Aromatic Claisen rearrangement The first reported Claisen rearrangement is the Sigmatropic reaction|[3,3]-sigmatropic rearrangement of an
allyl phenyl ether to intermediate 1, which quickly
tautomerizes to a 2-allyl
phenol. The Claisen rearrangement can occur in
domino fashion with a
Cope rearrangement, in which case the allyl group appears to attack the
para position on the ring: For example, electron withdrawing groups (such as bromide) at the
meta-position direct the rearrangement to the
ortho-position (71%
ortho product), while electron donating groups (such as methoxy), direct rearrangement to the
para-position (69%
para product). Additionally, presence of
ortho substituents exclusively leads to para-substituted rearrangement products. If an
aldehyde or
carboxylic acid occupies the
ortho or
para positions, the allyl side-chain displaces the group, releasing it as
carbon monoxide or
carbon dioxide, respectively.
Bellus–Claisen rearrangement The Bellus–Claisen rearrangement is the reaction of allylic ethers, amines, and thioethers with ketenes to give γ,δ-unsaturated esters, amides, and thioesters. This transformation was serendipitously observed by Bellus in 1979 through their synthesis of an intermediate to an
insecticide, pyrethroid. Halogen substituted ketenes (R1, R2) are often used in this reaction for their high electrophilicity. Numerous reductive methods for the removal of the resulting α-haloesters, amides and thioesters have been developed. The Bellus-Claisen offers synthetic chemists a unique opportunity for ring expansion strategies.
Eschenmoser–Claisen rearrangement The Eschenmoser–Claisen rearrangement proceeds by heating allylic alcohols in the presence of
N,
N-dimethylacetamide dimethyl acetal to form a γ,δ-unsaturated amide. This was developed by
Albert Eschenmoser in 1964. Eschenmoser-Claisen rearrangement was used as a key step in the total synthesis of morphine. Mechanism: The rearrangement proceeds via silylketene acetal, which is formed by trapping the lithium enolate with chlorotrimethylsilane. Like the Bellus-Claisen (above), Ireland-Claisen rearrangement can take place at room temperature and above. The
E- and
Z-configured silylketene acetals lead to anti and syn rearranged products, respectively. There are numerous examples of enantioselective Ireland-Claisen rearrangements found in literature to include chiral boron reagents and the use of chiral auxiliaries.
Johnson–Claisen rearrangement The Johnson–Claisen rearrangement is the reaction of an
allylic alcohol with an
orthoester to yield a
ester. Weak acids, such as propionic acid, have been used to catalyze this reaction. This rearrangement often requires high temperatures (100–200 °C) and can take anywhere from 10 to 120 hours to complete. However, microwave assisted heating in the presence of KSF-clay or propionic acid have demonstrated dramatic increases in reaction rate and yields. Mechanism: While different metal salts can be used to form the enolate, the use of
zinc chloride results in the highest yield and gives the best stereospecificity. The enolate species rearranges at –20 °C to form an amino acid with an allylic side chain in α-position. This method was described by Uli Kazmaier in 1993.
Photo-Claisen rearrangement The Claisen rearrangement of aryl ethers can also be performed as a
photochemical reaction. In addition to the traditional
ortho product obtained under thermal conditions (the [3,3] rearrangement product), the photochemical variation also gives the
para product ([3,5] product), alternate isomers of the allyl group (for example, [1,3] and [1,5] products), and simple loss of the ether group, and even can rearrange alkyl ethers in addition to allyl ethers. The photochemical reaction occurs via a stepwise process of radical-cleavage followed by bond-formation rather than as a concerted
pericyclic reaction, which therefore allows the opportunity for the greater variety of possible substrates and product isomers. The [1,3] and [1,5] results of the photo-Claisen rearrangement are analogous to the
photo-Fries rearrangement of aryl esters and related acyl compounds. ==Hetero-Claisens==