1678940715481_oc regents.pptxhxhxjjdjxjddj

COREY CHAYKOVSKY REACTION
The Corey-Chaykovsky reaction or sometimes known as Johnson-Corey-Chaykovsky
reaction is employed in modern organic synthesis to prepare three membered rings like
epoxides (oxiranes), thiiranes, aziridines and cyclopropanes by reacting sulfur ylides with
electrophiles such as carbonyls, thiocarbonyls, imines and olefins.
Dimethylsulfoxonium methylide (Corey’s ylide) or dimethylsulfonium methylide are the
common sulfur ylides used in this reaction.

SULFUR YLIDES
* The sulfur ylides are generated in situ by the deprotonation of sulfonium halides with
strong bases like NaH in solvents like DMSO.
E.g. The corey ylide, dimethylsulfoxonium methylide can be generated easily by treating
trimethylsulfoxonium iodide with NaH in DMSO.
* The sulfur ylides are stabilized when electron withdrawing groups are attached to it.
Usually the groups like phenyl, carbonyl, ester etc., stabilize the ylide. Whereas the
electron releasing groups like alkyl tend to destabilize the ylides.
E.g. The dimethylsulfoxonium methylide is more stable than dimethylsulfonium
methylide due to presence of S=O group.
Sometimes the course of the reaction is influenced by the stability of the sulfur ylides.

MECHANISM OF COREY CHAYKOVSKY REACTION
In the first step, the ylide carbon, bearing negative charge, acts as nucleophile and makes
bond with electrophilic carbon attached to 'X' atom.
* Now the ylide carbon becomes electrophilic and is attacked by the negatively charged 'X'
atom, acting as intramoleuclar nucleophile to achieve ring closure to furnish a three membered
ring.
* The sulfoxide (or sulfide) moiety acts as leaving group. The overall reaction is a 1,2
addition.

Reaction of sulfur ylides with Michael acceptors - kinetic vs thermodynamic control
(1,2 addition vs 1,4 addition)
* When Michael acceptors are used, the choice of products formed in Corey-
Chaykovsky reaction depends on the stability of sulfur ylides.
With unstabilized ylides
* Usually 1,2-addition products are formed predominantly when unstabilized
ylides are used.
E.g. The kinetically favored epoxide is formed when dimethylsulfonium
methylide (an unstabilized sulfur ylide) is made to react with methyl vinyl
ketone, a Michael acceptor.
The epoxide is formed due to irreversible 1,2 addition directly at C=O,
which occurs faster than 1,4-addtion. The intermediate formed is unstable and
undergoes immediate ring closure due to intramolecular displacement of
sulfide leaving group by nucleophilic oxygen leading to formation of epoxide.

E.g. With dimethylsulfoxonium methylide (a stabilized sulfur ylide)
cyclopropanation occurs instead of epoxidation on methyl vinyl ketone.
Cyclopropane ring is formed rather than epoxide due to 1,4-addition.
However the 1,2-addition also occurs even more faster with stabilized ylides.
Since the intermediate is stable, this step is also reversible. Hence the sulfonium
ylide is re-expelled before the formation of epoxide.
Meanwhile, some ylide adds to methyl vinyl ketone in 1,4
fashion irreversibly as in Michael reactions. This step is irreversible because of
formation of stronger C-C σ bond at the expense of weaker π bond of C=C. This
step is followed by intramolecular ring closure to give cyclopropane as a
thermodynamically favored product.

In short, with Michael acceptors, epoxidation is major route when unstable ylides are used,
whereas cyclopropanation is the major route with stable ylides.
And also remember that, whether the ylide is stable or not, only epoxide is formed when
the double bond is not in conjugation (unless the double bond is very much activated by
EWG groups).
STEREOCHEMISTRY
The Corey-Chaykovsky cyclopropanation reactions are usually diastereoselective i.e., and
both (E)- and (Z)-olefins give the trans cyclopropanes. This is because the bond rotation is
faster than the ring closure as illustrated below.

However, the stereochemistry of olefin is maintained i.e., cis-olefins give cis cyclopropanes
and trans-olefins give trans cyclopropanes when the bond rotation is restricted or slow. This is
observed when diphenylsulfonium methylide derivatives, Ph2S=CH2 are used as sulfur ylides.
1) Benzaldehyde can be converted to 2-phenyloxirane by treating it with dimethylsulfonium
methylide, which is generated in situ from trimethylsulfonium iodide and NaH in DMSO.

2) Epoxidation of Carvone occurs when it is treated with unstabilized
ylide, dimethylsulfonium methylide. It is direct 1,2 addition on C=O.
Whereas, cyclopropanation occurs when a stabilized sulfur ylide, dimethylsulfoxonium
methylide is used. It is an example of conjugate 1,4 addition (MIRC).

3) In the following MIRC type of reaction on acrolein with a stable sulfur ylid, the
expected trans product is formed predominantly.
4) Imines react with sulfur ylides to give aziridines. The following reaction illustrates the
formation of an aziridine, 1-phenyl-1-azaspiro[2.5]octane from an imine, N-
cyclohexylideneaniline.

Nef Reaction
The conversion of nitro compounds into carbonyls is known as the Nef Reaction.
Various methodologies have been developed, but the most important is the standard procedure: a
preformed nitronate salt is poured into strong aqueous acid (pH < 1). Some oxidative variations have
also found wide application, and some reductive methods have even been developed.

Mechanism of the Nef Reaction
Nitroalkanes are relatively strong carbon acids, and deprotonation leads to the nitronate salt. The hydrolysis of this
intermediate must take place in strong acid, to prevent the formation of side products such as oximes or hydroxynitroso
compounds:
The procedure using the commercial reagent Oxone® is mechanistically
interesting:

The reductive method leads to oximes, which may be hydrolyzed to the corresponding
carbonyl compound. Ti(III) serves to reduce the N-O bond, and titanium's strong affinity
towards oxygen facilitates the hydrolysis to complete the conversion:

Recent Literature
Unprecedented, selective Nef reaction of secondary nitroalkanes promoted by DBU under basic homogeneous conditions
Silicon-Catalyzed Conversion of Nitro Compounds into Ketones and Poly(1,3-diketones)

KMnO4-Mediated Oxidation as a Continuous Flow Process
Cu-Catalyzed Enantioselective Conjugate Addition of Alkylzincs to Cyclic
Nitroalkenes: Catalytic Asymmetric Synthesis of Cyclic α-Substituted Ketones

One-Pot Synthesis of γ-Diketones, γ-Keto Esters, and Conjugated Cyclopentenones from Nitroalkanes
Boron Trifluoride Mediated Ring-Opening Reactions of trans-2-Aryl-3-nitro-cyclopropane-
1,1-dicarboxylates. Synthesis of Aroylmethylidene Malonates as Potential Building Blocks
for Heterocycles

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) is the chemical reagent with formula
C6Cl2(CN)2O2. This oxidant is useful for the dehydrogenation of alcohols,[3]
phenols,[4]
and steroid
ketones[5]
in organic chemistry. DDQ decomposes in water, but is stable in aqueous mineral acid.
Preferred IUPAC name 4,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-
dicarbonitrile[2]
•Other names 2,3-Dichloro-5,6-dicyano-p-benzoquinone
•4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile
•Dichlorodicyanobenzoquinone

Preparation
Synthesis of DDQ involves cyanation of chloranil. Thiele and Günther first reported a 6-step
preparation in 1906.[7]
The substance did not receive interest until its potential as a dehydrogenation agent was
discovered. A single-step chlorination from 2,3-dicyanohydroquinone was reported in 1965.
[8]
Reactions
The reagent removes pairs of H atoms from organic molecules. The stoichiometry of its action
is illustrated by the conversion of tetralin to naphthalene:
2 C6Cl2(CN)2O2 + C10H12 → 2 C6Cl2(CN)2(OH)2 + C10H8
The resulting hydroquinone is poorly soluble in typical reaction solvents (dioxane, benzene,
alkanes), which facilitates workup.
Solutions of DDQ in benzene are red, due to the formation of a charge-transfer complex

Dehydrogenation
Aromatization Cross-Dehydrogenative Coupling

DDQ is an effective reagent for the dehydrogenation of hydroaromatic compounds to give aromatic compounds. The
procedure can be applied for the synthesis heterocyclic compounds such as pyrroles, pyrazoles, indoles, furans and
thiophenes. Many substituents do not interfere in the reaction. For example, using DDQ in boiling benzene tetralin and
acenaphthene can be converted into naphthalene and acenaphthylene, respectively (Scheme 5).
Aromatization
In the case of hydroaromatic compound with blocking group rearrangement has been
observed. For example, in 1,1-dimethyl-1,2,3.4-tetrahydronaphthalene, the aromatization
takes place with 1,2-rearrangement of the methyl group (Scheme 6).

This process has been extensively used in steroid chemistry for
aromatization. For example, DDQ has been used for aromatization in the
synthesis of equilin (Scheme 7).
Formation of Conjugated Double Bonds
DDQ is used for dehydrogenation of organic compound for extending conjugation (Scheme
8). For example, 1,2-diphenylehane can be converted into trans-stilbene in high yield. In a
similar way, ketones can be transformed into a,b-unsaturated carbonyl compounds, which
have been considerably employed in steroid chemistry. The products are generally obtained
in high yield and the substituents commonly encountered are not affected.

Allylic Oxidation
The oxidation of benzylic C-H bonds can be carried with DDQ to afford carbonyl
compounds.
The reactions in aqueous acetic acid proceeds via an intermediate benzylic acetate, which is
hydrolyzed under the reaction conditions (Scheme 9). In some cases, the benzylic acetate
can be isolated (Scheme 10).
Scheme 10
Scheme 9

Oxidative Cyclization
DDQ has been extensively employed for the cyclodehydrogenation reactions of phenolic and
carboxylic acids. These processes afford effective route for the synthesis of oxygen
heterocycles
Scheme 10
Scheme 11
such as coumarins, chromones, benzofurans and lactones. For example, 8-
diphenylmethyl-1-naphthoic acid undergoes oxidative cyclization to give δ-lactone
(Scheme 11). Likewise, DDQ can be employed for the cyclodehydrogenation of
phenols (Scheme 12).

Isomerization
The compounds that are difficult to dehydrogenate give a mixture of isomeric products
(Scheme 13).
Scheme 13
The isomeric products could be formed due to fragmentation of
intermediate carbonium ion followed by ring closure and dehydrogenation.

Deprotection of p-Methoxybenzyl Ethers
p-Methoxybenzyl ether could be deprotected selectively using DDQ
in the presence of other protecting groups such as acetals, RO-Bn,
RO-MOM, RO-MEM, RO-THP, RO-TBS, benzoyl, tosyl, acetate
groups or epoxides (Scheme 14).

What products would you expect in the following reactions ?

1678940715481_oc regents.pptxhxhxjjdjxjddj

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