Direct synthesis of quinazolinones via the carbon-supported acid-catalyzed cascade reaction of isatoic anhydrides with amides and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2021.152835

A novel catalytic system is reported for the construction of quinazolinones via the carbon-supported acid-catalyzed cascade coupling of isatoic anhydrides with amides and aldehydes. Subsequent selective hydrosilylation of the quinazolinones using a hydrogen-transfer strategy was also explored to provide dihydroquinazolines with structural diversity. The developed methodology proceeds with a broad substrate scope, excellent functional group tolerance, and utilizes a reusable catalyst and air as a green oxidant.

Full text of DOI:10.1016/j.tetlet.2021.152835

Tetrahedron Letters 66 (2021) 152835
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct synthesis of quinazolinones via the carbon-supported
acid-catalyzed cascade reaction of isatoic anhydrides with amides
and aldehydes
⇑
⇑
Xiangyu Zhang, Chujun Luo, Xiaoyong Chen, Weilin Ma, Bin Li , Zirui Lin, Xiuwen Chen, Yibiao Li, Feng Xie
School of Chemical & Environmental Engineering, Wuyi University, Jiangmen 529020, Guangdong Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel catalytic system is reported for the construction of quinazolinones via the carbon-supported acid-
catalyzed cascade coupling of isatoic anhydrides with amides and aldehydes. Subsequent selective
hydrosilylation of the quinazolinones using a hydrogen-transfer strategy was also explored to provide
dihydroquinazolines with structural diversity. The developed methodology proceeds with a broad sub-
strate scope, excellent functional group tolerance, and utilizes a reusable catalyst and air as a green
oxidant.
Received 8 December 2020
Revised 3 January 2021
Accepted 7 January 2021
Available online 1 February 2021
Keywords:
Reusable acid
Ó 2021 Elsevier Ltd. All rights reserved.
Cascade coupling
Quinazolinones
Hydrosilylation
Dihydroquinazolines
Introduction
tionalization steps, and difficult to recycle catalysts. Therefore,
from a sustainable and green chemistry perspective, the direct syn-
Quinazolinones are an important class of nitrogen-containing
heterocycles, which are widely found in numerous natural prod-
ucts and synthetic drugs (Scheme 1) [1]. This class of compounds
exhibits wide-ranging biological and pharmaceutical activities,
such as antihypertensive, antibacterial, antitumor, and antidiabetic
properties [2]. Due to their applications in medicinal chemistry, the
design and synthesis of quinazolinone derivatives has received sig-
nificant attention [3]. As shown in Scheme 2, conventional
approaches to access this important motif are as follows: (a) con-
densation of o-aminobenzamides with aldehydes [4a], alcohols
[4b], and phenylacetic acid [4c]; (b) dehydrogenative annulation
of anthranilonitriles with aldehydes or their equivalents [5]; (c)
Cu-catalyzed intramolecular SNAr reaction of 2-halobenzamides
with nitriles [6]; (d) palladium-catalyzed carbonylative cyclization
of anthranilamides with aryl bromides using CO as a carbon source
[7]; (e) aerobic annulation of amines with formaldehyde employ-
ing an imine-protection strategy [8]; and (f) palladium-catalyzed
oxidative coupling of anthranilamides with isocyanides and aryl-
boronic acids [9]. Despite impressive achievements, these
approaches often suffer from limitations, including the use of harsh
acids and less ecofriendly oxidants, the need for multiple prefunc-
thesis of quinazolinones from readily available feedstocks using
recyclable catalysts, remains a challenging goal.
Typical features of supported catalysts include high stability as
well as easy separation and recycling, affording them an important
position in green catalysis [10]. In general, inert inorganic materi-
als, such as active carbon, SiO2, Al2O3, and molecular sieves, have
been utilized as supports for heterogeneous catalysts [11]. Com-
mon features of these carriers are high specific surface areas, active
functional groups, and tunable pores, which favor the diffusion and
transmission of substrates [12]. In recent years, the use of for-
mamides as an ammonia synthon or amines to construct quina-
zolinones has received considerable interest [13]. Moreover,
compared with amines, formamides have the merits of being inex-
pensive and easy to handle [14].
As part of our continued research interest in the construction of
N-heterocycles using highly efficient nanocatalysts [15], we have
recently reported the oxidative functionalization of cyclic amines
to give quinazolinones using nanocobalt [16]. Furthermore, the
Cai group has disclosed the ring-opening of isatoic anhydride and
tandem oxidative isocyanide insertion to obtain quinazolinones
[17]. Inspired by our previous work and this in-situ amidation for-
mation strategy, herein we report the straightforward preparation
of quinazolinones via the reusable carbon-supported acid-cat-
alyzed direct amidation and cascade annulation of isatoic
⇑
Corresponding authors.
E-mail addresses: andonlee@163.com (B. Li), xiefeng0401@126.com (F. Xie).
https://doi.org/10.1016/j.tetlet.2021.152835
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

X. Zhang, C. Luo, X. Chen et al.
Tetrahedron Letters 66 (2021) 152835
Results and discussion
Initially, we selected the model reaction of isatoic anhydride
(1a) with benzaldehyde (2a) and N-methylformamide (3a) to
screen different reaction parameters. Gratifyingly, the reaction
proceeded without any additive, affording 4a in 18% yield (Table 1,
Entry1). Notably, adding CF3CO2H (TFA) significantly improved the
yield to 56% (Entry 2). p-TSA was the most effective additive among
the various homogeneous protonic or Lewis acids examined
(Entries 3–7). Because p-TSA was readily soluble in the reaction
mixture and difficult to separate and reuse, a series of reusable
porous materials were used as supports. Active-carbon-supported
p-TSA was the best choice among the heterogeneous acid catalysts
examined (Entries 8–11). Furthermore, using N-methylformamide
as both the substrate and solvent was found to increase the yield
(Entry 12). Increasing the amount of 2a also resulted in an
increased yield (Entry 13). Temperature screening (Entry 14)
showed that 120 °C was sufficient for the reaction. Finally, increas-
ing the amount of p-TSA/C slightly improved the yield (Entries 15
and 16). Therefore, the optimal conditions were determined as
those described in Entry 15.
Scheme 1. Selected quinazolinone containing alkaloids and drugs.
Scheme 2. Representative methods for the synthesis of quinazolinones.
With the optimum conditions in hand, we next examined the
substrate scope and functional group tolerance of the protocol.
First, the reactions of 1a with various aldehydes were examined
(for structures, see Scheme S1 in the ESI). As shown in Scheme 3,
the desired products were obtained in moderate to excellent yields
(4a–o). Various functional groups (e.g. AOMe, AMe, naphthyl,
ACN, halogens, ASO2Me) on the aryl ring of aldehyde 2 were well
tolerated, with the electronic properties of these substituents only
slightly affecting the yields. In particular, electron-deficient groups
(4f–h) afforded higher yields compared with electron-donating
groups (4b–e). This can be attributed to the electron-withdrawing
substituents enhancing the electrophilicity of the carbonyl group,
which favors the coupling process. An ortho-substituted aromatic
anhydride with amides and aldehydes. Additionally, we explored
the selective Ru-catalyzed hydrosilylation of quinazolinones with-
out C@N bond reduction using an inexpensive silane as the hydro-
gen donor. Despite significant achievements in the Ru-catalyzed
hydrosilylation of primary amides [18], the selective hydrosilyla-
tion of quinazolinones to prepare dihydroquinazolines using
cost-effective silanes remains to be explored.
Table 1
Optimization of the reaction conditions.a
:
Entry
Additive
Yield 4a (%)b
1
–
18
2
CF3COOH
56
3
Yb(OTf)3
43
4
Ce(OTf)3
48
5
Er(OTf)3
52
6
7
Benzoic acid
p-TSA
50
60
8
9
p-TSA/Al2O3 (12 wt%)
p-TSA/diatomite (12 wt%)
p-TSA/polyaniline (12 wt%)
p-TSA/C (12 wt%)
p-TSA/C
p-TSA/C
p-TSA/C
p-TSA/C
p-TSA/C
68
70
69
71
10
11
12
13
14
15
16
[62, 38, 26, 41, 81]c
[76, 85]d
[74, 86]e
90f
89g
a
Unless otherwise stated, all reactions were performed with 1a (0.25 mmol), 2a
(0.3 mmol), 3a (2.5 mmol), additive (20 mol%), p-xylene (1 mL), 120 °C, 12 h.
b
GC yield.
c
Reactions were conducted in toluene, 1,4-dioxane, t-AmOH, DMF, and N-
methylformamide, respectively.
d
Reactions were conducted using 0.25 mmol and 0.375 mmol of 2a, respectively,
N-methylformamide (1 mL).
e
Reactions were conducted at 110 and 130 °C, respectively, using 2a
(0.375 mmol).
f
N-Methylformamide (1 mL), 2a (0.375 mmol), p-TSA/C (25 mol%, 12 wt%,
89 mg).
g
Scheme 3. Variation of the aldehydes. a Reagents and conditions: 1a (0.25 mmol), 2
(0.375 mmol), 3a (1 mL), p-TSA/C (25 mol%, 89 mg), 120 °C, 12 h. Isolated yield.
N-Methylformamide (1 mL), 2a (0.375 mmol), p-TSA/C (30 mol%, 12 wt%,
b
107 mg).
2

X. Zhang, C. Luo, X. Chen et al.
Tetrahedron Letters 66 (2021) 152835
aldehyde gave the desired product (4g) in a lower yield than the
para-substituted derivative (4f), which could be attributed to steric
hindrance. Gratifyingly, a series of heteroaryl aldehydes were
effectively coupled with 1a to afford the corresponding products
(4k–m). Notably, challenging aliphatic aldehydes were also amen-
able to this transformation, affording 2,3-alkyl-substituted quina-
zolinones in moderate yields (4n–o).
To further explore the substrate scope, various isatoic anhy-
drides were then reacted with different types of amides and alde-
hydes (for structures, see Scheme S1 in the ESI). Gratifyingly, all
substrates afforded the desired products in moderate to excellent
yields (4p–z, 4bc–jf, Scheme 4). Isatoic anhydrides containing elec-
tron-donating substituents (4p–r) gave higher yields than those
with electron-poor substituents (4s–u). This was attributed to
the electron-rich groups enhancing the nucleophilicity of interme-
diate aminobenzamide 1–1, which arises from the amidation of
isatoic anhydrides by amides, favoring addition to the aldehydes.
Furthermore, N-substituted isatoic anhydrides were also tolerated
in this transformation, affording dearomatized 2,3-dihydroquina-
zolinones in moderate yields (4v-w). Interestingly, several chal-
lenging amides (3b–d) were effective coupling partners, affording
the corresponding products in moderate yields (4x–z).
Scheme 5. Synthetic utility of the quinazolinones.
Next, we were interested in exploring the synthetic utility of
quinazolinones to construct 3,4-dihydroquinazoline derivatives,
which exhibit diverse bioactivities and act as potential pharma-
cophores for T-type calcium channel blockers and inhibitors of try-
panothione reductase [19]. All substrates underwent selective
hydrosilylation to afford the desired products in good yields with-
out reduction of the C@N bond using commercially available RuHCl
(CO)(PPh3)3 as the catalyst and phenylsilane as the hydrogen donor
(Scheme 5, 5a–f). Furthermore, dihydroquinazolinone 4v was also
tolerated in this reaction, affording 1,2,3,4-tetrahydroquinazoline
(5g) in moderate yield. Notably, 2-phenylquinazolinone (4x)
underwent aromatization to give 2-phenyl pyrimidine (5h).
To assess the stability and reusability of p-TSA/C, the model
reaction of isatoic anhydride (1a) with benzaldehyde (2a) and N-
methylformamide (3a) was performed in five successive runs. As
shown in Fig. 1, the reaction maintained high catalytic activity,
albeit with a slight decline in yield as the number of cycles
increased, demonstrating the high durability of this catalyst. The
loss of catalytic activity was attributed to the following reasons:
(i) coke formation from the supported acid resulting in pore block-
age; and (ii) reduction in active p-TSA due to mechanical abrasion-
induced leaking during the reaction process.
To gain insight into the reaction mechanism, several control
experiments were conducted (Scheme 6). First, the model reaction
was interrupted after 2 h to analyze the intermediates. In addition
to the desired product 4a (54% yield), incomplete dehydrogenation
product dihydroquinazolinone 4a-1 and intermediate aminoben-
zamide 1a-1 were observed in 22% and 13% yield, respectively
(Eq. 1). The model reaction using p-xylene was conducted to elim-
a
Scheme 4. Variation of the coupling partners. Reagents and conditions:
(0.25 mmol), 2 (0.375 mmol), 3 (1 mL), p-TSA/C (25 mol%, 89 mg), 120 °C,12 h.
Isolated yield.
1
b
Fig. 1. Reusability of the p-TSA/C catalyst.
3

X. Zhang, C. Luo, X. Chen et al.
Tetrahedron Letters 66 (2021) 152835
produce dihydroquinazolinone 4–1. Finally, the dehydrogenation
of 4–1 provides the desired product 4 using air as an oxidant.
Conclusion
In summary, we have developed a novel and straightforward
method for the synthesis of various quinazolinones via the reusa-
ble carbon-supported acid-catalyzed cascade coupling of isatoic
anhydrides with amides and aldehydes. Furthermore, we have
explored the selective Ru-catalyzed hydrosilylation of quinazoli-
nones without C@N bond reduction using a cost-effective silane
as the hydrogen donor. The cascade coupling transformation is
characterized by a broad substrate scope, excellent functional tol-
erance, and a reusable catalyst using air as the oxidant. This work
might aid the rapid and efficient construction of quinazolinone and
dihydroquinazoline derivatives with potential biological and phar-
maceutical properties.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We thank the National Natural Science Foundation of China
(21702148), Department of Education of Guangdong province
(2019KZDXM052, 2018KQNCX272, 2020KQNCX093), the Science
Foundation for Young Teachers of Wuyi University (2019td06),
the Innovation Industry Project of Wuyi University (2019CX24,
202011349025) and ‘‘Climbing Program” Special Funds of Guang-
dong Province (pdjh2021b0516) for financial support.
Scheme 6. Control experiments.
inate the interference effect of the solvent. This reaction proceeded
smoothly, affording 4a and condensed by-product 4a-2 in 76% and
8% yield, respectively (Eq. 2). As expected, the direct aromatization
of 4a-1 gave 4a in almost quantitative yield, while the dehydro-
genation reaction of 4a-1 without catalyst gave 4a in only 12%
yield (Eq. 3). Furthermore, the cyclization of 1a-1 with aldehyde
2a assisted by the supported acid afforded 4a in 92% yield, while
the condensation of 1a-1 and 2a in the absence of p-TSA/C gave
4a and 4a-1 in 48% and 28% yield, respectively (Eq. 4). These results
indicate that 4a-1 and 1a-1 serve as the main reaction intermedi-
ates. Additionally, p-TSA/C contributes to the cyclization of 1a-1
and the dehydroaromatization of 4a-1. Notably, acetamide 3e
could also be coupled with 1a and 2a to afford 4a in high yield
(Eq. 5), indicating amides can be used as an amine synthon.
With the results above and previous reports [20], a plausible
reaction pathway was proposed (Scheme 7). Initially, amide 3
undergoes nucleophilic addition to isatoic anhydride 1 to form
intermediate 10. Cleavage of the amide CAN bond assisted by
H2O in the presence of the acid catalyst affords 1–1 and HCOOH
[21]. Next, intermediate 1–1 undergoes condensation to afford
intermediate 1–2, which subsequently undergoes cyclization to
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152835.
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5