C-C coupling of ketones with methanol catalyzed by a N-heterocyclic carbene-phosphine iridium complex

Article abstract of DOI:10.1002/chem.201405990

An N-heterocyclic carbene-phosphine iridium complex system was found to be a very efficient catalyst for the methylation of ketone via a hydrogen transfer reaction. Mild conditions together with low catalyst loading (1 mol%) were used for a tandem process which involves the dehydrogenation of methanol, C=C bond formation with a ketone, and hydrogenation of the new generated double bond by iridium hydride to give the alkylated product. Using this iridium catalyst system, a number of branched ketones were synthesized with good to excellent conversions and yields.

Full text of DOI:10.1002/chem.201405990

DOI: 10.1002/chem.201405990
Communication
&
CÀC Coupling Reactions
CÀC Coupling of Ketones with Methanol Catalyzed by a
N-Heterocyclic Carbene–Phosphine Iridium Complex
Xu Quan, Sutthichat Kerdphon, and Pher G. Andersson *[a]
from the oxidation of the alcohol reduces this newly generated
Abstract: An N-heterocyclic carbene–phosphine iridium
complex system was found to be a very efficient catalyst
for the methylation of ketone via a hydrogen transfer re-
action. Mild conditions together with low catalyst loading
(1 mol%) were used for a tandem process which involves
the dehydrogenation of methanol, C=C bond formation
with a ketone, and hydrogenation of the new generated
double bond by iridium hydride to give the alkylated
product. Using this iridium catalyst system, a number of
branched ketones were synthesized with good to
excellent conversions and yields.
intermediate to give the final product. The hydrogen transfer
reactions of alcohols have more recently also been applied to
CÀC bond formation.[6] This method allows the a-alkylation of
ketones using alcohols as the electrophiles. Advances in this
field have been made by a number of groups,[7] but the scope
of the reaction has mostly been focused on the alkylation of
methyl ketones, using mainly long-chain primary alcohols or
benzylic alcohol as the electrophile. The simplest alcohol,
methanol, is playing an increasingly important role in the
chemical industry, and its transition-metal catalyzed dehydro-
genation has been described by Beller,[8] Grꢀtzmacher[9] and
Milstein[10] who have reported on the potential application of
methanol in CÀC bond formation via hydrogen transfer reac-
tions. However, only a few successful examples have been
published so far. Krische and co-workers[11] developed an ele-
gant method for CÀC bond formation using methanol and al-
lenes, Jun and colleagues[12] described dialkyl ketone formation
with methanol. Glorius[13] and Li[14] and their co-workers used
methanol in metal-catalyzed N-formylation and methylation of
amines. Very recently, the groups of Donohoe[15] and Obora[16]
reported independently on the success in hydrogen transfer
methylation of ketones with methanol. In their catalyst sys-
tems, [{Cp*RhCl2}2] and [{Cp*IrCl2}2] were used as pre-catalysts,
5 mol% of iridium or rhodium dimers, which means that in
effect there was 10 mol% of monomer catalysts in the reaction
solution, and additionally high temperatures were required
when using [{Cp*RhCl2}2]. With the aim of developing new cat-
alysts for hydrogen transfer reactions, our N-heterocyclic car-
bene iridium homogeneous system stands out as being one of
the most efficient catalysts for the hydrogen transfer alkylation
of amines. Herein we report on the high catalytic activity of
the hydrogen transfer methylation of ketones using methanol
as the electrophile.
The preparation and reactivity of transition-metal complexes of
N-heterocyclic carbenes is a field in rapid development within
organometallic chemistry. Compared with their phosphine
analogues, N-heterocyclic carbenes offer stronger metal–ligand
bond formation and better stability properties, and the study
of their synthesis[1] and catalytic activities continues to attract
considerable attention.[2] Recently, we found a highly efficient
N-heterocyclic carbene iridium complex that can catalyze hy-
drogen transfer alkylation of amines with alcohols.[3] The transi-
tion-metal catalysts normally require either high temperature
or large catalyst loadings for the hydrogen transfer alkylation
of amine with alcohol.[4] For example, using [RuCl2(PPh3)3],
which was one of the most widely studied catalysts for alkyla-
tion of amines, the reaction was carried out at above 1008C. In
the case of iridium catalytic systems, Fujita and co-workers in-
troduced the use of [{Cp*IrCl2}2],[5] which gave full conversion
at 1108C in 17 h. Further study demonstrated that this chemi-
cal transformation is a highly efficient method to synthesize
a wide range of amines and N-heterocyclic compounds from
alcohols. The N-heterocyclic carbene iridium complex was
found to be the first catalyst that worked at room temperature
with low catalyst loading (1.0 mol%). In these transition-metal
catalyzed hydrogen transfer reactions, the catalyst removes the
hydrogen atoms from an alcohol to generate an aldehyde,
which undergoes bond formation with another nucleophile in
a condensation reaction, after which the metal hydride formed
The phenyl ketone 1 was used as a benchmark substrate for
this reaction and the results are shown in Table 1. Both the re-
activity and selectivity of the reaction was found to be highly
dependent on the base and the amount of base being used.
In the presence of tetrabutylammonium chloride and pyri-
dine (Table 1, entries 1 and 2), the reactions were inhibited.
The reduced alcohol 1b was the only product when using
sodium carbonate, sodium tert-butoxide, or potassium tert-but-
oxide (entries 3, 5, and 6). The use of potassium or cesium car-
bonate led to the formation of desired 1a in 7% and 11% re-
spectively (Table 1, entries 4 and 7). Use of cesium hydroxide
(Table 1, entry 8) did not improve the methylation reaction.
Increasing the amount of base, using 5 equiv of cesium
[a] X. Quan, S. Kerdphon, Prof. P. G. Andersson
Department of Organic Chemistry
Stockholm University
The Arrhenius laboratory, 10691 Stockholm (Sweden)
E-mail: phera@organ.su.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405990.
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Table 1. Iridium-catalyzed methylation of 1[a]
Table 2. Iridium-catalyzed methylation of propiophenone derivatives.[a]
Substrate
Product
Isolated
yield [%]
R=H
2
3
4
5
6
7
8
95
93
91
95
92
96
93
R=Me
R=OMe
R=Cl
R=F
R=Br
Entry
Catalyst
Base (equiv)
1a [%]
1b [%]
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
A
B
C
D
A
Bu4NCl (2)
pyridine (2)
Na2CO3 (2)
K2CO3 (2)
tBuONa (2)
tBuOK (2)
Cs2CO3 (2)
CsOH H2O (2)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
n.d.
n.d.
n.d.
7
n.d.
n.d.
11
8
n.d.
n.d.
61
37
65
57
18
54
R=CF3
R=Cl
9
92
95
93
90
R=Me
R=Br
R=CF3
10
11
12
9
63
53
33
n.d.
n.d.
n.d.
10
11
12
13[b]
R=Cl
R=Me
R=F
13
14
15
16
89
90
88
85
complex mixture
99 (97)[c]
<1
[a] Reaction conditions: ketone 1 (0.1 mmol), base (2 equiv), A (1.0 mol%)
in MeOH (2.0 mL) at 658C for 24 h. [b] Reaction conditions: ketone
1 (0.1 mmol), base (5 equiv), A (1.0 mol%) in MeOH (0.5 mL) at 658C for
24 h. [c] Isolated yield.
R=CF3
17
18
91
80
carbonate gave 63% of the desired product 1a with a trace
amount of 1b. Changing the substituents at the imidazole and
phosphine did not result in any improvements (entries 10 and
11). Running the reaction at higher concentration, (Table 1,
entry 13) was found to suppress the formation of the reduced
product 1b, and led to full conversion with 97% isolated yield.
The corresponding rhodium complex was not an efficient
catalyst for the methylation reaction (entry 12).
[a] Reaction conditions: ketone (0.1 mmol), base (4 equiv), A (1.0 mol%)
in MeOH (0.5 mL) at 658C for 24 h.
case of ethyl benzyl ketone 22, the conversion was 83% and
80% of 22a was isolated. Only trace amounts of dimethylated
product 23a implies a strong dependency of the chemoselec-
tivity on the pKa value of the a-carbon.[16,17] Other benzylic
ketones 24 and 25 gave full conversions and high isolated
yields.
With the optimized reaction conditions in hand, the scope
of the catalyst was tested using a range of different ketones.
As shown in Table 2, the catalyst system maintained high activ-
ity for the halogenated derivatives; high conversions were
obtained for different halogen substituents on all three ortho,
meta, and para positions on the phenyl ring. Ketones 3, 10,
and 14 were converted to the methylation products complete-
ly in 24 h, whereas the ketone 4 with the methoxy group gave
96% conversion with 91% isolated yield. Full conversion was
obtained with trifluoromethylated ketones 8, 12, and 16. Using
standard conditions (0.5 mL of methanol), 83% of the sub-
strate 18 was converted to desired product in 80% isolated
yield. Further reduction occurred to generate the correspond-
ing alcohol, which means that after the methylation was
complete, the iridium catalyst continued to transfer hydrogen
from methanol to the carbonyl group.
Several experiments were carried out to shed some light on
the mechanism, which is proposed to start from dehydrogena-
tion of the methanol to form formaldehyde, followed by aldol
condensation with the ketone to obtain the conjugated
ketone and then, final reduction of the unsaturated ketone
intermediate (Scheme 1).
When a longer aliphatic chain was introduced on the
ketone, slower reaction rates were observed (Table 3). Com-
pared with ethyl ketone 2, which gave full conversion in 24 h,
5 equivalents of cesium carbonate were required to achieve
high conversions for butyl and hexyl phenyl ketones (19 and
20 with 98% and 94% yields, respectively). Using these condi-
tions the ketone 21 was fully converted in 24 h as well. In the
Scheme 1. Proposed mechanism of methylation with iridium catalyst.
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in more than 95% selectivity (Scheme 2c). These results are
both in agreement with the fact that a) the reaction appears
to follow an aldol condensation pathway, and b) it involves hy-
drogenation of a C=C bond by iridium hydride. Since also the
formaldehyde and ketone 2 were unable to generate either 27
or 28 (Scheme 2d) under standard reaction conditions without
the iridium catalyst, the iridium catalyst seems also be involved
in the aldol step (Scheme 1, from 2 to 27 and 28) perhaps by
binding with formaldehyde to increase its electrophilicity.[6e]
The mercury poisoning test was carried out in the presence
of 5 equiv of mercury with substrate 2, which gave 97% con-
version in 24 h, whereas 99% conversion occurred without
mercury. In the time-dependent experiment of the reaction of
2, 1% of the conversion was detected in the first 24 min,
which revealed that there was a pre-activation process of the
iridium complex A (see Figure S1 in the Supporting Informa-
tion). Furthermore, when complex A was replaced by the cat-
ionic iridium complex [Ir(cod)2]+BArFÀ, it led to a dramatic loss
of both reactivity and selectivity of the reaction. Alongside the
desired product, alcohols stemming from the reduction of the
starting material together with various methylated products
were formed, which clearly shows that the N-heterocyclic
carbene phosphine ligand remains bound to the iridium
center during the catalytic cycle.
Table 3. Methylation of ketones 19–26.[a]
Substrate
Product
Isolated
Yield [%]
19
20
21
22
23
19a
20a
21a
22a
23a
98
94
97
80
96
24
24a
96
25
26
25a
2a
95
In summary, we have reported the use of methanol in the al-
kylation of ketones via a hydrogen transfer reaction catalyzed
by an N-heterocyclic carbene phosphine iridium complex with
high reactivity and good selectivity. Compared with the com-
mercially available [{Cp*IrCl2}2] catalyst system, the catalyst
loading could be decreased from 10 mol% to 1 mol% when
iridium complex A was used, and full conversions were ob-
tained in most cases. This catalyst system was found to be ap-
plicable to a wide variety of ketones. Experiments suggest that
the new bond formation passes through an aldol-type path-
way, in which all steps probably are mediated by the iridium
catalyst; however, the exact reaction mechanism still remains
to be uncovered.
96[b]
[a] Reaction conditions: ketone (0.1 mmol), base (5 equiv), A (1.0 mol%)
in MeOH (0.5 mL) at 658C for 24 h. [b] Reaction conditions: ketone
(0.1 mmol), base (5 equiv), A (3.0 mol%) in MeOH (0.5 mL) at 658C for
24 h.
The two proposed intermediates 27 and 28 were prepared
separately and both converted smoothly to product 2a when
subjected to the standard reaction conditions (Scheme 2a and
b). The use of [D4]methanol as solvent resulted in the clean for-
mation of the deuterated compound 29, which was obtained
Experimental Section
To an oven-dried pressure vessel with a magnetic stir
bar, base and iridium complex were added. The vessel
was sealed, degassed by vacuum pump and refilled
three times with nitrogen. The ketone substrates in de-
gassed methanol were added under a nitrogen atmos-
phere, and the reaction mixture was heated to 658C for
24 h. The reaction mixture was cooled to ambient tem-
perature and aqueous hydrochloride solution (1m, 1 mL)
and diethyl ether (2 mL) were added. The aqueous
phase was separated and extracted with diethyl ether
(2ꢂ2mL), and all the combined organic phases were
washed with brine, dried over sodium sulfate, and the
organic solvent was removed under vacuum. The con-
version was determined by 1H NMR spectroscopy, and
further purification was carried out by column chroma-
tography.
Scheme 2. Methylation of possible intermediates 27 and 28
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Acknowledgements
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This project was supported by Swedish Research Council (VR),
Stiftelsen Olle Engkvist Byggmꢃstare, the Swedish Energy
Agency, the Knut and Alice Wallenberg Froundation, the Swed-
ish Governmental Agency for Innovation Systems (VINNOVA)
through the Berzelii Center EXSELENT on Porous Materials and
SYNFLOW (FP7) supported this work. The authors thank Dr. T.
Singh and Mr. B. Peters for useful discussions.
Keywords: CÀC coupling reactions · hydrogen transfer ·
iridium · ketones · methylation
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Received: November 6, 2014
Published online on January 14, 2015
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