C -Methylation of Alcohols, Ketones, and Indoles with Methanol Using Heterogeneous Platinum Catalysts

Article abstract of DOI:10.1021/acscatal.7b04442

A versatile, selective, and recyclable heterogeneous catalytic method for the methylation of C-H bonds in alcohols, ketones, and indoles with methanol under oxidant-free conditions using a Pt-loaded carbon (Pt/C) catalyst in the presence of NaOH is reported. This catalytic system is effective for various methylation reactions: (1) the β-methylation of primary alcohols, including aryl, aliphatic, and heterocyclic alcohols, (2) the α-methylation of ketones, and (3) the selective C3-methylation of indoles. The reactions are driven by a borrowing-hydrogen mechanism. The reaction begins with the dehydrogenation of the alcohol(s) to afford aldehydes, which subsequently undergo a condensation reaction with the nucleophile (aldehyde, ketone, or indole), followed by hydrogenation of the condensation product by Pt-H species to yield the desired product. In all of the methylation reactions explored in this study, the Pt/C catalyst exhibits a significantly higher turnover number than other previously reported homogeneous catalytic systems. Moreover, it is demonstrated that the high catalytic activity of Pt can be rationalized in terms of the adsorption energy of hydrogen on the metal surface, as revealed by density functional theory calculations on different metal surfaces.

Full text of DOI:10.1021/acscatal.7b04442

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Article
C-Methylation of Alcohols, Ketones, and Indoles with
Methanol Using Heterogeneous Platinum Catalysts
S. M. A. H. Siddiki, Abeda S. Touchy, Md. A. R. Jamil, Takashi Toyao, and Ken-Ichi Shimizu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b04442 • Publication Date (Web): 21 Feb 2018
Downloaded from http://pubs.acs.org on February 21, 2018
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CꢀMethylation of Alcohols, Ketones, and Indoles with Methanol Using
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Heterogeneous Platinum Catalysts
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S. M. A. Hakim Siddiki,† Abeda S. Touchy,† Md. A. R. Jamil,† Takashi Toyao,†,‡ Kenꢀichi
Shimizu*†,‡
† Institute for Catalysis, Hokkaido University, Nꢀ21, Wꢀ10, Sapporo 001ꢀ0021, Japan
‡ Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Katsura, Kyoto
615ꢀ8520, Japan
*Corresponding author
Kenꢀichi Shimizu
Eꢀmail: kshimizu@cat.hokudai.ac.jp
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ABSTRACT
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A versatile, selective, and recyclable heterogeneous catalytic method for the methylation of C–H
bonds in alcohols, ketones, and indoles with methanol under oxidantꢀfree conditions using a
Ptꢀloaded carbon (Pt/C) catalyst in the presence of NaOH is reported. This catalytic system is
effective for various methylation reactions: (1) the βꢀmethylation of primary alcohols, including aryl,
aliphatic, and heterocyclic alcohols, (2) the αꢀmethylation of ketones, and (3) the selective
C3ꢀmethylation of indoles. The reactions are driven by a borrowingꢀhydrogen mechanism. The
reaction begins with the dehydrogenation of the alcohol(s) to afford aldehydes, which subsequently
undergo a condensation reaction with the nucleophile (aldehyde, ketone, or indole), followed by a
hydrogenation of the condensation product by Pt–H species to yield the desired product. In all the
methylation reactions explored in this study, the Pt/C catalyst exhibits a significantly higher turnover
number than other previously reported homogeneous catalytic systems. Moreover, it is demonstrated
that the high catalytic activity of Pt can be rationalized in terms of the adsorption energy of hydrogen
on the metal surface, as revealed by density functional theory calculations on different metal
surfaces.
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KEYWORDS: heterogeneous catalysis, methylation, borrowingꢀhydrogen reaction, platinum, density
functional theory
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1. INTRODUCTION
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C–C bond formation reactions are of great interest and importance in organic chemistry. Much effort
has been devoted especially to the development of atomꢀefficient and environmentally friendly
processes owing to their economic importance and significance in the industrial and academic
context.1–4 Nevertheless, many processes still rely on conventional methods that involve cation–
anionꢀbased nucleophilic substitution reactions between organometallic reagents and
organohalides.5,6 Although these conventional systems are very important, the inevitable workup
procedures, which include hazardous quenching steps, filtrations, and repeated extractions, as well
as the concomitant formation of undesirable waste, are problematic, especially on an industrial scale.
Another shortcoming of these systems is the use of organometallic agents as homogeneous
catalysts. The organometallic agents are often airꢀ and moistureꢀsensitive, and can thus be difficult to
handle.7 From the viewpoint of green and sustainable chemistry, it is highly desirable to develop new
processes that do not rely on these toxic and hazardous materials, with the aim to eventually realize
ideal yet practical processes.8
Toward this aim, borrowingꢀhydrogen reactions have attracted much attention in recent years.9–
17 These reactions enable the catalytic formation of not only C–C bonds but also of many other types
of linkages, including C–N bonds, using alcohols as the alkylating reagents, and are thus regarded
as an atomꢀeconomical manufacturing approach for bulk and fine chemicals.18–24 Among the variety
of alcohols used as alkylating reagents, methanol is of particular interest owing to its great potential
as a sustainable resource.25 Methanol is currently obtained from natural gas, coal, and biomass.
However, in the near future, methanol from CO2 and sustainable H2 will provide a sustainable C1
feedstock for a “methanol economy”, in which methanol will serve as the source material for a wide
range of chemical intermediates and products.26–29 It is therefore hardly surprising that great efforts
have been devoted to the synthesis of H2, other fuels, and bulk chemicals from methanol.30 However,
selective organic transformations of methanol into fine chemicals remain in their infancy, mostly due
to the fact that the reactivity of methanol is relatively low compared to that of other conventional
methylation reagents such as methyl iodide, dimethyl sulfone, diazomethane, and formaldehyde,
which are all considered genotoxic impurities in pharmaceutical manufacturing.31 In addition, the use
of methanol as a synthetic building block requires its selective activation for further transformation.
This is particularly difficult for heterogeneous catalysts and, therefore, only very few methylation
reactions employing methanol for synthetic applications have been reported so far.
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Recently, substantial progress has been made in borrowingꢀhydrogenꢀtype catalytic methylation
reactions
using
homogeneous transitionꢀmetal
catalysts.32–46
Borrowingꢀhydrogenꢀtype
Cꢀmethylation methods are classified into the following three reaction types: (1) the βꢀmethylation of
alcohols,33–35 (2) the αꢀmethylation of ketones,36–41 and (3) the methylation of phenols42,43 and
heterocycles,44–46 which includes the C3ꢀmethylation of indoles. Methylation methods typically
employ homogeneous (or colloidal) Ru, Ir, or Rh catalysts, although all of these suffer from low
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turnover numbers (TONs) and difficulties associated with the catalyst/product separation and the
recycling of the catalyst. Another drawback of these methods is their limited synthetic scope. Most
methods are applicable only to activated (aromatic) substrates, and a single catalyst that is generally
applicable to all the aforementioned Cꢀmethylation reactions has not yet been reported.
Herein, we report a heterogeneous catalytic system for the three Cꢀmethylation processes
mentioned above, employing methanol as the methylating agent (Scheme 1). The synthesis is
carried out using Pt nanoparticles loaded on carbon (Pt/C) in the presence of NaOH. This is a highly
versatile catalytic methylation system that proceeds via a borrowingꢀhydrogen mechanism. In
addition to the development of this catalytic system, we describe the rationalization of the catalytic
properties based on density functional theory (DFT) calculations. The observed catalytic activity of a
variety of transitionꢀmetal catalysts correlates well with the adsorption energy of hydrogen on
different metal surfaces. Our results suggest that the adsorption energy of hydrogen can be
effectively used as a simple descriptor for C–C bond formation reactions.
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Scheme 1. Cꢀmethylation reactions employing methanol as the methylating agent. The three types
of Cꢀmethylation reactions are successfully realized by a Ptꢀnanoparticlesꢀloaded carbon catalyst
(Pt/C).
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2. EXPERIMENTAL SECTION
General
Commercially available organic and inorganic chemicals (Tokyo Chemical Industry, Wako Pure
Chemical Industries, Kishida Chemical, or Mitsuwa Chemicals) were used without further purification.
Methanolꢀd3 (CD3OH; 99.8 atom% D) was purchased from SigmaꢀAldrich. GC (Shimadzu GCꢀ2014)
and GCMS (Shimadzu GCMSꢀQP2010) analyses were carried out using an Ultra ALLOY capillary
column UA+ꢀ1 (Frontier Laboratories Ltd.) with N2 or He as the carrier gas. 1H and 13C NMR spectra
were recorded at ambient temperature on a JEOLꢀECX 600 spectrometer operating at 600.17 and
150.92 MHz, respectively, with tetramethylsilane as the internal standard. HAADFꢀSTEM images
were taken on a JEMꢀARM200F microscope equipped with a JEDꢀ2300 EDX spectrometer (JEOL) at
an acceleration voltage of 200 kV. The Csꢀcorrector CESCOR (CEOS) was used in the STEM mode.
The samples were prepared by dropping ethanol suspensions of the catalysts on carbonꢀsupported
copper grids.
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Catalyst Preparation
Standard carbon (296 m2 gꢀ1, Kishida Chemical) and SiO2 (Qꢀ10, 300 m2 gꢀ1, Fuji Silysia Chemical
Ltd.) supports were obtained commercially. CeO2 (JRCꢀCEO3, 81 m2 gꢀ1), MgO (JRCꢀMGOꢀ3), TiO2
(JRCꢀTIOꢀ4), and H+ꢀexchanged β zeolite (Hβ, SiO2/Al2O3 = 25±5, JRCꢀZꢀHB25) were supplied by
the Catalysis Society of Japan. γꢀAl2O3 was prepared by calcination of γꢀAlOOH (Catapal B Alumina,
Sasol) at 900 °C for 3 h. ZrO2 was prepared by hydrolysis of zirconium oxynitrate 2ꢀhydrate in an
aqueous solution of NH4OH, followed by filtration, washing with distilled water, drying at 100 °C for 12
h, and finally calcination at 500 °C for 3 h. Nb2O5 was prepared by calcination of Nb2O5—nH2O (CBMM)
at 500 °C for 3 h. The Pt/C precursor was prepared by the following impregnation method: a mixture
of carbon (10 g) and an aqueous HNO3 solution of Pt(NH3)2(NO3)2 that contained 4.96 wt% of Pt
(10.62 g) and 50 mL of ionꢀexchanged water was added to a roundꢀbottom flask (500 mL). The
mixture was then stirred (200 rpm) for 15 min at room temperature. Subsequently, the reaction
mixture was evaporated to dryness at 50 °C, followed by drying at 90 °C under ambient pressure for
12 h. Prior to each catalytic experiment, a Pt/C sample with 5 wt% Pt loading was prepared by
preꢀreduction of the precursor in a Pyrex tube under a H2 flow (20 cm3 minꢀ1) at 300 °C for 0.5 h.
Other supported Pt catalysts (5 wt% Pt loadings) were prepared by the same method. M/C (M = Rh,
Ir, Ru, Pd, Re, Cu, Ni) catalysts with 5 wt% metal loadings were prepared in a similar manner using
aqueous HNO3 solutions of Rh(NO3)3 or Pd(NH3)2(NO3)2, or aqueous solutions of metal nitrates (for
Ni, Cu), IrCl3—nH2O, RuCl3, or NH4ReO4.
Typical Procedure for the Catalytic Reactions
Pt/C (39 mg; 1 mol% Pt with respect to 1 mmol of substrate) reduced at 300 °C was used as the
standard catalyst.47,48 After the reduction, the catalyst was placed in a closed glass tube sealed with
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a septum inlet and cooled to room temperature under H2. Methanol (10 or 20 mmol) was injected
through the septum inlet into the glass tube containing the preꢀreduced catalyst. Next, the septum
was removed under air, and 1 mmol of the substrate (alcohol, ketone, or indol), NaOH (0.1 or 1.5
mmol), nꢀdodecane (0.25 mmol), and a magnetic stirring bar were added to the tube, which was then
introduced in a stainless steel autoclave (28 cm3). After sealing, the autoclave was charged with 1
bar N2 and heated at 100 or 120 °C under stirring (500 rpm). After the reaction, the reactor was
cooled to room temperature, before the catalyst was removed by filtration. For the optimization
studies (Tables 1 and 2) and the kinetic experiments, the conversions and yields of the products
were determined by GC using nꢀdodecane as the internal standard, while the GCꢀsensitivity was
estimated from commercial compounds or the isolated products. For the substrate scope studies, the
products were isolated by column chromatography on silica gel 60 (spherical, 40–100 ꢁm, Kanto
Chemical Co. Ltd.) using hexane/ethyl acetate (9:1, v/v) as the eluent, and the yields of the isolated
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products were determined. The products were identified by H and 13C NMR spectroscopy in
combination with GCMS, whereby the mass spectrometer was equipped with the same column as
that used for the GC analyses.
For the recycling experiments, after each catalytic cycle, 2ꢀpropanol (3 mL) was added to the
mixture. The catalyst was separated by centrifugation and washed with water (3 mL) and acetone (6
mL). The catalyst was then dried at 100 °C for 3 h and reduced at 300 °C for 0.5 h under an
atmosphere of H2. Subsequently, the reactor was charged with a mixture of the substrate and NaOH
and the recovered Pt/C catalyst. It should be noted that the initial formation rates for reactions with
yields below 30% were obtained on the basis of the product yield after a reaction time of 2 h for
βꢀmethylation of 2ꢀphenylethanol and 1 h for methylation αꢀmethylation of propiophenone and
C3ꢀmethylation of indole.
Computational Methods
All calculations were performed with the Vienna abꢀinitio simulation package (VASP)49,50 using
projectorꢀaugmented wave potentials51 and the Perdew–Burke–Ernzerhof (PBE) functional.52 The
dispersionꢀcorrected DFTꢀD2 method was employed to account for van der Waals interactions.53 The
lattice constants of the bulk structures were calculated with an energy cutꢀoff of 400 eV and a 15 × 15
× 15 kꢀpoint mesh and used in all subsequent calculations. The Ni(111), Cu(111), Rh(111), Pd(111),
Ir(111), Pt(111), Ru(0001), and Re(0001) surfaces were modeled by a supercell slab consisting of a 3
× 3 surface unit cell with four atomic layers. It should be noted that the most stable and common
planes were used for each metal. The (111) surface (Ni, Cu, Rh, Pd, Ir, and Pt) presents a
faceꢀcenteredꢀcubic (fcc) structure, while the (0001) surface (Ru and Re) has
a
hexagonalꢀcloseꢀpacked (hcp) structure. The slab was separated in the vertical direction by a
vacuum void (height: 15 Å). An energy cutꢀoff of 400 eV and a 5 × 5 × 1 point mesh were used for the
slab model calculations. The energy of the isolated H atom was obtained using the same parameters
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as those in the freeꢀsurface slab calculations. The geometryꢀconvergence criterion was set at Fmax
<
0.03 eV Åꢀ1, where Fmax is the maximum force acting on a mobile atom. Spinꢀpolarized calculations
were carried out for all systems. The adsorption energy (Eads) was calculated as the difference in
energy between the molecule absorbed on the surface (Emolecule/surface), the individual adsorbate
molecule (Emolecule), and the surface (Esurface) according to:
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Eads = Emolecule/surface – Emolecule + Esurface
(6)
The location of the adsorption sites on the adsorbates was initially determined, which showed
that the most stable adsorption sites for hydrogen are the 3ꢀfold hollow sites (Fig. S1; fcc sites for the
fcc metals). The adsorption energies employed in this study were calculated for the structures where
hydrogen was more strongly adsorbed.
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3. RESULTS AND DISCUSSION
Catalyst Characterization
A carbonꢀsupported Pt nanoparticles catalyst (Pt/C) was obtained from a facile impregnation method,
followed by H2 reduction at 300 °C, according to a previous study using the same Pt/C catalyst.47
Figure 1 shows the annular bright field scanning transmission electron microscopy (ABFꢀSTEM)
image and highꢀangle annular darkꢀfield STEM (HAADFꢀSTEM) images of the Pt/C catalyst together
with the corresponding energyꢀdispersive Xꢀray spectrometry (EDX) elemental mapping. The Pt
nanoparticles are highly dispersed over the entire carbon support. The additional characterization
data for Pt/C, e.g., temperatureꢀprogrammed H2ꢀreduction (H2ꢀTPR) and Xꢀray absorption fine
structure (XAFS) analyses, which have been provided in our previous study, confirmed that the
deposited Pt nanoparticles are in the metallic state.47
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Figure 1. ABFꢀ and HAADFꢀSTEM images and EDX mapping for Pt/C.
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β-Methylation of Alcohols
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The βꢀmethylation of 2ꢀphenylethanol (1a) was selected as the benchmark reaction for the
βꢀmethylation of alcohols with different heterogeneous catalysts. A catalyst screening was carried out
for the reaction of 1a (1 mmol) and methanol (20 mmol) with NaOH (1.5 mmol) at 120 °C for 24 h. It
should be noted that the reaction was carried out in a glass reactor that was inserted in a stainless
steel autoclave, in which the reactor was heated to temperatures beyond the boiling point of
methanol. Initially, we tested a series of Ptꢀloaded (5 wt%) heterogeneous catalysts (39 mg in total; 1
mol% Pt with respect to 1a). Table 1 lists the yields obtained for 2ꢀphenylꢀ1ꢀpropanol (2a) as the
desired product. The reaction did not occur in the absence of a transitionꢀmetal catalyst (entry 1),
and carbonꢀsupported platinum oxide (PtOx/C) afforded 2a in merely 2% yield (entry 2). The results
show that the combination of a base (NaOH) and platinum oxide does not catalyze the reaction. In
contrast, carbon loaded with metallic Pt nanoparticles (Pt/C, entry 3) afforded 2a in 91% yield.
Exposure of the asꢀreduced Pt/C catalyst to air at room temperature for 0.5 h resulted in a lower yield
of 2a (42%, entry 4), most likely due to airꢀoxidation of the superficial Pt0 sites, i.e., the active sites of
Pt/C. Thus, metalꢀloaded catalysts reduced under H2 at 300 °C were used for the subsequent
reactions in the absence of air (entries 5–19). Ptꢀmetal particles supported on different metal oxides
(entries 5–12) generated lower yields of 2a (7–32%) than Pt/C. Subsequently, we compared the
activity of various transition metal nanoparticles on the same support (carbon; entries 13–19),
whereby the catalytic performance followed the order: Pt > Ir > Rh > Ru > Ni > Pd > Re > Cu. The
results in Table 1 indicate that Pt/C (entry 3) is the most suitable catalyst for the βꢀmethylation of 1a
in the presence of 1.5 equiv NaOH. The effect of the Pt loading in the Pt/C catalyst was investigated
by employing a Pt/C catalyst with 1 wt% of Pt (Table S1). The results show that the Pt/C catalyst with
5 wt% Pt loading exhibited better catalytic performance.
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Table 1. Catalyst screening for the βꢀmethylation of 2ꢀphenylethanol (1a)
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Entry
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Catalyst
None
PtOX/C
Pt/C
Pt/Cꢀair
Pt/Al2O3
Pt/CeO2
Pt/MgO
Pt/ZrO2
Pt/Nb2O5
Pt/TiO2
Pt/SiO2
Pt/Hβ
Rh/C
Ir/C
Ru/C
Pd/C
Re/C
Cu/C
Ni/C
Yield (%)a
0
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a GC yield.
With the best catalyst in hand, we examined further potential optimizations of the reaction
conditions (Table 2). The reaction did not proceed in the absence of a base (entry 1), which indicates
that Pt/C alone does not promote the reaction, and that the addition of a base is essential. The
results with different additives (entries 2–11) revealed that the efficacy of the base follows the order
NaOH > NaOMe > NaOtBu > KOtBu > KOH > NaOEt > Cs2CO3 > Na2CO3 > K2CO3 > Et3N. Catalytic
runs with different loadings (0.5–2.0 mmol) of NaOH (entries 2, 12–14) confirmed that 1.5 equiv of
NaOH afford the highest yield of 2a. Finally, varying the methanol loading (5–60 mmol, entries 2, 15–
18) revealed the optimal amount of methanol (20 mmol).
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Table 2. Optimization of the reaction conditions for the βꢀmethylation of 2ꢀphenylethanol
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Entry
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CH3OH (mmol)
Base (x)
None
NaOH (1.5)
KOH (1.5)
Yield (%)a
0
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20
5
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49
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51
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53
54
55
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57
58
59
60
Na2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5)
NaOtBu (1.5)
KOtBu (1.5)
NaOMe (1.5)
NaOEt (1.5)
Et3N (1.5)
NaOH (0.5)
NaOH (1.0)
NaOH (2.0)
NaOH (1.5)
NaOH (1.5)
NaOH (1.5)
NaOH (1.5)
9
10
11
12
13
14
15
16
17
18
10
40
60
83
90
52
a GC yield.
Under the optimized conditions, we studied the catalytic performance of the Pt/Cꢀcatalyzed
βꢀmethylation of various alcohols with methanol. Table 3 shows the scope of primary alcohols for the
present catalytic βꢀmethylation system. For all the substrates except the linear aliphatic alcohols
(entries 14 and 15), full conversion of the alcohol was observed. The yields of the isolated
βꢀmethylation products are listed in Table 3. 2ꢀPhenylethanol (entry 1) and its derivatives with
electronꢀdonating (entries 2–4) and electronꢀwithdrawing (entry 5) groups at the paraꢀposition were
successfully methylated to give the corresponding βꢀmethylated alcohols in good to high isolated
yield (76–87%). 2ꢀNaphthaleneꢀ1ꢀyl ethanol (entry 6), 3ꢀphenylpropanꢀ1ꢀol (entry 7), and
3ꢀ(4ꢀbromophenyl)propanꢀ1ꢀol (entry 8) afforded methylated alcohols in good to high yield.
Heteroaromatic alcohols with indoleꢀ3ꢀpropyl (entry 9), pyridinyl (entry 10), and thienyl (entry 11)
groups, or with a 2ꢀ(benzyloxy)ethanꢀ1ꢀol moiety (entry 12) were well tolerated and furnished the
corresponding βꢀmethylated alcohols in high yield (83–95%). Aliphatic primary alcohols (entries 13–
15) also underwent this βꢀmethylation reaction to afford the corresponding products in good yield
(73–85%), thus demonstrating the high versatility of this heterogeneous catalytic system for the
βꢀmethylation of aliphatic alcohols with methanol.
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3
Table 3. Pt/Cꢀcatalyzed βꢀmethylation of primary alcohols
4
5
6
7
8
9
Entry
1
Alcohol
Product
t (h)
Yield (%)a
87
OH
OH
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
24
24
78
81
H3C
OH
H3CO
4
5
6
7
8
30
24
78
76
OH
OH
F
36
24
24
88
92
73
OH
OH
Br
OH
9
12
95
N
H
OH
10
11
12
24
24
24
83
88
86
N
OH
13
14
15
24
30
30
85
77
73
a Isolated yield.
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Recently, Obora and coꢀworkers have reported the first example of the βꢀmethylation of
secondary alcohols with methanol.34 Equation (1) shows the results for the βꢀmethylation of
secondary alcohols by our method using 1 mol% of Pt/C catalyst with 1.5 equiv of NaOH at 120 °C
for 24 h. 1ꢀPhenylethanol and its derivatives with electronꢀdonating (methyl, methoxy) groups at the
paraꢀposition were converted into bisꢀmethylated products (alcohols and ketones) in 83–88% yield.
catalyst,33
i.e.,
a
combination
of
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18
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In
the
literature,
only
one
homogeneous
carbonylchlorohydrido{bis[2ꢀ(diphenylphosphinomethyl)ethyl]amino}ethyl]amino}Ru(II) (RuꢀMACHO)
and Shvo’s diruthenium complex, and one heterogeneous catalyst,34 i.e., colloidal Ir nanoclusters,
have been reported to catalyze the βꢀmethylation of a variety of alcohols with methanol. Table 4
compares the catalytic performance of our system to that of these previously reported catalysts.
While the previous methods are effective only for activated substrates, i.e., aromatic alcohols, our
method is effective for aromatic and aliphatic (nonꢀactivated) alcohols. As shown in equation (2), a
gramꢀscale reaction of 1a (5 mmol) with 20 equiv of methanol and 1.5 equiv of NaOH using 0.025
mol% of the Pt/C catalyst for 90 h afforded 2a in high yield (82%). This value corresponds to a TON
of 3280, which is one order of magnitude higher than those of the previous methods for the
βꢀmethylation of 1a.33,34
Table 4. βꢀMethylation of alcohols with methanol using different catalysts
Catalyst
Substrate scope
2ꢀArylethanols
3ꢀArylpropanols
Aliphatic alcohols
1ꢀPhenylethanol
2ꢀArylethanols
2ꢀArylethanols
1ꢀPhenylethanol
TONa
Catalyst reuse
Ref.
Pt/C
3280
5 runs
This work
Ru complex
435
356
No
No
33
34
Ir nanocluster
a TON per number of total metal atoms in the catalysts for the βꢀmethylation of 2ꢀphenylethanol.
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Next, we examined the heterogeneous nature and reusability of the Pt/C catalyst. After a
standard reaction (entry 1 in Table 3), 2ꢀpropanol (3 mL) was added to the mixture and Pt/C was
removed by filtration, followed by inductively coupled plasma atomic emission spectrometry
(ICPꢀAES) analysis of the reaction mixture, which showed that the content of Pt in the solution was
below the detection limit (10 ppb). After a standard workup and catalyst recovery,54 the spent catalyst
was reused four times, whereby a significant loss of activity was not observed (Fig. 2). In addition to
the final yield, the initial product formation rates were investigated for each cycle, and the results are
shown in Fig. S2 in the Supporting Information. These results do not show a significant decrease in
activity, which confirms the high durability of the catalyst. The necessity of H2 reduction prior to each
recycling test was examined (Table S2). The yield for the second run decreased when the catalyst
was used without prior H2 reduction, which indicates that H2 reduction is indispensable for the
recycling the catalyst. These results unequivocally demonstrate that Pt/C is a reusable
heterogeneous catalyst for this reaction.
Considering the previously proposed mechanisms for such reactions,33,34 our βꢀmethylation
method may likely follow a borrowingꢀhydrogen mechanism (Scheme 2). To examine this hypothesis,
we carried out the following kinetic and mechanistic experiments. Figure 3 shows the time course of
the products (GC analysis) for the Pt/Cꢀcatalyzed βꢀmethylation of 2ꢀnaphthaleneꢀ1ꢀyl ethanol (1b).
Initially (t < 5 h), 2ꢀ(naphthalenꢀ1ꢀyl)acetaldehyde (4b) is generated, although its content decreases
with time. For 5 h < t < 35 h, the molar fraction of 2ꢀ(naphthalenꢀ1ꢀyl)acrylaldehyde (3b) initially
increases, and then decreases. Finally (t > 35 h), the amount of 2ꢀnaphthaleneꢀ1ꢀyl propanol (2b)
reaches its highest value. This is a time course typical for consecutive reactions. Aldehyde 4b
represents the initial intermediate, which is subsequently transformed into the α,βꢀunsaturated
aldehyde intermediate 3b, which serves as the precursor for the hydrogenated product 2b.
Figure 4 shows the results of the kinetic isotope effect (KIE) analysis for the βꢀmethylation
reaction of the standard substrate 2ꢀphenylethanol (1a). The zeroꢀorder rate constant for CH3OH
(kCH), estimated from the initial slope of the plot, is larger than that for CD3OH (kCD), and a moderate
KIE (kCH/kCD) value of 1.8 was obtained. This suggests that the catalytic cycle involves the
dissociation of a C–H bond in methanol as a kinetically important step. As shown in eqn (3), the
crossꢀaldol condensation of the dehydrogenated intermediates (formaldehyde and
phenylacetaldehyde) was catalyzed by 0.5 equiv of NaOH (in the absence of Pt/C) under N2 at a
relatively low temperature (80 °C). In the presence of Pt/C and NaOH at 120 °C, the reaction of
formaldehyde and phenylacetaldehyde under H2 furnished 2ꢀphenylꢀ1ꢀpropanol (2a), the final
product for the standard βꢀmethylation of 2ꢀphenylethanol (1a) with methanol.
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9
CH2
O
O
(3)
0.5 equiv NaOH
O
+
H
H
1 mL toluene
80 °C, 12 h, N2
(paraformaldehdye)
63% yield
1 mmol
1 mmol
20 mmol
CH3
1 mol% Pt/C
O
O
OH
+
(4)
0.5 equiv NaOH
1 atm H2
H
H
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48
49
50
51
52
53
54
55
56
57
58
59
60
20 mmol
46% yield
120 °C, 12 h
Based on these mechanistic results, we conclude that this catalytic system is driven by a
borrowingꢀhydrogen mechanism (Scheme 2). Both alcohols, i.e., the starting reagent and methanol
are dehydrogenated to give the corresponding aldehydes and four atoms of hydrogen on the catalyst
surface. The aldehydes undergo a crossꢀaldol condensation to generate an α,βꢀunsaturated
aldehyde intermediate, which is then reduced by the four hydrogen atoms on the Pt surface.
100
80
60
40
20
0
1
2
3
4
5
Cycle number
Figure 2. Catalyst recyclability for the βꢀmethylation of 2ꢀphenylethanol (1a) with methanol and the
Pt/C catalyst. The conditions used are those of entry 1 in Table 3.
Figure 3. Reaction course for (1b) 2ꢀnaphthaleneꢀ1ꢀyl ethanol, (2b) 2ꢀnaphthaleneꢀ1ꢀyl propanol,
(3b) 2(naphthalenꢀ1ꢀyl)acrylaldehyde, and (4b) 2ꢀ(naphthalenꢀ1ꢀyl)acetaldehyde.
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60
Scheme 2. Proposed catalytic cycle for the βꢀmethylation of alcohols.
CH3OH
0.3
0.2
0.1
CD3OH
kCH / kCD = 1.8
0
1
2
3
4
5
t / h
Figure 4. Kinetic isotopic effect analysis for the Pt/Cꢀcatalyzed βꢀmethylation of 1b under the
conditions shown in Fig. 3. The KIE (kCH/kCD) value estimated from the zeroꢀorder rate constants (the
slope of the lines) is shown.
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α-Methylation of Ketones
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5
6
7
8
9
The same catalytic system, i.e., Pt/C and NaOH, is also effective for the αꢀmethylation of ketones
with methanol. In the literature, several homogeneous catalysts have been reported to catalyze this
reaction, but the known methods suffer from drawbacks, usually associated with scope limitations
and/or low TONs.36–41 Here, we present a reusable catalyst with wide scope and high TONs. Initially,
we carried out the optimization of the catalyst and reaction conditions for the αꢀmethylation of
propiophenone. Based on the results (not shown), we adopted the following optimized reaction
conditions: ketone (1 mmol), methanol (10 mmol), 1 mol% of Pt/C, 10 mol% NaOH, 100 °C, and 15 h.
Table 5 summarizes the general applicability of the present system for the αꢀmethylation of aromatic
ketones. The examined aromatic and aliphatic ketones are mainly monoꢀmethylated at the αꢀposition.
Propiophenone (entry 1), butyrophenone (entry 2), benzyl phenyl ketones (entries 3 and 4), other
benzyl ketones (entries 5 and 6), and linear and cyclic aliphatic ketones (entries 7–10) can be
converted into the corresponding αꢀmethylation products in good to high yield (73–94%). Note that
doubly methylated compounds were observed as minor products for entries 7, 8, and 10. Figure 5
shows the results for the catalyst recyclability in the αꢀmethylation of propiophenone under the
standard conditions shown in Table 5 (entry 1). Using the standard method for the catalyst
separation and regeneration,54 the Pt/C catalyst was reused four times, demonstrating that Pt/C is a
robust heterogeneous catalyst for this reaction. The examination of the initial product formation rates
for each cycle confirms the high durability of the catalyst (Figure S3).
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11
12
13
14
15
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17
18
19
20
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49
50
51
52
53
54
55
56
57
58
59
60
Table 6 lists the results for the αꢀmethylation of methyl ketones and aliphatic ketones with
methanol. Acetophenone (entry 1) and its derivatives with electronꢀdonating (entries 2 and 3) and
electronꢀwithdrawing (entry 4) groups were selectively bisꢀmethylated, while monoꢀmethylated
products were not observed by GC analysis. Aliphatic ketones (entries 5 and 6), including linear and
branched ketones, were predominantly monoꢀmethylated at the terminal position, albeit that minor
amounts of 1,3ꢀdimethylated (14% and 18%) and 1,1,3ꢀtrimethylated (8% and 7%) products were
also obtained.
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Table 5. Pt/Cꢀcatalyzed αꢀmethylation of aromatic and aliphatic ketones.
4
5
6
7
8
9
Entry
1
Ketone
Methylated product(s)
Yield (%)a
90
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14
15
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60
2
3
88
94
4
5
85
89
6
7
87
O
73b, 19b
,
,
8
74b, 16b
88b
9
10
93, 3b
,
a Isolated yield, b GC yield.
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0
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59
60
1
2
3
4
5
Cycle number
Figure 5. Catalyst recyclability for the αꢀmethylation of propiophenone with methanol and the Pt/C
catalyst. The conditions used are those described in Table 5 (entry 1).
Table 6. Pt/Cꢀcatalyzed αꢀmethylation of methyl ketones and aliphatic ketones.
O
O
O
1 mol% Pt/C
R1
CH3
CH3
CH3OH
+
CH3
R1
R1
0.1 equiv NaOH
100 °C, 15 h
or
1 mmol
10 mmol
Entry
1
Ketone
Methylated product(s)
Yield (%)a
91
2
93
3
4
5
6
88
79
76b, 14b, 8b
71b, 18b, 7b
,
,
,
,
a Isolated yield, b GC yield.
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The method was also successfully applied to the gramꢀscale methylation of several ketones.
Scheme 3 summarizes the isolated yields of the products for the αꢀmethylation of 10 mmol of various
ketones for 90 h using only 0.025 mol% of the Pt/C catalyst. Acetophenone was transformed into
isobutyrophenone in 84% yield. A variety of aromatic and aliphatic ketones were converted into the
corresponding monoꢀmethylated products in 78–86% yield. The TON values for these reactions
were >3000. Several homogeneous catalysts, such as [Cp*RhCl2]2, [Cp*RuCl2]2, and [Cp*IrCl2]2
catalyze the αꢀmethylation of ketones with methanol.36–41 Table 7 compares the performance of our
method to that of the representative catalysts [Cp*RhCl2]2 and [Cp*IrCl2]2 in the αꢀmethylation of
ketones. Again, these homogeneous catalytic systems are only effective for activated (aromatic)
ketones, while our method is effective for aromatic and aliphatic (nonꢀactivated) ketones. In the
αꢀmethylation of 2ꢀpropiophenone, the TON of the Pt/C catalyst (3440) is two orders of magnitude
higher than those of the previous methods for the same reaction.39,40 Based on the mechanistic
results for the βꢀmethylation of alcohols, a reasonable catalytic cycle for this reaction is proposed in
Scheme 4. Methanol is dehydrogenated to give formaldehyde and two atoms of hydrogen on the
catalyst surface. Formaldehyde and the ketone substrate then undergo a crossꢀaldol condensation
reaction to give an α,βꢀunsaturated intermediate, which is finally reduced by the two hydrogen atoms
on the Pt surface.
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44
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Gramꢀscale αꢀmethylation of ketones.
Table 7. αꢀMethylation of ketones with methanol using different catalysts
Catalyst
Pt/C
Additives
0.1 equiv NaOH
TON a
3440
15
Catalyst reuse
5 runs
No
Ref.
This work
36
Rh complex 5 equiv Cs2CO3, O2
Ir complex
4 equiv Cs2CO3
95
No
40
a TON per number of total metal atoms in the catalysts for the αꢀmethylation of 2ꢀpropiophenone.
Scheme 4. Proposed catalytic cycle for the αꢀmethylation of ketones.
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C3-Methylation of Indoles
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8
9
The developed catalytic system (Pt/C and NaOH) was furthermore applied to the C3ꢀmethylation of
indoles with methanol. Only one homogeneous catalytic method has so far been reported for this
reaction, but the method suffers from low TONs as well as difficulties associated with the removal
and recycling of the catalyst.45 Thus, the development of more efficient and reusable heterogeneous
catalysts is highly desirable. Preliminary experiments for the optimization of this reaction revealed
the optimum conditions: indole (1 mmol), methanol (10 mmol), Pt/C (1 mol%), NaOH (10 mol%),
100 °C, and 14 h. Under these optimized conditions, the C3ꢀmethylation of a variety of indoles
afforded the desired products (Table 8). The reactions of indole (entry 1), C5ꢀsubstituted indoles with
electronꢀdonating and electronꢀwithdrawing groups (entries 2–5), 2,5ꢀdimethylindole (entry 6), and
2ꢀmethylꢀindole (entry 7) proceeded smoothly to give the corresponding C3ꢀmethylated products in
high yield (81–95%). 3ꢀMethyl indole (entry 8) and Nꢀmethyl indole (entry 9) did not undergo such a
C3ꢀmethylation. This result is consistent with a proposed reaction route (Scheme 5) that involves a
nucleophilic attack of the C3ꢀcarbon of the indole to the formaldehyde molecule. It should be noted
that neither 3,3’ꢀbisindolylmethane nor its derivatives are generated by this method, which supports
the borrowingꢀhydrogen mechanism depicted in Scheme 5.
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Catalyst recycling tests were carried out for the C3ꢀmethylation of indole using the standard
method for catalyst separation and regeneration.54 As shown in Figure 6, the spent Pt/C catalyst was
reused at least four times, which demonstrates that Pt/C is a robust heterogeneous catalyst for this
reaction. The initial product formation rates were examined for each cycle in addition to the final
yields (Fig. S4). A significant loss of the initial rate was not observed, which suggests that Pt/C is a
robust heterogeneous catalyst. Using a low Pt/C loading (0.025 mol%), a gramꢀscale reaction of 5
mmol indole with 50 mmol methanol at 100 °C for 90 h resulted in a high isolated yield of the product
(88%), corresponding to a TON of 3520 (eqn (5)). Table 9 compares the main features of the present
method with those of the previously reported system with a homogeneous [Cp*IrCl2]2 catalyst for the
C3ꢀmethylation of indole. Our method is superior to the reported one in terms of the TON (two orders
of magnitude higher) and catalyst reusability. These results demonstrate that this heterogeneous
catalytic system, which is based on Pt/C and NaOH, is highly versatile for Cꢀmethylation
transformations, including the βꢀmethylation of primary alcohols, the αꢀmethylation of ketones, and
the C3ꢀmethylation of indoles. Importantly, all these reactions use methanol as a sustainable C1
source, and additional hydrogen sources are not required.
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Table 8. Pt/Cꢀcatalyzed C3ꢀmethylation of indoles
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5
6
7
8
9
Entry
1
Indole
Product
Yield (%)a
CH3
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60
95
88
85
83
N
H
N
H
2
3
4
5
6
81b
86
H3C
CH3
CH3
N
H
7
8
9
93
0
0
a Isolated yield, bGC yield
Scheme 5. Proposed catalytic cycle for the C3ꢀmethylation of indole.
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Cycle number
Figure 6. Catalyst recyclability for the C3ꢀmethylation of indole with methanol and the Pt/C catalyst.
The conditions used are those described in Table 8 (entry 1).
Table 9. Catalyst comparison for the C3ꢀmethylation of indole
Catalyst
Pt/C
Ir complex
Additives
0.1 equiv NaOH
1 equiv KOtBu
TON a
3520
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Catalyst reuse
5 runs
No
Ref.
This work
45
a TON per number of total metal atoms in the catalysts.
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Relationship between the catalytic activity and the adsorption energy of hydrogen: Volcano
plots
Rationalizing the properties of catalysts and establishing theories for heterogeneous catalysis are
challenging but inevitable tasks in order to understand the underlying phenomena and ultimately
develop improved catalysts.55,56 Recent findings in this area, obtained from density functional theory
(DFT) calculations, have shown that the adsorption energy of atoms, molecules, and related species
can serve as a simple descriptor to rationalize the activity and selectivity of heterogeneous catalysts.
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This is based on the knowledge that adsorption is a fundamental step for surfaceꢀcatalyzed
reactions following the Brønsted–Evans–Polanyi (BEP) relation.61,62 It is also wellꢀknown that a
Sabatierꢀtype tradeꢀo exists between the adsorption of reactants and the desorption of products, so
that catalysts that exhibit optimal adsorption energies afford maximal catalytic activities.63,64
Therefore, volcano plots are usually obtained for catalytic processes. This rationalization has been
applied to relatively simple catalytic reactions involving gas molecules as products, but not
extensively to organic transformation reactions.65 Here, we disclose that the adsorption energy of
hydrogen on different metal surfaces correlates well with the catalytic activity of the metals in
methylation reactions. Atomic hydrogen was chosen as the adsorbate, as methylation reactions are
considered to typically proceed via a hydrogenꢀborrowing mechanism, implying that adsorbed
hydrogen species are involved in the catalytic cycle. The adsorption energy of H on Ni(111), Cu(111),
Rh(111), Pd(111), Ir(111), Pt(111), Ru(0001), and Re(0001) surfaces was initially determined
theoretically by means of DFT calculations, and subsequently employed as descriptors to explain the
catalytic activity of different catalysts (see the experimental section for computational details and the
Supporting Information for the optimized structures). Figure 7 plots the reaction rates (per number of
total metal atoms in the catalyst) for the βꢀmethylation of 2ꢀphenylethanol, the αꢀmethylation of
2ꢀpropiophenone, and the C3ꢀmethylation of indole, over a series of metalꢀloaded carbon catalysts
as a function of the hydrogen adsorption energy. Platinum, which is the most active metal tested,
displays a moderate hydrogen adsorption energy, and volcanoꢀtype correlations are observed for all
three reactions. These observations indicate that the adsorption energy of hydrogen on metal
surfaces serves as a good descriptor to explain the activity of a catalyst in certain organic
transformation processes. This finding should thus contribute to the rationalization of the catalytic
activity of metals in hydrogenꢀborrowing reactions and to the future design of catalysts without the
need for extensive trialꢀandꢀerror experimental testing.
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Figure 7. (A) Adsorption models for H on the Pt(111) surface; top (left) and side (right) view. Reaction
rates (based on the total number of metal atoms in the catalyst) for (B) the βꢀmethylation of
2ꢀphenylethanol, (C) the αꢀmethylation of 2ꢀpropiophenone, and (D) the C3ꢀmethylation of indole by
metal(M)ꢀloaded carbon catalysts as a function of the adsorption energy of hydrogen on the metal
surface.
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CONCLUSIONS
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Highly versatile, selective, and recyclable heterogeneous catalytic processes were developed for
three Cꢀmethylation reactions using methanol as a sustainable C1 source: (1) the βꢀmethylation of
primary alcohols, (2) the αꢀmethylation of ketones, and (3) the C3ꢀmethylation of indoles. These
catalytic systems are driven by
a
borrowingꢀhydrogen mechanism, wherein the
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Ptꢀnanoparticlesꢀcatalyzed dehydrogenation of methanol (and alcohols) to aldehydes is followed by
a condensation of formaldehyde with the corresponding nucleophile (aldehyde, ketone, or indole) to
yield unsaturated intermediates, which are subsequently hydrogenated by Pt–H species on the
catalyst. Compared to previous catalytic methods for borrowingꢀhydrogenꢀtype Cꢀmethylation
reactions, our method presents the following advantages: (1) easy catalyst/product separation, (2)
catalyst recyclability, (3) excellent TONs (up to two orders of magnitude higher than those previously
reported), and (4) wide substrate scope. Furthermore, DFT calculations have shown that the
adsorption energy of hydrogen correlates well with the catalytic activity of various active metals
employed in these reactions. These results should be helpful to rationalize the properties of catalytic
systems, and serve as a practical guide for future catalyst design.
AUTHOR INFORMATION
Corresponding author
Kenꢀichi Shimizu
Eꢀmail: kshimizu@cat.hokudai.ac.jp
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org. A representative structure model for DFT calculations, results of recycling studies,
and NMR data.
ACKNOWLEDGEMENT
This work was supported by JSPS KAKENHI grant 17H01341 and 16H06595 from the Japan Society
for the Promotion of Science (JSPS) and by the Japanese Ministry of Education, Culture, Sports,
Science, and Technology (MEXT) within the projects "Integrated Research Consortium on Chemical
Sciences (IRCCS)" and "Elements Strategy Initiative to Form Core Research Center", as well as by
the JSTꢀCREST project JPMJCR17J3. In this research work we used the supercomputer of ACCMS,
Kyoto University. The authors thank Ms. Naomi Hirai, the Open Facility of Hokkaido University, for
her help with STEM analysis and are indebted to the technical division of the Institute for Catalysis
(Hokkaido University) for the manufacturing of experimental equipment.
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