TheJohnson–Corey–Chaykovsky reaction (sometimes referred to as theCorey–Chaykovsky reaction orCCR) is achemical reaction used inorganic chemistry for the synthesis ofepoxides,aziridines, andcyclopropanes. It was discovered in 1961 by A. William Johnson and developed significantly byE. J. Corey and Michael Chaykovsky. The reaction involves addition of a sulfurylide to aketone,aldehyde,imine, orenone to produce the corresponding 3-membered ring. The reaction isdiastereoselective favoringtrans substitution in the product regardless of the initialstereochemistry. The synthesis ofepoxides via this method serves as an importantretrosynthetic alternative to the traditionalepoxidation reactions ofolefins.

The reaction is most often employed for epoxidation viamethylene transfer, and to this end has been used in several notabletotal syntheses (SeeSynthesis of epoxides below). Additionally detailed below are the history, mechanism, scope, and enantioselective variants of the reaction. Several reviews have been published.^{[1][2][3][4][5][6]}

The original publication by Johnson concerned the reaction of 9-dimethylsulfonium fluorenylide with substitutedbenzaldehyde derivatives. The attemptedWittig-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."^[7]

The subsequent development of (dimethyloxosulfaniumyl)methanide, (CH₃)₂SOCH₂ and (dimethylsulfaniumyl)methanide, (CH₃)₂SCH₂ (known asCorey–Chaykovsky reagents) by Corey and Chaykovsky as efficient methylene-transfer reagents established the reaction as a part of the organic canon.^[8]

Thereaction mechanism for the Johnson–Corey–Chaykovsky reaction consists ofnucleophilic addition of theylide to thecarbonyl orimine group. A negative charge is transferred to theheteroatom and because thesulfoniumcation is a goodleaving group it gets expelled forming the ring. In the relatedWittig reaction, the formation of the much strongerphosphorus-oxygendouble bond preventsoxirane formation and instead,olefination takes place through a 4-membered cyclic intermediate.^[4][9]

Thetransdiastereoselectivity observed results from the reversibility of the initial addition, allowing equilibration to the favoredantibetaine over thesyn betaine. Initial addition of the ylide results in a betaine with adjacent charges;density functional theory calculations have shown that therate-limiting step is rotation of the central bond into the conformer necessary forbackside attack on the sulfonium.^[1]

The degree of reversibility in the initial step (and therefore the diastereoselectivity) depends on four factors, with greater reversibility corresponding to higher selectivity:^[1]

1. Stability of the substrate with higher stability leading to greater reversibility by favoring the starting material over the betaine.
2. Stability of the ylide with higher stability similarly leading to greater reversibility.
3. 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.
4. Solvation of charges in the betaine bycounterions such aslithium with greater solvation allowing more facile rotation in the betaine intermediate, lowering the amount of reversibility.

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 withelectrophiles 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.

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.^[1]

A sulfoxonium ylide, derived from asulfoxide, is more stable than a sulfonium ylide. Consequently reagent preparation is less demanding: theonium salt can be deprotonated with weaker bases, and the ylide lasts longer in storage.^[10] The sulfoxideby-products reagents are also greatly preferred to the significantly more toxic, volatile, and odoroussulfide by-products from sulfonium reagents.^[1] Contrariwise, sulfoxonium ylides undergo the J-C-C reaction more slowly (or equivalently, require higher temperatures for the same). Sulfinamidonium ylides (derived from asulfinamide) are stabler still, and are primarily used forasymmetric synthesis.^[10]

The vast majority of reagents are monosubstituted at the ylide carbon (either R₁ or R₂ as hydrogen). Disubstituted reagents are much rarer but have been described:^[1]

1. If the ylide carbon is substituted with anelectron-withdrawing group (EWG), the reagent is referred to as astabilized ylide. These, similarly to sulfoxonium reagents, react much slower and are typically easier to prepare. They have limited use, as the reaction can become prohibitively sluggish: examples involvingamides are widespread, with many fewer involvingesters and virtually no examples involving other EWG's. In such cases, the relatedDarzens reaction is typically more appropriate.
2. If the ylide carbon is substituted with anaryl orallyl group, the reagent is referred to as asemi-stabilized ylide. These have been developed extensively, second only to the classicalmethylene reagents (R₁=R₂=H). The substitution pattern on aryl reagents can heavily influence the selectivity of the reaction as per the criteria above.
3. If the ylide carbon is substituted with an alkyl group the reagent is referred to as anunstabilized ylide. The size of the alkyl groups are the major factors in selectivity with these reagents.

The R-groups on the sulfur, though typicallymethyls, have been used to synthesize reagents that can performenantioselective variants of the reaction (See Variations below). The size of the groups can also influencediastereoselectivity inalicyclic substrates.^[1]

Reactions of sulfur ylides withketones andaldehydes to formepoxides 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.^[11][12]

The reaction has been used in a number of notable total syntheses including theDanishefsky Taxol total synthesis, which produces thechemotherapeutic drugtaxol, and theKuehne Strychnine total synthesis which produces the pesticidestrychnine.^[13][14]

The synthesis ofaziridines fromimines is another important application of the Johnson–Corey–Chaykovsky reaction and provides an alternative toamine transfer fromoxaziridines. Though less widely applied, the reaction has a similar substrate scope andfunctional group tolerance to the carbonyl equivalent. The examples shown below are representative; in the latter, an aziridine formsin situ and is opened vianucleophilic attack to form the correspondingamine.^[3][11]

For addition of sulfur ylides to enones, higher1,4-selectivity is typically obtained with sulfoxonium reagents than with sulfonium reagents. One explanation based on theHSAB theory states that it is because sulfoxonium reagents have a less concentrated negative charge on the carbon atom (softer), so it prefers 1,4-attack on the softer nucleophilic site. Another explanation supported bydensity functional theory (DFT) studies suggests an irreversible 1,4-attack leading to the cyclopropane is energetically favored versus a reversible 1,2-attack that would lead to the epoxide.^[15] With extended conjugated systems 1,6-addition tends to predominate over 1,4-addition.^[3][11] Many electron-withdrawing groups have been shown promote the cyclopropanation includingketones,esters,amides (the example below involves aWeinreb amide),sulfones,nitro groups,phosphonates,isocyanides and even some electron deficient heterocycles.^[16]

In addition to the reactions originally reported by Johnson, Corey, and Chaykovsky, sulfur ylides have been used for a number of relatedhomologation reactions that tend to be grouped under the same name.

• Withepoxides andaziridines the reaction serves as a ring-expansion to produce the correspondingoxetane orazetidine. The long reaction times required for these reactions prevent them from occurring as significantside reactions when synthesizing epoxides and aziridines.^[11]

• Severalcycloadditions wherein the ylide serves as a "nucleophiliccarbenoid equivalent" have been reported.^[11]

• Living polymerizations usingtrialkylboranes as the catalyst and (dimethyloxosulfaniumyl)methanide as the monomer have been reported for the synthesis of various complex polymers.^[17]

The development of anenantioselective (i.e. yielding anenantiomeric excess, which is labelled as "ee") variant of the Johnson–Corey–Chaykovsky reaction remains an active area of academic research. The use ofchiral sulfides in astoichiometric fashion has proved more successful than the correspondingcatalytic 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.^[2]

The most successful reagents employed in a stoichiometric fashion are shown below. The first is abicyclic oxathiane that has been employed in the synthesis of the β-adrenergic compounddichloroisoproterenol (DCI) but is limited by the availability of only one enantiomer of the reagent. The synthesis of theaxial diastereomer is rationalized via the 1,3-anomeric effect which reduces the nucleophilicity of theequatoriallone pair. Theconformation of the ylide is limited bytransannular strain and approach of the aldehyde is limited to one face of the ylide by steric interactions with the methyl substituents.^[5][2]

The other major reagent is acamphor-derived reagent developed byVarinder Aggarwal of theUniversity of Bristol. Bothenantiomers are easily synthesized, although the yields are lower than for the oxathiane reagent. The ylide conformation is determined by interaction with thebridgehead hydrogens and approach of the aldehyde is blocked by the camphormoiety. The reaction employs aphosphazene base to promote formation of the ylide.^[5][2]

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 andaliphaticaldehydes. The trouble stems from the need for anucleophilic sulfide that efficiently generates the ylide which can also act as a goodleaving 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.^[5][2]

Aggarwal has developed an alternative method employing the same sulfide as above and a novel alkylation involving arhodiumcarbenoid formedin situ. The method too has limited substrate scope, failing for anyelectrophiles possessing basic substituents due tocompetitive consumption of the carbenoid.^[2]

• Animation of the mechanism

• Addition reactions
• Carbon-carbon bond forming reactions
• Epoxidation reactions
• Name reactions

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