Palladium-catalyzed four-component carbonylative synthesis of 2,3-disubstituted quinazolin-4(3H)-ones: Convenient methaqualone preparation

Article abstract of DOI:10.1016/j.jcat.2018.06.007

A palladium-catalyzed four-component carbonylative cyclization reaction for the synthesis of 2,3-disubstituted quinazolin-4(3H)-ones has been developed. A range of different 2,3-disubstituted quinazolin-4(3H)-one derivatives were prepared in moderate to good yields employing simple and readily accessible 2-iodoanilines, nitro compounds and acid anhydrides as the synthetic precursors. Mo(CO)₆ acted both as a solid CO source and a reductant. Notably, methaqualone as a sedative and hypnotic medication can be prepared easily in 68% yield (4b) under our conditions as well.

Full text of DOI:10.1016/j.jcat.2018.06.007

Journal of Catalysis 365 (2018) 10–13
Contents lists available at ScienceDirect
Journal of Catalysis
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Priority Communication
Palladium-catalyzed four-component carbonylative synthesis of
,3-disubstituted quinazolin-4(3H)-ones: Convenient methaqualone
preparation
2
Jin-Bao Peng a, , Hui-Qing Geng , Wei Wang , Xinxin Qi , Jun Ying , Xiao-Feng Wu
⇑
a
a
a
a
a,b,
⇑
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed four-component carbonylative cyclization reaction for the synthesis of 2,3-
disubstituted quinazolin-4(3H)-ones has been developed. range of different 2,3-disubstituted
quinazolin-4(3H)-one derivatives were prepared in moderate to good yields employing simple and read-
ily accessible 2-iodoanilines, nitro compounds and acid anhydrides as the synthetic precursors. Mo(CO)
Received 9 April 2018
Revised 22 May 2018
Accepted 4 June 2018
A
6
acted both as a solid CO source and a reductant. Notably, methaqualone as a sedative and hypnotic med-
ication can be prepared easily in 68% yield (4b) under our conditions as well.
Ó 2018 Elsevier Inc. All rights reserved.
Keywords:
Palladium catalyst
Carbonylation
Domino reaction
Quinazolinone
Heterocycle synthesis
Cyclization
1
. Introduction
Quinazolin-4(3H)-ones represent a privileged structure motif
including our group have developed a series of carbonylative
cyclization reactions for the synthesis of quinazolinones (Scheme 1)
[6]. For example, Zhu and co-workers realized a novel concept on
quinazolinones synthesis via palladium-catalyzed carbonylative
intramolecular cyclization of N-arylamidines and N-aryl-2-
that is widely existed in pharmaceutical compounds and natural
products [1]. Among them, 2,3-disubstituted quinazolin-4(3H)-
one derivatives exhibit divers biological activities including anti-
malaria, anticonvulsant and anti-inflammatory properties (Fig. 1)
aminopyridines [6a,6n]. Willis and co-workers reported
a
palladium-catalyzed carbonylative procedure for the synthesis of
[
2]. For example, methaqualone, piriqualone and afloqualone are
2,3-disubstituted quinazolin-4(3H)-ones with N-(o-halophenyl)
sedative and hypnotic medications on the market. Ispinesib is a
selective inhibitor of kinesin spindle protein (KSP) with IC50 value
of 0.5 nM [3]. Due to its important applications as potential thera-
peutic candidates, several efficient methods have been developed
for the preparation of functionalized quinazolin-4(3H)-ones [4].
Traditionally, 2-aminobenzamide and its derivatives were usually
used as the starting materials. However, the commercial availabil-
ity of 2-aminobenzamide is limited, thus prevented the wide appli-
cation of these procedures.
imidates as the substrates [6b]. Wu’s group developed
convenient palladium-catalyzed carbonylative cyclization of 2-
bromoformanilides and organo nitro compounds with Mo(CO)
a
6
as a multiple promoter [6f]. Despite their own advancements, the
main drawback of these reactions is that the starting materials
are not readily available and some of them are difficult to
prepare. Wu, Beller and their co-workers reported a palladium-
catalyzed four-component carbonylative coupling reaction for the
synthesis of quinazolinones with commercially available 2-
bromoanilines, trimethyl orthoformate and amines as the
substrates under CO pressure [6g]. Although several other
carbonylative procedures start from 2-bromofluorobenzenes and
other have been developed by us as well [6k], only 3-substituted
or fused quinazolin-4(3H)-ones can be obtained. Notably,
Watanabe and co-workers reported an interesting work on the
synthesis of (3H)-quinazolinone derivatives from N-(2-
nitrobenzoyl)amides via reductive N-heterocyclization [6o]. By
On the other hand, transition metal-catalyzed carbonylation
reactions has now emerged as a potent method for the synthesis
of carbonyl-containing compounds [5]. Several research groups
⇑
Corresponding authors at: Department of Chemistry, Zhejiang Sci-Tech Univer-
sity, Hangzhou, Zhejiang 310018, People’s Republic of China (X.-F. Wu).
E-mail addresses: pengjb_05@zstu.edu.cn (J.-B. Peng), xiao-feng.wu@catalysis.de
(
X.-F. Wu).
https://doi.org/10.1016/j.jcat.2018.06.007
021-9517/Ó 2018 Elsevier Inc. All rights reserved.
0

J.-B. Peng et al. / Journal of Catalysis 365 (2018) 10–13
11
Fig. 1. Selected examples of bioactive 2,3-disubstituted quinazoline-4(3H)-ones.
using ruthenium or platinum complex as the catalyst, good yields
of the desired products can be achieved under 20–40 bar of CO.
Considering the importance of 2,3-disubstituted quinazolin-4
(3H)-one derivatives, developing general and economic methods
for accessing this class of compounds from simple and readily
available materials are still highly desirable.
Herein, we report a palladium-catalyzed four-component car-
bonylative cyclization reaction for the synthesis of 2,3-
disubstituted quinazolin-4(3H)-ones. The biggest challenge of this
multi-component reaction is that the anilines, generated in situ
from the reduction of nitro compounds [6f,7], would react with
the anhydrides as well to generate amides. The formation of
amides would block the nucleophilic addition to the acyl-
palladium intermediate. Thus, the combination of suitable
components and the control of the reactivity of each step is the
key to this multi-component transformation. In our system, we
employ 2-iodoanilines, nitro compounds and anhydrides as the
starting materials, and Mo(CO) as both the solid CO source [8]
6
and the reductant, 2,3-disubstituted quinazolin-4(3H)-ones were
produced in moderate to good yields.
At the start of our study, 2-iodoaniline (1a), 4-nitrobenzene (2d)
and acetic anhydride (3a) were selected as the model substrates.
To our delight, stirring
nitrobenzene, acetic anhydride and Mo(CO)
Pd(OAc) and BuPAd in 1,4-dioxane at 120 °C, the four-
a
solution of 2-iodoaniline, 4-
6
in the presence of
2
2
component carbonylative cyclization reaction proceeded success-
fully. The desired product 2-methyl-3-(p-tolyl)quinazolin-4(3H)-
one (4d) was obtained in 30% yield (Table 1, entry 1). Amide 5d
was obtained as the major by-product. Subsequently, various phos-
phine ligands were investigated. It was found that electron-rich
and sterically bulky phosphine ligand was benefit for this reaction.
For example, monodentate triarylphosphine ligands showed lower
reactivity and gave lower yields (Table 1, entry 2, also see details in
t
SI). Comparably, when tricyclohexylphosphine and P( Bu)
3
ÁHBF
4
were used as the ligands, the desired product 4d were produced
in 24% and 57% yields, respectively (Table 1, entries 3 and 4).
Bidentate phosphine ligand such as DPPF and Xantphos were also
effective for this reaction (Table 1, entries 5 and 6). The selection
of solvent also played an important role in this reaction. The yield
was improved to 62% when toluene was used as the solvent
Scheme 1. Palladium-catalyzed carbonylative synthesis of quinazolinones.
reaction was performed bellow 100 °C (Table 1, entry 11, see
details in SI). The screening of the bases revealed that Et N was
3
the optimal base, the use of DiPEA and inorganic bases resulted
in lower yields (Table 1, entry 12, also see details in SI). Further-
(Table 1, entry 8), while coordinative solvent such as THF, DMF
more, we examined the amount of Mo(CO)
6
and found that
and MeCN decreased the yields (Table 1, entry 7, also see details
in SI). This might be resulted from the competing coordination of
the solvent to the palladium catalyst. Then, different palladium
1 equivalent of Mo(CO) was essential for effective transformation
(see details in SI). It should be noted that the amount of acid anhy-
dride played a crucial role to the formation of 4d. The best result
6
catalyst precursors were tested and Pd
2
(dba)
3
gave the best result
2
was obtained when 0.8 equivalent Ac O was used (Table 1, entry
(Table 1, entries 9 and 10). The reaction temperature influenced
13). Further increasing the amount of anhydride increase the
the reaction dramatically. A slightly improved yield of 70% was
obtained when increasing the reaction temperature to 140 °C,
however, no carbonylative product was observed when the
formation of 5d and reduced the yields of 4d. Finally, addition of
2
different additives such as H O or molecular sieve failed to further
improve the outcome (Table 1, entry 14, also see details in SI).

1
2
J.-B. Peng et al. / Journal of Catalysis 365 (2018) 10–13
Table 1
Table 2
a
Optimization of the reaction conditions.
2,3-Disubstituted quinazolin-4(3H)-ones synthesis.
Entry
[Pd]
Ligand
BuPAd
Solvent
Yield
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
30
13
24
57
40
56
34
62
63
66
PPh
3
PCy
P( Bu)
DPPF
3
t
3
ÁHBF
4
Xantphos
t
P( Bu)
3
3
3
3
3
3
ÁHBF
ÁHBF
ÁHBF
ÁHBF
ÁHBF
ÁHBF
4
4
4
4
4
4
t
P( Bu)
t
PdCl
2
P( Bu)
t
10
11
12
13
14
Pd
2
Pd
2
Pd
2
(dba)
(dba)
(dba)
3
3
3
P( Bu)
t
b
P( Bu)
70
42
t
b,c
P( Bu)
t
b,d
Pd
Pd
2
(dba)
(dba)
3
P( Bu)
3
ÁHBF
ÁHBF
4
76
t
b,d,e
2
3
P( Bu)
3
4
50
a
Reaction condition: 2-iodoaniline (1.0 mmol), 4-nitrotoluene (1.2 mmol), Ac
1.5 mmol), [Pd] (2 mol%), Ligand (6 mol% for monodentate ligand; 3 mol% for
bidentate ligand), Mo(CO) (1 equiv.), Et N (2.5 equiv.), solvent (2 mL), 120 °C, 14 h,
isolated yield calculated based on 2-iodoaniline added.
2
O
(
6
3
b
1
40 °C.
DiPEA was used instead of Et
Ac O (0.8 mmol).
.0 equiv. of H O was added.
c
d
e
3
N.
2
1
2
With the optimized reaction conditions in hand (Table 1, entry
3), we studied the scope of the reaction with different iodoanili-
1
Reaction conditions: 2-iodoanilines 1 (1.0 mmol), nitro compounds
nes 1, nitro-compounds 2 and anhydrides 3. As summarized in
Table 2, firstly, a series of nitro-compounds 2 were subjected to
the optimized condition and produced the corresponding 2,3-
disubstituted quinazolin-4(3H)-ones were obtained in moderate
to good yields. Both electron-donating group (Table 2, 4b–4g)
and electron-withdrawing group (Table 2, 4h–4j) substituted
nitrobenzenes were well tolerated and delivered the correspond-
ing quinazolin-4(3H)-ones in 17–76% yields. Notably, employing
t
2
(1.2 mmol), Pd
2
(dba)
3
(1 mol%), P( Bu)
3
ÁHBF
4 6
(6 mol%), Mo(CO) (1
equiv.), Et N (2.5 equiv.), anhydride 3 (0.8 mmol), toluene (2 mL),
3
140 °C, 14 h, isolated yields calculated based on 2-iodoanilines
added.
2
-nitrotoluene 2b as the substrate, methaqualone was synthesized
in 68% yield (Table 2, 4b). Functional groups like ether and
thioether were compatible in this reaction and produced the corre-
sponding products in moderate yields (Table 2, 4e and 4f). It
should be mentioned that fluoro- and bromo-substituted
substrates were well tolerated in this transformation as well
(Table 2, 2i, 2j and 2m). However, when 1-nitro-4-vinylbenzene
was used in this reaction, only 17% yield of desired product was
obtained (Table 2, 4g). This might be caused by further transforma-
tions of the CAC double bond. Heteroaryl nitro compounds such as
2
-nitrothiophene was also suitable substrate and the correspond-
ing product was conveniently generated in 67% yield (Table 2,
k). In addition to aromatic nitro compounds, aliphatic nitro com-
4
pound such as nitromethane was tolerated as well and gave the
corresponding quinazolinone in 20% yield (Table 2, 4l). On the
other hand, substituted 2-iodoanilines were also tolerated, and
the corresponding quinazolin-4(3H)-ones were synthesized in
moderate yields (Table 2, 4m and 4n). Finally, several other anhy-
drides such as trifluoroacetic anhydride, propionic anhydride and
butyric anhydride were tested. Moderate to good yields can be
achieved without further optimization (Table 2, 4o, 4p and 4q).
Based on our results and the previous literatures, a plausible
reaction pathway is proposed with 4a as an example in Scheme 2.
First, 2-iodoaniline 1a reacted with acetic anhydride to give inter-
mediate 6. Then, the oxidative addition of CAI bond to the in situ
generated Pd(0) give the aryl-palladium complex 7. Coordination
Scheme 2. Plausible reaction mechanism.
followed by migratory insertion delivered the acyl-palladium com-
plex 8. Meanwhile, the nitro compound 2a was reduced by Mo
(CO)
6
and palladium to form the corresponding amine [6f].
Nucleophilic attacks of amine to the acylpalladium complex 8
produce the corresponding amide 9 and regenerated the catalyst
to complete the catalytic cycle. Finally, promoted the catalytic
6
of CO, which was released from Mo(CO) , to palladium centre

J.-B. Peng et al. / Journal of Catalysis 365 (2018) 10–13
12369–12377;
13
system intramolecular condensation of 9 generated the desired
final product 4a.
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2
,3-disubstituted quinazolin-4(3H)-ones. Using simple and readily
accessible 2-iodoanilines, nitro compounds and anhydrides as the
synthetic precursors, series of different 2,3-disubstituted
quinazolin-4(3H)-one derivatives were formed in moderate to
good yields. Mo(CO) acted as both a solid CO source and a reduc-
a
8
(
2
6
tant. With 2-nitrotoluene as substrate, sedative and hypnotic med-
ication methaqualone was synthesized in 68% yields.
(
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[
[
t
2
3
3
ÁHBF
4
(6 mol%) were transferred
(
into an 15 mL glass pressure tube which was filled with nitrogen.
Subsequently, toluene (2 mL), triethylamine (2.5 mmol),
(
(
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40 °C for 14 h. After the reaction was completed, the reaction
6
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1
mixture was filtered and concentrated under vacuum. The crude
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1
(
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(
Acknowledgements
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g) L. He, H. Li, H. Neumann, M. Beller, X.-F. Wu, Angew. Chem. Int. Ed. 53
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The authors thank the financial supports from NSFC (21472174,
2
1602201, 21602204, 21772177), education department of
Zhejiang Province (Y201636555), Zhejiang Sci-Tech University
16062095-Y) and Zhejiang Natural Science Fund for Distinguished
16110;
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(
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Appendix A. Supplementary material
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