View source for Chemistry:Johnson–Corey–Chaykovsky reaction

{{Short description|Chemical reaction in organic chemistry}}
{{Reactionbox
|Name = Johnson-Corey–Chaykovsky reaction
|Type = Ring forming reaction
|NamedAfter = A. William Johnson <br/> [[Biography:Elias James Corey|Elias James Corey]] <br/> Michael Chaykovsky
|Section3 = {{Reactionbox Identifiers
|OrganicChemistryNamed = corey-chaykovsky-reaction
}}
}}
The '''Johnson–Corey–Chaykovsky reaction''' (sometimes referred to as the '''Corey–Chaykovsky reaction''' or '''CCR''') is a [[Chemistry:Chemical reaction|chemical reaction]] used in [[Chemistry:Organic chemistry|organic chemistry]] for the synthesis of [[Chemistry:Epoxide|epoxide]]s, [[Chemistry:Aziridine|aziridine]]s, and [[Chemistry:Cyclopropane|cyclopropane]]s. It was discovered in 1961 by A. William Johnson and developed significantly by E. J. Corey and Michael Chaykovsky. The reaction involves addition of a sulfur [[Chemistry:Ylide|ylide]] to a [[Chemistry:Ketone|ketone]], [[Chemistry:Aldehyde|aldehyde]], [[Chemistry:Imine|imine]], or [[Chemistry:Enone|enone]] to produce the corresponding 3-membered ring. The reaction is diastereoselective favoring ''trans'' substitution in the product regardless of the initial [[Chemistry:Stereochemistry|stereochemistry]]. The synthesis of [[Chemistry:Epoxide|epoxide]]s via this method serves as an important [[Chemistry:Retrosynthetic analysis|retrosynthetic]] alternative to the traditional epoxidation reactions of olefins.

[[File:JCCRintro.png|center|320px|Johnson–Corey–Chaykovsky Reaction]]

The reaction is most often employed for epoxidation via [[Chemistry:Methylene (compound)|methylene]] transfer, and to this end has been used in several notable total syntheses (See Synthesis of epoxides below). Additionally detailed below are the history, mechanism, scope, and enantioselective variants of the reaction. Several reviews have been published.<ref name="Aggrawal2003">{{cite journal |author1=Aggarwal, V. K.|author2=Richardson, J. |title=The complexity of catalysis: origins of enantio- and diastereocontrol in sulfur ylide mediated epoxidation reactions|journal=Chemical Communications|year=2003|issue=21 |pages=2644–2651|doi=10.1039/b304625g|pmid=14649793 }}</ref><ref name="Aggrawal2004">{{cite journal | title=Catalytic, Asymmetric Sulfur Ylide-Mediated Epoxidation of Carbonyl Compounds: Scope, Selectivity, and Applications in Synthesis|author1=Aggarwal, V. K. |author-link1=Varinder Aggarwal|author2=Winn, C. L. |journal=[[Chemistry:Accounts of Chemical Research|Accounts of Chemical Research]]|year=2004|volume=37|issue=8 |pages=611–620|doi=10.1021/ar030045f|pmid=15311960 }}</ref><ref name="Golobov1987">{{cite journal |author1=Gololobov, Y. G. |author2=Nesmeyanov, A. N. |author3=lysenko, V. P. |author4=Boldeskul, I. E. |title=Twenty-five years of dimethylsulfoxonium ethylide (corey's reagent)|journal=Tetrahedron|year=1987|volume=43|issue=12 |pages=2609–2651|doi=10.1016/s0040-4020(01)86869-1}}</ref><ref name="Aggrawal1997">{{cite journal |author1=Li, A.-H. |author2=Dai, L.-X. |author3=Aggarwal, V. K.|author-link3=Varinder Aggarwal|title=Asymmetric Ylide Reactions: Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement|journal=[[Chemistry:Chemical Reviews|Chemical Reviews]]|year=1997|volume=97|issue=6 |pages=2341–2372|doi=10.1021/cr960411r|pmid=11848902 }}</ref><ref name="Aggrawal1998">{{cite journal |last1=Aggarwal|first1=Varinder K.|author-link1=Varinder Aggarwal|last2=Ford|first2=J. Gair|last3=Fonguerna|first3=Sílvia|last4=Adams|first4=Harry|last5=Jones|first5=Ray V. H.|last6=Fieldhouse|first6=Robin|date=1998-08-08|title=Catalytic Asymmetric Epoxidation of Aldehydes. Optimization, Mechanism, and Discovery of Stereoelectronic Control Involving a Combination of Anomeric and Cieplak Effects in Sulfur Ylide Epoxidations with Chiral 1,3-Oxathianes|journal=[[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]|year=1998|volume=120|issue=33|pages=8328–8339|doi=10.1021/ja9812150|pmid=}}</ref><ref name="Aggrawal2007">{{cite journal |author1=McGarrigle, E. M. |author2=Myers, E. L. |author3=Illa, O. |author4=Shaw, M. A. |author5=Riches, S. L. |author6=Aggarwal, V. K.|author-link6=Varinder Aggarwal|journal=[[Chemistry:Chemical Reviews|Chemical Reviews]]|title=Chalcogenides as Organocatalysts|year=2007|volume=107|issue=12 |pages=5841–5883|doi=10.1021/cr068402y|pmid=18072810}}</ref> 

==History==
The original publication by Johnson concerned the reaction of 9-dimethylsulfonium fluorenylide with substituted [[Chemistry:Benzaldehyde|benzaldehyde]] derivatives. The attempted [[Chemistry:Wittig reaction|Wittig-like reaction]] failed and a benzalfluorene oxide was obtained instead, noting that "reaction  between  the sulfur  ylid and benzaldehydes  did  not  afford benzalfluorenes as had  the phosphorus  and  arsenic ylids."<ref name="Johnson">{{cite journal |author1=Johnson, A.W. |author2=LaCount, R.B. |title=The Chemistry of Ylids. VI. Dimethylsulfonium Fluorenylide—A Synthesis of Epoxides|journal=J. Am. Chem. Soc.|year=1961|volume=83|issue=2|pages=417–423|doi=10.1021/ja01463a040}}</ref>

[[File:Johnson-Corey-Chaykovsky Reaction Example.png|center|300px|The first example of the Johnson–Corey–Chaykovsky reaction]]

The subsequent development of (dimethyloxosulfaniumyl)methanide, (CH<sub>3</sub>)<sub>2</sub>SOCH<sub>2</sub> and (dimethylsulfaniumyl)methanide, (CH<sub>3</sub>)<sub>2</sub>SCH<sub>2</sub> (known as '''Corey–Chaykovsky reagents''') by Corey and Chaykovsky as efficient methylene-transfer reagents established the reaction as a part of the organic canon.<ref name="Corey">{{cite journal |last1=Corey |first1=E. J. |last2=Chaykovsky |first2=M.|title=Dimethyloxosulfonium Methylide ((CH<sub>3</sub>)<sub>2</sub>SOCH<sub>2</sub>) and Dimethylsulfonium Methylide ((CH<sub>3</sub>)<sub>2</sub>SCH<sub>2</sub>). Formation and Application to Organic Synthesis|journal=J. Am. Chem. Soc.|year=1965|volume=87|issue=6|pages=1353–1364|doi=10.1021/ja01084a034}}</ref>

[[File:CCReagent.png|center|270px|Corey–Chaykovsky Reagent]]

==Mechanism==
The [[Physics:Reaction mechanism|reaction mechanism]] for the Johnson–Corey–Chaykovsky reaction consists of [[Chemistry:Nucleophilic addition|nucleophilic addition]] of the [[Chemistry:Ylide|ylide]] to the carbonyl or [[Chemistry:Imine|imine]] group. A negative charge is transferred to the [[Chemistry:Heteroatom|heteroatom]] and because the [[Physics:Sulfonium|sulfonium]] cation is a good [[Chemistry:Leaving group|leaving group]] it gets expelled forming the ring. In the related [[Chemistry:Wittig reaction|Wittig reaction]], the formation of the much stronger [[Chemistry:Phosphorus|phosphorus]]-[[Chemistry:Oxygen|oxygen]] [[Chemistry:Double bond|double bond]] prevents oxirane formation and instead, olefination takes place through a 4-membered cyclic intermediate.<ref name="Aggrawal1997"/>

[[File:CCR Mechanism V.1.svg|center|450px|Mechanism of the Johnson–Corey–Chaykovsky reaction]]

The ''trans'' diastereoselectivity observed results from the reversibility of the initial addition, allowing equilibration to the favored ''anti'' [[Chemistry:Betaine|betaine]] over the ''syn'' betaine. Initial addition of the ylide results in a betaine with adjacent charges; [[Density functional theory|density functional theory]] calculations have shown that the rate-limiting step is rotation of the central bond into the conformer necessary for [[Chemistry:Nucleophilic addition|backside attack]] on the sulfonium.<ref name="Aggrawal2003"/>

[[File:CCR Mechanism (Newman) V2.png|center|650px|Selectivity in the Johnson–Corey–Chaykovsky reaction]]

The degree of reversibility in the initial step (and therefore the diastereoselectivity) depends on four factors, with greater reversibility corresponding to higher selectivity:<ref name="Aggrawal2003"/>
# ''Stability of the substrate'' with higher stability leading to greater reversibility by favoring the starting material over the betaine.
# ''Stability of the ylide'' with higher stability similarly leading to greater reversibility.
#''Steric hindrance in the betaine'' with greater hindrance leading to greater reversibility by disfavoring formation of the intermediate and slowing the rate-limiting rotation of the central bond.
#''Solvation of charges in the betaine'' by [[Chemistry:Counterion|counterion]]s such as [[Chemistry:Lithium|lithium]] with greater solvation allowing more facile rotation in the betaine intermediate, lowering the amount of reversibility.

==Scope==
The application of the Johnson–Corey–Chaykovsky reaction in organic synthesis is diverse. The reaction has come to encompass reactions of many types of sulfur ylides with [[Chemistry:Electrophile|electrophile]]s well beyond the original publications. It has seen use in a number of high-profile total syntheses, as detailed below, and is generally recognized as a powerful transformative tool in the organic repertoire.

===Types of ylides===
[[File:CCReagentGeneral.png|thumb|right|90px|General form of ylide reagent used]]
Many types of ylides can be prepared with various functional groups both on the anionic carbon center and on the sulfur. The substitution pattern can influence the ease of preparation for the reagents (typically from the sulfonium halide, e.g. trimethylsulfonium iodide) and overall reaction rate in various ways. The general format for the reagent is shown on the right.<ref name="Aggrawal2003"/>

Use of a sulfoxonium allows more facile preparation of the reagent using weaker bases as compared to sulfonium ylides. (The difference being that a sulfoxonium contains a doubly bonded oxygen whereas the sulfonium does not.)  The former react slower due to their increased stability. In addition, the [[Chemistry:Dimethyl sulfoxide|dialkylsulfoxide]] by-products of sulfoxonium reagents are greatly preferred to the significantly more toxic, volatile, and odorous dialkylsulfide by-products from sulfonium reagents.<ref name="Aggrawal2003"/>

The vast majority of reagents are monosubstituted at the ylide carbon (either R<sub>1</sub> or R<sub>2</sub> as hydrogen). Disubstituted reagents are much rarer but have been described:<ref name="Aggrawal2003"/>
#If the ylide carbon is substituted with an [[Chemistry:Electron-withdrawing group|electron-withdrawing group]] (EWG), the reagent is referred to as a ''stabilized ylide''. These, similarly to sulfoxonium reagents, react much slower and are typically easier to prepare. These are limited in their usefulness as the reaction can become prohibitively sluggish: examples involving [[Chemistry:Amide|amide]]s are widespread, with many fewer involving [[Chemistry:Ester|ester]]s and virtually no examples involving other EWG's. For these, the related [[Chemistry:Darzens reaction|Darzens reaction]] is typically more appropriate.
#If the ylide carbon is substituted with an [[Chemistry:Aryl|aryl]] or [[Chemistry:Allyl|allyl]] group, the reagent is referred to as a ''semi-stabilized ylide''. These have been developed extensively, second only to the classical [[Chemistry:Methylene group|methylene]] reagents (R<sub>1</sub>=R<sub>2</sub>=H). The substitution pattern on aryl reagents can heavily influence the selectivity of the reaction as per the criteria above.
#If the ylide carbon is substituted with an alkyl group the reagent is referred to as an ''unstabilized ylide''. The size of the alkyl groups are the major factors in selectivity with these reagents.

The R-groups on the sulfur, though typically methyls, have been used to synthesize reagents that can perform enantioselective variants of the reaction (See Variations below). The size of the groups can also influence diastereoselectivity in alicyclic substrates.<ref name="Aggrawal2003"/>

===Synthesis of epoxides===
Reactions of sulfur ylides with [[Chemistry:Ketone|ketone]]s and [[Chemistry:Aldehyde|aldehyde]]s to form [[Chemistry:Epoxide|epoxide]]s are by far the most common application of the Johnson–Corey–Chaykovsky reaction. Examples involving complex substrates and 'exotic' ylides have been reported, as shown below.<ref name="Namerxnhet">{{Cite book |last=Li|first=Jack Jie|title=Named Reactions in Heterocyclic Chemistry|publisher=John Wiley & Sons, Inc |year=2005|location=Hoboken, New Jersey|pages=2–14|isbn=9780471704140|url=https://books.google.com/books?id=4k0jI7Sf6iwC&pg=PA2}}</ref><ref name="Namerxnsynth">{{Cite book |author1=Mundy, Bradford, P. |author2=Ellerd, Michael D. |author3=Favaloro, Frank G. Jr. |title=Name Reactions and Reagents in Organic Chemistry|edition=2|publisher=John Wiley & Sons, Inc |year=2005|location=Hoboken, New Jersey|pages=174–175, 743|isbn=9780471739869 |url=https://books.google.com/books?id=vlS1a5LdFMMC&pg=174}}</ref>

[[File:CCREpox1.png|center|320px|Example 1 of epoxidation with CCR]]
[[File:CCREpox2.png|center|320px|Example 1 of epoxidation with CCR]]

The reaction has been used in a number of notable total syntheses including the [[Chemistry:Danishefsky Taxol total synthesis|Danishefsky Taxol total synthesis]], which produces the [[Medicine:Chemotherapy|chemotherapeutic]] drug taxol, and the [[Chemistry:Strychnine total synthesis#Kuehne synthesis|Kuehne Strychnine total synthesis]] which produces the pesticide [[Chemistry:Strychnine|strychnine]].<ref name="Danishefsky">{{cite journal |author1=Danishefsky, S. J. |author2=Masters, J. J. |author3=Young, W. B. |author4=Link, J. T. |author5=Snyder, L. B. |author6=Magee, T. V. |author7=Jung, D. K. |author8=Isaacs, R. C. A. |author9=Bornmann, W. G. |author10=Alaimo, C. A. |author11=Coburn, C. A. |author12=Di Grandi, M. J. |title=Total Synthesis of Baccatin III and Taxol|journal=[[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]|year=1996|volume=118|issue=12 |pages=2843–2859|doi=10.1021/ja952692a}}</ref><ref name="Kuehne">{{cite journal |author1=Kuehne, M. E. |author2=Xu, F. |title=Total synthesis of strychnan and aspidospermatan alkaloids. 3. The total synthesis of (.+-.)-strychnine|journal=The Journal of Organic Chemistry|year=1993|volume=58|issue=26 |pages=7490–7497|doi=10.1021/jo00078a030}}</ref>

[[File:TaxolCCR.png|center|550px|Taxol synthesis CCR step]]
[[File:StrychnineCCR.png|center|700px|Strychnine synthesis CCR step]]

===Synthesis of aziridines===
The synthesis of [[Chemistry:Aziridine|aziridine]]s from [[Chemistry:Imine|imine]]s is another important application of the Johnson–Corey–Chaykovsky reaction and provides an alternative to [[Chemistry:Amine|amine]] transfer from [[Chemistry:Oxaziridine|oxaziridine]]s. Though less widely applied, the reaction has a similar substrate scope and [[Chemistry:Functional group|functional group]] tolerance to the carbonyl equivalent. The examples shown below are representative; in the latter, an aziridine forms ''in situ'' and is opened via nucleophilic attack to form the corresponding [[Chemistry:Amine|amine]].<ref name="Golobov1987"/><ref name="Namerxnhet"/>

[[File:AziridinationCCR.png|center|450px|Aziridination with the Johnson–Corey–Chaykovsky reaction]]

===Synthesis of cyclopropanes===
For addition of sulfur ylides to enones, higher [[Chemistry:Nucleophilic conjugate addition|1,4-selectivity]] is typically obtained with sulfoxonium reagents than with sulfonium reagents. Many electron-withdrawing groups have been shown compatible with the reaction including [[Chemistry:Ketone|ketone]]s, [[Chemistry:Ester|ester]]s, and [[Chemistry:Amide|amide]]s (the example below involves a Weinreb amide). With further conjugated systems 1,6-addition tends to predominate over 1,4-addition.<ref name="Golobov1987"/><ref name="Namerxnhet"/>

[[File:CCRcycloprop.png|center|400px|Cyclopropanation with the Johnson–Corey–Chaykovsky reaction]]

===Other reactions===
In addition to the reactions originally reported by Johnson, Corey, and Chaykovsky, sulfur ylides have been used for a number of related [[Chemistry:Homologation reaction|homologation reaction]]s that tend to be grouped under the same name.

*With [[Chemistry:Epoxide|epoxide]]s and [[Chemistry:Aziridine|aziridine]]s the reaction serves as a ring-expansion to produce the corresponding [[Chemistry:Oxetane|oxetane]] or [[Chemistry:Azetidine|azetidine]]. The long reaction times required for these reactions prevent them from occurring as significant [[Chemistry:Side reaction|side reaction]]s when synthesizing epoxides and aziridines.<ref name="Namerxnhet"/>

[[File:CCRoxetane.png|center|300px|Oxetane and Azitidine synthesis with the Johnson–Corey–Chaykovsky reaction]]

*Several [[Chemistry:Cycloaddition|cycloaddition]]s wherein the ylide serves as a "nucleophilic [[Chemistry:Carbenoid|carbenoid]] equivalent" have been reported.<ref name="Namerxnhet"/>

[[File:CCR41.png|center|320px|[4+1] cycloaddition with Corey–Chaykovsky reagent]]

*[[Chemistry:Living polymerization|Living polymerization]]s using trialkylboranes as the catalyst and (dimethyloxosulfaniumyl)methanide as the monomer have been reported for the synthesis of various complex polymers.<ref>{{cite journal |author1=Luo, J. |author2=Shea, K. J. |title=Polyhomologation. A Living C1 Polymerization|journal=[[Chemistry:Accounts of Chemical Research|Accounts of Chemical Research]]|year=2010|volume=43|issue=11 |pages=1420–1433|doi=10.1021/ar100062a|pmid=20825177 }}</ref>

[[File:CCRPolymer.png|center|500px|Living polymerization with Johnson–Corey–Chaykovsky Reaction]]

==Enantioselective variations==
The development of an enantioselective (i.e. yielding an [[Chemistry:Enantiomeric excess|enantiomeric excess]], which is labelled as "ee") variant of the Johnson–Corey–Chaykovsky reaction remains an active area of academic research. The use of [[Biology:Chirality|chiral]] sulfides in a stoichiometric fashion has proved more successful than the corresponding catalytic variants, but the substrate scope is still limited in all cases. The catalytic variants have been developed almost exclusively for enantioselective purposes; typical organosulfide reagents are not prohibitively expensive and the racemic reactions can be carried out with equimolar amounts of ylide without raising costs significantly. Chiral sulfides, on the other hand, are more costly to prepare, spurring the advancement of catalytic enantioselective methods.<ref name="Aggrawal2004"/>

===Stoichiometric reagents===
The most successful reagents employed in a stoichiometric fashion are shown below. The first is a bicyclic oxathiane that has been employed in the synthesis of the β-adrenergic compound ''dichloroisoproterenol'' (DCI) but is limited by the availability of only one enantiomer of the reagent. The synthesis of the axial diastereomer is rationalized via the 1,3-[[Chemistry:Anomeric effect|anomeric effect]] which reduces the nucleophilicity of the equatorial [[Chemistry:Lone pair|lone pair]]. The [[Chemistry:Conformational isomerism|conformation]] of the ylide is limited by transannular strain and approach of the aldehyde is limited to one face of the ylide by steric interactions with the methyl substituents.<ref name="Aggrawal1998"/><ref name="Aggrawal2004"/>

[[File:CCRoxathiane.png|center|650px|chiral oxathiane reagent for the Johnson–Corey–Chaykovsky reaction]]

The other major reagent is a [[Chemistry:Camphor|camphor]]-derived reagent developed by [[Biography:Varinder Aggarwal|Varinder Aggarwal]] of the [[Organization:University of Bristol|University of Bristol]]. Both [[Chemistry:Enantiomer|enantiomer]]s are easily synthesized, although the yields are lower than for the oxathiane reagent. The ylide conformation is determined by interaction with the [[Physics:Bicyclic molecule|bridgehead]] hydrogens and approach of the aldehyde is blocked by the camphor [[Chemistry:Moiety|moiety]]. The reaction employs a [[Chemistry:Phosphazene|phosphazene]] base to promote formation of the ylide.<ref name="Aggrawal1998"/><ref name="Aggrawal2004"/>

[[File:CCRcamphor.png|center|550px|chiral camphor-derived reagent for the Johnson–Corey–Chaykovsky reaction]]

===Catalytic reagents===
Catalytic reagents have been less successful, with most variations suffering from poor yield, poor enantioselectivity, or both. There are also issues with substrate scope, most having limitations with methylene transfer and aliphatic [[Chemistry:Aldehyde|aldehyde]]s. The trouble stems from the need for a nucleophilic sulfide that efficiently generates the ylide which can also act as a good [[Chemistry:Leaving group|leaving group]] to form the epoxide. Since the factors underlying these desiderata are at odds, tuning of the catalyst properties has proven difficult. Shown below are several of the most successful catalysts along with the yields and enantiomeric excess for their use in synthesis of (E)-stilbene oxide.<ref name="Aggrawal1998"/><ref name="Aggrawal2004"/>

[[File:CCRchiralcat.png|center|350px|chiral catalysts for the Johnson–Corey–Chaykovsky reaction]]

Aggarwal has developed an alternative method employing the same sulfide as above and a novel alkylation involving a [[Chemistry:Rhodium|rhodium]] [[Chemistry:Transition metal carbene complex|carbenoid]] formed ''[[Biology:In situ|in situ]]''. The method too has limited substrate scope, failing for any [[Chemistry:Electrophile|electrophile]]s possessing basic substituents due to [[Physics:Reaction rate|competitive consumption]] of the carbenoid.<ref name="Aggrawal2004"/>

[[File:CCRcatcarbene.png|center|550px|chiral catalyst with carbenoid alkylation for the Johnson–Corey–Chaykovsky reaction]]

==See also==
{{colbegin}}
*[[Chemistry:Darzens reaction|Darzens reaction]]
*[[Chemistry:Wittig reaction|Wittig reaction]]
*Epoxidation
*[[Chemistry:Ylide|Ylide]]
*E.J. Corey
*Taxol total synthesis
*[[Chemistry:Strychnine total synthesis|Strychnine total synthesis]]
{{colend}}

== References ==
{{Reflist|2}}

== External links ==
* [https://commons.wikimedia.org/wiki/File:J_C_C_startAnimGif.gif Animation of the mechanism]

{{DEFAULTSORT:Johnson-Corey-Chaykovsky reaction}}
[[Category:Addition reactions]]
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Epoxidation reactions]]
[[Category:Name reactions]]

{{Sourceattribution|Johnson–Corey–Chaykovsky reaction}}