A Convenient Ruthenium-Catalysed α-Methylation of Carbonyl Compounds using Methanol

Article abstract of DOI:10.1002/adsc.201600562

An efficient ruthenium catalyst is reported, for the first time, to catalyse the α-methylation of ketones and esters using methanol as a green methylating agent. The in situ generated catalyst from the complexes [RuCp*Cl₂]₂or [RuCp*Cl₂]_nwith dpePhos provided up to quantitative yields in the presence of only 20 mol% of lithium tert-butoxide (LiO-t-Bu) as a base. Regioselective mono- or multi-methylation could be effectively controlled by temperature. This catalyst system was also effective for the one-pot sequential α-alkylation–α-methylation of methyl ketones and conjugate reduction–α-methylation of α,β-unsaturated ketones to synthesise α-branched ketones. An application of the α-methylation of esters using the ruthenium catalyst was demonstrated for an alternative catalytic synthesis of Ketoprofen. (Figure presented.).

Full text of DOI:10.1002/adsc.201600562

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DOI: 10.1002/adsc.201600562
A Convenient Ruthenium-Catalysed a-Methylation of Carbonyl
Compounds using Methanol
a
a,
Tuan Thanh Dang and Abdul Majeed Seayad *
a
Organic Chemistry, Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, #07-01 Neuros, Singapore
138665
Fax : (+65)-6464-2102; phone: (+65)-6799–8527; e-mail: abdul_seayad@ices.a-star.edu.sg
Received: May 25, 2016; Revised: August 16, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600562.
[
6]
Abstract: An efficient ruthenium catalyst is report-
ed, for the first time, to catalyse the a-methylation
of ketones and esters using methanol as a green
methylating agent. The in situ generated catalyst
from the complexes [RuCp*Cl ] or [RuCp*Cl ]
2 n
spasms. In addition, the a-methylcarboxylic acid
group is present in the “profen family” (e.g., Supro-
fen, Ibuprofen, Naproxene, Ketoprofen, Flurbiprofen
and Fenoprofen) of drugs that are used as non-steroi-
[
7]
dal anti-inflammatory agents.
2
2
with dpePhos provided up to quantitative yields in
the presence of only 20 mol% of lithium tert-butox-
ide (LiO-t-Bu) as a base. Regioselective mono- or
multi-methylation could be effectively controlled by
temperature. This catalyst system was also effective
for the one-pot sequential a-alkylation–a-methyla-
tion of methyl ketones and conjugate reduction–a-
methylation of a,b-unsaturated ketones to synthe-
sise a-branched ketones. An application of the a-
methylation of esters using the ruthenium catalyst
was demonstrated for an alternative catalytic syn-
thesis of Ketoprofen.
The conventional methods for methylation of ke-
tones and other active methylene compounds are
based on the use of reactive and genotoxic methyl
halides or diazomethane or other electrophilic com-
[
8]
pounds as methylating agents. In addition, the use
of an excess amount of base and the generation of
toxic halogenated waste makes such processes envi-
[
9]
ronmentally unfriendly. Hence, developing sustaina-
[
10]
ble
methylation protocols by exploiting readily
available and greener methylating agents is highly de-
[
11]
sirable. Methanol is one such promising methylat-
ing agent and could be potentially activated through
the formation of a transient reactive formaldehyde in-
Keywords: borrowing hydrogen strategy; esters; ke-
tones; ketoprofen synthesis; methanol activation;
a-methylation; ruthenium catalyst
Methylation is one of the fundamental organic trans-
formations having a pivotal role in the synthesis and
[
1]
functionalisation of bioactive molecules. The methyl
fragment is present in many top selling pharmaceuti-
cal compounds and is, in part, responsible for adjust-
ing both physical and biological properties of the
[2]
compound. Accordingly, efficient methods to intro-
duce the methyl group into organic molecules have
been a topic of active research both in academia and
[3]
industry.
a-Methyl ketones appear in many important natu-
ral products and pharmaceutically active compounds
[
4]
(
Figure 1). For instance, Eperisone and Tolperisone
[5]
are antispasmodic agents, Eprazinone (trade name Figure 1. Example of natural products and drugs containing
Eftapan) is a mucolytic agent and relieves broncho- a-methyl groups.
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termediate following the catalytic borrowing hydro-
[
12]
gen (BH) strategy or hydrogen auto-transfer (HA).
Due to the difficulty in the dehydrogenation of meth-
anol that needs a higher activation energy in compari-
son to other higher alcohols, for example, ethanol
À1 [13]
(
DH= +84 vs. +68 kJmol ), only a few reports on
the transition metal-catalysed methylation of ketones
using methanol have been published so far.
Figure 2. Reports on transition metal-catalysed a-methyla-
tion of ketones following the BH strategy.
Although several transition metal catalysts were re-
ported to be efficient for the a-alkylation of ketones
[
14]
[15]
using higher alcohols,
only iridium
and rhodi- the a-methylation of esters using methanol following
[16]
um based catalysts were reported for the a-methyl- the BH strategy.
ation of ketones using methanol. However, rutheni- Encouraged by our recent findings that activation
um-based catalysts were recently reported for the ac- of methanol is possible using a ruthenium catalyst
1
8d
[
17]
tivation of methanol towards hydrogen production
system [RuCp*(dpePhos)Cl] and is efficient for the
[
18]
and N-methylation reactions. The only C-methyla- hydrogenation of an in situ formed imine towards N-
tion reported so far using ruthenium catalysts follow- methylation, we believe that a-methylation of an
ing the borrowing hydrogen strategy was by Beller active methylene compound could also be possible if
and co-workers for the methylation of 2-arylethanols the ruthenium catalyst is effective in the hydrogena-
as a substrate in the presence of a mixture of two tion of the in situ formed C=C double bond following
ruthenium precatalysts such as Ru-MACHO and the a BH mechanism. We were delighted to observe an
[19]
Shvo catalysts.
initial yield of up to 36% and 52% for the a-methy-
One of the first reports on the a-methylation of ke- lated ketone 3a (2-methyl-1-phenylbutan-1-one) from
tones using methanol following the borrowing hydro- butyrophenone (1a) and methanol (2) with the in situ
gen strategy was from Feng Li and co-workers using generated catalyst from [RuCp*Cl2]2 and dpePhos
an iridium-Cp* complex coordinated with a non-inno- when 0.2 equivalents of KO-t-Bu and LiO-t-Bu were
[
15a]
cent bipyridonate ligand.
Up to 85% yield was re- used as bases, respectively at 908C for 18 h (Table 1,
ported under reflux conditions for 12–18 h in the pres- entries 1 and 2).
ence of 2 mol% of catalyst and 30 mol% of CsCO as
LiO-t-Bu is found to the more suitable base com-
3
a base. Later, Ogawa and Obora reported an Ir-phos- pared to others (entries 3–5). This may be due to the
phine catalyst in the presence of 0.5 equivalents of ready formation of LiOMe as well as the effective sta+-
KOH at 1208C for 15 h, achieving up to 91% bilisation of various intermediates by the smaller Li
[15b]
yield.
Recently, Donohoe and co-workers demon- cation towards the in situ formation of the active
strated an Ir-phosphine-catalysed methylation and Ru(II)-OMe species (see the Supporting Informa-
methylation–conjugate addition reaction of ketones at tion). [Ru(cod)Cl ] gave a lower yield of 29% with
2
2
6
58C in presence of three equiv. of KOH under an at- 30% conversion (entry 6), while other ruthenium pre-
[15c]
mosphere of oxygen for 48 h.
An N-heterocyclic cursors such as Ru(acac) and RuCl ·xH O (entries 7
3 3 2
carbene-phosphine-Ir complex was reported by An- and 8) gave inferior results. Phosphine ligands such as
dersson and co-workers in the presence of five equiv- xantphos, dppe, dppb, dppf (entries 9 to 12) were
[
15d]
alents of CsCO at 658C for 24 h.
A Rh-phosphine found to be less effective compared to dpePhos. The
3
complex was also reported by Donohoe and co-work- flexibility of the dpePhos backbone could be an im-
ers in the presence of oxygen gas at 608C for 48– portant factor for this enhanced catalytic performance
[16]
72 h.
In this case, five equivalents of KOH or under the present set of conditions. Increasing the
Cs CO as a base were required to achieve the prod- temperature to 1008C resulted in up to 95% conver-
2
3
ucts in up to 98% yield.
sion with the formation a-methylated product (3a) in
Until now, only expensive metal catalysts such as up to 92% yield using [RuCp*Cl ] or [RuCp*Cl ] as
2
2
2 n
Rh, Ir complexes could be used for the a-methylation the catalyst precursor and dpePhos as the ligand
of ketones using methanol. In this context, developing (entry 13). No appreciable amounts of side products
a more general and less expensive catalyst such as were observed in this reaction. In the absence of
[20]
ruthenium (a well-known metal catalyst for alcohol [RuCp*Cl ] or [RuCp*Cl ] , no product was observed
2
2
2 n
activation for alkylation) could be advantageous for indicating the necessity of the ruthenium catalyst in
developing future sustainable manufacturing technol- this reaction.
ogies. Herein we report, for the first time, an efficient
ruthenium-catalysed a-methylation of ketones ed the substrate scope of this in situ formed
Figure 2) and esters in the presence of sub-stoichio- Ru-Cp*(dpePhos)Cl-catalysed a-methylation reac-
With the optimised conditions in hand, we evaluat-
(
metric amount of base. To the best of our knowledge, tion. For this purpose, the reaction conditions were
no efficient metal catalysts were reported so far for slightly changed to 1108C for 24 h compared to the
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[a]
Table 1. Optimisation of the Ru-catalysed a-methylation of butyrophenone.
o
[b]
No.
Ru cat.
Ligand
Base
Temp. [ C]
Conv. [%]
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
[RuCp*Cl2]2
[RuCp*Cl2]2
[RuCp*Cl2]2
[RuCp*Cl2]2
[RuCp*Cl2]2
dpePhos
dpePhos
dpePhos
dpePhos
dpePhos
dpePhos
dpePhos
dpePhos
xantphos
dppe
KO-t-Bu
LiO-t-Bu
LiOH
90
90
90
90
90
90
90
90
90
90
90
90
100
100
38
53
32
25
21
30
n.d
n.d
n.d.
19
36
52
32
24
21
29
–
NaOH
K CO
2
3
[Ru(cod)Cl ]
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
2
c]
2
[
Ru(acac)3
RuCl ·xH O
[c]
–
4
2
2
[RuCp*Cl2]2
[RuCp*Cl2]2
[RuCp*Cl2]2
[RuCp*Cl2]2[
[RuCp*Cl2]2
–
0
1
2
3
4
17
20
25
92
–
dppp
dppf
dpePhos
dpePhos
21
25
95
n.d.
d]
[
[
[
[
a]
Ketone 1a (1 mmol), methanol (1 mL), Ru cat. (0.5 mol%), ligand (1.2 mol%), base (20 mol%).
Yields were determined by H NMR using mesitylene as the internal standard.
b]
1
c]
1
mol% of Ru cat. is used.
d]
A similar result was achieved with the polymeric [RuCp*Cl ] .
2
n
optimised conditions (Table 1, entry 13) to ensure cles (1n) were also found to be promising substrates
complete conversion even when less reactive sub- providing the corresponding a-methylated products in
strates were used.
A
preformed RuCp*(dpe- up to 90% isolated yield.
[18d]
Phos)Cl
complex could also be used as a pre-cata-
lyst that gives similar results as that of the in situ
formed catalyst (see the Supporting Information).
Excellent isolated yields were achieved for the a-
methylated ketone products 3a (96%) and 3b (98%)
from the corresponding ketones, butyrophenone (1a)
and propinophenone (1b), as shown in Scheme 1.
Cyclic phenyl ketones were also promising substrates
and up to 93% (3c) yield was achieved in the case of
six-membered tetralone (1c), while the five-mem-
bered indanone (1d) gave up to 70% (3d) isolated
yield under the present reaction conditions.
Aryl methyl ketones generally provided the double
methylated products (3e, 3h–3n) in up to 96% yield.
The presence of hydroxy (3e, 3f), chloro (3g, 3h),
bromo (3i) and iodo (3j) functionalities was well toler-
ated. The reducible nitro (3k) functionality was toler-
ated, however 3k was isolated in a lower yield of 23%
at a conversion of about 75%. In this case, side prod-
ucts such as condensation products and transfer hy-
drogenation of the ketone were observed. Increasing
the temperature did not improve the yield and partial
reduction of the NO group was observed. Interesting-
2
ly, the cyclic amino group was also tolerated and pref-
erential a-methylation of the ketone occurred and the
product 3g was isolated in 73% yield. In this case, no
appreciable N-methylation was observed. Methyl ke- Scheme 1. Substrate scope for the Ru-catalysed a-methyla-
tones with fused aromatic rings (1l, 1m) and heterocy- tion of ketones using methanol.
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The scale-up potential of this promising Ru-cata- 1308C, the second methylation also occurred to give
lysed a-methylation procedure was investigated by the a,a’-double methylated product 4p in up to 95%
performing a gram-scale reaction. Considering the isolated yield. In the case of benzyl methyl ketone
higher pressure generated (vapour pressure and the (1q), preferential mono-methylation occurred at the
potential generation of hydrogen) at 1108C with the benzylic position at a temperature of 1108C and the
higher amount of methanol, the reaction was per- mono-methylated product 3q was isolated in up to
formed in a 25-mL high-pressure Parr stirred reactor. 79% yield. Prolonged reaction (72 h) at this tempera-
The standard reaction of a-methylation of butyrophe- ture did not produce any further methylated products.
none (1a) was scaled up to 10-mmol scale (1.34 g) in However increasing the temperature to 1308C provid-
8
1
mL of methanol using only 0.1 mol% Ru catalyst at ed the triple methylated product 4q in up to 74% iso-
208C for 72 h, achieving up to 71% yield with lated yield.
a TON of 710.
We have shown in Scheme 1 and Scheme 2 that the
Substrates having two a-carbons that are prone to in situ formed Ru-Cp*(dpePhos)Cl catalyst is effec-
potential methylation, generally pose selectivity tive in producing a-branched ketones from the corre-
issues. Interestingly, we found that the present catalyst sponding aryl alkyl or cyclic ketones through mono-
system offers
a temperature-controlled selective methylation or from aryl methyl ketones through
mono-, di-, or tri-methylation depending upon the double-methylation. Accordingly, we envisaged that
substrate used (Scheme 2). For example, the selective this “single in situ formed Ru-Cp*(dpePhos)Cl cata-
monomethylation of cyclohexanone was achieved lyst” could be used for the preparation of various a-
when the reaction was performed at a lower tempera- branched ketones in a one-pot sequential a-alkylation
ture of 908C achieving 3o in up to 68% isolated yield. followed by a-methylation of aryl methyl ketones
With an increase in temperature to 1108C, the second under the current optimised reaction conditions. Such
methylation also occurred to give the a,a’-double me- a protocol was demonstrated by Donohoe and co-
[
16]
thylated product 4o in 71% isolated yield. However, workers using a “dual catalyst” system involving an
the five-membered cyclopentanone gave a mixture of initial iridium-catalysed alkylation followed by rhodi-
products (methylated and condensation products, see um-catalysed methylation as well as by Ogawa and
[
15b]
the Supporting Information) even at a lower tempera- Obora by using an iridium catalyst at 1408C.
ture of 508C. With higher membered aliphatic cyclic We were delighted to see that the present Ru cata-
ketones such as cyclododecanone (1p), the selective lyst system is effective for this sequential reaction and
mono-methylation was achieved at 1058C, providing notably, only 0.5 mol% of catalyst and 20 mol% of
up to 78% isolated yield of 3p. At a temperature of LiO-t-Bu were required under moderate conditions of
Scheme 2. Temperature-dependent selective a-methylation of ketones.
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Scheme 4. Ru-catalysed sequential conjugate reduction–a-
methylation of chalcone.
Scheme 3. Ru-catalysed sequential a-alkylation–a-methyla-
tion of ketones.
mediates 8a and 8b along with the product 9 suggests
208C. As shown in Scheme 3 (other reaction condi- a possible pathway involving initial Ru-catalysed re-
1
tions are the same as entry 13, Table 1), up to 91% duction followed by a-methylation in the presence of
isolated yield was achieved for 6a, when 4-methylace- methanol (see the Supporting Information).
tophenone was used as the substrate together with
After successful a-methylation of ketones, we
benzyl alcohol and methanol. Long chain aliphatic al- turned our attention to the a-methylation of potential
[
21]
[22]
cohols could also be used and the product 6b was ob- substrates such as nitriles 10 and esters 12a, b. As
tained in 75% yield when 1-hexanol was used as the shown in Scheme 5, 2-(4-methoxyphenyl)acetonitrile
alcohol. Short chain alcohols such as ethanol and n-
propanol could be potentially used, however the se-
lectivity during the first alkylation was slightly lower
due to side reactions such as transfer hydrogenation
(
see the Supporting Information). A methylated
ketone with a cyclopropylethyl a-branching (6c) was
also readily obtained in 82% yield when cyclopropyl-
ACHTUNGTRENNUNGe thanol and methanol were used in this sequential a-
alkylation–a-methylation protocol. A one-pot, one-
step procedure as reported by Ogawa and Obora for
this sequential reaction was not successful and the
only product isolated was the double methylated
ketone showing the preferential activation of metha-
nol in the presence of other alcohols with the present
in situ formed Ru-Cp*(dpePhos)Cl catalyst system.
Scheme 5. Ru-catalyzed a-methylation of representative ni-
trile and ester.
Another interesting fact is that no appreciable di-al- (10) provided a promising yield of 87% at 1308C for
kylation was observed when using alcohols other than 24 h of the corresponding a-methylated nitrile prod-
methanol. Hence a one-pot, two-step procedure is uct 11. However, under these conditions, the ester 12a
preferred for this Ru-catalysed sequential a-alkyla- provided low conversion. Esters are particularly chal-
tion-methylation protocol.
lenging substrates for a-alkylation using alcohols (fol-
The promising results from this sequential reaction lowing the BH strategy) with only a few reports avail-
[
22]
encouraged us to investigate the reduction of a conju- able so far. Only iridium-based catalysts were re-
gate double bond followed by a-methylation using ported with higher alcohols as alkylating agents either
methanol. Interestingly, reaction of methanol with the with activated esters as substrates or in the presence
a,b-unsaturated ketone 7 in the presence of the pres- of over-stoichiometric amounts of base. A quick opti-
ent Ru catalyst system provided the saturated a-me- misation using the present Ru catalyst system resulted
thylated ketone 9 in up to 74% isolated yield, possibly in up to 62% isolated yield under microwave condi-
via sequential reactions involving an initial conjugate tions after 8 h of reaction at 1608C in the presence of
reduction of 7 to form 8 (see the Supporting Informa- 20 mol% of base (Scheme 5). To the best of our
tion) followed by a-methylation (Scheme 4, other re- knowledge, this is the first report of a ruthenium-cata-
action conditions are the same as entry 13, Table 1). lysed a-alkylation, particularly, a-methylation of
In order to understand the reaction pathway, an inter- esters following the BH strategy.
mediate sample was analysed by GC-MS to observe
An application of this ruthenium-catalysed a-meth-
the reaction intermediates. Identification of the inter- ylation of esters was demonstrated for a concise alter-
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[
23]
native synthesis of Ketoprofen,
a representative
non-steroidal anti-inflammatory agent from the
profen” family. Although improvements are re-
“
quired, this two-step catalytic pathway (Scheme 6)
Scheme 6. Ru-catalysed a-methylation in an alternative syn-
thesis of Ketoprofen.
Scheme 7. Proposed mechanism for Ru-catalysed a-methyla-
tion of ketones (or esters) using methanol.
leading to the ketoprofen methyl ester could poten-
tially circumvent the direct use of genotoxic methyl methanol to generate the product and the complex II
iodide. Methylation of bromide-functionalized ester for the next catalytic cycle.
12b using the optimised in situ formed Ru-Cp*(dpe-
In conclusion, we have demonstrated, for the first
Phos)Cl catalyst system afforded the methylated time, an efficient and economically attractive rutheni-
product 13b in up to 65% yield. The methyl ester of um-catalysed a-methylation of ketones and esters
Ketoprofen (14) was successfully prepared in 83% using methanol as a greener and more sustainable
isolated yield through a palladium-catalysed carbony- methylating agent, following the catalytic borrowing
[
24]
lative coupling with phenylboronic acid.
The hydrogen (BH) strategy. Key to the success is the use
methyl ester could be readily hydrolysed to the race- of an in situ generated Ru-Cp*(dpePhos)Cl catalyst
[24]
mic Ketoprofen.
together with sub-stoichiometric amount of LiO-t-Bu
Both the a-methylation of ketones and esters could as a base. Scale-up possibility was demonstrated using
follow a borrowing hydrogen strategy and a possible a gram-scale reaction of a-methylation of ketone
catalytic cycle starting from the preformed complex I using 0.1 mol% of catalyst, achieving up to a TON of
is proposed in Scheme 7. Complex I could readily 710. This catalyst system is also effective for the syn-
form under the reaction conditions from [RuCp*Cl2]2 thesis of a-branched ketones from methyl ketones
or [RuCp*Cl ] in the presence of dpePhos, LiO-t-Bu through a one-pot sequential alkylation–methylation
2
n
[
18d,25]
and methanol (see the Supporting Information).
as well as conjugate reduction–methylation strategies.
Complex I could activate methanol in the presence of Nitriles and esters having a-benzylic carbons were
LiO-t-Bu/LiOMe through the intermediate ruthenium found to be promising substrates. An application of
methoxide complex II to form formaldehyde and the this Ru-catalysed methylation of esters was demon-
ruthenium[ hydride complex III as shown in strated for an alternative two-step catalytic synthesis
16d]
Scheme 7.
Formaldehyde condenses with ketone of the methyl ester of Ketoprofen from readily avail-
(
or ester) through an aldol condensation pathway and able starting materials.
the resultant unsaturated ketone gets reduced by the
ruthenium hydride complex III in the presence of
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Experimental Section
ler 4848). The reactor was closed, purged with nitrogen and
was heated to 1208C under stirring. After 72 h, the reaction
mixture was allowed to cool to room temperature, depres-
surised and the sample collected for analysis. The yield of
product (71%) was determined by GC using mesitylene as
an internal standard.
General Procedure 1 for the a-Methylation of
Ketones using Methanol
The Ru precursor [RuCp*Cl ] (3.1 mg, 0.5 mol%), dpePhos
2
2
(
6.4 mg, 1.2 mol%), LiO-t-Bu (16.0 mg, 20 mol%), and
ketone (1.0 mmol) were charged under an argon atmosphere
in a 5-mL glass pressure reaction tube. 1 mL of dry metha-
nol was added into the mixture, the reaction tube was closed
with the cap and was heated in an oil bath to the desired
temperature under magnetic stirring. After the desired reac-
tion time, the reaction mixture was allowed to cool to room
temperature and diluted with methanol (5 mL). SiO2
Acknowledgements
This work was funded by GSK-EDB Singapore Partnership
for Green and Sustainable Manufacturing and the Institute of
Chemical and Engineering Sciences (ICES), Agency for Sci-
ence, Technology and Research (A*STAR), Singapore.
(
400 mg) was added into the crude mixture. The organic sol-
vent was removed under vacuum and the product was puri-
fied by column chromatography. The product was analysed
by NMR spectroscopy.
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General Procedure 2 for Sequential a-Alkylation–a-
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2
2
(
6.4 mg, 1.2 mol%), LiO-t-Bu (16.0 mg, 20 mol%), and
[
[
[
[
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A Convenient Ruthenium-Catalysed a-Methylation of
9
Carbonyl Compounds using Methanol
Adv. Synth. Catal. 2016, 358, 1 – 9
Tuan Thanh Dang, Abdul Majeed Seayad*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
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These are not the final page numbers!