Direct synthesis of quinazolinones by acceptorless dehydrogenative coupling of o-aminobenzamide and alcohols by heterogeneous Pt catalysts

Article abstract of DOI:10.1039/c4cy00092g

HBEA zeolite-supported Pt metal nanoclusters (Pt/HBEA) effectively catalyze direct dehydrogenative synthesis of quinazolinones from o-aminobenzamide and alcohols under promoter-free conditions. This is the first heterogeneous catalytic system for this reaction, which has a turnover number (TON) more than 25 times higher than previous homogeneous catalysts as well as wide scope for aliphatic and aromatic alcohols. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cy00092g

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Direct synthesis of quinazolinones by acceptorless
dehydrogenative coupling of o-aminobenzamide
and alcohols by heterogeneous Pt catalysts†
Cite this: Catal. Sci. Technol., 2014,
4, 1716
Received 22nd January 2014,
Accepted 14th February 2014
S. M. A. Hakim Siddiki, a Kenichi Kon,b Abeda Sultana Touchyb
*
and Ken-ichi Shimizuab
DOI: 10.1039/c4cy00092g
www.rsc.org/catalysis
HBEA zeolite-supported Pt metal nanoclusters (Pt/HBEA) effec-
tively catalyze direct dehydrogenative synthesis of quinazolinones
from o-aminobenzamide and alcohols under promoter-free condi-
tions. This is the first heterogeneous catalytic system for this reac-
tion, which has a turnover number (TON) more than 25 times
higher than previous homogeneous catalysts as well as wide scope
for aliphatic and aromatic alcohols.
produces stoichiometric amounts of dimethyl sulfide as a haz-
ardous byproduct. A ZnI2-catalyzed oxidative transformation of
o-aminobenzamide with benzyl alcohols was recently devel-
oped by Wu et al.,19 but the method required large amounts of
catalyst (10 mol%) and excess amounts of expensive oxidant
Table 1 Quinazolinone synthesis with 5 wt% metal-loaded catalystsa
The synthesis of heterocyclic compounds from readily
available alcohols is one of the most important branches of
organic synthesis.1–5 Quinazolinones exist in a variety of
natural products, and they are important structures in drug
development due to their biological and pharmacological
activities.6–17 A number of different synthetic methods for
quinazolinones have been reported. Some quinazolinones
were synthesized through the coupling between 2-halobenzoic
acid derivatives and ammonia sources, including amidines,9
benzylamines,10 amino acids11 and amides,12 but this method
has drawbacks such as a need for stoichiometric amounts of
the bases used and the formation of salt wastes. A classical but
more general method is the condensation between aldehydes
and o-aminobenzamides to give aminal intermediates, followed
by their oxidation to quinazolinones.13–17 However, the method
has serious drawbacks such as the use of chemically unstable
aldehydes and excess amounts of hazardous oxidants (KMnO4,13
CuCl,14 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),15 I2,16
and MnO217). Recent reports gave improved catalytic methods
using alcohols as more benign and readily available reagents
than aldehydes. Wei and a co-worker18 reported an iodine cata-
lyzed one-pot two-step oxidative system for the cyclization of
primary alcohols with o-aminobenzamide to quinazolinones
using DMSO as the oxidant. The system is convenient, but it
Entry
Catalyst
1 conv. (%)
Yield (%)
1
2
3
4
5
6
7
8
Pt/TiO2
Ir/TiO2
87
25
9
13
11
2
22
0
39
27
5
18
17
5
9
9
70
11
0
3
7
0
13
0
21
18
2
10
11
1
Re/TiO2
Ru/TiO2
Pd/TiO2
Rh/TiO2
Ni/TiO2
Cu/TiO2
Pt/MgO
Pt/Y2O3
Pt/CeO2
Pt/ZrO2
9
10
11
12
13
14
15
16
17
18
19
20
21
22b
23c
Pt/Al2O3
Pt/SnO2
Pt/SiO2
6
5
Pt/C
Pt/Nb2O5
Pt/SiO2–Al2O3
Pt/HMFI
Pt/HBEA
PtOx/HBEA
Pt/HBEA–air
HBEA
74
95
55
100
9
55
75
42
99
0
75
9
56
0
a Elements Strategy Initiative for Catalysts and Batteries, Kyoto University,
Katsura, Kyoto 615-8520, Japan. E-mail: hakim@cat.hokudai.ac.jp
b Catalysis Research Center, Hokkaido University, N-21, W-10,
Sapporo 001-0021, Japan
a
The conversion of 1 and the yield of 3 were determined by gas
chromatography (GC). The catalysts were pre-reduced in H2 at 300 °C
b
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cy00092g
for 0.5 h except for entries 21 and 23. Pre-reduced Pt/HBEA was
exposed to air at room temperature for 0.5 h. 0.1 g HBEA.
c
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Table 2 Alkylation of o-aminobenzamide with different alcohols using
Table 2 (continued)
Pt/HBEA
Isolated
Entry
13
Alcohol
Product
yield (%)
90
95
95
92
88
14
15
16
17
Isolated
Entry
1
Alcohol
Product
yield (%)
95(99)a
2b
3
(95)a
86
18
19
80
4
90
78
5
6
7
82
20
90a
76a
72a
a
GC yield. b Pt = 0.001 mmol, 80 h.
(tert-butyl hydroperoxide (TBHP)). Williams et al.20 reported
the cyclization of primary alcohols with o-aminobenzamide
to quinazolinones using a homogeneous Ru catalyst, but the
method required excess amounts of oxidant (crotononitrile).
Yokoyama et al.21 reported the synthesis of 4-phenyl-quinazolinones
via a domino reaction of o-aminobenzamides and benzylalcohols
involving a benzylation/benzylic C–H amidation methodology
catalyzed by 5 mol% homogeneous Pd catalyst. However, the
method required an expensive ligand and was limited to
benzylalcohols. Compared with the above methods, [Cp*IrCl2]2-
catalyzed cyclization of primary alcohols with o-aminobenzamides
to quinazolinones developed by Zhou and Fang is more atom-
efficient, because it does not require an oxidant, and H2 and H2O
are the byproducts.22 This method was applied to the synthesis
of 2,3-disubstituted natural quinazolinones.23 However, from a
practical viewpoint, the turnover number (TON) of the system is
still low. As a part of our continuing interest in heterogeneous
Pt nanocluster catalysis for acceptorless dehydrogenation of
alcohols and dehydrogenation-driven coupling reactions via
hydrogen-transfer methodologies,24–27 we report herein the first
heterogeneous catalytic system for acceptorless cyclization of
primary alcohols with o-aminobenzamide to quinazolinones
using Pt-loaded HBEA zeolite.
8
75
9
65a
78
10
11
12
85
93
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Table 3 Catalysts for direct quinazolinone synthesis from o-aminobenzamide and benzylalcohol
Catalyst
mol%
Oxidant
T (°C)
t (h)
Yield (%)
TON
Ref.
Pt/HBEA
Ir[Cp*IrCl2]2
0.1
2.5
5
5
10
165
140
120
115
110
80
36
16
24
16
95
93
93
72
90
950
37
19
14
9
This study
22
21
20
19
Pd(OAc)2/TPPMSa
Ru(PPh3)3(CO)(H)2/Xantphos
ZnI2
2.5 eq. crotononitrile
4 eq. TBHP
a
sodium (diphenylphosphino) benzene-3-sulfonate
We chose the reaction of equimolar amounts of
benzylalcohol and o-aminobenzamide as a model system in
order to optimize the catalytic conditions. Table 1 (entries 1–8)
summarizes the results of the initial catalyst screening test
under the same reaction conditions (reflux in mesitylene for
24 h under N2) using various transition metal (Pt, Ir, Re, Ru,
Pd, Rh, Ni, Cu) catalysts supported on TiO2 pre-reduced
in H2 at 300 °C. Among the catalysts tested, Pt/TiO2 showed
the highest conversion of amide to the corresponding
quinazolinone, 3. Entries 9–20 show the effect of the support
on Pt-loaded catalysts pre-reduced at 300 °C. Among the vari-
ous supports (TiO2, MgO, Y2O3, CeO2, ZrO2, Al2O3, SnO2, SiO2,
C, Nb2O5, SiO2–Al2O3, HMFI, HBEA), HBEA (entry 20) gave the
highest yield of quinazolinone 3 (99%) with 100% conversion
of o-aminobenzamide. Acidic supports such as TiO2, Nb2O5,
SiO2–Al2O3, and HMFI also gave good yields (42–75%). HBEA
itself (entry 23) was completely inactive for this reaction and
the unreduced catalyst precursor, PtOx/HBEA (platinum
oxide-loaded HBEA) was also inactive (entry 21). Considering
the Pt metal diameter of 1.8 nm (CO adsorption experiment),
these results suggest that both Pt metal nanoclusters and the
acidic sites of HBEA are required for this catalytic system. The
catalyst, named Pt/HBEA–air, prepared by exposing Pt/HBEA to
ambient conditions for 0.5 h, gave a lower yield (56%) than as-
reduced Pt/HBEA (99%). This suggests that the metallic Pt0
species on the surface of the Pt nanoparticles are the active
species and re-oxidation of them by O2 under ambient condi-
tions results in a decrease in the catalyst’s activity.
confirmed that the content of Pt in the solution was below
the detection limit.
Under the optimized conditions with Pt/HBEA, we studied
the general applicability of the present catalytic system.
Table 2 shows the isolated yields of the quinazolinones from
o-aminobenzamide with various primary alcohols using 1 mol%
of the catalyst. Both electron rich (entries 3, 4, 7) and
electron poor (entries 5, 6) benzylalcohols were tolerated to
give excellent isolated yields (82–95%) with 100% conversions
of o-aminobenzamide and the alcohols. The reaction of a ste-
rically hindered o-substituted benzylalcohol (entry 7) also
proceeded in good yield. Heteroaromatic alcohols with thienyl
(entry 8), furanyl (entry 9) and pyridinyl (entry 10) groups were
also tolerated with good yields (75%, 65% and 78%, respec-
tively). It is important to note that various aliphatic alcohols,
including linear and branched aliphatic alcohols (entries 11–19),
were tolerated, giving 100% conversion of o-aminobenzamide
and good to excellent isolated yields (78–95%) of the
quinazolinones. Considering the fact that previous methods18–22
did not tolerate branched aliphatic alcohols, our system is the
first general method of quinazolinone synthesis from aliphatic
alcohols. Although the reaction with the hydrogen acceptor
group containing alcohol (4-pentene-1-ol (entry 20)) was not
successful, a high yield (90%) of quinazolinone was obtained
with complete reduction of the terminal double bond due to
the availability of hydrogen as a byproduct in the reaction
system through the PtH species. Using small amounts of the
catalyst (0.1 mol%), cyclization of o-aminobenzamide to
quinazolinones with benzylalcohol (entry 2) gave 95% yield,
corresponding to a TON of 950. Table 3 compares the cata-
lytic activity of our heterogeneous system with those of previ-
ous homogeneous systems for direct quinazolinone synthesis
from o-aminobenzamide and benzylalcohol. The TON of
Pt/HBEA is more than 25 times higher than those of previous
The heterogeneous nature of this catalytic system is
confirmed by the following results. For the standard reaction,
Pt/HBEA was removed from the reaction mixture at a 26%
yield of 3 (t = 3 h). Further heating of the filtrate for 21 h
under the reflux conditions did not increase the product
yield. Inductively coupled plasma (ICP) analysis of the filtrate
Scheme 1 Possible mechanism for Pt/HBEA-catalyzed quinazolinone formation.
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catalytic systems, which clearly demonstrates the higher cata-
lytic efficiency of the present system.
Notes and references
As proposed in a previous paper on oxidant-free quinazolinone
formation from o-aminobenzamide and alcohols by an
Ir-complex,22 the present reaction can proceed through a dehy-
drogenative coupling pathway (Scheme 1), which is evidenced by
the following results. First, we have reported that supported Pt
metal clusters catalyze acceptor-free dehydrogenation of alcohols.24
Second, the reaction of benzaldehyde and o-aminobenzamide
under catalyst-free conditions resulted in the quantitative forma-
tion of the condensation product, aminal 3a (eqn (1)). Aminal
3a, which was then isolated, was dehydrogenated by Pt/HBEA
under N2 to give quinazolinone 3 in a quantitative yield
(eqn (2)). Based on these results, we propose a possible mecha-
nism of the present catalytic system in Scheme 1. The reaction
begins with the Pt-catalyzed dehydrogenation of the primary alco-
hol to the aldehyde accompanied by the generation of H2. Then,
non-catalytic condensation of the aldehyde and o-aminobenzamide
gives aminal 3a, which undergoes Pt-catalyzed dehydrogena-
tion to quinazolinone 3. We studied the temperature effect for
the model reaction from Table 1 and found that the lower tem-
perature reaction at 150 °C slows down the dehydrogenation of
aminal 3a (eqn (2)) to quinazolinone 3.
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In summary we have developed the first heterogeneously cat-
alyzed direct synthesis of quinazolinones from primary alcohols
with o-aminobenzamide under additive-free conditions using
the HBEA-supported Pt nanocluster catalyst. This method works
for a wide scope of alcohols and shows more than a 25 times
higher TON than the previous homogeneous catalytic systems
(with expensive organic ligands or excess amounts of oxidant),
and hence the method provides one of the most environmen-
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Acknowledgements
This work was supported by a MEXT program “Elements Strategy
Initiative to Form Core Research Center” (since 2012), Japan.
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Catal. Sci. Technol., 2012, 2, 730.
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