Manganese(I)-Catalyzed β-Methylation of Alcohols Using Methanol as C1 Source

Article abstract of DOI:10.1002/anie.201909035

Highly selective β-methylation of alcohols was achieved using an earth-abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)₂Br[HN(C₂H₄PⁱPr₂)₂]] 1 ([HN(C₂H₄PⁱPr₂)₂]=MACHO-ⁱPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β-methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β-position, opening a pathway to “biohybrid” molecules constructed entirely from non-fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn-pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C?C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules.

Full text of DOI:10.1002/anie.201909035

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Accepted Article
Title: Manganese(I)-Catalyzed β-Methylation of Alcohols using
Methanol as C1 Source
Authors: Markus Hoelscher, Akash Kaithal, Pit van Bonn, and Walter
Leitner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909035
Angew. Chem. 10.1002/ange.201909035
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Angewandte Chemie International Edition
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COMMUNICATION
Manganese(I)-Catalyzed -Methylation of Alcohols using
Methanol as C
1
Source
[a]
[a]
[a]
[a][b]
Akash Kaithal, Pit van Bonn, Markus Hölscher and Walter Leitner*
Abstract: Highly selective β-methylation of alcohols was achieved
using an earth-abundant first row transition metal in the air stable
i
molecular manganese complex [Mn(CO)
2
Br[HN(C
2
H
4 2 2
PPr ) ]]
1
i
i
(
2 4 2 2
[HN(C H PPr ) ] = MACHO-Pr). The reaction requires only low
loadings of 1 (0.5 mol%), methanolate as base and MeOH as
methylation reagent as well as solvent. Various alcohols were
β-methylated with very good selectivity (>99%) and excellent yield
(up to 94%). Pharmaceutical important molecules such as ibuprofen
and naproxen alcohols are thus accessible. Biomass derived
aliphatic alcohols and diols were also selective methylated to
β-position opening a pathway to “biohybrid” molecules constructed
entirely from non-fossil carbon. Mechanistic studies indicate that the
reaction proceeds via a hydrogen-borrowing pathway involving
metal-ligand cooperation at the Mn-pincer complex. This
transformation
provides
a
convenient,
economical,
and
environmentally benign pathway for the selective C‒C bond
formation with potential applications for the preparation of advanced
biofuels, fine chemicals and biologically active molecules.
The formation of carbon-carbon bonds using commercially
available building blocks is an important transformation for the
toolbox of organic synthesis.[1] In particular, the introduction of
methyl groups in aliphatic carbon chains could open useful
pathways for late stage generation of chain branches in
functionalized molecules. As
a structurally very important
chemical motif, many pharmaceuticals and biologically active
molecules contain at least one methyl group.[2] Methyl branches
are also favorable structural units in tailor-made fuel
components
with
advanced
combustion
properties.[3]
Conventionally, methylation reactions are performed using
reagents such as Grignard reagents, methyl iodide, or methyl
sulfate, diazomethane, which in general are highly flammable,
toxic and explosive.[4] Methanol provides a highly attractive
alternative in the framework of the Green Chemistry principles,
Scheme 1. Traditional and metal-catalyzed approach for the preparation of
β-methylated alcohols.
Recently, the selectively β-methylation of primary and secondary
alcohols with methanol received increasing attention, but reports
concerning this potentially useful reaction are still rare. Beller
and co-workers reported a homogeneous catalytic system for
the selective β-methylation of 2-aryl ethanols using a mixture of
two Ru-complex catalyst.[7] Heterogeneous catalyst reports
in particular when produced from biomass or from CO
2
and H
-based
2
.[5]
The methylation of biogenic substrates with CO
2
[
6]
methanol opens pathways to “biohybrid” molecules bridging
between the bioeconomy and power-to-X concepts.
based on Ir and Pt metals also showed promising activity for this
transformation.[8] We demonstrated that the reaction can be
achieved by a single Ru(II) pincer complex bearing the MACHO
ligand.[9] Mechanistic studies suggest that the Ru (II) catalyst
affects the dehydrogenation of alcohol and MeOH to the
[
[
a]
b]
M.Sc. A. Kaithal, B.Sc. P.van Bonn, Dr. M. Hölscher, Prof. Dr. W.
Leitner
Institut für Technische und Makromolekulare Chemie,
RWTH Aachen University
Worringer Weg 2, 52074 Aachen, Germany
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
corresponding aldehyde/ketone and formaldehyde.
A base
mediates the aldol condensation between the carbonyl
compounds. Subsequently the catalyst re-hydrogenates the
carbonyl bond and C–C coupled bond to provide the final
β-methylated product and complete the catalytic cycle.
Metal-ligand cooperativity is of vital importance for the
dehydrogenation/rehydrogenation steps in the complex reaction
network.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Increasing efforts are currently devoted to develop
synthetic protocols where precious platinum group metals are
replaced by earth abundant and cheap 3d-metals in
homogeneously catalyzed organic transformations.[10] Lately,
there is an increasing evidence suggesting that Ru(II) centers
can be replaced by more economical and environmental benign
5
6
5 (0.5 mol%)
1 (0.2 mol%)
1 (0.5 mol%)
1 (0.5 mol%)
10
66
76
77
0
52
70
70
[
c]
7
8
[d]
[a] 6a (1ꢀmmol), MeOH (1ꢀmL as a reagent and solvent), Mn precatalyst
o
(0.5ꢀmol%), and NaOMe (2ꢀmmol) at 150ꢀ C for 24ꢀh. [b] Conversion and yield
were measured by 1HꢀNMR and mesitylene was used as an internal standard.
Mn(I).[10a,
11]
A number of reactions such as hydrogenation,
[12]
transfer-hydrogenation,[13]
hydro-elementation,
[5e,
14]
and
o
[c] Reaction was carried out at 125ꢀ C. [d] 1 mmol of NaOMe was used.
hydrogen-borrowing reactions[15] were reported using Mn(I)
complexes. In particular, selective alkylation reactions of
secondary alcohols using primary alcohols as an alkylating
reagent were reported with manganese and other 3d metal
catalysts.[15b, 16] The selective α-methylation of ketones was also
shown using Mn(I) pincer complexes by Sortais and Rueping et.
al.[17] Intrigued by these studies, we assume that the Ru(II)/Mn(I)
substitution is particularly favorable due to the diagonal
relationship between the two ions in the periodic table. Thus, we
decided to explore whether this approach might allow the
development of Mn(I) catalysts for the selective β-methylation of
alcohols. While this manuscript was under revision, we became
aware of an independent parallel study by the group of Morrill.
They reported the selective β-methylation of substituted aryl
alcohols using an iron complex.[18] The complex showed good
reactivity towards the selective β-methyaltion of substituted
Using the standard conditions, various 2-aryl ethanols were
investigated as substrates for selective β-methylation (Table 2).
Similar high conversions and good yields as for 6a were
observed for substrates with electron donating substituents such
as 2-(p-tolyl)ethanol (6b) and 2-(4-methoxyphenyl)ethanol (6d).
Somewhat lower yield was obtained for 6e bearing the methoxy
substituent in meta-position, while 2-(4-chlorophenyl)ethanol
(
8
6g) and 2-(4-fluorophenyl)ethanol (6h) were also converted with
1% and 87% yield, respectively. Heterocyclic alcohol such as
thiophene substituted ethanol (6i) was well tolerated and
afforded 77% yield to the corresponding methylated product 7i.
The reaction with pyridine substituted 2-(pyridin-2-yl)ethan-1-ol
gave a mixture of products (not shown). However, indole
substituted ethanol (6j) yielded 54% of the desired β-methylated
product. Notably, pharmaceutical important molecules such as
ibuprofen alcohol and naproxen alcohol could be prepared also
with very good yields (7c and 7f, respectively).
2-arylethanols. However, the reaction with secondary alcohols or
aliphatic alcohols revealed very low reactivity towards the
desired methylated product.
Table 2. Mn(I) catalyzed β-methylation of 2-arylethanols with methanol[a,ꢀb]
At the outset, 2-phenyl ethanol (6a) was selected
as
a
benchmark substrate to validate the rational of
catalyst selection and for optimization of the reaction
conditions (Table 1). As predicted, the Mn(I)-MACHO complex
i
[
Mn(CO)
2
Br[HN(C
2
H
4
PPr
2
)
2
] (1) showed by far the highest
activity and selectivity from a range of pre-catalysts 1-5.
Variation of reaction parameters such as catalyst loading,
temperature and amount of base lead to the definition of a
standard set of conditions using 0.5 mol% of complex 1 with
NaOMe (2 equiv. with respect to 6a) at 150 oC for 24 h.
Conversion of 6a reached 97% under these conditions forming
selectively the β-methylated product 7a with 92% as evidenced
by NMR analysis of the reaction mixture. Product 7a was
isolated in 85% yield after column chromatography.
Table 1. Mn (I) catalyzed β-methylation of 6a with methanol: Influence of
catalyst precursors and reaction conditions.[a,ꢀb]
[
a] 6 (1 mmol), MeOH (1ꢀmL as a reagent and solvent), Mn precatalyst 1
o
(
0.5ꢀmol%), and NaOMe (2ꢀmmol) at 150ꢀ C for 24ꢀh. [b] Yields were
determined by 1HꢀNMR analysis using mesitylene as an internal standard.
Yields in parenthesis correspond to the isolated yield after performing column
chromatography. [c] Reaction time: 14 h
#
1
2
3
4
Catalyst
Conv. (%)
Yield (%)
Next, we focused on the selective β-methylation of secondary
alcohols (Table 3). 1-Phenyl ethanol (8a) was chosen as parent
substrate for this class of compounds. Upon increasing the
amount of a base to 4 equivalents and using 0.5 mol% of 1 at
1 (0. mol%)
2 (0.5 mol%)
3 (0.5 mol%)
4 (0.5 mol%)
97
42
51
23
92
21
24
6
50 oC for 36 h, the selectively di-methylated product 9a was
1
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Angewandte Chemie International Edition
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COMMUNICATION
observed with
a
77% yield. Reaction of 1-(naphthalen-2-
substrate worked best for this transformation. Under these
conditions, 3-phenyl-ethanol (10a) was selectively converted
with a 71% yield to the desired β-methylated product. The
chloro-substituent in para-position of 3-phenyl-ethanol (10b) was
well tolerated resulting in 64% yield. Upon increasing the length
of the carbon chain between the aromatic ring and the reactive
position, yields dropped slightly, but around 60% of the desired
product was found consistently (10c, 10d). Gratifyingly, these
conditions could be applied also to biomass-derived aliphatic
alcohols and diols. Reacting ethanol in presence of complex 1 in
methanol/methanolate, selective formation of isobutanol (11e)
was obtained with 46% yield. These conditions were also
implemented to other aliphatic alcohols such as 1-butanol (10f)
and 1-pentanol (10g) which also revealed good to moderate
yield to the selective β-methylated product. Interestingly, when
the length of the carbon chain was increased, yields also
increased up to 75% for long chain alcohols as derived from
fatty acids. Diols were also methylated at both possible positions
with nearly equal efficiency, as shown for 1,6-hexanediol (10l)
and 1,10-decanediol (10m).
yl)ethan-1-ol (8b) and 1-(p-tolyl)ethanol (8c) with methanol
under these conditions led to selective formation to the di-
methylated product with a yield of 82% and 73%, respectively.
However, substrate 8d resulted only in 29% di-methylated
product probably reflecting an unfavorable steric influence of the
ortho-methyl substituent. The methoxy-substituent in para-
position of 1-phenyl ethanol (8e) yielded 57% of the di-
methylated product 9e. The electron withdrawing fluoro
substituent in para-substituted (8f) resulted 44% yield to the di-
methylated product under standard reaction conditions.
Prolonging the reaction time to 42 h increased the yield of the
desired di-methylated product 9f to 61%. Furan was tolerated as
substituent affording the desired product 9g in 63% yield. 1-
cyclohexylethan-1-ol (8h) exhibited lower reactivity with 31%
yield of di-methylated product 9h. Complex 1 showed excellent
activity for the selective β-methylation of 5-, 6- and 7- membered
ring alcohols (8i-8k), with preferential formation of the trans
isomers.
Table 3. Mn(I) catalyzed β-methylation of secondary alcohols with
[
a,ꢀb]
methanol.
Table 4. Mn(I) catalyzed β-methylation of aliphatic alcohols and diols with
methanol.[
a, b]
[
a] 10 (1ꢀmmol), MeOH (1ꢀmL as a reagent and solvent), Mn precatalyst 1
o
(
0.5ꢀmol%), and NaOMe (2ꢀmmol) at 150ꢀ C for 24ꢀh. [b] Yields were
[
a] 8 (1ꢀmmol), MeOH (1ꢀmL as a reagent and solvent), Mn precatalyst 1
determined by 1H NMR using mesitylene as an internal standard. Yields in
parenthesis correspond to the isolated yield after performing column
chromatography. [c] Reaction time: 14 h. [d] Reaction time: 36 h. [e] 4 mmol of
NaOMe was used and reaction time was increased to 48 h.
o
(
0.5ꢀmol%), and NaOMe (4ꢀmmol) at 150ꢀ C for 36ꢀh. [b] Yields were
determined by 1HꢀNMR using mesitylene as an internal standard. Yields in
parenthesis correspond to the isolated yield after performing column
chromatography. [c] Reaction time was increased to 42 h.
In particular, this includes 1,3-propanediol (10k), were
selectively catalytic β-methylated using Mn-complex 1 gave
Encouraged by these results, we further investigated the
selective β-methylation of aliphatic alcohols (Table 4). It turned
out that 2 equivalents of methanolate with respect to the
2-methyl-1,3-propanediol (MPO, 11k) in 73% yield under
standard conditions. MPO is an important large volume product
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COMMUNICATION
with chemical and consumer use that is produced exclusively
from fossil feedstocks today. The new pathway demonstrated
here makes this product accessible as “biohybrid” molecule
entirely from renewable carbon sources.
In order to validate the concept of a mechanistically driven
substitution of Ru(II) catalysts by Mn(I) complexes, a series of
control experiments was carried out (Scheme 2). Using 13CH
OH
3
together with sodium tert-butoxide as the base in toluene as the
solvent unequivocally showed that methanol was the source of
the methyl group. Using CD OD led to deuterium incorporation
3
in - as well as -position, supporting a hydrogen borrowing
mechanism. Reaction of 2-phenyl ethanol (6a) with
paraformaldehyde in presence of hydrogen gave 17% yield of
the β-methylated product 7a. Considering the limited solubility of
paraformaldehyde in toluene, this result supports the
assumption of formaldehyde as intermediate. Vice versa, the
transformation of acetophenone (14) with methanol also led to
the dimethylated product 9a with a yield of 7%. A variety of side
Scheme 3. Spectroscopically identified Mn(I) intermediates obtained by
stoichiometric reaction with Mn complex 1.
Within the first 2 h of reaction, conversion reaches already close
to 70%, while the yield of the methylated product amounts only
to 41%. In general, there is a significant and growing gap
between conversion and yield during the first 10ꢀh of reaction
until the reaction reaches close to full consumption of the
starting material 6a. Then, the selectivity starts to catch up until
conversion and yield are both above and close to 90% after 24ꢀh.
This can be rationalized assuming that 2-phenyl ethanol (6a)
and methanol are both converted relatively fast to
phenylacetaldehyde (6a’) and formaldehyde with the liberation
1
products were observed in the H NMR spectrum resulting from
Aldol-type side reactions at the high concentration of 14.
Stoichiometric reactions of the complex 1 with base, followed by
addition of alcohol 6a or methanol confirmed the formation of
alcoholate complexes 16 and 17 via the unsaturated Mn-amide
complex 15 (scheme 3).[12b, 19] In case of methanol, formation of
the hydride complex 18 together with formaldehyde and H
2
2
of H . With the base-catalyzed aldol condensation being the
clearly demonstrated the dehydrogenation activity of the active
species 15.
slowest step in the catalytic network, the formation of the final
product is delayed relative to substrate conversion.[
Consequently, the use of (over-)stoichiometric amounts of base
is beneficial to achieve practical reaction rates. While only small
amounts of base would be necessary to activate the Mn-catalyst,
its role to accelerate the aldol condensation is critical. Otherwise,
the build-up of the carbonyl intermediates in solution and
hydrogen in the gas phase shifts the first equilibria back to the
substrates. This would block the pathway to the desired
products completely as encountered for example in other studies
on alkylation reactions based on the borrowing hydrogen
concept.[7] The formation of alkene-type aldol coupling
20]
1
intermediates was observed in H NMR while performing the
time-conversion profile.
100
90
80
70
60
50
yield
Scheme 2. Labeling experiments with 13C and 2H labeled methanol and
40
conversion
reactivity of plausible intermediates.
30
20
10
0
Analysis of the composition of reaction mixtures after different
reaction times for the selective β-methylation of 2-phenyl-ethanol
6a using complex 1 under standard conditions shows a very
0
2
4
6
8
10 12 14 16 18 20 22 24
distinct development of conversion and yield over time (Figure 1).
time (h)
Figure 1. Conversion/time profile for the -methylation of 1-phenyletahnol (6a)
using Mn(I)-MACHO complex 1 in methanol as solvent as derived from
1HꢀNMR analysis of reaction mixtures at given time intervals. 6a (1 mmol),
o
MeOH (1 mL), Mn precatalyst 1 (0.5 mol%), and NaOMe (2 mmol), 150 C.
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Angewandte Chemie International Edition
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COMMUNICATION
Based on these observations and in accord with literature
Keywords: manganese catalysis•methylation•methanol•
alcohols•hydrogen borrowing
[
7, 21]
knowledge on Ru(II)-based hydrogen borrowing catalysis
[
12d, 13a, 19, 22]
and Mn(I) H-transfer reactions,
a plausible
mechanism for the Mn(I)-MACHO (1) catalysed β-methylation
can be proposed as shown in Figure 2. Ligand-assisted de-/re-
hydrogenation is the prominent feature for the metal-catalysed
steps, Further experimental and computational efforts are
required to elucidate these catalytic networks in detail.
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using the earth abundant first row transition metal manganese in
form of its pincer complex 1 as pre-catalyst and methanol as
1
solvent and C source. The activity of 1 for β-methylation is
[
9]
applicable to a large variety of alcohols such as secondary,
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The studies were performed as part of our activities in the
framework of the “Fuel Science Center” funded by the Deutsche
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Why not manganese? A molecular
catalyst based on Manganese as
central metal allows the use of
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methanol as benign reagent to install
methyl groups in -position to alcohol
functionalities, opening novel synthetic
pathways to methyl-branched
products in line with Green Chemistry
principles.
Title
((Insert TOC Graphic here))
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Akash Kaithal, Pit van Bonn, Markus
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Manganese(I)-Catalyzed -
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Methylation of Alcohols using
1
Methanol as C Source
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