α-Methylation of Ketones with Methanol Catalyzed by Ni/SiO2-Al2O3

Article abstract of DOI:10.1002/ejoc.201900602

α-Methylation of ketones with methanol catalyzed by a cheap and easy to handle Ni/SiO₂-Al₂O₃ was explored. After optimization of the reaction between propiophenone and methanol, the desired product was obtained in 95 % isolated yield. A wide range of ketones was methylated under the optimized conditions (16 examples). This procedure was extended to a three-component cross-benzylation-methylation of acetophenone.

Full text of DOI:10.1002/ejoc.201900602

A Journal of
Accepted Article
Title: α-Methylation of ketones with methanol catalyzed by Ni/SiO2-
Al2O3
Authors: Aubin Charvieux, Nicolas Duguet, and Estelle Métay
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900602
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α-Methylation of ketones with methanol catalyzed by Ni/SiO2-
Al2O3
Aubin Charvieux,[a] Nicolas Duguet*[a] and Estelle Métay*[a]
Abstract: α-Methylation of ketones with methanol catalyzed by a
cheap and easy to handle Ni/SiO2-Al2O3 was explored herein. After
optimization of the reaction between propiophenone and methanol,
the desired product was obtained in 95% isolated yield. A wide
range of ketones was methylated in the optimized conditions (16
examples). This procedure was extended to a three-component
cross-benzylation-methylation of acetophenone.
expensive metals, and there is to date no example of non-noble
metal heterogeneous catalysts. We have previously reported
that Ni/SiO2-Al2O3 is an efficient, inexpensive and recyclable
supported catalyst for the α-alkylation of ketones by benzylic and
long chain aliphatic alcohols.[21] Herein, we report the α-
methylation of ketones catalyzed by Ni/SiO2-Al2O3 using
methanol as an alkylating agent (Scheme 1).
Introduction
Methylation is an essential transformation for the synthesis of
biologically active molecules.[1] However, classical methylating
agents, such as methyl iodide, dimethylsulfate, or diazomethane,
are highly toxic or explosive.[2] In recent years, methylation
methods were developed with greener agents, such as CO2,[3]
formic acid[4] or dimethyl carbonate.[5] Other alternative reagents
such as dimethylsulfite[6] and trimethylphosphate[7] were also
proposed by our group. The borrowing hydrogen methodology
allows the use of alcohols as alkylating agents through an
aldehyde intermediate, generating water as the sole by-
product.[8] However, this methodology has been mostly
developed with benzylic and long chain aliphatic alcohols.[9] The
most challenging one, the methylation with methanol has been
less explored, possibly due to the high dehydrogenation energy
of methanol (ΔH = 84 kJ.mol-1 vs. 68 kJ.mol-1 for ethanol).[10] And
yet, methanol is a cheap, abundant and renewable molecule, as
it can be also synthesized from H2 and CO2.[11] In the past
decade, methanol has been successfully used for the α-
methylation of ketones through the borrowing hydrogen
methodology (Scheme 1). This reaction has been mainly
reported with homogeneous Ir,[12] Ru[13] and Rh[14) complexes
(Scheme 1a). More recently, it has been shown that non-noble
metal complexes of Co,[15] Mn,[16] Ni[17] and Fe[18] could efficiently
catalyze this reaction (Scheme 1b). Pd supported on polymers[19]
and Pt/C[20] are the only examples of heterogeneous catalysts
for the α-methylation of ketones with methanol (Scheme 1c).
Though most of these catalysts can be used in mild conditions, a
large excess of base (up to 500 mol%) is generally required.
Moreover, the works previously cited mostly rely on noble and
Scheme 1. α-Methylation of ketones with methanol.
Results and Discussion
Propiophenone 1a was selected as a model substrate for the
optimization of the α-methylation with methanol catalyzed by
Ni/SiO2-Al2O3. The base screening was carried out with 9
equivalents of MeOH, 20 mol% of Ni catalyst and 10 mol% of
base. The mixture was heated at 175°C for 15h without added
solvent (Table 1). Using KOAc gave a high selectivity but a low
yield of the desired product 3a (13% GC ratio, Table 1, entry 1).
t
Improved yields were obtained with BuOLi and KOH (Table 1,
entries 2-3). However, 2,4-dibenzoyl-pentane 4a was observed
as a byproduct under these conditions. This undesired product is
probably formed by the Michael addition of 1a on the product of
aldol-condensation between formaldehyde and propiophenone.
This kind of product has been previously observed by other
groups.[14,16] Although a high conversion was obtained with
K2CO3, the yield was still moderate (45% GC ratio, Table 1,
entry 4). The use of K3PO4 improved the ratio of 3a to 66% and
gave a high selectivity (Table 1, entry 5). This high selectivity
was attributed to the drastic reduction of byproduct 4a. K3PO4
was therefore selected as the most suitable base for this
transformation. Other parameters of the reaction, such as the Ni
catalyst and base loading, the temperature and the quantity of
MeOH, were then optimized. Increasing the quantity of MeOH to
18 equivalents while keeping the same volume, increased the
GC ratio of 3a to 74%, albeit with a reduced selectivity (Table 1,
entry 6). The quantity of the nickel catalyst could be
advantageously decreased to 10 mol%, affording the desired
product 3a in a good 83% GC ratio (Table 1, entry 7). A further
decrease of this loading to 5 mol% highly impacted the
selectivity, as the desired product 3a was formed in 24% GC
ratio, while the undesired product 4a was obtained in a 71% GC
ratio (Table 1, entry 8). A slight increase of temperature to
185°C increased the GC ratio of 3a to 87% (Table 1, entry 9).
[a]
Aubin Charvieux, Dr Nicolas Duguet, Dr Estelle Métay
Univ Lyon, Université Claude Bernard Lyon1, CNRS, INSA-Lyon,
CPE-Lyon, Institut de Chimie et Biochimie Moléculaires et
Supramoléculaires, ICBMS, UMR 5246, Equipe CAtalyse, SYnthèse
et ENvironnement (CASYEN), Campus LyonTech La Doua,
Bâtiment Lederer, 1 rue Victor Grignard, F-69100 Villeurbanne,
France
E-mails: nicolas.duguet@univ-lyon1.fr, estelle.metay@univ-lyon1.fr
Homepage: www.icbms.fr
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900602
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Finally, increasing the quantity of MeOH to 21 equivalents led to
an excellent 95% isolated yield for the desired product 3a (Table
1, entry 10).
Table 1. α-Methylation of propiophenone catalyzed by Ni/SiO2-Al2O3. [a]
Entry
Base
Ni cat.
(mol%)
2
(eq)
Conv.
(%)b)
3a GC
ratio
4a GC
ratio
(%)c)
(%)c)
1
2
3
4
5
6
7
8
9
10
KOAc
tBuOLi
KOH
20
20
20
20
20
20
10
5
9
14
13
24
46
45
66
74
83
24
87
0
9
28
4
9
69
20
36
6
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
9
82
9
78
18
18
18
18
21
98
24
15
71
9
>99
97
10
10
>99
98
97
0
(95)d)
[a] Reaction conditions: 1a (1 equiv.), 2 (86.9 mmol, 3.6 mL), 65wt%Ni/SiO2-
Al2O3, base (10 mol%), under Ar atmosphere, 175°C, 15h. [b] GC
conversion of 1a. [c] 185°C. [d] isolated yield.
Scheme 3. α-Methylation of various ketones with methanol:
Scope and limitations. Reaction conditions: 1b-o (4.14 mmol,
[a]
In order to evaluate the scalability of our methodology, the α-
methylation of propiophenone with methanol was studied
starting from 17.4 g of ketone (30-fold scale-up) in the optimized
conditions (Scheme 2). The reaction was performed in a 300-mL
autoclave reactor equipped with mechanical stirring. It was
noticed that the reaction could run smoothly under air. After 72h
at 185°C, the product was obtained in a 91% yield (18.6 g, 94%
GC purity).
1 equiv.), MeOH (86.9 mmol, 21 equiv.), 65wt%Ni/SiO2-Al2O3
(10 mol%), K3PO4 (10 mol%), under Ar, 185°C, 15h unless
[b]
[c]
[d]
otherwise noted.
GC ratios.
24h. 24 : 76 mixture of diastereomer.
For p-methoxyacetophenone, time was increased to 24h in order
to obtain a good yield: in 15h, the mono-α-methylated product
was obtained with 23% yield along with the desired product
(43% yield). The effect of steric hindrance on the aromatic ring
was studied with methyl group. A slight decrease of the yield
was observed from the para to ortho position (78-66% from 3c to
3e).
A
ketone with two electron-donating group, 3’,4’-
dimethoxyacetophenone, gave product 3g in a moderate yield
(47%). p-Trifluoromethylacetophenone was tested, affording a
mixture of mono-α-methylated product 3h (11%) and di-α-
methylated product 3h’ (14%), both in low yield. Surprisingly, p-
chloroacetophenone gave mono-methylated product 3i as the
sole product, in a very low yield (5%). In this case, the
conversion was low and dehalogenation product was obtained
only in traces. Reaction with 1- and 2-acetonaphthones afforded
the desired products 3j and 3k in good yields (60 and 73%).
More hindered ketones were finally tested. Butyrophenone and
α-tetralone gave 3l and 3m in good yields (80 and 89%). α-
Tetralones with electron-donating groups, such as 5,7-dimethyl-
1-tetralone and 6-methoxy-1-tetralone afforded the desired
Scheme 2. Scale-up reaction. Reaction conditions: 1a (17.25 mL, 0.124 mol, 1
equiv.), 2 (108 mL, 2.61 mol, 21 equiv.), 65wt%Ni/SiO2-Al2O3 (10 mol%, 1.14
g), K3PO4 (10 mol%, 2.64 g), under air, 185°C, in a 300 mL autoclave reactor,
72h.
The scope of the α-methylation of ketones was then investigated
under the optimized conditions (Scheme 3). The reaction was
firstly studied with acetophenones. Acetophenone and
substituted acetophenones with para-electron-donating groups
such as methyl and methoxy afforded good yields (73, 78 and
77%, 3b, 3c and 3f).
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products 3n and 3o in good yields (85 and 64%). Interestingly,
with 6-methoxy-1-tetralone, low amounts of 6-methoxy-2,4-
dimethylnaphthalen-1-ol were observed as a by-product. Some
aliphatic ketones were also tested. Reaction with cyclohexanone
afforded the dimethylated product 3p in 24% yield, as a 76 : 24
mixture of diastereomers. The monomethylation product was not
observed. 2-Octanone underwent total conversion under the
reaction conditions, affording four different products as a mixture.
Monomethylated product 3q was obtained in 31% GC yield,
dimethylated compounds 3q’ and 3q’’ in 27% and 18% GC yield
respectively and the trimethylated product 3q’’’ in 24% GC yield.
Selectivity toward one particular compound could not be
improved by increasing/decreasing the time or the amount of
MeOH nor changing the nature of the base. Some other ketones
were
tested,
such
as
p-fluoroacetophenone,
p-
bromoacetophenone,
1-phenylbutane-1,3-dione,
dibenzoylmethane, p-nitroacetophenone and 4-acetylcyanide,
but the desired products could not be obtained (see SI for more
details).
Figure 1. Recycling study of the Ni/SiO2-Al2O3 for the α-methylation of
In order to further explore the possibilities of the reactions of
alcohols with ketones catalyzed by Ni/SiO2-Al2O3, the three-
component cross-benzylation-methylation of acetophenone with
benzyl alcohols and methanol was studied (Scheme 4).
propiophenone.
An ICP analysis showed the presence of soluble Ni species in
the filtrate obtained after 3h of reaction between 1a and MeOH
in the optimized conditions. (NB: hot filtration could not be
performed due to the low boiling point of MeOH). The
concentration of soluble Ni in this filtrate was found to be 14.23
mg.L-1, which corresponds to 59 µg of Ni, namely 0.03% of the
initial nickel quantity. In order to assess the activity of the soluble
Ni species, the filtrate was heated at 185°C for 12h. The
contents of the crude mixture before filtration and after filtration
and heating were compared, showing slight differences. GC
conversion of 1a increased from 23% to 33%. GC ratio of 3a
slightly increased, from 26% to 29%, while GC ratio of 4a
increase from 41% to 48%. The increase of conversion of 1a
and GC ratio of 4a could be explained by the presence of
dissolved formaldehyde in the filtrate, which makes the
formation of 4a possible. The increase of GC ratio of 1a does
not seem significant. These observations show that the leaching
of the catalyst does not play a decisive role in the deactivation of
the recycled catalyst. The recyclability of the Ni catalyst for the
-methylation of ketones with methanol is in contrast with the
excellent recyclability of the same catalyst for the alkylation of
acetophenones with other alcohols.21 Further studies will be
performed to fully understand how the catalyst deactivates in the
presence of methanol under these conditions.
Scheme 4. Cross-benzylation-methylation of acetophenone with benzyl
alcohols and methanol. Reaction conditions: 1b (4.14 mmol, 1 equiv.), 5 (8.28
mmol, 2 equiv.), MeOH (86.9 mmol, 21 equiv.), 65wt%Ni/SiO2-Al2O3 (10
mol%), K3PO4 (10 mol%), under Ar atmosphere, 185°C, 15h.
The reactions between acetophenone 1b, methanol and either
benzyl alcohol 5a or 4-methoxybenzyl alcohol 5b successfully
gave 6a and 6b in good yields (56% and 58%, respectively).
Such reactions have already been studied by other groups with
expensive noble metal catalyst only, such as Ru,[13b] Ir[12a] and
Pd.[19b] Therefore, the promising results in this work constitute
the first example of
a three-component cross-alkylation-
methylation of ketones with methanol and higher alcohols
catalyzed by a supported non-noble metal.
Finally, the recyclability of the Ni/SiO2-Al2O3 catalyst was studied
with the model reaction, over 4 runs (Figure 1). The catalyst was
filtered between each run, washed with water and acetone, dried
in an oven and reengaged for the next run (see ESI for the full
procedure). In these conditions, a 58% GC ratio for the desired
product 3a was initially obtained with the fresh catalyst. However,
this yield could not be maintained during the 3 other runs: it was
divided by about 2 after each run. In each run, formation of 4a
was observed, which explains the difference between the GC
ratio of 3a and the conversion of 1a.
Conclusions
To conclude, we have demonstrated that cheap and easy to
handle Ni/SiO2-Al2O3 could efficiently catalyze the α-methylation
of propiophenone with methanol using catalytic amount of K3PO4
(10 mol%). In the optimized conditions, the desired product was
obtained in 95% isolated yield. This model reaction was
successfully scaled-up to afford 18.6 g of product (91% yield).
The scope of the reaction was explored and a range of
methylated products was obtained (16 examples). Finally, we
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have shown that the method developed here could be
incorporated
in
a
three-component
cross-benzylation-
methylation of acetophenone using benzyl alcohols and
methanol simultaneously.
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General procedure for the α-methylation of ketones by methanol
catalyzed by nickel supported on silica alumina in the optimized
conditions. 65wt% Ni/SiO2,Al2O3 (38 mg, 0.1 equiv) and K3PO4 (88 mg,
0.1 equiv), ketone (4.14 mmol, 1 equiv) and MeOH (3.6 mL, 86.9 mmol,
21 equiv) were introduced in that order in a 15 mL pressure tube, which
was then sealed with a cap. The mixture was stirred at 185°C for 15h.
After this duration, a sample of the crude mixture was diluted in ethyl
acetate, filtered and analyzed by GC. 2-3 g of silica was added to the
crude mixture, which was then concentrated under reduced pressure and
purified by flash chromatography (ethyl acetate/cyclohexane) to afford
the desired compounds. See Supporting Information for the
characterisation of all compounds. It should be noted that this procedure
includes risks due to the high pressure, which could lead, in the case of a
damaged pressure tube, to its explosion. Therefore, this reaction should
only be done under a protective shield.
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Procedure for scaled-up α-methylation of propiophenone by
methanol catalyzed by nickel supported on silica alumina in the
optimized conditions. 65wt% Ni/SiO2,Al2O3 (1.14 g, 0.1 equiv) and
K3PO4 (2.04 g, 0.1 equiv), propiophenone (17.25 mL, 132 mmol, 1 equiv)
and MeOH (108 mL, 2.78 mol, 21 equiv) were introduced in that order in
a 300 mL autoclave reactor, which was then sealed. The mixture was
mechanically stirred (~1200 rpm) at 185°C for 72h. After reaction, the
mixture was filtered on Millipore filter (0.1 µm) on the solids were washed
with MeOH. The filtrate was concentrated under reduced pressure and
the desired product was distilled in the rotary evaporator. 18.6 g of the
desired product were obtained (91% yield, 94% GC purity).
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Acknowledgments
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The authors thank the Ministère de l’Enseignement Supérieur,
de la Recherche et de l’Innovation (MESRI) for a Ph.D. grant to
A. C.
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Keywords: Methylation • Ketones • Methanol • Nickel catalysis
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Methylation
Aubin Charvieux, Nicolas Duguet,*
Estelle Métay*
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α-Methylation of ketones with
The-methylation of ketones with methanol is a challenging topic due to the high
dehydrogenation energy of methanol. Herein, we demonstrate that a range of
ketones could be efficiently alkylated with methanol using a cheap and easy to
handle Ni/SiO2-Al2O3 catalyst. A cross-benzylation-methylation of acetophenone is
also reported.
methanol catalyzed by Ni/SiO2-Al2O3
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