Highly selective 1,3-isomerization of allylic alcohols via rhenium oxo catalysis

Article abstract of DOI:10.1021/ja044054a

Two reaction strategies are developed to promote the highly selective 1,3-isomerization of a variety of allylic alcohols using O₃ReOSiPh₃ as a catalyst. The first strategy utilizes substrates whose 1,3-regioisomer contains a conjugated alkene, which relies on thermodynamics to obtain high selectivity. The second strategy employs N,O-bis(trimethylsilyl)acetamide as an additive to selectively and irreversibly remove the product from the reaction equilibrium and works well for the isomerization of tertiary allylic alcohols into primary allylic alcohols containing trisubstituted alkene components. High stereoselectivity is also observed in the 1,3-isomerization of enantioenriched allylic alcohols. Copyright

Full text of DOI:10.1021/ja044054a

Published on Web 02/10/2005
Highly Selective 1,3-Isomerization of Allylic Alcohols via Rhenium Oxo
Catalysis
Christie Morrill and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratory of Chemical Synthesis, DiVision of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California 91125
Received September 29, 2004; E-mail: rhg@caltech.edu
Table 1. 1,3-Isomerization of Allylic Alcohols Catalyzed by 1a
Allylic alcohols and their derivatives serve as useful precursors
for numerous synthetic transformations, including Claisen1 and
Cope2 rearrangements, directed epoxidations3 and cyclopropana-
tions,4 carbonyl formation,5 and palladium-catalyzed electrophilic
substitutions.6 The 1,3-isomerization of allylic alcohols (eq 1) is a
useful reaction because one regioisomer is often more difficult to
prepare than the other. Various transition metal oxo complexes
catalyze this transformation: early catalysts required temperatures
above 120 °C,7 but later catalytic isomerizations proceeded at
ambient temperatures.8,9 O3ReOSiPh3 (1),10 reported by Osborn and
co-workers, is currently the most efficient catalyst for this isomer-
ization process, allowing these reactions to attain equilibrium within
5 min at 0 °C.11 Calculations12 on the mechanism indicate a [3,3]
sigmatropic rearrangement, which proceeds through a chairlike
transition state containing an anionic perrhenate moiety and a
cationic allyl moiety (eq 1), suggesting that the high catalytic
activity of 1 arises from the stabilizing effect of its spectator oxo
ligands.
Rhenium catalyst 1 has the potential to provide ready access to
allylic alcohols, but this isomerization typically results in a
thermodynamic mixture of regioisomers, limiting its utility. We
a 0.4 mmol scale, 2 mol % 1, 0.2 M in diethyl ether. b Determined by
report herein reaction strategies that realize the highly selective 1,3-
isomerization of a variety of allylic alcohols, both racemic and
enantioenriched, while maintaining short reactions times, low
catalyst loadings, and mild conditions.
300 Mz NMR. c Determined by GC. d CH2Cl2 used as solvent. e 4 mol %
1. f 70% of 13 recovered.
The reactivity of an allylic alcohol depends strongly upon its
electronic properties. For example, substrates containing electron-
poor allyl moieties (5a, 5b, 7b) undergo 1,3-isomerization efficiently
only at or above 0 °C. However, substrates with electron-rich allyl
moieties (2, 4, 5c, 7a, 7c, 9) readily isomerize at -50 °C and exhibit
extensive side product formation at higher temperatures. These
observations are consistent with the formation of a partially cationic
allyl moiety in the proposed transition state (eq 1).
While this procedure enables the selective formation of conju-
gated allylic alcohols, it still affords product mixtures with sub-
strates that lack conjugation (e.g., Table 1, entry 11). To broaden
the reaction scope, we developed a more general isomerization
procedure that employs N,O-bis(trimethylsilyl)acetamide (BSA).
The addition of BSA (1.2 equiv) promotes the nearly quantitative
isomerization of tertiary allylic alcohols to form primary alcohols
(Table 2). Because silylation by BSA is faster for primary alcohols
than for tertiary alcohols, the product is selectively and irreversibly
silylated, removing it from the reaction equilibrium.14 The products
can be deprotected and isolated in high yields, demonstrating the
efficiency of this procedure for the synthesis of allylic alcohols
containing either conjugated or nonconjugated trisubstituted alkenes.
Our first approach to promoting a selective reaction utilized
allylic alcohols whose regioisomers contained conjugated alkenes.
Previous work with other catalysts8b,d,e has shown that the more
conjugated isomer predominates at equilibrium, thus capitalizing
on thermodynamics to obtain high yields. Our initial experiments
with catalyst 1 resulted in extensive dehydration and condensa-
tion reactions.13 For example, the reaction of 1 with alcohol 7a
(CH2Cl2, rt) leads to a product distribution of 7a/8a/side products
) 0:15:85 (1H NMR) within 2 min. However, with the proper
solvent and sufficiently low reaction temperatures, the side reactions
are completely suppressed, leading to the selective 1,3-isomerization
of various allylic alcohols within about 30 min (Table 1). The side
products presumably result from a competing reaction pathway
involving the formation of an allylic cation,8b,d which should be
more easily suppressed with lower temperatures. These reactions
are highly E-selective, regardless of the initial alkene geometry
(entries 1 and 2). This selectivity may be due to a destabilizing
steric interaction between the axial aryl group and a rhenium oxo
ligand that is present in the proposed chairlike transition state
leading to Z-isomer formation.12
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10.1021/ja044054a CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. BSA-Assisted 1,3-Isomerization of Tertiary Allylic
Alcoholsa
In summary, we have developed two different reaction strategies
to efficiently promote the 1,3-isomerization of allylic alcohols with
catalyst 1. The procedures feature low catalyst loadings and short
reaction times, delivering products in high yields and E-selectivities
for substrates with either aryl or alkyl substitution. The fundamental
reaction properties that we have observed, namely the lower reac-
tivity of electron-poor substrates, the dependence of E-selectivity
on the steric bulk surrounding tertiary alcohols, and the correlation
between the alkene geometry and the absolute configuration of
enantioenriched allylic alcohols, are all consistent with the proposed
chairlike transition state that contains a partially cationic allyl
moiety.
a 0.4 mmol scale, 2 mol % 1, 1.2 equiv of BSA, 0.2 M in diethyl ether.
b Determined after deprotection via K2CO3/MeOH. c Determined by GC.
d 4 mol % 1. e 4.0 mmol scale.
Table 3. 1,3-Isomerization of Enantioenriched Allylic Alcoholsa
Acknowledgment. The authors thank the National Institutes of
Health for financial support, Professor Brian M. Stoltz and Professor
David MacMillan for suggestions concerning the usage of silicon
protecting groups, and Dr. Brian T. Connell, Dr. Anna G. Wenzel,
and especially Dr. Gregory L. Beutner for helpful suggestions and
insight.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a 0.4 mmol scale, 3 mol % 1, 0.2 M in diethyl ether, -78 °C, 2 h. b Only
the E-isomers were visible by 300 MHz NMR. c Determined by chiral
HPLC. d EtOH, 29-30 °C, c ) 2.5. e Determined by GC.
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In general, these reactions proceed with high E-selectivity, which
increases with increasing steric bulk around the tertiary alcohol (e.g.,
entries 1-3: t-Bu . Cy > n-Bu). It is also noteworthy that the
favored regioisomer (i.e., the primary alcohol) in these BSA-assisted
isomerizations is actually the thermodynamically disfavored re-
gioisomer (Table 1, entry 11).8a,d,15
Substrate 11 isomerizes in high yield in the absence of BSA to
afford conjugated alkene 12 only at or below -40 °C, which
necessitates long reaction times and a higher catalyst loading (Table
1, entry 10). Both 11 and 12 readily undergo dehydration, con-
densation, and E/Z-isomerization at higher temperatures. However,
BSA addition dramatically improves the 1,3-isomerization of 11
(Table 2, entry 4), resulting in higher yields and E-selectivity, since
the product is trapped by silylation before side reactions can occur.
Consequently, lower catalyst loadings, higher temperatures, and
significantly shorter reaction times can now be employed.
Since all of the allylic alcohols employed during our studies
possessed a stereogenic center, we wondered if chirality could be
transferred during the 1,3-isomerization of nonracemic allylic
alcohols.16 As shown in Table 3, the isomerization of enantioen-
riched substrates 19 and 21 is highly stereoselective, proceeding at
-78 °C with only a small loss of enantiopurity.17 The absolute
configuration of products 20 and 22 is controlled by the alkene
geometry of the respective starting materials and can be rationalized
by consideration of a chairlike transition state (eqs 2 and 3),
therefore providing experimental evidence to support the proposed
reaction mechanism. The observed minor loss of enantiopurity is
likely the result of competing reaction pathways, such as that
invoking an allylic cation.8b,d
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(13) See page S8 of the Supporting Information for details.
(14) Trimethylsilyl allylic ethers undergo 1,3-isomerization at room temperature
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Am. Chem. Soc. 2000, 122, 11262-11263) and with VO(acac)
2 (ref 8a).
(17) Reaction temperatures above -78 °C lead to a greater loss of enantiopurity.
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