Iridium-catalyzed isomerization of primary allylic alcohols

Article abstract of DOI:10.2533/chimia.2009.35

A readily accessible iridium hydrogenation catalyst displays high reactivity for the isomerization of primary allylic alcohols under mild reaction conditions. Key to the efficiency of the catalytic system is to deviate from the conventional hydrogenation route in favor of the desired isomerization pathway by adequately tuning the reaction conditions as indicated by preliminary mechanistic investigations. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2009.35

Yo u n g Ac A d e m ic s in sw it z e r l A n d PA r t i
CHIMIA 2009, 63, No. 1/2 35
doi:10.2533/chimia.2009.35
Chimia 63 (2009) 35–37 © Schweizerische Chemische Gesellschaft
Iridium-Catalyzed Isomerization of
Primary Allylic Alcohols
Luca Mantilli and Clément Mazet*
Abstract: A readily accessible iridium hydrogenation catalyst displays high reactivity for the isomerization of
primary allylic alcohols under mild reaction conditions. Key to the efficiency of the catalytic system is to deviate
from the conventional hydrogenation route in favor of the desired isomerization pathway by adequately tuning
the reaction conditions as indicated by preliminary mechanistic investigations.
Keywords: Allylic alcohols · Homogeneous catalysis · Iridium · Isomerization
The isomerization of primary and second-
ary allylic alcohols to the corresponding
aldehydes and ketones is a reaction of
significant synthetic value.[1] Interested
by the high versatility of aldehydes, we
have recently initiated a research program
to investigate this transformation. To date,
there is no general and practical catalyst
that functions under mild reaction condi-
tions and displays a wide substrate gen-
erality, in particular for less reactive pri-
mary allylic alcohols with sterically hin-
dered and/or highly substituted olefins.[1,2]
This is somewhat surprising regarding
the level of achievement attained for the
related isomerization of allylic amines
to enamines, a reaction that stands out as
one of the most studied, understood and
accomplished processes in homogeneous
catalysis.[3]
In transition metal-catalyzed hydroge-
nation reactions, undesired isomerization
of the reacting olefin is the most com-
mon competing process. Increasing the
hydrogen pressure or tuning the steric and
electronic requirements of the surrounding
ligands usually leads to partial or complete
suppression of this side-reaction.[4] We
initially reasoned that, under appropriate
experimental conditions, certain hydroge-
nation catalysts may preferentially follow
a productive isomerization pathway rather
than the hydrogenation route.[2] Herein, we
report the identification of a highly active
catalyst that promotes the isomerization of
diverse primary allylic alcohols under very
mild reaction conditions.
After two years of
undergraduate stud-
ies in the laboratory
of the late Prof. John
A. Osborn, Univer-
sity of Strasbourg
(France), Clément
Mazet carried out
his PhD research
lar for less reactive densely substituted
unfunctionalized alkenes.[5] In addition,
Stork and Kahne[6] and Crabtree and Da-
vies[7] have convincingly demonstrated
that 1 is effective in the directed reduc-
tion of cumbersome allylic alcohols and
homoallylic alcohols. Nevertheless, previ-
ous attempts to use this catalyst in exclu-
sive isomerization of olefins have proven
elusive since the high loadings usually
employed (10–20 mol%) lead to repro-
ducibility[8] and/or selectivity[9] issues. In
hydrogenation reactions, the bulky, highly
work under the guid-
ance of Prof. Lutz
H. Gade at the same university. In 2003,
he moved to Basel where he worked as a
post-doctoral fellow in the group of Prof.
Andreas Pfaltz. In 2006 he was awarded
a Marie Curie International Outgoing Fel-
lowship and spent nearly two years work-
ing with Prof. Eric. N. Jacobsen at Harvard
University (USA). He joined the Organic
Chemistry Department of the University of
Geneva in November 2007. His research
interests include mechanistic and synthet-
ic chemistry with particular emphasis on
asymmetric catalysis.
lipophilic, BArF (B[(3,5-(CF3)2)C6H )4]–)
–
counter-anion was shown to favor o3lefin
coordination and to slow down deactiva-
tion processes due to very weak and non-
competitive ion-pairing interactions.[10,11]
Superior catalytic performances of 2 over 1
in hydrogenation reactions have been inde-
pendently reported by Buriak and cowork-
ers [10c] and Pfaltz and coworkers.[10e]
Our preliminary investigations started
with a comparative study of catalysts 1 and
2 for the isomerization of primary allylic
alcohols. As anticipated, the experimental
set-up of the reaction turned out to be cru-
cial for the success of the process. Activa-
tion of the precatalysts by hydrogenating
off the cyclooctadiene co-ligand was per-
formed by bubbling molecular hydrogen
directly through the solution followed by
two freeze-pump-thaw cycles to extrude
the excess of hydrogen gas from the re-
action media prior to substrate addition.
Reactions were carried out using (E)-4-
methyl-3-phenyl-2-pentenol as model sub-
strate in THF at room temperature and 5
mol% of precatalyst (Scheme 1). Crabtree
catalyst analogue 2 afforded the aldehyde
quantitatively while the original Crabtree
catalyst 1 gave only 74% of the isomer-
ization product. In both cases no saturated
alcohol was detected. If the substrate was
added before activation of the precatalyst
or, if the hydrogen atmosphere was main-
tained throughout the reaction, partial or
Although numerous transition metals
have been investigated, rhodium and ruthe-
nium catalysts clearly dominate the field
of the isomerization of allylic alcohols.[1,2]
We were initially interested in testing the
commercially available cationic iridium
complex [(Cy3P)(pyridine)Ir(COD)]PF6 1
(COD = 1,5-cyclooctadiene) – also known
as the Crabtree catalyst – because it is a
potent hydrogenation catalyst in particu-
*Correspondence: Dr. C. Mazet
University of Geneva
Department of Organic Chemistry
Quai Ernest Ansermet 30
CH-1211 Geneva
Tel.: +41 22 379 6288
Fax: + 41 22 379 3215
E-mail: clement.mazet@unige.ch

36 CHIMIA 2009, 63, No. 1/2
Yo u n g Ac A d e m ic s in sw it z e r l A n d PA r t i
Scheme 1. Comparative study between 1
and 2 for the isomerization of (E)-4-methyl-3-
phenyl-2-pentenol as model substrate.
complete hydrogenation of the substrate
was observed respectively. When reducing
the catalyst loading down to 1 mol%, cata-
lyst 2 still furnished the desired aldehyde
quantitatively whereas a complete loss of
activity was observed for 1.
The scope of the isomerization reac-
tion using catalyst 2 was investigated next
(Scheme 2). 3,3-Dialkyl-substituted alde-
hydes were obtained from the correspond-
ing allylic alcohols 3–6 using low catalyst
loadings (0.25–1.0 mol%) in very short re-
action time (0.5–2 h). Using 5 mol% of 2 Scheme 2. Scope of the isomerization reaction using 2.
for the isomerization of the sterically more
demanding (E)-3,4,4-trimethylpent-2-enol
7 afforded quantitatively the desired prod-
uct within 16 h. Cinnamyl alcohol 8 and
analogous electron-rich heterocycles 15
and 16 also reacted under very mild condi-
tions. Less reactive analogues 9–12 bearing
an additional 3-alkyl substituent required
slightly increased amount of catalyst as
well as reaction time to undergo complete
conversion. Substrates with a 2,3-substitu-
tion pattern reacted in a contrasted manner,
presumably reflecting the relative stability
of the enols. Whereas a methyl group on
the 2-position (13) readily produces the
expected α-substituted aldehyde, a phe-
nyl ring (14) considerably decelerates the
reaction and requires higher loadings of
catalyst. Finally, under more forcing con-
ditions (10 mol% of 2, 65 °C), allylic al-
cohol 17 with a tetrasubstituted olefin was
converted to a 1:1 mixture of cis and trans
isomerization products.
Activation of (P,N)-iridium complexes
by molecular hydrogen generates inter-
mediates of type 19 where both hydrides
are located cis to the P atom (Scheme
3).[4,12,13] According to our initial hy-
pothesis, discrimination between hydro-
genation and isomerization pathways is
expected to arise from intermediates 20a
and 20b depending whether migratory in-
sertion occurs preferentially at C(2) or at
C(3) respectively.
Scheme 3. Mechanistic hypothesis.

Yo u n g Ac A d e m ic s in sw it z e r l A n d PA r t i
CHIMIA 2009, 63, No. 1/2 37
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Scheme 4. Labeling experiments.
Labeling experiments using 1,1-dideu- lyst loadings (0.25–5.0 mol%). Unprec-
terated model substrate and variable load- edented isomerization of a primary allylic
ings of complex 2 were carried out under alcohol with a tetrasubstituted olefin was
standard conditions (Scheme 4). In each achieved using higher catalyst loading and
case, monodeuterated aldehyde, indica- temperature. Preliminary investigations
tive of an intermolecular process, was un- support our initial mechanistic hypothesis.
equivocally observed by EI-HRMS. Fur- The catalyst stability and accessibility as [5] R. H. Crabtree, Acc. Chem. Res. 1979, 12, 331.
1
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of hydrogen at C(3) was twice proportional
to the initial loading in 2. Complete trans-
fer of hydrogen to the product implicates
rapid exchange between the two hydrides
in 19. This was independently confirmed
by 2D ROESY experiments measured in
the hydride region (–15 to –35 ppm) after
generating 19 in THF-d and degassing. In
addition, if the substra8te coordinates via
both the olefin and the hydroxyl group as
demonstrated by Stork[6] and Crabtree[7]
in their hydrogenation studies, the bind-
ing of the alcohol must be reversible to al-
low β-H1-elimination in the isomerization
pathway (21a 22, Scheme 3).
In conclusion, we have designed an ex-
perimentalprotocolthatrevealedtheability
of an air-stable Crabtree catalyst analogue
2 to promote cleanly the isomerization of
a wide range of primary allylic alcohols
in the corresponding aldehydes. Reac-
tions were run at room temperature with
appreciable reaction rates using low cata-
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Acknowledgments
Financial support from the University
of Geneva is gratefully acknowledged. We
thank D. Gérard and S. Torche for assistance
in synthesis, and B. Vitorge and A. Pinto for
assistance in NMR measurements. Johnson-
Matthey is also thanked for generous loan of
iridium precursors.
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Received: January 5, 2009
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