Ruthenium(II)-Catalyzed β-Methylation of Alcohols using Methanol as C1 Source

Article abstract of DOI:10.1002/cctc.201900788

Selective introduction of methyl branches into the carbon chains of alcohols can be achieved with low loadings of ruthenium precatalyst [RuH(CO)(BH₄)(HN(C₂H₄PPh₂)₂)] (Ru-MACHO-BH) using methanol both as methylating reagent and as reaction medium. A wide range of structurally divers alcohols was β-methylated with excellent selectivity (>99 %) in fair to high yields (up to 94 %) under standard conditions, and turnover numbers up to 18,000 could be established. The overall reaction rate of the complex catalytic network appears to be governed by interconnection of the individual subcycles through availability of the reactive intermediates. The synthetic procedure opens pathways to important structural motifs following the Green Chemistry principles.

Full text of DOI:10.1002/cctc.201900788

DOI: 10.1002/cctc.201900788
Communications
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Ruthenium(II)-Catalyzed β-Methylation of Alcohols using
Methanol as C Source
1
[a]
[a]
[a]
[a, b]
Akash Kaithal, Marc Schmitz, Markus Hölscher, and Walter Leitner*
Selective introduction of methyl branches into the carbon
chains of alcohols can be achieved with low loadings of
ruthenium precatalyst [RuH(CO)(BH )(HN(C H PPh ) )] (Ru-MA-
allowing their use as alkylating reagents for α- and β-
1
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1
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1
1
1
1
1
1
2
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2
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4
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5
[7]
alkylations. However, the alkylation with methanol is much
[8]
more challenging. Only few catalytic systems have been
disclosed for the use of methanol as reagent for methylation at
4
2
4
2 2
CHO-BH) using methanol both as methylating reagent and as
reaction medium. A wide range of structurally divers alcohols
was β-methylated with excellent selectivity (>99%) in fair to
high yields (up to 94%) under standard conditions, and
turnover numbers up to 18,000 could be established. The
overall reaction rate of the complex catalytic network appears
to be governed by interconnection of the individual subcycles
through availability of the reactive intermediates. The synthetic
procedure opens pathways to important structural motifs
following the Green Chemistry principles.
3
[9]
sp carbons. The α-methylation of ketones was described
[
9b,d,f]
using Ir-, Rh- and Ru-complexes at high catalyst loadings.
Reports on β-methylation of alcohols have appeared even more
scarcely. Heterogeneous catalysts based on platinum on carbon
and iridium nanoparticles stabilized by solvent or carbon
nanotubes were shown to exhibit promising activities and
[9e,10]
substrate scopes for this transformation.
In 2014, Beller
et al. reported the only currently known molecular catalytic
[9a]
system. While the ruthenium hydrido chloro complex [RuCl
H)(CO)[HN(C H PPh ) ] (HN(C H PPh ) =MACHO) was found to
(
2
4
2 2
2
4
2 2
exhibit some catalytic activity, their optimized system com-
prised its cooperative combination with the Ru-Shvo catalyst.
Turnover numbers (TONs) in the range of 500 were demon-
strated for 2-arylethanols as substrates.
Methyl groups branching of alkyl chains are among the most
fundamental and ubiquitous structural motifs in many chemical
[1]
products, biologically active molecules, and pharmaceuticals.
In general, approximately 67% of all drug molecules contain at
In the present paper, we report the effective β-methylation
of a broad range of arylic, aliphatic, and cyclic alcohols to the
corresponding methyl-branched products using MeOH as the
C1 source with a single component organometallic catalyst. The
reaction is enabled by the borane adduct of the Ru-dihydrido
complex [RuH(CO)(BH )(HN(C H PPh ) )] (Ru-MACHO-BH; 1) with
[2]
least one methyl group. Therefore, the development of
sustainable synthetic methods for the selective formation of
methyl groups from C1-building blocks is highly desirable in
chemical production and medicinal chemistry. Methanol would
seem a highly attractive methylation agent following the Green
4
2
4
2 2
TONs reaching up to 18,000. Fair to high yields are achieved at
low catalyst loadings (50%–94% yield at 0.1 mol% Ru routinely,
even decreased to 0.005 mol% for selected cases).
[3]
Chemistry principles. It is significantly less toxic and/or hazard-
ous than standard reagents such as methyl iodide, methyl
[4]
sulfate, or diazomethane. Furthermore, methanol can be
At the outset, 1-phenylethan-1-ol (2a) was chosen as a
model substrate to identify a catalyst lead structure for β-
methylation. Substrate 2a (1 mmol), was reacted in MeOH
obtained from biomass or from CO2 and H , offering the
2
possibility to introduce renewable carbon and to harvest
[5]
t
renewable energy into the products. While the use of
methanol is well established in high-temperature gas phase
(1 mL) in the presence of NaO Bu (2 mmol) using a series of Ru
pre-catalysts (0.1 mol%) as shown in Table 1 at 150°C for 24 h.
Ruthenium complexes were chosen for the screening due to
their established performance in similar redox-neutral alkylation
reactions as discussed above. Already the simple unmodified
complex ruthenium(III) acetylacetonate exhibited moderate
activity resulting in 33% yield for 3a and 11% yield for 4a
[6]
methylation of ethanol and propanol to iso-butanol, its use for
selective methylation of aliphatic carbon chains in functional-
ized molecules is emerging only most recently.
It is well established that Ir-, Rh-, and Ru-complexes are
effective catalysts for the dehydrogenation of higher alcohols
(entry 1, Table 1). While p-cymene type complexes were less
effective (entries 2, 3, Table 1), the yield of desired product was
increased significantly when phosphine ligands were used
[
a] A. Kaithal, M. Schmitz, Dr. M. Hölscher, Prof. Dr. W. Leitner
Lehrstuhl für Technische Chemie und Petrolchemie
RWTH Aachen University
(entries 4–10, Table 1). The best catalytic performance was
Worringer Weg 2, 52074 Aachen
obtained with the tridentate PÀ NÀ P-type pincer ligand in [RuH
[b] Prof. Dr. W. Leitner
Max-Planck-Institut für chemische Energiekonversion
Stiftstraße 34–36, 45470 Mülheim a.d. Ruhr
E-mail: walter.leitner@cec.mpg.de
(CO)(BH )[HN(C H PPh ) ] (Ru-Macho-BH, 1) enabling the β-
4
2
4
2 2
methylation of 2a with 75% yield for 3a (dimethylation) and
1
1% yield for 4a (monomethylation).
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201900788
The reaction conditions were optimized further for catalyst
(for details see the Supporting information, Table S2).
1
This manuscript is part of the Special Issue on New Concepts in Homo-
geneous Catalysis.
Increasing the Ru-loading from 0.1 mol% to 1 mol% or raising
ChemCatChem 2019, 11, 1–5
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[a,b]
Table 1. β-methylation of 1-phenyl ethanol (2a) with various ruthenium
precatalysts.
Table 2. Ru-catalyzed reactions of secondary aryl alcohols 2 with MeOH.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
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[
a,b]
#
Catalyst
Conv. (%)
Yield (3a/4a)
d
e
Conversion (%)/Yield (3:4) /Isolated Yield of dimethylated product 3
1
2
3
4
5
6
7
8
9
1
Ruthenium(III) acetylacetonate
51
33
36
88
40
89
64
86
97
92
33/11
13/11
28/3
50/6
21/9
40/22
47/16
65/5
75/11
84/8
[Ru(p-cymene)Cl]
[Ru(p-cymene)Cl(proline)]
RuHCl(CO)(PPh
RuHCl(CO)(PPr
[RuHCl(CO)(PNN)]
[Ru(Acriphos)(PPh
[Ru-(triphos)(tmm)]
Ru-MACHO-BH(1)
Ru-MACHO-BH (1)
2 2
Cl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
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4
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4
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5
5
5
5
5
3
)
3
i
3
)
3
b
3
2
)(Cl)(PhCO )]
c
0
[
a] Conditions: 2a (1 mmol), MeOH (1 mL as a reagent and solvent), Ru
t
precatalyst (0.1 mol%), and NaO Bu (2 mmol) at 150°C for 24 h. [b]
1
Conversions and yields were determined by H NMR analysis using
mesitylene as internal standard. [c] 2a (1 mmol), MeOH (1 mL as a reagent
t
and solvent), Ru precatalyst (0.1 mol%) and NaO Bu (3 mmol) at 150°C for
2
4 h. PNN=2-(di-tertbutylphosphinomethyl)-6-(diethylaminomethyl)pyri-
dine, tmm=trimethylene methane.
[
a] Conditions: 2 (1 mmol), MeOH (1 mL as a reagent and solvent), 1
(0.1 mol%), and NaOMe (3 mmol) at 150°C for 24 h. [b] Yields were
the reaction temperature above 150°C did not result in a
1
determined by H NMR analysis using mesitylene as internal standard. [c] 2
significant improvement. Inorganic bases such as Cs CO and
(1 mmol), MeOH (1 mL as a reagent and solvent), 1 (0.1 mol%) and NaOMe
2
3
(
1.5 mmol) at 150°C for 20 h. [d] Number in parentheses show the yield of
KOH were less effective, but NaOMe led to excellent activities
fully comparable to NaO Bu. Increasing the amount of meth-
3 and 4. [e] Isolated yield of dimethylated product 3.
t
anolate from two to three equivalents increased the overall
yield further and shifted the product selectivity to the di-
alkylated product (entry 10, Table 1).
Using these parameters as standard set of conditions,
several arylic secondary alcohols were explored as substrates
for β-methylation and isolated yields were determined in
selected cases (Table 2). For the standard substrate 2a, the
overall conversion to methylated products 3a/4a was 92% with
a selectivity of 91% for 3a which could be isolated in 74%
Next, the β-methylation of 2-arylethanols was investigated
(Table 3). The conditions were adjusted to this substrate class
with 2-phenylethanol (5a) as test substrate, using 28 h as
standard reaction time. The amount of base could be reduced
to 1 equiv. of NaOMe, reflecting most likely the higher acidity of
the β-CH in benzylic position and opening the possibility for
mono-methylation only. Electron donating as well as electron
withdrawing substituents in the aromatic ring were tolerated
(5b–5f). However, the somewhat lower yields with m-methoxy
(5e) and p-fluoro (5g) substituents indicate a reduced reactivity
for very electron deficient aromatic rings. Notably, the catalytic
transformation opened a hitherto unprecedented route for the
direct synthesis of ibuprofen alcohol (6c) and naproxen alcohol
(6f) with good yield and selectivity.
To the best of our knowledge, there is currently no
homogeneous catalytic method available to perform the
selective β-methylation of aliphatic alcohols. Encouraged by the
effective performance of the catalytic system, we therefore
decided to systematically increase the carbon chain between
the reactive position and the aryl group, finally omitting the
aryl group completely (Table 3). Initially, 3-phenylpropan-1-ol
(5h) was tested. Adjusting the reaction parameters revealed
that 2 equiv. of base were required. With these optimized
conditions, 5h was converted with 78% yield to the desired β-
methylated product (6h).
(
entry 3a). Similar high conversions and good yields were
obtained for 1-naphtylethanol (3b) and 1-p-tolylethanol (3d).
Introducing the electron withdrawing chloro substituent in
para-position (2c) still showed good overall conversion (82%),
but an increased amount of mono-alkylated product reaching
up to 30% was obtained. The scope was extended to 1-
arylpropanols (2e–2f) and cyclic substrates (2g–2i) for which
only mono-methylation is possible. Good to high yields
between 60%–90% were obtained using only 1.5 mmol of base
for these substrates. The methyl group was installed preferen-
tially in trans-position to the alcohol function, albeit the
strereoselectivity was not very pronounced especially for larger
ring size. To validate the stability of the catalyst under the
conditions, catalyst loading was reduced to 0.005 mol%, with
substrate 2e (10 mmol), NaOMe (15 mmol), methanol 2 mL for
3
6 h at 150°C temperature. Product 3e was formed with 88.9%
yield and 90.3% yield in two independent reactions, respec-
tively, which corresponds to a TON of ca. 18.000, confirming the
excellent productivity of complex 1 and the robustness of the
method.
Longer alkyl chains reduced the yields somewhat, but
around 60% of the desired product was obtained consistently
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[
a,b]
Table 3. Ru-catalyzed reactions of aliphatic alcohol 5 with MeOH.
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1
Figure 1. Reaction progress based on H NMR. 2e (1 mmol), MeOH (1 mL as
a reagent and solvent), Ru precatalyst 1 (0.1 mol%), and NaOMe (1.5 mmol)
at 150°C.
The very distinct kinetic regimes can be rationalized
assuming a sequence of de-hydrogenation (A/B) and re-hydro-
genation (D/E) processes coupled with aldol condensation (C)
[
9a,b,d,e]
as plausible mechanistic pathway (“hydrogen borrowing”).
[
(
a] Conditions: 5 (1 mmol), MeOH (1 mL as a reagent and solvent), 1
0.1 mol%) and NaOMe (2 mmol) at 150°C for 28 h. [b] Yields were
The corresponding complex catalytic network involving metal-
and base-catalyzed steps is depicted for substrate 2e in
Scheme 1. A detailed experimental and computational study of
this reaction mechanism will be described in a separate
1
determined by H NMR analysis using mesitylene as internal standard. [c] 5
(1 mmol), MeOH 1 mL as a reagent and solvent), 1 (0.1 mol%) and NaOMe
(
measured by GC analysis. [f] Isolated yield of the monomethylated product
6
1 mmol) at 150°C for 28 h. [d] reaction time:30 h. [e] Yields were
.
[12]
publication.
(6i–6k). The substrate 4-(pyren-1-yl)butan-1-ol which is com-
monly used in photochemistry was also β-methylated to
[11]
provide the product (6l) in 76% isolated yield. Gratifyingly,
the procedure could be readily extended to purely aliphatic
alcohols. The β-methylation of ethanol resulted in the di-
methylated product iso-butanol 6m albeit at rather low yield of
1
7%. The β-methylation of C3-C5 aliphatic alcohols gave the
mono-methylated branched products (6n–6p) in respectable
yields of 54%–57% yield. Longer chain aliphatic alcohols such
as 1-heptanol, 1-octanol and 1-decanol resulted in even higher
yields around and above 70% (6q–6s).
The conversion/time-profile for the selective β-methylation
of 1-phenylpropanol 2e was mapped out by performing
individual experiments over different reaction times. Two
distinct kinetic regimes are apparent from the data depicted in
Figure 1. In the initial phase, the reaction is very fast reaching
over 40% conversion within the first 15 minutes. The methy-
lated alcohol 3e was formed with 24% yield at this stage,
accompanied by significant amounts of the corresponding
Scheme 1. Catalytic network of integrated subcycles A–E for the β-methyl-
ation of alcohols using methanol as C1-source exemplified for substrate 2e.
Assuming that all activation barriers of the individual
transformations A–E are well below the thermal energy
provided by the reaction temperature, the overall rate of
product formation is governed by the flux through the
integrated subcycles. This is determined by the availability of
species that enter each individual cycle driving them forward. In
the early stage of the reaction, substrate 2e is converted readily
to 2e’ fueling the subsequent step C. However, the availability
1
ketone 3e’ ( H NMR at δ 1.13 ppm (d, J=8 Hz)). The ketone is
consumed in the further course of the reaction, suggesting that
is acts as intermediate in the overall process. After about 30
minutes and 60% conversions, the reaction slows down
significantly, but continuous steadily to reach 83% with
excellent selectivity for 3e after 20 h.
of H formed from de-hydrogenation is a limiting factor for the
2
re-hydrogenation in steps D and E at this point corresponding
to a low partial pressure in the closed system. Thus, the re-
hydrogenation is not complete, resulting in a build-up of
compound 3e’. With increasing conversion and concomitant
decreasing concentration of 2e, non-productive dehydrogenat
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of excess methanol (B) becomes significant leading to an Conflict of Interest
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increasing availability of H in the system. Now ketone hydro-
2
genation will be favored, leading on the one hand to a push-
back of the reversible formation of 2e and at the same time to
more effective forward reactions in cycles D and E. While this
increases the consumption of intermediate 3e’, it also shifts the
first equilibrium of cycle A back to the starting material and the
overall reaction slows down drastically. This rational is sup-
ported by the detection of H2 in the gas phase when 2e
The authors declare no conflict of interest.
Keywords: methylation · ruthenium · homogeneous catalysis ·
alcohols · borrowing hydrogen
(
(
7
2 mmol) was reacted with an equimolar amount of MeOH
2 mmol) in toluene (1 mL) under standard reaction condition at
4% yield of 3e. Furthermore, the reaction was retarded
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
246.
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1
significantly under H pressure (10 bar), where yield of 3e after
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2
2
hours reaction time amounted to only 13% vs 47% in absence
of H2.
In conclusion, ruthenium catalyzed methylation using
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1
290; b) Y. Yokoyama, K. Mochida, J. Organomet. Chem. 1995, 499; c) J.-
methanol as a C1 source is demonstrated to be a widely
applicable synthetic strategy for the generation of β-methyl-
branched primary and secondary alcohols. While a number of
Ru-complexes exhibit principle activity, the complex [RuH(CO)
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BH )[HN(C H PPh ) ] (Ru-Macho-BH, 1) was identified as most
4 2 4 2 2
effective pre-catalyst. The maximum turnover number of 18,000
achieved with the Ru-MACHO catalyst surpasses greatly that of
previously reported homogeneous and heterogeneous cata-
lysts. The molecular nature of the catalyst opens the possibility
for future systematic optimization to master the complex
reaction network. This opens synthetic routes to important
structural motifs in chemical products and biologically active
compounds based on methanol as “green” C1 building block
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General procedure for the selective β-methylation of alcohols using
Ru-Macho-BH (1): All manipulations involving metal catalysts were
performed under argon atmosphere. The catalytic reactions were
carried out in externally heated 10 mL stainless autoclaves
equipped with a glass inlet and a magnetic stir bar. Ru-precursor
and base were weighed into the glass inlet and transferred to the
autoclave inside a glovebox. After sealing, the autoclave was
purged with argon three times. The required amounts of alcohol
substrate and methanol were added by syringe through a needle
valve under argon flow at room temperature. The autoclave was
sealed and heated to the reaction temperature. After the given
reaction time, the autoclave was cooled to room temperature and
carefully vented under continuous stirring. The reaction mixture
was passed through a small pad of acidic alumina and its
composition quantified directly by NMR or gas chromatography.
Isolation of pure products was achieved by column chromatog-
raphy for selected examples.
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12] A. Kaithal, M. Schmitz, M. Hölscher, W. Leitner, manuscript in
preparation.
The studies were performed as part of our activities in the
framework of the Cluster of Excellence “Fuel Science Center”. A.K.
gratefully acknowledges financial support by the Erasmus Mundus
Action 1 Programme SINCHEM (FPA2013-0037). We are grateful
for helpful discussions with Dr. O. Martinez-Ferrate.
Manuscript received: April 30, 2019
Version of record online: ■■■, ■■■■
ChemCatChem 2019, 11, 1–5
www.chemcatchem.org
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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
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COMMUNICATIONS
A. Kaithal, M. Schmitz, Dr. M.
Hölscher, Prof. Dr. W. Leitner*
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Ruthenium(II)-Catalyzed β-Methyl-
ation of Alcohols using Methanol
Once you C1 you see them all:
synthetic strategy for the generation
of β-methyl-branched primary and
secondary alcohols.
as C Source
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ruthenium catalyzed methylation
using methanol as a C1 source is dem-
onstrated to be a widely applicable