The
,3Wittig rearrangement is the transformation of an
allylic ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be ...
into a homoallylic
alcohol via a concerted,
pericyclic process. Because the reaction is concerted, it exhibits a high degree of stereocontrol, and can be employed early in a synthetic route to establish stereochemistry. The Wittig rearrangement requires strongly basic conditions, however, as a carbanion intermediate is essential.
Wittig rearrangement">,2Wittig rearrangement is a competitive process.
Introduction
,3Sigmatropic
A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular reaction. The name ''sigmatropic'' is the result of a compounding of the long ...
rearrangements occur for a variety of groups X and Y (see below). When X is a
carbanion and Y an
alkoxide, the rearrangement is called the
,3Wittig rearrangement and the products are pent-1-en-5-ols. The
,2Wittig rearrangement, which produces
isomeric
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Is ...
pent-5-en-1-ols, is a competitive process that takes place at high temperatures. Because of the high atom economy and
stereoselectivity
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of ...
of the
,3rearrangement, it has gained considerable synthetic utility. The carbanion is generated by direct lithiation of moderately acidic substrates, tin
transmetallation Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form:
:M1–R + M2–R′ → M1–R′ + M2–R
where R and R′ can be, but ...
, or reductive lithiation of O,S-acetals. Stereoselective methods employing
chiral
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from i ...
starting materials have been used to effect either asymmetric induction or simple diastereoselection
''(1)''
Mechanism and stereochemistry
Prevailing mechanism
After carbanion formation, the
,3Wittig rearrangement is rapid and selective at low temperatures. However, if the reaction mixture is allowed to reach temperatures above −60 °C,
,2rearrangement becomes competitive.
''(2)''
The postulated transition state possesses a five-membered, envelope-like structure. The group attached to the carbanion (G) can occupy either a pseudoequatorial or pseudoaxial position, although the former is usually preferred. Large substituents on the other side of the ether oxygen prefer to occupy the ''exo'' position (R
E) to avoid A
1,3 strain. These restrictions lead to a preference for the ''syn'' product from (''Z'') isomers and ''anti'' products from (''E'') isomers; however, some exceptions to this rule are known.
''(3)''
Stereoselective variants
Stereoselective variants of the
,3Wittig rearrangement have employed three strategies: diastereoselection based on an existing, established stereocenter, placement of a chiral auxiliary on the starting material whose configuration is unaffected by the reaction, and the use of a chiral base. The relative diastereoselection strategy works well only for a limited number of G groups, but usually results in high yields because no chiral auxiliary group needs to be removed or modified. The stereocenter opposite the carbanion usually must be tertiary (rather than quaternary) in order to enforce the placement of the largest substituent in the R
E position.
''(4)''
The
asymmetric induction approach relies on stereocenters already set in the starting material that are unaffected by the reaction (chiral auxiliaries). The most success has been achieved by placing these stereocenters either in the G group or in a substituent attached to the end of the double bond. Diastereomeric ratios in excess of 90:10 are common for these reactions; however, removal of the chiral auxiliary is sometimes difficult.
''(5)''
The use of chiral bases has afforded enantioenriched rearrangement products in a few cases, although this method does not appear to be general. Enantioselectivity in these reactions is often low, suggesting that the association between the conjugate acid of the base and the rearranging carbanion is likely weak.
''(6)''
Scope and limitations
A variety of allylic ethers undergo the Wittig rearrangement—the fundamental requirement is the ability to generate the appropriate carbanion in the substrate. This demands either acidic hydrogens, a reducible functional group, or a carbon-metal bond. Historically,
alkenyl
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, a ...
,
alkynyl
\ce
\ce
Acetylene
\ce
\ce
\ce
Propyne
\ce
\ce
\ce
\ce
1-Butyne
In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and ...
, and
phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
groups have been used to acidify the α position. Free terminal alkynes are tolerated, although yields are higher when silyl-protected alkynes are used.
''(7)''
When an alkene is used as the anion-stabilizing group G, issues of selectivity arise concerning the site of the carbanion. Anion-stabilizing groups such as (trimethyl)silyl or methylthio provide essentially complete site selectivity.
''(8)''
Carbonyl groups may also be used as the anion-stabilizing group; carbonyl groups are particularly useful for asymmetric rearrangements that employ chiral auxiliaries.
''(9)''
A highly enantioselective method employing chromium carbonyl complexes involves the use of the acidified phenyl ring as an anion-stabilizing group.
''(10)''
That the substrate must contain acidic hydrogens adjacent to the ether oxygen was a significant limitation of the original reaction. Thus, the development of transmetallation methods that allowed the selective generation of carbanions from carbon-tin bonds represented a profound methodological advance. The scope of the groups that could be attached to the anionic center expanded dramatically as a result.
''(11)''
Synthetic applications
The products of the
,3Wittig rearrangement of bis(allylic) ethers are 1,5-dien-3-ols. These substrates may undergo the
oxy-Cope rearrangement
In organic chemistry, the oxy-Cope rearrangement is a chemical reaction. It involves reorganization of the skeleton of certain unsaturated alcohols. It is a variation of the Cope rearrangement in which 1,5-dien-3-ols are converted to unsaturated ca ...
upon
deprotonation
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...
, affording δ,ε-unsaturated carbonyls. This tandem sigmatropic strategy has been employed in the synthesis of some natural products, including brevicomine and oxocrinol.
''(12)''
Variations
One variation of the 2,3-Wittig rearrangement is the Wittig-Still rearrangement
[ ]
Experimental conditions and procedure
Typical conditions
Rearrangements must be carried out at temperatures below −60 °C to avoid competitive
,2rearrangement. Typically, simple treatment of the substrate with ''n''-butyllithium is sufficient to cause rearrangement. Reactions involving butyllithium should be carried out under nitrogen or argon with strict exclusion of water.
See also
*
Smiles rearrangement The Smiles rearrangement is an organic reaction and a rearrangement reaction named after British chemist Samuel Smiles. It is an intramolecular nucleophilic aromatic substitution of the type:
where X in the arene compound can be a sulfone, a ...
References
{{DEFAULTSORT:2,3-Wittig rearrangement
Name reactions
Rearrangement reactions
Chemical reactions of ethers