The Synthesis of Quinazolinones from Olefins, CO, and Amines over a Heterogeneous Ru-clusters/Ceria Catalyst

Article abstract of DOI:10.1002/anie.201806266

Quinazolinones, an important class of heterocyclic compounds, have been widely used in pharmaceuticals because of their biological activity. However, the efficient and economical synthesis of quinazolinones has remained a challenge. A novel synthetic approach has now been developed to produce quinazolinones from olefins, CO, and amines over heterogeneous Ru-clusters/ceria catalyst in the absence of acids, bases, and oxidants. Furthermore, H₂O is generated as the only by-product. A series of quinazolinones with aromatic or non-aromatic substituents can be obtained in yields of up to 99 %. The Ru-clusters/ceria can be reused at least four times. The analysis of the E-factor (environmental impact factor) for the synthesis of 2-ethyl quinazolinone suggests that this system is more environmentally friendly than other processes reported previously.

Full text of DOI:10.1002/anie.201806266

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Accepted Article
Title: The Synthesis of Quinazolinones from Olefins, CO and Amines
over Heterogeneous Ru-clusters/Ceria Catalyst
Authors: Jinghua An, Yehong Wang, Zhixin Zhang, Zhitong Zhao, Jian
Zhang, and Feng Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806266
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10.1002/anie.201806266
Angewandte Chemie International Edition
COMMUNICATION
The Synthesis of Quinazolinones from Olefins, CO and Amines
over Heterogeneous Ru-clusters/Ceria Catalyst
Jinghua An, Yehong Wang, Zhixin Zhang, Zhitong Zhao, Jian Zhang and Feng Wang*
Abstract: Quinazolinones, one class of important heterocyclic
compounds, have been widely used in pharmaceuticals due to
their biological activities. However, until now, to synthesize
quinazolinones efficiently and economically is still a challenge.
Herein, a novel synthetic approach is developed to produce
quinazolinones from olefins, CO and amines over
building blocks, olefins have been used in the synthesis of high
value-added chemicals such as esters,[12] amides[13] and
aldehydes.[14]. Further extending the transformation of olefins not
only has great significance in academic research, but also
presents broad prospects in industrial application.
Herein, we developed a novel method for the synthesis of
heterogeneous Ru-clusters/ceria catalyst in the absence of acids, quinazolinones from olefins, CO and amines over
bases and oxidants. Furthermore, H2O is generated as the only
by-product. A series of quinazolinones with either aromatic or
non-aromatic substituents, can be obtained in up to 99%
isolated yields. The catalysis here is truly heterogeneous and
Ru-clusters/ceria can be reused for at least four times. The
analysis of E-factor (environmental impact factor) for the
synthesis of 2-ethyl quinazolinone is conducted and it suggests
that this system is more friendly to the environment compared to
other processes reported previously.
heterogeneous Ru-clusters/ceria catalyst (Scheme 1(b)).
Compared with the processes reported previously, there are
some significant features listed in the following: 1) high activity
and wide scope of substrates. A series of quinazolinones with
either aromatic or non-aromatic substituents can be obtained in
up to 99% isolated yields; 2) easy to be scaled up. 12-fold scale
transformation of o-aminobenzamide was carried out and 1.042
g of 2-ethyl substituted quinazolinone could be obtained in 99%
isolated yield; 3) heterogeneous catalysis and good stability of
catalyst. The catalysis here is truly heterogeneous and the
catalyst can be reused for at least four times; 4) friendly to
environment. The values of sE-factor, cE-factor and E-factor are
much lower than that of other processes reported previously.
Quinazolinones are one class of important six-membered
nitrogen heterocycles and have been widely used in anticancer,
antimalarial, anti-inflammatory and antituberculosis due to their
diverse biological activities.[1] Traditionally, they are synthesized
via the acid/base-promoted condensation reactions from
aldehydes, carboxylic acids, esters with amides (Scheme 1(a),
route 1).[2] However, these methods generally suffer from
drawbacks such as the complex homogeneous catalytic systems
or expensive feedstocks. Recent examples of oxidative
condensation reactions from alcohols,[3] methyl arenes[4] and
amines[5] often require excess amounts of oxidants (Scheme
1(a), route 2). Wu and coworkers reported a palladium-catalyzed
carbonylation reaction to synthesize quinazolinones from o-
aminobenzamides, bromobenzenes and carbon monoxide (CO)
(Scheme 1(a), route 3).[6] Only 2-aryl quinazolinones could be
obtained via this method. In addition, they also reported the
synthesis of quinazolinones from 2-bromoanilines, trimethyl
orthoformate, amines and CO, but ligands and alkaline additives
were indispensable (Scheme 1(a), route 4).[7] Therefore, to
develop an efficient and economical method to synthesize
quinazolinones is still a challenge.
Olefins, especially alpha-olefins, are important hydrocarbons
with wide sources. For example, ethylene and propylene can be
obtained from coal,[8] biomass,[9] methanol[10] and syngas.[11] As
Scheme 1. Different catalytic systems for the synthesis of quinazolinones.
Initially, the synthesis of 2-ethyl substituted quinazolinone (3)
from ethylene (2), CO and o-aminobenzamide (1) was carried
out with tetrahydrofuran (THF) as solvent (Table 1). No target
product (3) was obtained in the absence of catalyst (Table 1,
entry 1). No reaction occurred when Pd(OAc)2, the most efficient
catalyst reported,[6] was used as catalyst even increasing the
reaction temperature from 120 °C to 160 °C (Table 1, entries 2-
3). In our previous work, we have reported the excellent catalytic
performance of Ru-clusters/ceria in the carbonylation reaction
transforming olefins to esters.[15] Thus here, Ru-clusters/ceria
was also applied in the synthesis of quinazolinones from olefins,
CO and amines. The results showed that the reaction could
[*]
J.H. An, Y.H. Wang, Z.X. Zhang, Z.T. Zhao, J. Zhang. Prof. F. Wang
State Key Laboratory of Catalysis (SKLC)
Dalian National Laboratory for Clean Energy (DNL)
Dalian Institute of Chemical Physics (DICP),
Chinese Academy of Sciences, Dalian 116023 (China)
E-mail: wangfeng@dicp.ac.cn
J.H. An, Z.T. Zhao
University of Chinese Academy of Sciences, Beijing 100049 (China)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806266
Angewandte Chemie International Edition
COMMUNICATION
proceed smoothly in 38% GC yield of product 3. And then it
achieved higher than 99% when increasing the temperature to
160 °C (Table 1, entries 4-7). By comparison, RuCl3·nH2O, the
precursor of Ru for Ru-clusters/ceria, and ceria support showed
poor catalytic performances (Table 1, entries 8-9). These results
suggested that Ru-clusters/ceria is the most efficient catalyst in
the synthesis of quinazolinone. The removal of Ru-clusters/ceria
catalyst in 1 h upon ~ 40% yield of 3 nearly stopped the reaction,
suggesting the real heterogeneous catalysis of this reaction over
Ru-clusters/ceria (Figure S1(a)). The Ru-clusters/ceria catalyst
could be reused for at least four times with slight decrease in
activity, suggesting the stability of the catalyst (Figure S1(b)).
Additionally, we hypothesized that the solvent tetrahydrofuran
(THF) might join the reaction. And then this possibility was
excluded by using THF-D8 as solvent instead of THF, because
no deuterium-labelled products were observed (Figure S2).
that the reaction intermediate was probably the amide species
(4), which was generated via the carbonylation of N-H for –NH2
group connected directly to benzene ring. The generation of
amide species during the reaction as the reaction intermediate is
also verified by the result of the time course for the synthesis of
3 over Ru-clusters/ceria catalyst (Figure S3).
Table 1. Synthesis of 2-ethyl substituted quinazolinone (3) from ethylene (2),
CO and o-aminobenzamide (1).[a]
Temperature
Entry
Catalyst
Yield of 3 / %
/ °C
160
120
160
130
140
150
160
160
160
1
2[b]
3[b]
4
No catalyst
Pd(OAc)2
0
0
Pd(OAc)2
0
Ru-clusters/ceria
Ru-clusters/ceria
Ru-clusters/ceria
Ru-clusters/ceria
RuCl3·nH2O
ceria
38
76
83
>99
13
0
5
6
7
8[b]
Figure 1. 13C NMR of the substrate 1 (a), the reaction mixture obtained after
reaction at 160 °C for 2 h (b) and product 3 (c). The symbols of , ,  and 
shown in Figure 1(b) were the assignments for substrate 1, product 3, the
trace amount of THF and trace amount of 2,6-di-tert-butyl-4-methylphenol
(BHT) in solvent, respectively.
9
[a] Reaction conditions: catalyst (0.1 g), 1 (0.5 mmol), ethylene (0.5 MPa), CO
(0.5 MPa), THF (2.0 mL), 12 h. Yield was determined by GC and calculated
based on 1. [b] Catalyst (0.02 mmol).
Table 2. Synthesis of amides from ethylene, CO and various amines.[a]
Then, 13C NMR spectroscopy was used to track the reaction
(Figure 1). Initially, before the reaction, a series of signals were
observed, all of which were assigned to the chemical shift of C
atoms for substrate (1). Additionally, no impurity was found
o
(Figure 1(a)). Then, the reaction was carried out at 160 C for 2
h and the reaction mixture was obtained to be examined by 13C
NMR (Figure 1(b)). Except for the signals assigned to the
chemical shift of C atoms for the unreacted substrate (1), a
number of new signals could be also observed. By comparison,
partial new signals located at 164.2, 157.6, 149.3, 134.8, 127.1,
126.4, 126.3, 120.5, 29.1 and 11.5 ppm were assigned to the
chemical shift of C atoms for product (3) (Figure 1(c)).
Consideration of the high selectivity in the synthesis of 3 in the
Ru-clusters/ceria catalytic system (Table 1, entry 7), we
proposed the left new signals at 171.9, 171.5, 139.7, 133.7,
132.2, 126.5, 121.5, 120.4, 30.5, 8.6 ppm were probably
assigned to the C atoms for the reaction intermediate. According
to the references, the signals at 30.5 and 8.6 ppm were
assigned to the chemical shift of C atoms for ethyl.[2i,4] And the
signals appearing at 139.7, 133.7, 132.2, 126.5, 121.5 and
120.4 ppm were assigned to the chemical shift of C atoms for
benzene ring.[2a] Two signals at 171.9 and 171.5 ppm were
assigned to the chemical shift of C atoms for carbonyl group.[16]
On the basis of the assignments of these signals, we concluded
[a] Reaction conditions: Ru-clusters/ceria (0.2 g), amine (0.5 mmol), ethylene
(0.5 MPa), CO (0.5 MPa), THF (3.0 mL), 160 °C, 24 h. [b] GC yield. [c]
Isolated yield. 1H NMR and 13C NMR spectra of 4a were shown in Supporting
Information.
When aniline was used as the substrate to react with ethylene
and CO, N-phenyl propionamide (4a) could be successfully
obtained in 67% isolated yield (Table 2. entry 1). Besides, other
amines including benzylamine, furfuryl amine, cyclohexylamine
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10.1002/anie.201806266
Angewandte Chemie International Edition
COMMUNICATION
and n-butylamine were also tolerated and the corresponding
amides were obtained in high yields (>99%) (Table 2. entries 2-
5). These results confirmed that it is feasible for the generation
of intermediate amide over Ru-clusters/ceria catalyst. And then
the target product quinazolinone was easily obtained via the
dehydration of intermediate amide, which could be catalyzed by
acid sites on Ru-clusters/ceria.[17]
Table 3. Substrate scope of olefins.[a]
O
N
O
N
O
Ru-clusters/ceria
NH
NH
NH2
+
R1
+
+
R1
CO
R1
160 oC
NH2
L
B
1
2a-2k
3a-3k
Entry
Olefin
Product
O
Yield[b] (%) (L/B)
NH
NH
NH
1
77 (79/21)
N
2a
3a (L)
To show the practical value of the present procedure, 12-fold
scale transformation of substrate (1) was carried out and 1.042 g
of product (3) could be obtained in 99% isolated yield (Scheme
2).
O
F
81 (86/14)
94 (95/5)
2
3
F
N
2b
3b (L)
Then, sE-factor, cE-factor and E-factor, metrics to quantify the
economy and sustainability of a process,[18] were used to
compare the synthesis of 3 in this work with that in other
processes reported previously. And the results showed that the
values of sE-factor, cE-factor and E-factor were much lower than
that of processes reported (Ref [2i], [2m], [2j], [4] and [2n]),
suggesting that this process produces less waste (Figure 2,
Table S2-S3).
O
F
N
F
2c
3c (L)
O
NH
72(58/42)
4
H3CO
N
2d
2e
3d (L)
OCH3
O
NH
NH
5
6
76 (64/16)
80 (64/16)
N
3e (L)
O
N
Cl
3f (L)
2f
Cl
Scheme 2. The scaled-up reaction to synthesize product (3).
O
N
NH
7[c]
180
79
sE-factor
2g
3g
cE-factor
E-factor
160
O
NH
NH
8[c]
51
N
O
30
20
10
0
2h
3h
9[d]
96 (56/44)
57 (83/17)
N
3i (L)
2i
O
NH
Ref [2m] Ref [2j] Ref [4] Ref [2n]
This work Ref [2i]
10[c]
N
3j (L)
2j
Figure 2. sE-factor, cE-factor and E-factor analysis of the synthesis of product
(3). Calculation details were shown in Supporting Information.
O
NH
Next, the scope of olefins were examined for this reaction.
Various styrenes with electron-donating (-OCH3 or -CH3) or
electron-withdrawing groups (-F or -Cl) reacted with substrate (1)
and CO to give 72-94% isolated yields. And the linear product
was majorly generated (Table 3, entries 1-6). Higher selectivities
(95% and 86%) of linear products were achieved when ortho or
meta-substituted styrenes were used as substrates. Moreover,
cycloolefins proved to be efficient coupling partners and were
converted into the corresponding quinazolinones in 79% yield for
cyclopentene and 51% yield for cyclohexene (Table 3, entries 7-
8). Even in the transformation of alpha-olefins, the
corresponding quinazolinones could be achieved in 96% yield
starting from 1-propylene, 57% yield from 1-pentene and 37%
yield from 1-hexene (Table 3, entries 9-11). To the best of our
knowledge, this is the first example to synthesize quinazolinones
employing alpha-olefins as the substrates over a heterogeneous
catalyst.
11[e]
37 (67/33)
N
2k
3k (L)
[a] Reaction conditions: Ru-clusters/ceria (0.2 g), 1 (0.5 mmol), olefin (2.0
mmol), CO (1.0 MPa), THF (3.0 mL), 160 °C, 16 h. L and B represent linear
and branched product, respectively. [b] Isolated yield of quinazolinones
including linear (L) and branched product (B). Ratios of L/B were determined
by the peak areas in GC-MS analysis. [c] 24 h. [d] Propylene (0.5 MPa), CO
(0.5 MPa), 24 h. [e] Ru-clusters/ceria (0.3 g), 36 h. 1H NMR and 13C NMR of
the linear products were given in the Supporting Information.
To further explore the scope of amines, substrate (1) with
electron-withdrawing (-Cl (1a), -F (1b) and -NO2 (1c)) or
electron-donating (-OCH3 (1d) and -CH3 (1e)) groups were also
investigated in the presence of ethylene and CO (Table 4,
entries 1-8). And the results showed that 1d or 1e led to a
higher yield of quinazolinones (88% and 87%) than 1a or 1b (70%
and 78%) (Table 4, entries 1-5). However, 1c, the electron-
withdrawing group (-NO2) substituted on 1, gave no product. It
shows that o-aminobenzamide (1) with electron-donating groups
are more favored to react than that with electron-withdrawing.
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10.1002/anie.201806266
Angewandte Chemie International Edition
COMMUNICATION
Further reaction using 1e as the substrate were conducted and
three quinazolinones could be obtained from propylene,
cyclohexene and styrene in up to 99% isolated yields except for
cyclohexene (52%) (Table 4, entries 6-8).
This work was supported by the National Natural Science
Foundation of China (21721004, 21706250, 21711530020) and
the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB17020300).
Table 4. Synthesis of quinazolinones from 1a-e, olefins, and CO.[a]
Keywords: quinazolinones • Ru-clusters • ceria • olefins
O
O
N
O
NH2
NH
Ru-clusters/ceria
160 oC
NH
R2
+
R3
+
CO
+
R3
R2
R2
NH2
R3
N
References:
L
B
1a-e
2/2i/2h/2a
3a'-e'/3ai/3ah/3aa
Entry
1a /1b
Olefin
Product
Yield[b] (%) (L/B)
[1] a) X. F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1-35; b) X. F.
Wu, X. Fang, L. Wu, R. Jackstell, H. Neumann, M. Beller, Acc. Chem.
Res. 2014, 47, 1041-1053; c) F. Zhu, Y. Li, Z. Wang, X. F. Wu, Angew.
Chem. Int. Ed. 2016, 55, 14151-14154; d) Y. Hu, Y. Xie, Z. Shen, H.
Huang, Angew. Chem. Int. Ed. 2017, 56, 2473-2477; e) H. Yu, G. Zhang,
H. Huang, Angew. Chem. Int. Ed. 2015, 54, 10912-10916; f) X. Li, X. Li, N.
Jiao, J. Am. Chem. Soc. 2015, 137, 9246-9249; g) Y. F. Liang, N. Jiao,
Acc. Chem. Res. 2017, 50, 1640-1653; h) A. Bunrit, C. Dahlstrand, S. K.
Olsson, P. Srifa, G. Huang, A. Orthaber, P. J. Sjoberg, S. Biswas, F. Himo,
J. S. Samec, J. Am. Chem. Soc. 2015, 137, 4646-4649; i) J. S. Samec, A.
H. Ell, J. E. Backvall, Chem. Eur. J. 2005, 11, 2327-2334.
[2] a) X. Liu, H. Fu, Y. Jiang, Y. Zhao, Angew. Chem. Int. Ed. 2009, 48, 348-
351; b) D. Huang, X. Li, F. Xu, L. Li, X. Lin, ACS Catal. 2013, 3, 2244-
2247; c) A. Das, S. S. Stahl, Angew. Chem. Int. Ed. 2017, 56, 8892-8897;
d) M. Liu, C. J. Li, Angew. Chem. Int. Ed. 2016, 55, 10806-10810; e) J. W.
Kim, K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2008, 47, 9249-
9251; f) A. E. Fernandes, O. Riant, K. F. Jensen, A. M. Jonas, Angew.
Chem. Int. Ed. 2016, 55, 11044-11048; g) B. Q. Hu, L. X. Wang, L. Yang,
J. F. Xiang, Y. L. Tang, Eur. J. Org. Chem. 2015, 2015, 4504-4509; h) H.
Li, L. He, H. Neumann, M. Beller, X. F. Wu, Green Chem. 2014, 16, 1336-
1343; i) Z. Li, J. Dong, X. Chen, Q. Li, Y. Zhou, S. F. Yin, J. Org. Chem.
2015, 80, 9392-9400; j) X. Chen, T. Chen, Y. Zhou, D. Han, L. B. Han, S.
F. Yin, Org. Biomol. Chem. 2014, 12, 3802-3807; k) R. Sharma, R. A.
Vishwakarma, S. B. Bharate, Adv. Synth. Catal. 2016, 358, 3027-3033; l)
S. Yao, K. Zhou, J. Wang, H. Cao, L. Yu, J. Wu, P. Qiu, Q. Xu, Green
Chem. 2017, 19, 2945-2951; m) G. Shen, H. Zhou, P. Du, S. Liu, K. Zou,
Y. Uozumi, RSC Adv. 2015, 5, 85646-85651; n) W. Xu, H. Fu, J. Org.
Chem. 2011, 76, 3846-3852.
O
O
Cl
Cl
NH2
NH2
NH
1[c]
70
N
O
3a'
3b'
1a
1b
2
2
O
F
F
NH
NH
NH2
2[c]
3[c]
4[c]
78
0
N
O
NH2
O
O2N
O2N
NH2
2
2
N
O
NH2
1c
1d
3c'
3d'
O
H3CO
H3CO
NH
NH
NH2
88
N
O
NH2
O
NH2
NH2
5[c]
87
N
O
1e
1e
2
3e'
NH
98 (58/42)[d]
6[c]
N
2i
3ei (L)
O
[3] a) H. Hikawa, Y. Ino, H. Suzuki, Y. Yokoyama, J. Org. Chem. 2012, 77,
7046-7051; b) S. M. A. Hakim Siddiki, K. Kon, A. S. Touchy, K. i. Shimizu,
Catal. Sci. Technol. 2014, 4, 1716-1719.
[4] K. Upadhyaya, R. K. Thakur, S. K. Shukla, R. P. Tripathi, J. Org. Chem.
2016, 81, 5046-5055.
[5] T. Kotipalli, V. Kavala, D. Janreddy, V. Bandi, C. W. Kuo, C. F. Yao, Eur.
J. Org. Chem. 2016, 2016, 1182-1193.
[6] X. F. Wu, L. He, H. Neumann, M. Beller, Chem. Eur. J. 2013, 19, 12635-
12638.
NH
NH
7
8
52
1e
1e
N
2h
2a
3eh
O
99 (83/17)[d]
N
3ea (L)
[7] L. He, H. Li, H. Neumann, M. Beller, X. F. Wu, Angew. Chem. Int. Ed.
2014, 53, 1420-1424.
[8] D. Xiang, Y. Qian, Y. Man, S. Yang, Appl. Energy 2014, 113, 639-647.
[9] S. P. Pyl, C. M. Schietekat, M. F. Reyniers, R. Abhari, G. B. Marin, K. M.
Van Geem, Chem. Eng. J. 2011, 176, 178-187.
[10] a) S. Wang, Y. Chen, Z. Wei, Z. Qin, H. Ma, M. Dong, J. Li, W. Fan, J.
Wang, J. Phys. Chem. C 2015, 119, 28482-28498; b) B. P. C. Hereijgers,
F. Bleken, M. H. Nilsen, S. Svelle, K. P. Lillerud, M. Bjørgen, B. M.
Weckhuysen, U. Olsbye, J. Catal. 2009, 264, 77-87; c) M. A. W. Alain
Sassi, Hee Jung Ahn, Paritosh Prasad, John B. Nicholas, and, J. F. Haw,
J. Phys. Chem. B, 2002, 106, 2294-2303.
[11] F. Jiao, J. Li, X. Pan, J. Xiao, H. Li, H. Ma, M. Wei, Y. Pan, Z. Zhou, M. Li,
S. Miao, J. Li, Y. Zhu, D. Xiao, T. He, J. Yang, F. Qi, Q. Fu, X. Bao,
Science 2016, 351, 1065-1068.
[12] K. Dong, R. Sang, X. Fang, R. Franke, A. Spannenberg, H. Neumann, R.
Jackstell, M. Beller, Angew. Chem. Int. Ed. 2017, 56, 5267-5271.
[13] H. Li, K. Dong, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2015, 54,
10239-10243.
[14] P. B. Webb, M. F. Sellin, T. E. Kunene, S. Williamson, A. M. Z. Slawin, D.
J. Cole-Hamilton, J. Am. Chem. Soc. 2003, 125, 15577-15588.
[15] J. An, Y. Wang, J. Lu, J. Zhang, Z. Zhang, S. Xu, X. Liu, T. Zhang, M.
Gocyla, M. Heggen, R. E. Dunin-Borkowski, P. Fornasiero, F. Wang, J.
Am. Chem. Soc. 2018, 140, 4172-4181.
[a] Reaction conditions: Ru-clusters/ceria (0.2 g), 1a or 1b (0.5 mmol), olefin
(2.0 mmol), CO (1.0 MPa), THF (2.0 mL), 24 h. [b] Isolated yields. Ratios of
L/B were calculated based on the isolated yields of linear and branched
products. [c] Olefins (0.5 MPa), CO (0.5 MPa). [d] 1H NMR and 13C NMR of the
linear products were given in the Supporting Information.
In summary, we have developed an effective method to
synthesize quinazolinones from olefins, CO and amines over a
heterogeneous Ru-clusters/ceria catalyst in the absence of acids,
bases, oxidants and with H2O as the only by-product. Amide is
verified as the reaction intermediate by 13C NMR. With this
method, a series of quinazolinones with either aromatic or non-
aromatic substituents can be obtained in up to 99% isolated
yields. Additionally, E-factor analysis shows that the values of
sE-factor, cE-factor and E-factor for the synthesis of 2-ethyl
quinazolinone are much lower than that of processes reported
previously, highlighting the economy and sustainability of this
reaction system. This method provides a new process with
olefins as the readily available feedstocks in the synthesis of
quinazolinone derivatives and related compounds, leading this
method more attractive.
[16] J. Liu, H. Li, A. Spannenberg, R. Franke, R. Jackstell, M. Beller, Angew.
Chem. Int. Ed. 2016, 55, 13544-13548.
[17] a) T. Montini, M. Melchionna, M. Monai, P. Fornasiero, Chem. Rev. 2016,
116, 5987-6041; b) M. Tamura, R. Kishi, A. Nakayama, Y. Nakagawa, J.
Y. Hasegawa, K. Tomishige, J. Am. Chem. Soc. 2017, 139, 11857-11867;
c) S. Tazawa, N. Ota, M. Tamura, Y. Nakagawa, K. Okumura, K.
Tomishige, ACS Catal. 2016, 6, 6393-6397; d) Y. Nakagawa, S. Tazawa,
T. Wang, M. Tamura, N. Hiyoshi, K. Okumura, K. Tomishige, ACS Catal.
2017, 8, 584-595; e) M. Cargnello, M. Grzelczak, B. Rodriguez-Gonzalez,
Z. Syrgiannis, K. Bakhmutsky, V. La Parola, L. M. Liz Marzan, R. J. Gorte,
M. Prato, P. Fornasiero, J. Am. Chem. Soc. 2012, 134, 11760-11766; f) T.
Montini, A. Speghini, L. D. Rogatis, B. Lorenzut, M. Bettinelli, M. Graziani,
P. Fornasiero, J. Am. Chem. Soc. 2009, 131, 13155-13160.
[18] R. A. Sheldon, Green Chem. 2017, 19, 18-43.
Acknowledgements
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10.1002/anie.201806266
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
The Synthesis of
Quinazolinones
from Olefins, CO
and Amines over
Heterogeneous
Ru-clusters/Ceria
Catalyst
Jinghua An, Yehong
Wang, Zhixin Zhang,
Zhitong Zhao, Jian
Zhang and Feng
Wang*
Page No. – Page
No.
The Synthesis of
Quinazolinones
from Olefins, CO
and Amines over
Heterogeneous Ru-
clusters/Ceria
Catalyst
This article is protected by copyright. All rights reserved.