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Cyclopropanation Ring Closure via Ionic Mechanism – SN2,Sulfur Ylides

Mechanism + Description

Addition of an anion or anion equivalent (ylide) to an electron poor Michael acceptor followed by a second nucleophilic ring closing reaction generating the cyclopropane ring.

 

General comments

A number of ionic mechanisms to form cyclopropane rings use an initial nucleophilic addition followed by a second nucleophilic ring closing reaction. This reaction is probably less versatile than the metal catalysed carbene addition since specific structural features of the substrate need to be present, i.e., the Michael acceptor andsite for the addition of the nucleophile. Typical synthons are ylides—usually sulfur-based—in the so-called Corey-Chaykovsky Cyclopropanation (although phosphorus ylides can also be employed). Alternative reagents can be used, e.g., anions with geminal leaving groups such as bromonitromethane.

 

Key references

Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides Mediated by Camphor-Derived Sulfur Ylides:  Rationale of Enantioselectivity, Scope, and Limitation. J. Am. Chem. Soc. 2006, 128, 9730–9740. 

Aggarwal, V. K.; Smith, H. W.; Jones, R. V. H.; Fieldhouse, R. Catalytic asymmetric cyclopropanation of electron deficient alkenes mediated by chiral sulfides. Chem. Commun. 1997, 18, 1785–1786.

Corey, E. J.; Chaykovsky, M. Methylsulfinylcarbanion. J. Am. Chem. Soc. 1962, 84, 866–867.  

Mamai, A.; Madalengoitia, J. S. Lewis acid mediated diastereoselective and enantioselective cyclopropanation of Michael acceptors with sulfur ylides. Tetrahedron Lett. 2000, 41, 9009–9014.

Vaitla, J.; Bayer, A. Sulfoxonium Ylide Derived Metal Carbenoids in Organic Synthesis. Synthesis, 2019, 51, 612–628. 

Lu, L.-Q.; Li, T.-R.; Wang, Q.; Xiao, W.-J. Beyond sulfide-centric catalysis: recent advances in the catalytic cyclization reactions of sulfur ylides. Chem. Soc. Rev. 2017, 46, 4135–4149. 

Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Asymmetric Ylide Reactions:  Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement. Chem. Rev. 1997, 97, 2341–2372.

Brunner, G.; Eberhard, L.; Oetiker, J.; Schröder, F. Tandem Cyclopropanation with Dibromomethane under Grignard Conditions. J. Org. Chem. 2008, 73, 7543–7554.  

Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound. Angew. Chem. Int. Ed. 2001, 40, 1433–1436.

Avery, T.; Taylor, D. K.; Tiekink, E. R. T. A New Route to Diastereomerically Pure Cyclopropanes Utilizing Stablized Phosphorus Ylides and γ-Hydroxy Enones Derived from 1,2-Dioxines:  Mechanistic Investigations and Scope of Reaction. J. Org Chem. 2000, 65, 5531–5546.

Johnson, C. R.; Schroeck, C. W. Chemistry of sulfoxides and related compounds. XV. Synthesis of optically active cyclopropanes and oxiranes using an optically active oxosulfonium methylide. J. Am. Chem. Soc. 1968, 90, 6852–6854.

 

Relevant scale up examples

Org. Process Res. Dev. 2010, 14, 692–700.
12g scale

 

Org. Process Res. Dev. 2010, 14, 912–917.
40 kg scale

 

Org. Process Res. Dev. 2014, 18, 1527−1534.
3 kg scale

 

Green Review

  1. Atom efficiency (by-products, molecular weight)
    This comes down to the leaving group Cl <Br <I. Sulfates and sulfonic esters produce as high or higher mol. wt. by-products than Cl or Br. Ylides giving Me2S or Me2SO are preferred over P-ylides giving high mol. wt. by-products like Ph3PO.
  2. Safety Concerns
    No major safety concerns with the operational aspects of cyclopropanation with SN2/Ylide methodologies
  3. Toxicity and environmental/aquatic impact
    No major concerns – by-products like Ph3PO are difficult to biodegrade.
  4. Cost, availability & sustainable feedstocks
    Most reagents readily available
  5. Sustainable implications
    Na or K bases preferred to Li or Cs bases