Hydrogen-borrowing and interrupted-hydrogen-borrowing reactions of ketones and methanol catalyzed by iridium

Article abstract of DOI:10.1002/anie.201410391

Reported herein is the use of catalytic [{Ir(cod)Cl}₂] to facilitate hydrogen-borrowing reactions of ketone enolates with methanol at 65°C. An oxygen atmosphere accelerates the process, and when combined with the use of a bulky monodentate phosphine ligand, interrupts the catalytic cycle by preventing enone reduction. Subsequent addition of pronucleophiles to the reaction mixture allowed a one-pot methylenation/conjugate addition protocol to be developed, which greatly expands the range of products that can be made by this methodology.

Full text of DOI:10.1002/anie.201410391

Angewandte
Chemie
DOI: 10.1002/anie.201410391
Synthetic Methods
Hydrogen-Borrowing and Interrupted-Hydrogen-Borrowing Reactions
of Ketones and Methanol Catalyzed by Iridium**
Di Shen, Darren L. Poole, Camilla C. Shotton, Anne F. Kornahrens, Mark P. Healy, and
Timothy J. Donohoe*
Abstract: Reported herein is the use of catalytic [{Ir(cod)Cl}2]
to facilitate hydrogen-borrowing reactions of ketone enolates
with methanol at 658C. An oxygen atmosphere accelerates the
process, and when combined with the use of a bulky mono-
dentate phosphine ligand, interrupts the catalytic cycle by
preventing enone reduction. Subsequent addition of pro-
nucleophiles to the reaction mixture allowed a one-pot
methylenation/conjugate addition protocol to be developed,
which greatly expands the range of products that can be made
by this methodology.
T
he use of transition metals to perform the alkylation of
ketone enolates using hydrogen-borrowing reactions is an
interesting and powerful alternative to enolate formation/
alkylation reactions under more traditional reaction condi-
tions (e.g. lithium amide bases coupled with alkyl halide
electrophiles).[1] Recently we disclosed that rhodium was an
effective metal for catalyzing the hydrogen-borrowing reac-
tions of methanol and we developed a reaction for the
methylation of ketones under relatively mild reaction con-
ditions (carbonate base and 658C reaction temperature;
Scheme 1).[2] Performing the reaction under an atmosphere of
oxygen was an important modification resulting in higher
yields and shorter reaction times (Scheme 1).
Scheme 1. Hydrogen borrowing with methanol and the concept of
interrupted hydrogen borrowing. The reduced form of the catalyst may
be MH or MH2. Cp*=C5Me5.
10 mol% of rhodium metal, thus making the sequence
potentially costly. Secondly, we predicted that it was difficult
for other more hindered alcohols to form branched products
from ketones because of adverse steric interactions in the
aldol intermediates formed en route to the alkylated prod-
ucts.
Our idea for producing diverse branched products was to
interrupt the hydrogen-borrowing process by preventing
enone reduction, thus enabling the introduction of a nucleo-
phile in situ. Subsequent conjugate addition could follow to
form a wide range of complex products. This concept is shown
in Scheme 1 (A!B). In this scenario we should be able to
incorporate functionality beyond a methyl group, yet harness
the enhanced reactivity which comes with methanol-based
hydrogen borrowing. There is a small amount of precedent for
interrupting hydrogen-borrowing alkylations using either
oxygen gas or a reactive alkene to intercept metal hydrides
in situ, but these methods go no further than the production of
unsaturated derivatives.[4]
Methanol is an important feedstock chemical that has
been utilized in a variety of chemical transformations which
involve dehydrogenation to formaldehyde.[3] It is also impor-
tant to note that the use of methanol in hydrogen borrowing is
exceptional in that it confers the ability (by the formation of
reactive formaldehyde) to form branched products from
enolates and allows the production of more complex carbonyl
compounds than previous cases.[2] However, our preliminary
studies revealed two areas in need of improvement. Firstly,
the ketone methylation reaction required between 5 and
[*] D. Shen, D. L. Poole, C. C. Shotton, A. F. Kornahrens,
Prof. T. J. Donohoe
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: timothy.donohoe@chem.ox.ac.uk
We sought to address both issues raised above by
examining
a relatively inexpensive iridium(I) catalyst
Dr. M. P. Healy
Novartis Institute for BioMedical Research
250 Massachusetts Avenue, Cambridge, MA 02139 (USA)
system which is precedented to participate in hydrogen
borrowing but works best with an added ligand.[5] This
requirement meant that we could adjust the balance of
reactivity between the hydrogen borrowing and hydrogen
returning events. Preliminary experiments with [{Ir(cod)Cl}2],
together with a variety of phosphine ligands proved promis-
ing. Reactions of the ketone 1 with low loadings of catalyst (1–
2 mol%) and different ligands are shown in Table 1. These
[**] We thank the EPSRC/Pharma Organic Synthetic Chemistry Stu-
dentships programme, EPSRC, Pfizer, Novartis, and the Oxford
Skaggs DPhil programme for financial support. We thank Dr.
Louis K. M. Chan for preliminary experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410391.
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Table 1: Effect of phosphine ligand and atmosphere on product
distribution.
Entry Conditions
Product distribution [%]
1
2
3
4
5
1
2
3
4
5
6
1 mol% [{Ir(cod)Cl}2], 4 mol%
PPh3, 2 equiv KOH, O2
1 mol% [{Ir(cod)Cl}2], 4 mol%
PPh3, 2 equiv KOH, Ar
2 mol% [{Ir(cod)Cl}2], 8 mol%
PCy3, 3 equiv KOH, O2
2 mol% [{Ir(cod)Cl}2], 8 mol%
cataCXium A, 3 equiv KOH, O2
2 mol% [{Ir(cod)Cl}2], 8 mol%
cataCXium A, 3 equiv KOH, Ar
1 mol% [{Ir(cod)Cl}2],
–
94
–
–
–
4
75
–
9
6
1
–
trace trace
12 23
50
75
13
14
–
–
2
4
Scheme 2. Methylenation of ketones. Yield is that of isolated products.
[a] Enone contaminated with a few percent of inseparable starting
material and/or methylated material. Yields adjusted accordingly.
50 29
–
–
–
83
5 equiv Cs2CO3, O2 (24h)
[a] Determined by 1H NMR spectroscopy of the material after chroma-
tography. CataCXium A=(adamantyl)2PBu, cod=1,5-cyclooctadiene.
have shown that the enone and methoxy adduct products are
in equilibrium, and so the ratio formed in a particular reaction
varies according to the precise substrate employed. Because
of this reversibility, we predicted that both products would be
equally useful in subsequent reactions.
experiments revealed that the ligand plays a crucial role in
determining the products which are formed. Compare entry 1
(PPh3 ligand, which forms the methylated compound 2) with
entries 3 and 4 (bulky PCy3 or cataCXium A[6] ligands which
form two interrupted intermediates, the enone 3 and methoxy
addition product 4 in 59–81% combined yield). Interestingly,
the beneficial role of oxygen in enhancing the efficiency of
both the methylation and methylenation reactions is also
clear (entries 2 and 5).[7] Note that the combination of
a hindered phosphine and an oxygen atmosphere is partic-
ularly effective in stopping enone reduction during the
hydrogen-borrowing cycle (entry 4).[8] We do not yet know
the precise mechanism by which the metal hydride (or
dihydride) is returned to the catalytic cycle after methanol
oxidation, but speculate that the recycling process involves
such a metal hydride being oxidized by molecular oxygen.[9]
Although the details are not yet clear, the reactivity of any
iridium hydrides formed in situ is clearly influenced by the
added ligand. Taken together, this set of results proves that
low loadings of iridium(I) can be used with methanol in both
hydrogen-borrowing and interrupted-hydrogen-borrowing
chemistry depending upon the ligand added.
For the following investigation, we decided to concentrate
on the reactions of p-methoxyphenyl ketones. This substrate
class is an interesting ketone because there are many
possibilities for the formation of functionalized esters, after
hydrogen-borrowing sequences, through a regioselective
Baeyer–Villiger reaction. Therefore, we examined the effi-
ciency of the optimized interrupted hydrogen-borrowing
methylenation conditions (Table 1, entry 4) with several aryl
ketones and found that this was a general process which
formed both the enone and methoxy addition product in good
combined yield (Scheme 2). Note that control experiments
The success of this iridium-catalyzed interrupted process
allowed us to develop a one-pot methylenation/conjugate
addition sequence (Scheme 3). The enone and methoxy
adduct were not isolated but reacted in situ with an external
nucleophile and extra base. In most cases we found it
beneficial to treat the crude reaction mixture with a metal
scavenging resin (SiliaMetS DMT)[10] while stirring the
solution, open to the atmosphere, for 1 hour, before the
addition of base and the external nucleophile. We suggest that
the resin removes most of the metal catalyst from solution and
prevents complications caused by methanol oxidation during
the second phase of the reaction. Moreover, stirring the
reaction vessel when it is open to the atmosphere concen-
trates the reaction and may remove unwanted formaldehyde.
We found that each set of nucleophiles required a minor
variation in the conditions to optimize the yields. The
supplementary nucleophiles which can be added to the
methylenation reaction are diverse, including nitro com-
pounds (14,15), ketones (16,17) and even tert-butyl hydro-
peroxide to form epoxides (18,19) in good to excellent yields,
and all in one pot from methylene ketones. In addition, we
were also able to perform a tandem rhodium-catalyzed
conjugate addition of a boroxine or boronic acid to form
the doubly benzylated compound 20, and analogue 21, again
in good overall yields for a sequence which involves multiple
reaction steps.[11] For this latter type of addition, the scavenger
resin was not added because it slowed down the metal-
catalyzed conjugate addition. The wide variety of nucleo-
philes which are compatible with this protocol greatly
enhance the types of products which can be accessed directly
from ketones through a hydrogen-borrowing-based method-
ology.
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Scheme 4. Iridium-catalyzed methylation and double alkylation of p-
methoxyphenyl-substituted aryl ketones. The KOH loading was depen-
dent on the substrate (see the Supporting Information for details).
Yield is that of isolated products.
Scheme 3. One-pot methylenation/conjugate addition of aryl ketones.
Yield is that of isolated products. [a] Reaction run under an atmos-
phere of oxygen. [b] SiliaMetS DMT scavenger resin not added to the
reaction mixture before addition of nucleophile. Reaction run under
argon.
Given the propensity of iridium to participate in methanol
hydrogen-borrowing processes,[12] we also examined the
alternative catalytic system shown in entry 1 of Table 1
(Ph3P, O2 atmosphere), to improve our recently reported
enolate methylation reaction, (Scheme 4, methylation). The
outcome was a broadly applicable methylation reaction of
alkyl ketones using lower loadings of iridium (2 mol% metal)
compared to rhodium (10 mol% metal).
This procedure was then extended to a one-pot double
alkylation of p-methoxyacetophenone with a primary alcohol
at 1008C (conditions developed by Ishii to form a monoalky-
lated ketone exclusively).[5] The subsequent methylation was
accomplished by cooling to the reaction mixture to 658C and
adding methanol, Ph3P, KOH, and a balloon of oxygen (22–
30; Scheme 4). A variety of different alcohols were subjected
to this regimen, thus demonstrating a useful double-alkyla-
tion reaction using 2 mol% of iridium to perform both
carbon–carbon bond-forming steps in good overall yields.
Finally, our goal was to showcase the synthetic utility of
the intermediates provided by this methodology. In this
regard, the pMeOC6H4 group is an ideal candidate for
regioselective migration during a Baeyer–Villiger oxida-
tion.[13] Scheme 5 shows that a variety of different esters
(31–36) can be made by reaction with mCPBA, including
those armed with a reactive epoxide functionality. This
Scheme 5. Regioselective Baeyer–Villiger and aromatizaton reactions
of the aryl ketone products. Yield is that of isolated products. Baeyer–
Villiger products formed with ꢀ20:1 regioselectivity in each case.
mCPBA=m-chloroperbenzoic acid, TFA=trifluoroacetic acid.
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borrowing reaction sequence and prevents enone reduction,
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to products at the carboxylic acid oxidation state.
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Received: October 23, 2014
Published online: && &&, &&&&
[10] SiliaMetS DMT is claimed by the manufacturer (SiliCycle Inc.)
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Keywords: hydrogen borrowing · iridium · Michael addition ·
.
oxidation · synthetic methods
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4
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Chemie
Communications
Synthetic Methods
On loan: [{Ir(cod)Cl}2] facilitates hydro-
gen-borrowing reactions of ketone eno-
lates with methanol at 658C as described.
Performing the reaction under an oxygen
atmosphere aids the process, and when
combined with a bulky monodentate
phosphine ligand, interrupts the catalytic
cycle by preventing enone reduction. The
addition of pro-nucleophiles to the reac-
tion mixture completes a one-pot meth-
ylenation/conjugate addition protocol.
D. Shen, D. L. Poole, C. C. Shotton,
A. F. Kornahrens, M. P. Healy,
T. J. Donohoe*
&&&& — &&&&
Hydrogen-Borrowing and Interrupted-
Hydrogen-Borrowing Reactions of
Ketones and Methanol Catalyzed by
Iridium
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