National Technical University of Ukraine 1

‘Igor Sikorsky Kiev Polytechnic Institute’

Reactivity of Organic Compounds

Pericyclic Reactions:
Claisen Rearrangements: Variants and
Applications
Andrey O. Kushko, Ph.D.,
Senior Lecturer

Kiev-KPI-2023
 2
Claisen Rearrangements: Variants and Applications

Reading Materials:

• F. E. Ziegler, Chem. Rev., 1988, 88, 1423-1452.

• Ana M. Martı´n Castro, Chem. Rev. 2004, 104, 2939-3002.

• J. Rehbein, M. Hiersemann, Synthesis 2013, 45, 1121–1159.

• J.-W. Jung, S.-H. Kim, and Y.-G. Suh, Asian J. Org. Chem.
2017, 6, 1117 – 1129.
 3
The Claisen Rearrangement
Claisen Rearrangements are commonly classified according to the substituent at C-2

R Variant Initial Report

C(sp3) Claisen 1912
H Hurd−Claisen 1938

R R OH Carroll−Claisen 1940
OMetal Arnold−Claisen 1949
O O NR2 Meerwein−Eschenmoser−Claisen 1961
COAr Barnes−Claisen 1963
OR Johnson−Claisen 1970
OSiR3 Ireland−Claisen 1972
CO2R Gosteli−Claisen 1972

CJ. Rehbein, M. Hiersemann, Synthesis 2013, 45, 1121–1159.

 4
Hurd−Claisen Rearrangement
The interest of this new rearrangement prompted the development of different methods for the
preparation of the starting materials. Hurd and Pollack described the synthesis of allyl vinyl
ethers by acidic or basic elimination as well as the rearrangement of such compounds into the
corresponding -unsaturated carbonyl compounds.

However, this method did not

provide general access to
allyl vinyl ethers.

Hurd, C. D.; Pollack, M. A. J. Am. Chem. Soc. 1938, 60, 1905.

 5
Hurd−Claisen Rearrangement

Several years later this procedure for the synthesis of allyl vinyl ethers was improved by the
interchange of alcohols with alkyl vinyl ethers catalyzed by Hg(OAc)2. Those compounds
once again proved to be excellent substrates to undergo a [3,3] rearrangement.

This mercury-catalyzed reaction

has become one of the typical
methods of preparation of allyl
vinyl ethers despite that the
yields of these reactions are
often low.

Burgstahler, A. W.; Nordin, I. C. J. Am. Chem. Soc. 1961, 83, 198.

 6
Carroll Rearrangement
The Carroll reaction, initially described in 1940, is a thermal rearrangement of allylic -
ketoesters followed by decarboxylation to yield -unsaturated ketones:

This reaction has not been widely

developed due to the drastic conditions
(temperatures of 130-220 °C after in
situ preparation of the -ketoester) that
are required to perform the
transformation.

Carroll, M. F. J. Chem. Soc. 1940, 704. (b) Carroll, M. F. J. Chem. Soc. 1940, 1266. (c) Carroll, M. F. J. Chem.
Soc. 1941, 507. Kimel, W.; Cope, A. C. J. Am. Chem. Soc. 1943, 65, 1992.
 7
Carroll Rearrangement
After the publication of these results, it was reported that dianions derived from allylic
acetoacetates, were prepared by treatment of acetoacetates with 2 equiv. of LDA,
rearranged under milder thermal conditions to give easily isolated -keto acids:

A dependence of the reaction rate

on the substitution pattern on the
allylic fragment (R, R’ = H, alkyl,
aryl) has also been detected. Thus,
acetoacetates derived from primary
alcohols rearrange more slowly
r.t. than those derived from secondary
and tertiary alcohols.

Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722.

 8
Eschenmoser Rearrangement
In 1964 Eschenmoser, based on observations previously reported by Meerwein on the
interchange of amide acetals with allylic alcohols, described the [3,3] rearrangement of N,O-
ketene acetals to yield -unsaturated amides

This reaction allows the formation of a

carbon-carbon bond at the -position to a
nitrogen atom, which is of great applicability
in alkaloid synthesis, although it has the
inconvenience of the difficulty inherent to the
preparation of more elaborated N,O-ketene
acetals, which usually requires elevated
temperatures leading, in some cases, to
decomposition of the resulting amides.

Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425. Wick, A. E.; Felix, D.; Gschwend-Steen,
K.; Eschenmoser, A. Helv. Chim. Acta 1969, 52, 1030.
 9
Johnson Ortho-Ester Claisen

First reported in 1970, the Johnson rearrangement,

which may afford trans-trisubstituted alkenes, was
originally described as the process consisting of
the heating of an allylic alcohol with an excess of
ethyl orthoacetate in the presence of trace
amounts of a weak acid (typically propionic acid).

Johnson, Faulkner, Peterson, J. Am. Chem. Soc., 1970, 92, 741-743.

 10
Ireland-Claisen Rearrangement
In 1972 Ireland reported the rearrangement of allyl trimethylsilyl ketene acetals, prepared by the
reaction of allylic ester enolates with trimethylsilyl chloride, to yield -unsaturated carboxylic acids:

Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868
 11
Ireland-Claisen Rearrangement
Enolization: Amide Bases
Stereoelectronic Requirements: The -C-H bond must be able to overlap with * C–O

Ireland, J. Am. Chem. Soc. 1976, 98, 2868.; Narula, Tetrahedron Lett. 1981, 22, 4119.; Ireland, J. Org. Chem.
1991, 56, 650.344e3
 12
Ireland-Claisen Rearrangement
Enolization: Amide Bases

Ireland, J. Am. Chem. Soc. 1976, 98, 2868.; Narula, Tetrahedron Lett. 1981, 22, 4119.; Ireland, J. Org. Chem.
1991, 56, 650.
 Ireland-Claisen Rearrangement 13

Substituted enolates afford an additional stereocenter:

Ireland, J. Org. Chem. 1991, 56, 650.

 Claisen Rearrangement and Chirality Transfer 14

Boat transition states are more accessible in Claisen than in Cope

rearrangements

A case where the chair-boat preference

depends on enol geometry:

Ireland study supports Bartlett's conclusions

Boat geometies can be favored in

these and related systems

Bartlett, J. Org. Chem. 1981, 46, 3896.; Ireland, J. Am. Chem. Soc. 1991, 56, 3572.
 Claisen Rearrangement and Chirality Transfer 15

Boat transition states more accessible in Claisen than in Cope

rearrangements

In this case the boat geometry is preferred

from either enol geometry

Ireland, J. Am. Chem. Soc. 1991, 56, 3572.

 16
Claisen Rearrangement and Chirality Transfer
Boat transition states more accessible in Claisen than in Cope
rearrangements

A further example:

boat-preferred
It appears that both of the
indicated interactions contribute
to the destabilization of chair
geometry

destabilizing

Ireland, J. Am. Chem. Soc. 1991, 56, 3572.

 17
Reformatsky-Claisen Rearrangement
[3,3] Sigmatropic rearrangement of zinc enolates, known as the Reformatsky-Claisen
rearrangement, has also been reported. These zinc enolates, generated by
Reformatsky reaction of -haloesters with zinc dust, lead to the corresponding -
unsaturated zinc carboxylates in good yields under neither acidic nor basic conditions.

Baldwin, J. E.; Walker, J. A. J. Chem. Soc., Chem. Commun. 1973, 117.

 18
Reformatsky-Claisen Rearrangement

Similar reaction conditions, in the presence of trimethylsilyl chloride, allowed the

synthesis of 2,2-difluoro-4-pentenoic acid starting from allyl chlorodifluoroacetate

Reformatsky-Claisen reaction did not occur in the absence of chlorotrimethylsilane.

This indicates that the ketene acetal is most likely a reaction intermediate.

Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett. 1988, 29, 3291.
 19
Gosteli-Claisen Rearrangement: General
The Claisen rearrangement of 2-alkoxy carbonyl-substituted allyl vinyl ethers, so-called
Gosteli-type allyl vinyl ethers, has evolved without attracting considerable attention.
However, some recently developed catalytic asymmetric Claisen rearrangements utilize
Gosteli-type allyl vinyl ethers.

Gosteli, J. Helv. Chim. Acta 1972, 55, 451.

 20
Gosteli-Claisen Rearrangement

Structure of Allyl Vinyl Ethers:

Configuration of the vinyl ether double bond

Configuration of the allyl ether double bond

J. Rehbein, S. Leick, and M. Hiersemann, J. Org. Chem. 2009, 74, 1531–1540.

 Gosteli-Claisen Rearrangement 21

Substrate-Reactivity Relationship:

(E)-1a The CO2i-Pr group has a significant

rate accelerating influence which is
further amplified by the additional methyl
group in (E)-1a. The amplification effect
is strongly dependent on the double-
bond configuration, as (Z)-1b and 1
show a comparable reactivity.
(Z)-1b
1

J. Rehbein, S. Leick, and M. Hiersemann, J. Org. Chem. 2009, 74, 1531–1540.

 Gosteli-Claisen Rearrangement 22

Substrate-Reactivity Relationship:

(E, E)-1c

(E)-1a

(E, Z)-1b

J. Rehbein, S. Leick, and M. Hiersemann, J. Org. Chem. 2009, 74, 1531–1540.

Qualitative Transition-State Model for the Gosteli-Claisen 23

Rearrangement

The experimentally determined substrate-reactivity

relationship can be rationalized by a qualitative
steric model that considers only the relative
stability of the transition-state structures to
predict the relative reactivity of the corresponding
substrates.
The Gosteli-Claisen rearrangement has lately
attracted attention in connection with the
development of catalyzed Claisen rearrangements.
Lewis acids and organocatalysts have been
successfully utilized to establish a catalytic
asymmetric aliphatic Claisen rearrangement

J. Rehbein, S. Leick, and M. Hiersemann, J. Org. Chem. 2009, 74,

1531–1540.
 Lewis Acid Mediated Claisen Rearrangements: 24

The Aluminum Age

The rate-accelerating effect of Lewis acids incorporating trivalent aluminum was developed in the early
1980s. Quite generally, in order to exploit aluminum(III) compounds as rate accelerators for aliphatic
Claisen rearrangements, at least stoichiometric amounts of the Lewis acid are required

Aluminum(III)-accelerated
Hurd–Claisen rearrangement
E/Z = 39:61 according to Oshima: ‘Sealed
tube thermolyses (180 °C,
20 min) of these ethers afforded
the almost homogeneous
rearranged aldehydes (>95%
E).’
E/Z = 52:48

Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 3985.; Takai, K.; Mori, I.; Oshima, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1984, 57, 446.; Mori, I.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron, 1984, 40, 4013.
 25
Lewis Acid Mediated Claisen Rearrangements:
The Aluminum Age
Assuming concertedness, the stereochemical course of the Hurd–Claisen rearrangement is dependent
on the nature of the σ-electrophilic aluminum(III) Lewis acid:

It was initially proposed that A would

enforce a concerted rearrangement
via the chair-like transition state
structure in which the isobutyl group
adopts a pseudo-axial position.

Stevenson, J. W. S.; Bryson, T. A. Tetrahedron Lett.

1982, 23, 3143.
 26
Aluminum(III) accelerated Hurd–Claisen Rearrangement

(±) [3,3] (±)-[1,3] The phenyl substituent

increases the propensity
for ionization and formation
A (2 equiv), CH2Cl2, −78 °C, 15–30 min: 31% + 49%
of the [1,3]-rearrangement
B (2 equiv), toluene, −20 °C, 15 min: 45% + 13% product by a stepwise
mechanism.

Nasveschuk, C. G.; Rovis, T. Org.

Biomol. Chem. 2008, 6, 240.
 27
Claisen Rearrangement: Catalysis by σ-Lewis Acids
Conceptualized catalytic cycle for a Claisen rearrangement using a σ-electrophilic catalyst
(cat.).

CJ. Rehbein, M. Hiersemann, Synthesis 2013, 45, 1121–1159.

 28
Claisen Rearrangement: Catalysis by σ-Lewis Acids

Using the minimum-energy paths for the catalyzed and

the uncatalyzed generic Claisen rearrangement in order
to conceptualize the selective transition-state
stabilization by a σ-electrophilic catalyst.

CJ. Rehbein, M. Hiersemann, Synthesis 2013, 45, 1121–1159.

 29
Claisen Rearrangement: Catalysis by σ-Lewis Acids

Competing rearrangement pathways in

the presence of a σ-electrophilic catalyst:
ab (x = pseudo-axial, boat-like), ac
(x = pseudo-axial, chair-like), ec (x =
pseudo-equatorial, chair-like), eb (x =
pseudo-equatorial, boat-like).

CJ. Rehbein, M. Hiersemann, Synthesis 2013, 45, 1121–1159.

 30
Aza-Claisen Rearrangement
The [3,3] sigmatropic rearrangement of N-allyl-Narylamines, known as the aza-Claisen rearrangement,
usually requires more drastic conditions than those required for the classic Claisen rearrangement of
oxygenated substrates (this rearrangement occurs at 200-350 °C). In addition, it affords the
corresponding anilines along with undesired byproducts.

Similar energetic conditions are needed for the aliphatic

aza-Claisen rearrangement to take place. The thermal
process requires higher temperatures than those
needed for oxygen substrates. In several cases, the
reaction only evolves under Lewis-acid catalysis.

Jolidon, S.; Hansen, H.-J. Helv. Chim. Acta 1977, 60, 978.; Bennett, G. B. Synthesis 1977, 589.
 Aza-Claisen Rearrangement 31

Advances in Aza-
Claisen-
Rearrangement-
Induced Ring-
Expansion Strategies

J.-W. Jung, S.-H. Kim, and Y.-G. Suh, Asian J. Org. Chem. 2017, 6, 1117 – 1129.
 32
The Claisen Rearrangement
An example of solving the problem:
As part of a program directed toward the synthesis of the pinnatoxins, Pelc and Zakarian reported
the single-pot conversion of sulfone A into cyclohexene B (Org. Lett., 2005, 7, 1629). Using clear
three-dimensional representations please provide a concise mechanism for this transformation and
predict the stereochemical outcome.

M. J. Pelc, and A. Zakarian, Org. Lett., 2005, 7, 1629-1631.

 33
Sequence of solving the problem: Step 1.

Identilfy
Claisen Retron

M. J. Pelc, and A. Zakarian, Org. Lett., 2005, 7, 1629-1631.

 34
Sequence of solving the problem: Step 2.

M. J. Pelc, and A. Zakarian, Org. Lett., 2005, 7, 1629-1631.

 35
Sequence of solving the problem: Step 3.

M. J. Pelc, and A. Zakarian, Org. Lett., 2005, 7, 1629-1631.

36