pharmaceuticals and natural products.

Reagents: Diiodomethane (CH₂I₂), zinc–copper couple (Zn(Cu))
Substrate: Alkene
Product: Cyclopropane
Reaction type: Addition

Practical Tips

1) Substrate scope. A wide range of alkenes participate in Simmons–Smith cyclopropanation, including simple alkenes, α,β-unsaturated aldehydes and ketones, and electron-rich alkenes such as enol ethers and enamines. Because the organozinc reagent is electrophilic, electron-rich alkenes generally react faster; however, increased substitution raises steric hindrance and can slow the reaction.

2) Stereospecificity. The Simmons–Smith reaction is highly stereospecific and generally retains the relative configuration of the starting alkene—that is, cis and trans alkenes give the correspondingly configured cyclopropane products.

3) Effect of heteroatom functional groups. When the alkene bears heteroatom groups such as hydroxyl, acetate, methoxy, benzyloxy, or amino (OH, OAc, OMe, OBn, NHR), these groups can influence stereoselectivity through inductive effects and coordination with the organozinc reagent, typically favoring attack of the cyclopropanating reagent from the face nearer the functional group.

4) Diastereoselectivity with cyclic alkenes. For cyclic enols, ring size strongly affects the diastereoselectivity of the product. Five-, six-, and seven-membered rings generally show high cis diastereoselectivity, whereas larger ring systems tend to give the trans diastereomer.

5) Modifications. The traditional protocol uses a zinc–copper couple (prepared by treating zinc powder with aqueous copper sulfate). Reactivity, reproducibility, and chemoselectivity can also be improved by changing the metal reagent, the carbon source, or additives:

• Furukawa modification: Uses diethylzinc (Et₂Zn) with diiodomethane (CH₂I₂) and offers good reproducibility.

• Shi modification: Adds acidic additives such as trifluoroacetic acid (CF₃CO₂H) to promote cyclopropanation of otherwise sluggish substrates.

• Molander modification: Uses systems such as Sm/Hg/CH₂I₂ and shows good chemoselectivity for the allylic alcohol double bond when multiple double bonds are present.

6) Asymmetric Simmons–Smith cyclopropanation. Enantioselective versions can be achieved through chiral substrate control, chiral additive induction, or chiral catalysis:

• Chiral substrate control: Uses the chiral environment of substrates such as chiral allylic ethers, acetals, or boronate esters to induce diastereoselectivity.

• Chiral additive induction: Methods developed by Charette and co-workers use chiral dialkoxyborane additives to effectively induce enantioselective cyclopropanation of allylic alcohols, achieving high enantiomeric excess (ee).

• Chiral catalysis: Catalytic systems using chiral sulfonamide ligands can also achieve asymmetric cyclopropanation; some systems show high enantioselectivity for allylic alcohol substrates.

Reaction Mechanism

Original Literature

• Howard E. Simmons; Ronald D. Smith: A NEW SYNTHESIS OF CYCLOPROPANES FROM OLEFINS. Journal American Chemical Society. 1958, 80 (19), 5323–5324.

Key Citations

• Simmons–Smith Cyclopropanation of Alkenyl 1,2-Bis(boronates): Stereoselective Access to Functionalized Cyclopropyl Derivatives. Journal of Organic Chemistry. 2022, 87(12), 7649–7657.

• Asymmetric Simmons–Smith Reaction of Allylic Alcohols with Al Lewis Acid/N Lewis Base Bifunctional Al(Salalen) Catalyst. Angewandte Chemie International Edition. 2008, 47(13), 2450-2453.

• Asymmetric Simmons−Smith Cyclopropanation of Unfunctionalized Olefins. Journal American Chemical Society. 2003, 125(45), 13632–13633.

Related Product

Reagents

• Diiodomethane, 99%, for synthesis, stabilized  CAS:75-11-6  Cat.No:923781
• Chloroiodomethane, 98%, for synthesis, stabilized with Copper chip  CAS:593-71-5  Cat.No:135417
• Diethylzinc,2.0 M solution in hexanes  CAS:557-20-0  Cat.No:969890
• Diethylzinc, 1.0 M solution in hexanes, J&KSeal  CAS:557-20-0  Cat.No:905172
• Zinc-Copper couple, 1 - 3% Cu  CAS:53801-63-1  Cat.No: 100268
• Copper(II) sulfate pentahydrate, 99%, AR  CAS:7758-99-8  Cat.No: 921535

Alkenes

• Cyclohexene  CAS:110-83-8  Cat.No: C0491
• 1-Hexene, 97%  CAS:592-41-6  Cat.No: 291472
• Styrene, 99.5%, for synthesis, stabilized with HQ  CAS:100-42-5  Cat.No: 946167

Solvents

• 1,2-Dichloroethane, 99.8%, SuperDry, water≤50 ppm, J&Kseal  CAS:107-06-2  Cat.No: 981955
• Cyclopentyl methyl ether, 99.5%, SuperDry, stabilized with BHT, J&KSeal  CAS:5614-37-9  Cat.No:459276