Acceptorless Dehydrogenative Synthesis of Pyrimidines from Alcohols and Amidines Catalyzed by Supported Platinum Nanoparticles

Article abstract of DOI:10.1021/acscatal.8b02814

A one-pot, acceptorless dehydrogenative method, using a carbon-supported Pt catalyst (Pt/C) along with KOtBu, has been developed for the synthesis of 2,4,6-trisubstituted pyrimidines from secondary and primary alcohols, and amidines. The reaction takes place efficiently using a wide range of substrate scopes (32 examples with isolated yields up to 92%). The Pt/C catalyst that promotes this process is reusable and has a higher turnover number (TON) than those employed in previously reported methods. The results of mechanistic studies suggest that the process takes place through a pathway that begins with Pt-catalyzed acceptorless dehydrogenation of the alcohol substrate, which is followed by sequential condensation, cyclization, and dehydrogenation. Measurements of the turnover frequency combined with the results of density functional theory calculations on different metal surfaces suggest that the adsorption energy of H on the Pt surface is optimal for the acceptorless dehydrogenation process, which causes the higher catalytic activity of Pt over those of other metals.

Full text of DOI:10.1021/acscatal.8b02814

Subscriber access provided by Kaohsiung Medical University
Article
Acceptorless Dehydrogenative Synthesis of Pyrimidines from
Alcohols and Amidines Catalyzed by Supported Pt Nanoparticles
Sharmin Sultana Poly, S. M. A. Hakim Siddiki, Abeda S. Touchy, Kah Wei
Ting, Takashi Toyao, Zen Maeno, Yasuharu Kanda, and Ken-Ichi Shimizu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02814 • Publication Date (Web): 10 Oct 2018
Downloaded from http://pubs.acs.org on October 10, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
Acceptorless Dehydrogenative Synthesis of Pyrimidines from
Alcohols and Amidines Catalyzed by Supported Pt
Nanoparticles
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
Sharmin Sultana Poly,† S. M. A. Hakim Siddiki,*† Abeda S. Touchy,† Kah Wei Ting,†
Takashi Toyao,†,‡ Zen Maeno,† Yasuharu Kanda,§ Ken-ichi Shimizu*†,‡
† Institute for Catalysis, Hokkaido University, N-21, W-10, Sapporo 001-0021, Japan
‡ Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Katsura, Kyoto
615-8520, Japan
§ Applied Chemistry Research Unit, College of Environmental Technology, Graduate School
of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan
*Corresponding authors
S. M. A. Hakim Siddiki, Ken-ichi Shimizu
E-mail: hakim@cat.hokudai.ac.jp, kshimizu@cat.hokudai.ac.jp
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 31
1
2
3
4
ABSTRACT
5
6
7
8
A one-pot, acceptorless dehydrogenative method, using a carbon-supported Pt catalyst (Pt/C) along
with KOtBu, has been developed for the synthesis of 2,4,6-trisubstitutedpyrimidines from secondary
and primary alcohols, and amidines. The reaction takes place efficiently using a wide range of
substrate scopes (32 examples with isolated yields up to 92%). The Pt/C catalyst that promotes this
process is reusable and has a higher turnover number (TON) than those employed in previously
reported methods. The results of mechanistic studies suggest that the process takes place through a
pathway that begins with Pt-catalyzed acceptorless dehydrogenation of the alcohol substrate, which
is followed by sequential condensation, cyclization and dehydrogenation. Measurements of the
turnover frequency combined with the results of density functional theory calculations on different
metal surfaces suggest that the adsorption energy of H on the Pt surface is optimal for the
acceptorless dehydrogenation process, which causes the higher catalytic activity of Pt over those of
other metals.
9
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
KEYWORDS: pyrimidines, acceptorless dehydrogenative coupling, multi-component reaction,
heterogeneous platinum catalysts, density functional theory
2
ACS Paragon Plus Environment

Page 3 of 31
ACS Catalysis
1
2
3
1. INTRODUCTION
4
5
6
7
8
Heterogeneous catalysts that promote one-pot reactions leading to value-added chemicals have
attracted much attention.1,2 Among various types of organic transformations that fall in this category,
H2 evolving, acceptorless dehydrogenation (AD) reactions have been developed to synthesize
various types of organic compounds.3 AD reactions have advantages not shared by traditional
reactions employing stoichiometric amounts of inorganic substances or O2 as oxidants, because they
do not require the use of oxidants or sacrificial hydrogen acceptors.4–6 As a result, AD reactions do
not generate stoichiometric amounts of waste.7 Gaseous H2 generated in these processes is also
valuable and can potentially be utilized as an energy source. Because homogeneous catalysts
normally suffer from product separation and catalysts recycling issues, their heterogeneous
counterparts are typically better suited for AD reactions.3,8 However, the development of
heterogeneous catalysts for reactions that produce value-added chemicals is challenging because of
the empirical approaches that are used in their development.9 Also, the complexity of surface
reactions makes predicting catalyst performance a formidable task.10 Consequently, an important
target in the development of environmentally friendly, atom-efficient AD reactions is the design of
heterogeneous catalysts showing high activities, stabilities and recyclabilities in the absence of
hydrogen acceptors.
9
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
Selective catalytic transformation of alcohols, which are readily available and sustainable
substrates, to fine chemicals is a growing area of interest in catalysis, organic synthesis and green
sustainable chemistry.5,11–18 One representative example of the transformation of alcohols to fine
chemicals is the catalytic one-pot synthesis of nitrogen-containing heterocycles (indoles,19–21
quinolines,22,23 pyrroles,24–32 pyridines,33–36 pyrimidines,37–39 and quinazolines40), which have broad
applications as pharmaceutical and flavoring agents, agrochemicals and other functional
chemicals.41,42 The methods are based on AD reactions of alcohols that initially form carbonyl
compounds, which are then transformed to products through multiple condensation/dehydrogenation
reactions occurring in the same vessel. A recent advance made in this area is the synthesis of
2,4,6-trisubstituted-pyrimidines from primary and secondary alcohols, along with amidines using
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 31
1
2
3
4
5
6
7
8
homogeneous transition metal catalysts with a basic additive (KOtBu). Following the first report by
Kempe et al. describing the use of a homogenous Ir catalyst to promote this process,37 Kirchner et
al.38 and Kempe et al.39 individually developed new methods using less expensive Mn complexes
9
as
homogeneous
catalysts.
These
catalytic
methods
for
the
preparation
of
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
2,4,6-trisubstituted-pyrimidines are more atom-efficient and sustainable than their conventional
counterparts, exemplified by reactions of amidines with α,β-unsaturated ketones,43 α,α-dibromo
oxime ethers with Grignard reagents,44 alkynes and nitriles using TfOH,45 and the cascade synthesis
of pyrimidines from propargylic alcohols and amidines using the transition metal catalysts BaMnO4.46
Although the catalytic method for synthesis of pyrimidines from alcohols and amidines is attractive, it
suffers from low turnover number (TON) and difficulties with catalyst/product separation and catalyst
recycling.37–39 Consequently, the development of a highly efficient heterogeneous catalyst for this
reaction, which have a wide scope, could overcome these problems. To date, however, only
homogeneous catalysts have been used to promote this process. Our group recently reported a
series of studies of AD reactions and acceptorless dehydrogenative coupling (ADC) reactions of
alcohols that are promoted by heterogeneous carbon-supported Pt catalysts (Pt/C).21,32,40,47-49 This
approach has advantages associated with the use of a recyclable heterogeneous catalyst and the
facility of catalyst preparation. It is anticipated that this catalytic system would find applications to
other challenging reactions that produce value-added chemicals in one-pot manner.
In studies described below, targeted at uncovering these applications, we developed a new
heterogeneous catalytic system to promote AD reactions that form 2,4,6-trisubstituted-pyrimidines
from diverse combinations of primary and secondary alcohols, along with amidines. The Pt/C
catalyst developed for these processes has reusability and displays a higher turnover number (TON)
than previously used homogeneous catalysts.37–39 In addition, the results of fundamental studies
have led to elucidate a plausible mechanism for the process and to an understanding of factors that
affect the catalytic activities of various metal nanoparticle catalysts.
4
ACS Paragon Plus Environment

Page 5 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
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
Scheme 1. Pyrimidine synthesis using AD reactions.
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 31
1
2
3
4
5
6
2. EXPERIMENTAL SECTION
General
7
8
9
Commercially available organic and inorganic compounds, except for the amidine-hydrochlorides,
(from Tokyo Chemical Industry, Wako Pure Chemical Industries, and Sigma Aldrich, Kishida
Chemical, or Mitsuwa Chemicals) were used without purification. Amidines were extracted twice from
commercially available amidine-hydrochlorides (0.1 mol) using 0.33 mol KOH, 70 mL H2O and 50 mL
CH2Cl2, and dried using a rotary evaporator before use in reactions. Benzyl-α,α-d2 alcohol
(BzCD2OH, 99.5 atom %D) and 1-phenylethan-1-d1-ol (C6H5CD(OH)CH3, 98 atom %D) were
obtained from Sigma Aldrich. GC (Shimadzu GC-14B and GC-2014) and GCMS (Shimadzu
GCMS-QP2010) analyses were performed with an Ultra ALLOY capillary column UA+-1 (Frontier
Laboratories Ltd.) using He or N2 as the carrier gas. 1H and 13C NMR measurements were performed
with JEOL-ECX 600 operating at 600.17 and 150.92 MHz, respectively. Tetramethylsilane was used
as the internal standard.
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
Catalyst Preparation
Carbon was obtained commercially from Kishida Chemical. SiO2 (Q-10) was supplied by Fuji Silysia
Chemical Ltd. CeO2 (JRC-CEO3), TiO2 (JRC-TIO-4), MgO (JRC-MGO-3), and H+-exchanged β
zeolite (Hβ, SiO2/Al2O3 = 25±5, JRC-Z-HB25) were obtained from the Catalysis Society of Japan.
ZrO2 was synthesized by hydrolysis of zirconium oxynitrate 2-hydrate 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. γ-Al2O3 was prepared by calcining γ-AlOOH (Catapal B Alumina, Sasol)
at 900 °C for 3 h. Nb2O5 was prepared by calcining Nb2O5·nH2O (Companhia Brasileira de
Metalurgia e Mineração (CBMM)) at 500 °C for 3 h. The Pt/C precursor was prepared by the
impregnation method as follows. A mixture of carbon (10 g) and an aqueous HNO3 solution of
Pt(NH3)2(NO3)2 containing 4.96 wt% of Pt (10.62 g) and 50 mL of ion-exchanged water was added to
a round-bottom flask (500 mL). The mixture was stirred for 15 min at room temperature (200 rpm).
The mixture was evaporated to dryness at 50 °C. This was followed by drying at 90 °C under ambient
pressure for 12 h. Prior to each experiment, a Pt/C catalyst (5 wt% Pt loading) was prepared by
6
ACS Paragon Plus Environment

Page 7 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
reducing the precursor in a Pyrex tube under a H2 flow (20 cm3 min-1) at 300 °C for 0.5 h. Other
supported Pt catalysts (5 wt% Pt loadings) were prepared in the same manner. In addition, M/C (M =
Rh, Ir, Ru, Pd, Re, Cu, Ni) catalysts were prepared in a similar method 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. Metal loadings were adjusted to 5 wt%. Platinum oxides-loaded
carbon (PtOx/C) was prepared by calcining the Pt(NH3)2(NO3)2-loaded carbon at 300 °C for 0.5 h in
air.
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
Catalyst Characterization
X-ray diffraction (XRD; Rigaku Miniflex) measurements were conducted using Cu K-α radiation. N2
adsorption measurements were carried out by using AUTOSORB 6AG (Yuasa Ionics Co.). The sizes
of supported metal particles were estimated by using transmission electron microscopy (TEM) using
a JEOL JEM-2100F TEM operated at 200 kV. CO adsorption experiments were carried out at room
temperature by using BELCAT (MicrotracBEL). Prior to each CO adsorption experiment, a sample
(0.1 g) was heated in a flow of 5% H2/Ar (20 mL min-1) at 300 °C for 10 min. Pt L3-edge X-ray
absorption near-edge structures (XANES) and extended X-ray absorption fine structures (EXAFS)
were determined in a transmittance mode at the BL01B1 with a Si(111) double crystal
monochromator in SPring-8 operated at 8 GeV (Proposal No. 2017B1279). The Pt/C catalyst
following the recycle study in Fig. 1 was sealed in cells made of polyethylene under N2, and then the
spectrum was measured at room temperature. The EXAFS analysis was carried out using the REX
ver. 2.5 program (RIGAKU). The parameters for Pt–O and Pt–Pt shells were provided by the FEFF6.
Typical Procedure for the Catalytic Reactions
Pt/C (39 mg; 1 mol% Pt with respect to benzamidine 3a) was used as the standard catalyst. After
reduction, the catalyst was placed in a closed glass tube sealed with a septum inlet and cooled to
room temperature under H2. Toluene (2 mL) was injected through the septum inlet into the glass tube
containing the pre-reduced catalyst. Next, the septum was removed, and secondary alcohol 1 (1.25
mmol), primary alcohol 2 (1.5 mmol), amidine 3 (1.0 mmol), KOtBu (1.5 mmol), n-dodecane (0.25
mmol) and a magnetic stirrer bar were added to the tube followed by filling N2 through the septum
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 31
1
2
3
4
5
6
7
8
9
inlet. Then, the resulting mixture was magnetically stirred (400 rpm) under reflux conditions. For the
standard catalyst screening reactions of 1-phenylethanol, benzyl alcohol and benzamidine (Table 1),
reaction optimizations (Table 2), kinetic studies and control reactions, the conversions and yields of
products were determined by using GC with n-dodecane as the internal standard. GC-sensitivities
were estimated using isolated products or commercial compounds. In substrate scope studies
(Schemes 1-4), products were isolated by using column chromatography on silica gel 60 (spherical,
40–100 μm, Kanto Chemical Co. Ltd.) using hexane/ethyl acetate (9:1, v/v) as the eluent, and yields
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
1
of the isolated products were determined. Products were identified by using H and 13C NMR
spectroscopy in combination with GCMS, in which the mass spectrometer was equipped with the
same column as that used for GC analyses. Analysis of the gaseous product (H2) was carried out by
using mass spectrometry (BELMASS).
Recycling experiments were performed with the following procedure. After each catalytic run,
2-propanol (3 mL) was added to the mixture. The catalyst was separated by using centrifugation and
washed with water (3 mL) and acetone (6 mL). Subsequently, the catalyst was dried at 110 °C for 3 h
and reduced at 300 °C for 0.5 h under an atmosphere of H2. Subsequently, the recovered Pt/C
catalyst was placed in the reactor with a mixture of the substrate and KOtBu. Note that the initial
rates were obtained on the basis of product yields after a reaction time of 1 h where the product
yields are below 30%.
8
ACS Paragon Plus Environment

Page 9 of 31
ACS Catalysis
1
2
3
3. RESULTS AND DISCUSSION
4
5
6
Optimization of the Catalyst and Reaction Conditions
7
8
9
In the initial phase of studies aimed at developing a heterogeneous catalytic system to promote
2,4,6-trisubstituted-pyrimidine forming AD reactions, catalyst screening was performed using the
reaction of 1-phenylethanol (1a, 1.25 mmol), benzyl alcohol (2a,1.5 mmol) and benzamidine (3a,1.0
mmol) and KOtBu (1.5 mmol) in refluxing toluene for 24 h. Table 1 shows the yields of
2,4,6-triphenylpyrimidine (4a), based on benzamidine, for various AD reactions promoted by Pt
nanoparticles on different support materials and various metal nanoparticles on carbon containing
0.01 mmol (1 mol%) of the active metal. Under these conditions, reactions do not take place in the
absence of the catalyst (entry 1). The results show that platinum oxides-loaded carbon (PtOx/C, entry
2) does not promote the reaction. In contrast, metallic Pt-loaded carbon (Pt/C), reduced with H2 at
300 °C, catalyzes a reaction that occurs in 95% yield (entry 3), while use of pre-reduced, air-exposed
Pt/C (Pt/C-air in entry 4) leads to a lower yield (57%). The yields of AD reactions promoted by Pt/C are
higher than those catalyzed by Pt-loaded metal oxides (ZrO2, Al2O3, CeO2, TiO2, SiO2, MgO, Hβ
zeolite, Nb2O5, entries 5-12). The Pt-loaded metal oxides catalysts were characterized by XRD
(Figure S1), N2 adsorption (Figure S2), and CO adsorption measurements as well as TEM and XAFS
measurements as previously reported.50 Moreover, the Pt/C catalyst promotes a higher yielding
reaction than do other transition metal nanoparticles supported on carbon (Ir/C, Ni/C, Pd/C, Rh/C,
Ru/C, Re/C, Cu/C, and Ag/C) shown in entries 13-20.
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
Using the most effective catalyst, Pt/C, we conducted a study targeted at finding optimal
conditions for the reaction of 1a, 2a, and 3a (Table 2). Inspection of the results arising from reactions
promoted by Pt/C and KOtBu in various solvents at reflux (entries 1-5) showed that reaction in toluene
(entry 1) forms 4a in the highest yield. A survey of reactions in refluxing toluene with different basic
additives (entries 1, 6-8) showed that KOtBu (entry 1) leads to a higher yield than with the other basic
additives (NaOtBu, NaOH, KOH). It was also demonstrated that the reaction hardly proceeds in the
absence of a base (entry 9). Consequently, we adopted refluxing toluene using Pt/C and KOtBu as the
standard conditions for reaction of 1a, 2a, and 3a.
9
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 31
1
2
3
4
5
Table 1. Catalyst screening for synthesis of pyrimidine 4a from 1-phenylethanol 1a, benzyl alcohol
2a and benzamidine 3a.
6
7
8
9
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
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Catalyst
None
PtOX/C
Pt/C
Pt/C-air
Pt/ZrO2
Pt/Al2O3
Pt/CeO2
Pt/TiO2
Pt/SiO2
Pt/MgO
Pt/Hβ
Pt/Nb2O5
Ir/C
Ni/C
Pd/C
Rh/C
Yield (%)a
0
0
95
57
70
67
65
63
61
53
43
38
45
36
34
31
26
19
15
11
16
17
18
19
Ru/C
Re/C
Cu/C
Ag/C
20
a GC yield.
Table 2. Optimization of the conditions for pyrimidine forming reaction of 1a, 2a and 3a.
Entry
1
2
3
4
5
6
7
Base
Solvent
toluene
Yield (%)a
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
NaOH
KOH
95
66
69
71
78
65
70
61
0
n-octane
o-xylene
mesitylene
tert-amyl alcohol
toluene
toluene
toluene
toluene
8
9
none
a GC yield.
10
ACS Paragon Plus Environment

Page 11 of 31
ACS Catalysis
1
2
3
Catalytic Properties and Scope of the Reaction
4
5
6
7
8
The heterogeneous nature and reusability of the catalytic system developed for the AD reactions
were confirmed by the results of the recycling test shown in Figure 1. After carrying out the standard
AD reaction for 24 h, the catalyst was separated from the mixture by using filtration, dried at 110 °C
for 3 h and then reduced in a H2 atmosphere at 300 °C for 0.5 h. The recovered catalyst was found to
promote an AD reaction to form 4a in high yields (88-95%) that gradually decrease over five cycles.
In a separate series of experiments, the initial rates of 4a formation were determined for each cycle.
The results (gray bars in Figure 1) show that the initial rates also gradually decrease with increasing
number of cycles. It should also be noted that a 2nd run without the H2 reduction step afforded 4a in
71% yield, which is lower than the yield obtained with an H2 reduction, indicating that the H2
reduction is necessary for optimal recycling.
9
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
To assess possible reasons for the gradual catalyst deactivation in the recycling processes
described above, structural characterization was carried out on the recovered Pt/C catalyst following
the 5th cycle of reactions by using X-ray absorption near-edge structural (XANES) and extended
X-ray absorption fine structure (EXAFS) analysis (Figure 2), and TEM analysis (Figure 3). The
results of EXAFS curve fitting analysis are shown in Table 3. Note, characterization of freshly
prepared Pt/C was reported in our previous study.49 The XANES feature of the fresh Pt/C catalyst is
similar to that of Pt foil, indicating that the Pt species are metallic. It was also found that the intensity
of white-line is slightly increased after 5th cycles of the reaction and decreased by the subsequent H2
reduction. This result indicates that the Pt species is oxidized during the reaction. Subsequent H2
reduction is necessary to obtain metallic Pt and thus effective for the optimal recycling. The EXAFS
of Pt/C after the 5th catalytic cycle followed by H2 reduction consists of Pt–Pt bonds at 2.74 Å, a
distance that is close to that of Pt foil (2.76 Å) with the coordination numbers of 10.1. This
observation shows that Pt in the catalyst after the 5th cycle followed by H2 reduction exist in the
metallic state, which is consistent with the XANES result. However, the particle size distribution,
estimated by using TEM analysis (Figure 3), shows that the fraction of Pt metal particles with
diameters above 7 nm increases during recycling. The volume-area mean diameter (D)51 of Pt
11
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 31
1
2
3
4
5
6
7
8
9
particles in the recycled Pt/C (6.5 ± 1.6 nm) is larger than that in fresh Pt/C (5.2 ± 1.1 nm), an
increase that is likely responsible for the slight decrease in the catalytic activity seen after the 5th
cycle. The coordination number for the catalyst after recycling and subsequent H2 reduction was
found to be 10.1, and this result is in accordance with these observations.
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
This catalytic system is applicable to gram scale synthesis of pyrimidines. This capability was
demonstrated by reaction of 12.5 mmol of 1a, 15 mmol of 2a, 10 mmol of 3a and 15 mmol of KOtBu
using 0.05 mol% of Pt/C catalyst for 120 h, which produces 4a in 89% yield corresponding to a TON
of 1780. As the data in Table 4 demonstrate, the new method has two advantages over those
previously developed including a more than 10 times higher TON and reusability of the catalyst.
Figure 1. Catalyst reuse for the synthesis of 4a from 1a, 2a, and 3a promoted by Pt/C and KOtBu
under the standard conditions shown in Table 2 (entry 1): (navy bars) 4a yields after 24 h and (gray
bars) initial rates of 4a formation.
Figure 2. Pt L3-edge (A) XANES spectra and (B) EXAFS Fourier transforms of Pt/C before and after
the catalyst recycling.
12
ACS Paragon Plus Environment

Page 13 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
Table 3. Curve-fitting analysis of Pt L3-edge EXAFS of Pt/C.
Sample
Pt/C
Shell
Pt
N a
9.9
8.3
R (Å) b
2.75
σ (Å) c
0.079
0.073
Rf (%) d
3.9
2.6
Pt/C (after 5th cycles)
Pt/C (after 5th cycles
followed by H2 reduction)
Pt
2.74
Pt
10.1
2.74
0.074
3.8
a Coordination numbers. b Bond distance. c Debye-Waller factor. d Residual factor.
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
Figure 3 Typical TEM images and Pt particle size distributions of Pt/C before and after recycling.
Table 4. TON and catalyst reusability for synthesis of 4a from 1a, 2a and 3a.
Catalyst
TON
158
172
48
Catalyst reuse
no
no
no
Ref.
37
39
38
Ir complex
Mn complex
Mn complex
Pt/C
1780
5th cycles
This study
The substrate scope of the Pt/C-catalyzed process was explored next. The results show that the
catalytic system is effective in promoting AD reactions of various primary alcohols (benzylic and
heterocyclic), secondary alcohols (aliphatic, 1-phenylethanol) and amidines. In these processes,
pyrimidines are generated in high yields (78-92%) (Scheme 2-5). The scope of secondary alcohols 1
in this process is seen by viewing the results in Scheme 2, which show that high yields of isolated
pyrimidines attend AD reactions of various secondary alcohols 1 with benzylalcohol 2a and
benzamidine 3a. Reactions of 1-phenylethanol and its derivatives with electron-withdrawing and
13
ACS Paragon Plus Environment

ACS Catalysis
Page 14 of 31
1
2
3
4
5
6
7
8
9
-donating groups at para-positions produce the corresponding pyrimidines (4a to 4e) with good to
excellent yields (82-92%). AD reaction of 1-(naphthalen-2-yl)ethan-1-ol with 2a and 3a also
generates the corresponding pyrimidine 4f in 81% yield. Finally, AD reaction with 3-methyl butan-2-ol
gave the pyrimidine 4g occurring in 84% yield, demonstrates the applicability of the method to
aliphatic secondary alcohols.
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
Scheme 2. Synthesis of pyrimidines from, 2a and 3a, and secondary alcohols. Isolated yields are
shown.
The results in Scheme 3 show the scope of primary alcohols 2, including aromatic, heterocyclic
and aliphatic alcohols, in the new AD reaction. Benzyl alcohols with different substituents at
para-positions react with 1-phenylethanol 1a and benzamidine 3a to produce the corresponding
pyrimidines (4h-4m) in good to high isolated yields (82-92%). 2-Naphthylmethanol also forms
pyrimidine analogue 4n in an acceptable 89% yield. Primary alcohols containing heterocycles groups,
such as piperonyl, pyridyl, furyl and thiophenyl, are converted to the corresponding pyrimidines
(4o-4r) in high isolated yields (78-89 %). Also, AD reactions of aliphatic primary alcohols,
cyclohexylmethanol and iso-butyl alcohol with 2a and 3a yield the corresponding pyrimidines (4s, 4t)
in high isolated yields. Significantly, (4-(trifluoromethyl)phenyl)methanol, 2-naphthylmethanol and
2-furylmethanol are the first examples of primary alcohols that undergo reactions with
1-phenylethanol and benzamidine to form trisubstituted-pyrimidines.
14
ACS Paragon Plus Environment

Page 15 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
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
Scheme 3. Synthesis of pyrimidines from 1a, primary alcohols and 3a. Isolated yields are shown.
The results of pyrimidine forming AD reaction of different benzamidines with 1-phenylethanol
and benzyl alcohol are displayed in Scheme 4. Benzamidines possessing strongly
(p-methoxyphenyl), weakly (p-methylphenyl) electron donating groups, and a weakly electron
withdrawing (p-chlorophenyl, p-fluorophenyl) groups react with 1a and 2a to produce the
corresponding pyrimidines (4u-4x) in excellent yields (85-91%). Guanidine and methylguanidine also
react with 1a and 2a to form the corresponding pyrimidines (4y and 4z) in excellent respective 91%
and 88% yields.
Scheme 4. Synthesis of pyrimidines from 1a, 2a and different amidines. Isolated yields are shown, a
GC yield.
15
ACS Paragon Plus Environment

ACS Catalysis
Page 16 of 31
1
2
3
4
5
6
7
8
9
Scheme 5 shows the results of AD reactions of para-substituted 1-phenylethanols, various
primary alcohols, including p-substituted benzylalcohols (4aa-4cc) and 2-butanol (4dd-4ff), with
various amidines (benzamidine and guanidine). The observations demonstrate that the new process
is applicable to various combinations of substrates, and it generates the corresponding pyrimidines
(4aa-4ff) in excellent isolated yields (87-93%). It should be noted that products 4ee and 4ff are
important intermediates in the total synthesis of rosuvastatin, which is used as a pharmaceutical drug
for treatment of patients with high levels of cholesterol.52 Compared to those previously devised, the
new heterogeneous catalytic system is characterized by the higher isolated yields of pyrimidine
forming reactions.
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
Scheme 5. Synthesis of pyrimidines from various secondary alcohols, primary alcohols and
amidines. Isolated yields are shown.
16
ACS Paragon Plus Environment

Page 17 of 31
ACS Catalysis
1
2
3
Mechanistic Study
4
5
6
7
8
The mechanism of the AD reaction was not discussed in reports of pioneering studies probing the use
of homogeneous catalysts owing to the lack of experimental information.37–39 In the current effort, we
carried out kinetic studies and control reactions, summarized in equations (1)-(6), which provide
observations that enable us to propose a possible mechanistic pathway for the reaction (Scheme 6).
First, the time course of AD reaction of 3a over Pt/C under the standard conditions was monitored
(Figure 4A). The results show that initially (t = 0.5 h), the amount of acetophenone 1a’ and
benzaldehyde 2a’ increases and then decreases as the reaction time is increased. Simultaneously,
the amount of benzylideneacetophenone (5a) increases with time until 2 h, after which it decreases
along with a corresponding increase in the amount of product, triphenylpyrimidine 4a. A measurement
of the evolution of H2 (eqn. 1) shows that an almost theoretical amount of this gas is formed at t = 0.5
h, demonstrating the occurrence of acceptorless dehydrogenation.
9
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
The above results suggest that the mechanistic pathway for the process, shown in Scheme 6,
begins with a step in which acceptorless dehydrogenations of primary and secondary alcohols take
place to form the corresponding aldehydes and ketones. The second step of the process involves
base-catalyzed Claisen-Schmidt condensation of acetophenone with benzaldehyde to form
chalcones. The roles played by Pt and KOtBu (base) is evidenced by the results of the control reaction
of acetophenone 1a’ and benzaldehyde 2a’ with KOtBu, which produces chalcone 5a in 95% yield
(eqn. 2), and by the observation that this reaction is not catalyzed by Pt/C in the absence of KOtBu
(result not shown) nor does reaction of 1-phenylethanol 1a and benzyl alcohol 2a with KOtBu in
refluxing toluene for 4 h yield chalcone 5a (eqn. 3). Moreover, in the presence of Pt/C and KOtBu,
17
ACS Paragon Plus Environment

ACS Catalysis
Page 18 of 31
1
2
3
4
5
6
7
8
9
reaction of 1-phenylethanol 1a and benzyl alcohol 2a generates chalcone 5a in 95% yield (eqn. 4),
while Pt/C does not catalyze the dehydrogenation reaction when base is absent (eqn. 5). These
results indicate that the dehydrogenation step catalyzed by Pt is assisted by KOtBu, which likely
promotes deprotonation of alcohols, and that the second condensation step is catalyzed by KOtBu.
The third step, involving condensation of 5a with benzamidine 3a, is followed by dehydrogenation of
the formed intermediate 2,4,6-triphenyl-1,6-dihydropyrimidine 6a that produces the final product 4a.
In the presence of Pt/C, reaction of 5a with 3a forms triphenylpyrimidine 4a in 90% yield (eqn. 6).
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
Scheme 6. Plausible mechanism for AD reaction of 1-phenylethanol, benzyl alcohol and
benzamidine that generates 2,4,6-triphenylpyrimidine.
18
ACS Paragon Plus Environment

Page 19 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
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
Figure 4. Plots of the amounts of benzamidine 3a, acetophenone 1a’, benzaldehyde 2a’, chalcone
5a and triphenylpyrimidine 4a versus reaction time over (A) Pt/C, (B) Pt/Al2O3, (C) Pt/ZrO2, and (D)
Pt/MgO catalysts.
In order to gain additional insight into the mechanism of the AD reaction, kinetic isotope effect
(KIE) studies were conducted using 1a (PhCH(OH)CH3 or PhCD(OH)CH3), 2a (PhCH2OH or
PhCD2OH) and 3a (Figure 5). The results show that the rate constant for reaction of PhCH(OH)CH3,
PhCH2OH, and 3a (kHH) is larger than that for the reaction of PhCD(OH)CH3, PhCD2OH, and 3a (kDD).
The difference corresponds to a KIE (kHH/kDD) of 2.8 (Figure 5B). Also, the KIE for the reaction of 1a
and 2a to 5a was found to be 1.5 (Figure 5A), which is smaller than that for reaction of 1a, 2a, and 3a
to form 4a. Based on these results, we suggest that step involving dehydrogenation of 6a to form 4a is
kinetically more important than dehydrogenation of 1a and 2a. This proposal is supported by a
comparison that show that the initial rate of the reaction in the 4th step is about 6-times smaller than
that of the 1st and 2nd steps (Scheme 7).
19
ACS Paragon Plus Environment

ACS Catalysis
Page 20 of 31
1
2
3
4
5
6
7
8
9
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
Scheme 7. Comparison of the initial rates of reactions corresponding to the 1st and 2nd steps (1a
and 2a to 5a) with that of the 4th step (5a and 3a to 4a).
Figure 5. Kinetic isotopic effect analysis (A) for chalcone (5a) formation and (B) for
triphenylpyrimidine (4a) formation under the conditions shown in Table 2 (entry 1).
20
ACS Paragon Plus Environment

Page 21 of 31
ACS Catalysis
1
2
3
Origin of the High Catalytic Activity of Pt/C
4
5
6
7
8
Summary of characterization and catalytic results for supported Pt catalysts tested in this study is
given in Table 5 in order to discuss the effect of supports. We employed the standard reaction of 1a,
2a and 3a for this discussion. Specific surface areas (SBET) were determined by using the
Brunauer-Emmett-Teller (BET) method. Volume-area mean diameter (D) of metal particles were
obtained from our previous reports describing particle size distributions using results of TEM analysis
of the same catalysts.50 To evaluate catalytic activity, initial rates of the product (4a) formation per
total metal atoms in the catalyst (NT) were measured under the conditions where conversion of 1a,
2a and 3a are below 50%. Finally, the multiple of initial rates and dispersion yields gives the turnover
frequency (TOF) per surface metal atoms given. Investigations on the initial reaction rates show that
Pt/ZrO2, Pt/Al2O3, and Pt/MgO catalysts also exhibit relatively high initial rates in addition to the Pt/C
catalyst. However, inspection of time course plots shows that the 4a yields for Pt/ZrO2, Pt/Al2O3, and
Pt/MgO leveled off after certain reaction time, resulting in the low 4a yields (Figure 4B-D), while the
4a yield for Pt/C monotonically increased over time (Figure 4A). In order to get insights of this
catalyst deactivation, CO adsorption experiments for the catalysts before and after the reaction were
performed. The obtained results are listed in Table 5. The number of CO adsorbed on Pt/C remained
almost unchanged even after the reaction. On the contrary, the number of CO adsorbed on the other
supported Pt catalysts markedly decreased after the reaction. These observations indicate that a
reason of the high performance of the Pt/C catalyst can be attributed to high tolerance of Pt on the
carbon support toward the reaction condition.
9
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
Origin of the high catalytic performance of Pt/C compared to other transition metals loaded carbon
catalysts is discussed next. The results of the kinetic studies described in the previous section show
that dehydrogenation of 6a to 4a is a kinetically important step in the AD reaction. In addition, the KIE
value of 1.5 for reaction of 1a with 2a to form 5a suggests that the first step involving dehydrogenation
of alcohols also contributes to the rate of the overall process. Generally, dehydrogenation activities of
metal surfaces depend on metal-hydrogen (M–H) bond energies or adsorption energies of a H atom
on the surface, which can be assessed theoretically by using density functional theory (DFT).53,54 The
21
ACS Paragon Plus Environment

ACS Catalysis
Page 22 of 31
1
2
3
4
5
6
7
8
9
first elementary step for the dehydrogenation processes on a metal surface forms a surface
adsorbed H atom. Metals with low H adsorption energy are not efficient promoters of this step, while
metals with very large H adsorption energies are not effective for the promoting the subsequent step,
namely removal of H2 from the surface via M–H bond dissociation. Considering the Brønsted–
Evans–Polanyi (BEP) relation and the Sabatier principle,55–57 it is reasonable to suggest that the new
one-pot reaction described above is most effectively catalyzed by a metal that has a moderate H
adsorption energy. In an attempt to verify this hypothesis, we conducted a quantitative analysis of the
activity trends for the standard reaction of 1a, 2a and 3a catalyzed by various transition metals
loaded carbon catalysts.
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
Table 6 lists the initial rates per NT as well as TOF per surface metal atoms. D of metal particles
were estimated using particle size distributions using results of TEM analysis of the catalysts (See
Fig. S3-S12 in the Supporting Information for more details). The D values of the catalysts were found
to have similar sizes in the range of 3.8-7.0 nm except for Ag/C (31.7 nm). It is known that dispersion
(fraction of the exposed metal atoms) of metal nanoparticles correlates with the D value owing to the
fact that D values estimated by TEM agrees with mean particle diameters estimated from the number
of surface atoms on the spherical particles.51 Considering the fact that the fraction of low coordination
surface atoms is relatively low for the metal particles above 3.8 nm,58 we employed the most stable
and common planes for each metal to obtain volume-area mean diameters in order to estimate the
dispersion from D and density of metal. Namely, the (111) surface was used for metals having a
face-centered-cubic (fcc) structure, while the (0001) surface was used for metals having a
hexagonal-close-packed (hcp) structure. In our recent study, we theoretically estimated the
adsorption energies of a H atom on Pt(111), Ir(111), Pd(111), Rh(111), Cu(111), Ni(111), Ru(0001),
and Re(0001) surfaces by using DFT calculations.59 Figure 6 shows the TOF per surface metal
atoms for various metal catalysts as a function of the adsorption energy of a H atom as well as the
d-band center, which is a well-known descriptor of catalytic activities.60–62 The plot shows the
existence of a volcano-type dependence of the catalytic activity on both the H adsorption energy and
the d-band center, and that Pt catalyst display the highest catalytic activities. The result suggests that
Pt catalysts that have an optimum strength of the Pt–H bond and the d-band center are suitable for
22
ACS Paragon Plus Environment

Page 23 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
promoting AD reactions, resulting in higher catalytic activity of Pt than the other metals. This
conceptional finding might be useful for the rational design of new catalytic systems for similar types
of metal nanoparticle catalyzed organic reactions without the need to conduct extensive
trial-and-error studies.
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
23
ACS Paragon Plus Environment

ACS Catalysis
Page 24 of 31
1
2
3
4
5
6
7
8
9
Table 5. Summary of characterization and catalytic results for supported Pt catalysts.
b
c
COads
COads after
(μmol g-1)
64.3
<0.1
2.8
<0.1
0.1
0.5
e
Catalyst
SBET a (m2 g-1)
D d (nm) V0 (mol molPt-1 h-1) TOF f (h-1)
(μmol g-1)
62.3
Pt/C
924
91
149
104
52
318
24
511
4.6
6.2
2.3
2.9
2.1
4.9
7.5
1.9
6.5
21
86.4
79.8
21.9
25.2
16.4
34.2
109.4
13.3
33.2
Pt/ZrO2
Pt/Al2O3
Pt/CeO2
Pt/TiO2
Pt/SiO2
Pt/MgO
Pt/Hβ
46.3
126.1
98.5
139.5
58.5
38.6
14.4
10.8
9.7
8.9
7.8
16.5
7.7
5.8
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
18.3
10.7
1.3
148.4
44.8
Pt/Nb2O5 74
a Determined form N2 adsorption isotherm.
b Number of CO adsorbed on the catalysts.50
c Number of CO adsorbed on the catalysts after reaction.
d Average particle size of the supported Pt before catalytic reactions estimated by CO adsorption
experiments.50
e Initial rate of 4a formation (mol h-1) divided by total metal atoms in the catalyst, NT (mol).
f TOF per surface metal atom defined as TOF = V0 (mol molPt-1 h-1) NS/NT. NS is the number of surface
metal atoms derived from CO adsorption experiments for fresh catalysts.
Table 6. Summary of characterization, catalytic results and details of analysis for various carbon
supported metal catalysts.
e
Supported
metal
Pt
Crystal
planeb
111
111
0001
111
111
0001
111
111
111
V0
Da (nm) Phase b
N c (nm-2) NS/NT
TOF f (h-1) EHad g (eV)
d
(mol molmetal-1 h-1)
21.0
8.0
2.4
6.5
12.7
4.5
4.4
4.9
3.9
8.3
3.8
6.4
31.7
9.3
7.0
fcc
fcc
hcp
fcc
fcc
hcp
fcc
fcc
fcc
14.6
14.6
15.1
14.8
15.6
16.3
13.3
17.7
18.8
0.31
0.26
0.35
0.17
0.35
0.21
66.9
30.9
6.8
39.6
36.2
21.2
10.1
15.3
41.9
-2.81
-2.74
-3.17
-2.99
-2.91
-2.99
-2.21
-2.6
Ir
Re
Pd
Rh
Ru
Ag
Cu
Ni
0.045 0.5
0.14
0.17
2.0
7.3
-2.92
a Volume mean diameter of supported metal particles estimated by TEM analysis.
b Crystal plane of the metal surface for calculation of dispersion and DFT study.
c Number of metal atoms per unit area (nm2) on the assumed surface.
d
Dispersion of supported metals, NS/NT, where NS is the number of surface metal atoms and NT is the
total number of metal atoms in the supported metals.
e Initial rate of 4a formation (mol h-1) divided by total metal atoms in the catalyst, NT (mol).
f TOF per surface metal atom defined as TOF = V0 (mol molmetal-1 h-1) NS/NT.
g Adsorption energy of a H atom on the assumed metal surface.59
24
ACS Paragon Plus Environment

Page 25 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Figure 6. TOF (per surface metal atoms) for the standard reaction promoted by various metal-loaded
carbon catalysts (M/C) as a function of (A) the adsorption energy of H on the metal surface and (B)
the d-band center.
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
25
ACS Paragon Plus Environment

ACS Catalysis
Page 26 of 31
1
2
3
4
CONCLUSIONS
5
6
7
8
In the effort described above, we developed a new catalytic system for the one-pot synthesis of
2,4,6-trisubstitutedpyrimidines by AD reaction of secondary and primary alcohols with amidines,
promoted by a Pt/C catalyst and KOtBu. The catalyst used in this process is heterogeneous and,
thus, recyclable. Compared with previously devised catalytic AD reactions, the new process has the
following advantages: (1) easy catalyst/product separation, (2) catalyst recyclability, (3) higher TON
and (4) higher isolated yields of pyrimidines even in reactions of challenging substrates such as
guanidine. The results of kinetic studies and DFT calculations on various metal surfaces suggest that
the higher activity of the Pt catalyst as compared to those of other metal catalysts is a consequence
of the optimum strength of Pt-hydrogen bond, which is required for efficient operation of the
acceptorless dehydrogenation steps. The results should be a useful guide to rationalizing the
properties of catalytic systems, and the design of new catalysts.
9
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
AUTHOR INFORMATION
Corresponding author
S. M. A. Hakim Siddiki, Ken-ichi Shimizu
E-mail: hakim@cat.hokudai.ac.jp, 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. TEM images and NMR data.
ACKNOWLEDGEMENT
This study was supported financially by a JSPS KAKENHI grant 17H01341, 18K14051 and
18K14057 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 JST-CREST project JPMJCR17J3. The authors are
indebted to the technical division of the Institute for Catalysis (Hokkaido University) for manufacturing
experimental equipment. X-ray absorption measurements were performed at the BL-01B1 facility of
SPring-8 at the Japan Synchrotron Radiation Research Institute (JASRI) (No. 2017B1279)
26
ACS Paragon Plus Environment

Page 27 of 31
ACS Catalysis
1
2
3
REFERENCES
4
5
6
7
8
9
(1)
(2)
Climent, M. J.; Corma, A.; Iborra, S. Heterogeneous Catalysts for the One-Pot Synthesis of
Chemicals and Fine Chemicals. Chem. Rev. 2011, 111, 1072–1133.
Miyamura, H.; Kobayashi, S. Tandem Oxidative Processes Catalyzed by
Polymer-Incarcerated Multimetallic Nanoclusters with Molecular Oxygen. Acc. Chem. Res.
2014, 47, 1054–1066.
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
(3)
(4)
Siddiki, S. M. A. H.; Toyao, T.; Shimizu, K. Acceptorless Dehydrogenative Coupling Reactions
with Alcohols over Heterogeneous Catalysts. Green Chem. 2018, 20, 2933–2952.
Kallmeier, F.; Kempe, R. Manganese Complexes for (De)Hydrogenation Catalysis: A
Comparison to Cobalt and Iron Catalysts. Angewandte Chemie-International Edition. 2018, 57,
46–60.
Gunanathan, C.; Milstein, D. Applications of Acceptorless Dehydrogenation and Related
Transformations in Chemical Synthesis. Science 2013, 341, 249−260.
Sawama, Y.; Asai, S.; Monguchi, Y.; Sajiki, H. Versatile Oxidation Methods for Organic and
Inorganic Substrates Catalyzed by Platinum-Group Metals on Carbons. Chem. Rec. 2016, 16,
261–272.
Crabtree, R. H. Homogeneous Transition Metal Catalysis of Acceptorless Dehydrogenative
Alcohol Oxidation: Applications in Hydrogen Storage and to Heterocycle Synthesis. Chem.
Rev. 2017, 117, 9228–9246.
Taniguchi, K.; Jin, X.; Yamaguchi, K.; Nozaki, K.; Mizuno, N. Versatile Routes for Synthesis of
Diarylamines through Acceptorless Dehydrogenative Aromatization Catalysis over Supported
Gold–palladium Bimetallic Nanoparticles. Chem. Sci. 2017, 8, 2131–2142.
Corma, A.; Iborra, S.; Velty, A. Chemical Routes for the Transformation of Biomass into
Chemicals. Chem. Rev. 2007, 107, 2411–2502.
(5)
(6)
(7)
(8)
(9)
(10) Calle-Vallejo, F.; Loffreda, D.; Koper, M. T. M.; Sautet, P. Introducing Structural Sensitivity into
Adsorption–energy Scaling Relations by Means of Coordination Numbers. Nat. Chem. 2015, 7,
403–410.
(11) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Transition Metal Catalysed Reactions of
Alcohols Using Borrowing Hydrogen Methodology. Dalt. Trans. 2009, 753–762.
(12) Yamaguchi, R.; Fujita, K.; Zhu, M. Recent Progress of New Catalytic Synthetic Methods for
Nitrogen Heterocycles Based on Hydrogen Transfer Reactions. Heterocycles 2010, 81, 1093–
1140.
(13) Guillena, G.; Ramón, D. J.; Yus, M. Hydrogen Autotransfer in the N-Alkylation of Amines and
Related Compounds Using Alcohols and Amines as Electrophiles. Chem. Rev. 2010, 110,
1611–1641.
(14) Obora, Y. Recent Advances in α-Alkylation Reactions Using Alcohols with Hydrogen
Borrowing Methodologies. ACS Catal. 2014, 4, 3972–3981.
(15) Shimizu, K. Heterogeneous Catalysis for the Direct Synthesis of Chemicals by Borrowing
Hydrogen Methodology. Catal. Sci. Technol. 2015, 5, 1412–1427.
(16) Yang, Q.; Wang, Q.; Yu, Z. Substitution of Alcohols by N-Nucleophiles via Transition
Metal-Catalyzed Dehydrogenation. Chem. Soc. Rev. 2015, 44, 2305–2329.
(17) Nandakumar, A.; Midya, S. P.; Landge, V. G.; Balaraman, E. Transition-Metal-Catalyzed
Hydrogen-Transfer Annulations: Access to Heterocyclic Scaffolds. Angew. Chemie-Int. Ed.
2015, 54, 11022–11034.
(18) Kozlowski, J. T.; Davis, R. J. Heterogeneous Catalysts for the Guerbet Coupling of Alcohols.
ACS Catal. 2013, 3, 1588–1600.
(19) Tsuji, Y.; Huh, K.; Yokoyama, Y. Ruthenium Catalysed N-Heterocyclisation: Lndoles from
2-Aminophenethyl Alcohols. J. Chem. Soc. Chem. Commun. 1986, 1575–1576.
(20) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Oxidative Cyclization of Amino Alcohols Catalyzed
by a Cp*Ir Complex. Synthesis of Indoles, 1,2,3,4-Tetrahydroquinolines, and
2,3,4,5-Tetrahydro-1-Benzazepine. Org. Lett. 2002, 4, 2691–2694.
(21) Moromi, S. K.; Touchy, A. S.; Siddiki, S. M. A. H.; Ali, M. A.; Shimizu, K. Synthesis of Indoles
via Dehydrogenative N-Heterocyclization by Supported Platinum Catalysts. RSC Adv. 2015, 5,
1059–1062.
(22) Taguchi, K.; Sakaguchi, S.; Ishii, Y. Synthesis of Quinolines from Amino Alcohol and Ketones
Catalyzed by [IrCl(Cod)]2 or IrCl3 under Solvent-Free Conditions. Tetrahedron Lett. 2005, 46,
27
ACS Paragon Plus Environment

ACS Catalysis
Page 28 of 31
1
2
3
4
4539–4542.
(23) Mierde, H. Vander; Van Der Voort, P.; De Vos, D.; Verpoort, F. A Ruthenium-Catalyzed
Approach to the Friedlander Quinoline Synthesis. European J. Org. Chem. 2008, 9, 1625–
1631.
(24) Schley, N. D.; Dobereiner, G. E.; Crabtree, R. H. Oxidative Synthesis of Amides and Pyrroles
via Dehydrogenative Alcohol Oxidation by Ruthenium Diphosphine Diamine Complexes.
Organometallics 2011, 30, 4174–4179.
5
6
7
8
9
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
(25) Michlik, S.; Kempe, R. A Sustainable Catalytic Pyrrole Synthesis. Nat. Chem. 2013, 5, 140–
144.
(26) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyrroles by Dehydrogenative
Coupling of β-Aminoalcohols with Secondary Alcohols Catalyzed by Ruthenium Pincer
Complexes. Angew. Chemie-Int. Ed. 2013, 52, 4012–4015.
(27) Iida, K.; Miura, T.; Ando, J.; Saito, S. The Dual Role of Ruthenium and Alkali Base Catalysts in
Enabling a Conceptually New Shortcut to N-Unsubstituted Pyrroles through Unmaskedꢀ
-Amino Aldehydes. Org. Lett. 2013, 15, 1436–1439.
(28) Zhang, M.; Neumann, H.; Beller, M. Selective Ruthenium-Catalyzed Three-Component
Synthesis of Pyrroles. Angew. Chemie-Int. Ed. 2013, 52, 597–601.
(29) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. General and Regioselective Synthesis of
Pyrroles via Ruthenium-Catalyzed Multicomponent Reactions. J. Am. Chem. Soc. 2013, 135,
11384–11388.
(30) Emayavaramban, B.; Sen, M.; Sundararaju, B. Iron-Catalyzed Sustainable Synthesis of
Pyrrole. Org. Lett. 2017, 19, 6–9.
(31) Forberg, D.; Obenauf, J.; Friedrich, M.; Hühne, S.-M.; Mader, W.; Motz, G.; Kempe, R. The
Synthesis of Pyrroles via Acceptorless Dehydrogenative Condensation of Secondary Alcohols
and 1,2-Amino Alcohols Mediated by a Robust and Reusable Catalyst Based on
Nanometer-Sized Iridium Particles. Catal. Sci. Technol. 2014, 4, 4188–4192.
(32) Siddiki, S. M. A. H.; Touchy, A. S.; Chaudhari, C.; Kon, K.; Toyao, T.; Shimizu, K. Synthesis of
2,5-Disubstituted Pyrroles via Dehydrogenative Condensation of Secondary Alcohols and
1,2-Amino Alcohols by Supported Platinum Catalysts. Org. Chem. Front. 2016, 3, 846–851.
(33) Michlik, S.; Kempe, R. Regioselectively Functionalized Pyridines from Sustainable Resources.
Angew. Chemie-Int. Ed. 2013, 52, 6326–6329.
(34) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of Pyridines and Quinolines by
Coupling of γ-Amino-Alcohols with Secondary Alcohols Liberating H2 Catalyzed by
Ruthenium Pincer Complexes. Chem. Commun. 2013, 49, 6632–6634.
(35) Pan, B.; Liu, B.; Yue, E.; Liu, Q.; Yang, X.; Wang, Z.; Sun, W. H. A Ruthenium Catalyst with
Unprecedented Effectiveness for the Coupling Cyclization of - Amino Alcohols and Secondary
Alcohols. ACS Catal. 2016, 6, 1247–1253.
(36) Hille, T.; Irrgang, T.; Kempe, R. Synthesis of Meta-Functionalized Pyridines by Selective
Dehydrogenative Heterocondensation of β- and γ-Amino Alcohols. Angew. Chemie - Int. Ed.
2017, 56, 371–374.
(37) Deibl, N.; Ament, K.; Kempe, R. A Sustainable Multicomponent Pyrimidine Synthesis. J. Am.
Chem. Soc. 2015, 137, 12804–12807.
(38) Mastalir, M.; Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K. Sustainable Synthesis of
Quinolines and Pyrimidines Catalyzed by Manganese PNP Pincer Complexes. J. Am. Chem.
Soc. 2016, 138, 15543–15546.
(39) Deibl, N.; Kempe, R. Manganese-Catalyzed Multicomponent Synthesis of Pyrimidines from
Alcohols and Amidines. Angew. Chemie-Int. Ed. 2017, 56, 1663–1666.
(40) Chaudhari, C.; Siddiki, S. M. A. H.; Tamura, M.; Shimizu, K. Acceptorless Dehydrogenative
Synthesis of 2-Substituted Quinazolines from 2-Aminobenzylamine with Primary Alcohols or
Aldehydes by Heterogeneous Pt Catalysts. RSC Adv. 2014, 4, 53374–53379.
(41) Rachwal, S.; Katritzky, A. R. Comprehensive Heterocyclic Chemistry III; 2008.
(42) Joule, J. A.; Mills, K. Heterocyclic Chemistry; 2010; Vol. 66.
(43) Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Antimalarial Activity of
2,4,6-Trisubstituted Pyrimidines. Bioorganic Med. Chem. Lett. 2005, 15, 1881–1883.
(44) Müller, T. J.; Braun, R.; Ansorge, M. A Novel Three-Component One-Pot Pyrimidine Synthesis
Based upon a Coupling-Isomerization Sequence. Org. Lett. 2000, 2, 1967–1970.
(45) Kakiya, H.; Yagi, K.; Shinokubo, H.; Oshima, K. Reaction of α,α-Dibromo Oxime Ethers with
Grignard Reagents: Alkylative Annulation Providing a Pyrimidine Core. J. Am. Chem. Soc.
28
ACS Paragon Plus Environment

Page 29 of 31
ACS Catalysis
1
2
3
4
5
6
7
8
9
2002, 124, 9032–9033.
(46) Bagley, M. C.; Lin, Z.; Pope, S. J. A. Barium Manganate in Microwave-Assisted Oxidation
Reactions: Synthesis of Solvatochromic 2,4,6-Triarylpyrimidines. Tetrahedron Lett. 2009, 50,
6818–6822.
(47) Kon, K.; Siddiki, S. M. A. H.; Shimizu, K. Size- and Support-Dependent Pt Nanocluster
Catalysis for Oxidant-Free Dehydrogenation of Alcohols. J. Catal. 2013, 304, 63–71.
(48) Moromi, S. K.; Siddiki, S. M. A. H.; Kon, K.; Toyao, T.; Shimizu, K. Acceptorless
Dehydrogenation of N-Heterocycles by Supported Pt Catalysts. Catal. Today 2017, 281, 507–
511.
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
(49) Siddiki, S. M. A. H.; Touchy, A. S.; Kon, K.; Shimizu, K. Direct Olefination of Alcohols with
Sulfones by Using Heterogeneous Platinum Catalysts. Chem. - A Eur. J. 2016, 22, 6111–
6119.
(50) Shimizu, K.; Onodera, W.; Touchy, A. S.; Siddiki, S. M. A. H.; Toyao, T.; Kon, K. Lewis
Acid-Promoted Heterogeneous Platinum Catalysts for Hydrogenation of Amides to Amines.
ChemistrySelect 2016, 1, 736–740.
(51) Kunimori, K.; Uchijima, T.; Yamada, M.; Matsumoto, H.; Hattori, T.; Murakami, Y. Percentage
Exposed of Supported Pt, Pd and Rh Catalysts Studied by Gas Adsorption, Tpr and Tem
Methods. Appl. Catal. 1982, 4, 67–81.
(52) Andrushko, N.; Andrushko, V.; König, G.; Spannenberg, A.; Börner, A. A New Approach to the
Total Synthesis of Rosuvastatin. European J. Org. Chem. 2008, 5, 847–853.
(53) Nørskov, J. K.; Bligaard, T.; Rossmeisl, J.; Christensen, C. H. Towards the Computational
Design of Solid Catalysts. Nat. Chem. 2009, 1, 37–46.
(54) Loffreda, D.; Delbecq, F.; Vigné, F.; Sautet, P. Fast Prediction of Selectivity in Heterogeneous
Catalysis from Extended Brønsted-Evans-Polanyi Relations: A Theoretical Insight. Angew.
Chemie-Int. Ed. 2009, 48, 8978–8980.
(55) Santen, R. A. Van; Neurock, M.; Shetty, S. G. Reactivity Theory of Transition-Metal Surfaces:
A Brønsted-Evans-Polanyi Linear Activation Energy: Free-Energy Analysis. Chem. Rev. 2010,
110, 2005–2048.
(56) Medford, A. J.; Vojvodic, A.; Hummelshøj, J. S.; Voss, J.; Abild-Pedersen, F.; Studt, F.;
Bligaard, T.; Nilsson, A.; Nørskov, J. K. From the Sabatier Principle to a Predictive Theory of
Transition-Metal Heterogeneous Catalysis. J. Catal. 2015, 328, 36–42.
(57) Toyao, T.; Suzuki, K.; Kikuchi, S.; Takakusagi, S.; Shimizu, K.; Takigawa, I. Toward Effective
Utilization of Methane: Machine Learning Prediction of Adsorption Energies on Metal Alloys. J.
Phys. Chem. C 2018, 122, 8315–8326.
(58) Umpierre, A. P.; DeJesús, E.; Dupont, J. Turnover Numbers and Soluble Metal Nanoparticles.
ChemCatChem 2011, 3, 1413–1418.
(59) Siddiki, S. M. A. H.; Touchy, A. S.; Jamil, M. A. R.; Toyao, T.; Shimizu, K. C-Methylation of
Alcohols, Ketones, and Indoles with Methanol Using Heterogeneous Platinum Catalysts. ACS
Catal. 2018, 8, 3091–3103.
(60) Ruban, A.; Hammer, B.; Norskov, J. K. Surface Electronic Structure and Reactivity of
Transition and Noble Metals. J. Mol. Catal. A, Chem. 1997, 115, 421–429.
(61) Takigawa, I.; Shimizu, K.; Tsuda, K.; Takakusagi, S. Machine-Learning Prediction of the
d-Band Center for Metals and Bimetals. RSC Adv. 2016, 6, 52587–52595.
(62) Shen, X.; Pan, Y.; Liu, B.; Yang, J.; Zeng, J.; Peng, Z. More Accurate Depiction of Adsorption
Energy on Transition Metals Using Work Function as One Additional Descriptor. Phys. Chem.
Chem. Phys. 2017, 19, 12628–12632.
29
ACS Paragon Plus Environment