Copper-catalyzed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)- ones from ortho-bromobenzamides and isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2010.11.010

Copper-catalyzed tandem reaction of ortho-bromobenzamides and isothiocyanates is described, which provides an efficient and practical route for the synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones. The optimal condition involved the following parameters: CuI as precatalyst, Cs ₂CO₃ as base, N,N′-dimethylethane-1,2-diamine as ligand, and toluene as solvent, with reaction temperature at 120 °C.

Full text of DOI:10.1016/j.tetlet.2010.11.010

Tetrahedron Letters 52 (2011) 231–235
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Tetrahedron Letters
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Copper-catalyzed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-
4(1H)-ones from ortho-bromobenzamides and isothiocyanates
Fei Wang a, Peng Zhao a, Chanjuan Xi a,b,
⇑
a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper-catalyzed tandem reaction of ortho-bromobenzamides and isothiocyanates is described, which
provides an efficient and practical route for the synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones.
The optimal condition involved the following parameters: CuI as precatalyst, Cs2CO3 as base, N,N0-
dimethylethane-1,2-diamine as ligand, and toluene as solvent, with reaction temperature at 120 °C.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 August 2010
Revised 27 October 2010
Accepted 2 November 2010
Available online 5 November 2010
Keywords:
Tandem reaction
ortho-Bromobenzamides
Isothiocyanates
2-Thioxo-2,3-dihydroquinazolin-4(1H)-one
2-Thioxo-2,3-dihydroquinazolin-4(1H)-one is an important
subclass of quinazolinones found to possess a variety of bioactivi-
ties.1 For example, altanserin (3-(2-(4-(4-fluorobenzoyl)-l-piperid-
inyl)-ethyl)-2,3-dihydro-2-thioxo-1H-quinazolin-4-one) and nitro
altanserin are drugs for 5-HT2A receptor antagonists.2 R59949, a
2,3-dihydro-2-thioxo-1H-quinazolin-4-one derivative, exhibits its
DGK (diacylglycerol kinases) inhibitor activity by activating PKC
(protein kinase C) by enhancing the levels of the endogenous li-
gand diacyl glycerol.3 The 2-thioxo-1H-4-quinazolinones are also
versatile intermediates for fused heterocycloquinazolinones,4 such
as 2-phenyl-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one, 3-(4-
bromophenyl)-2H,6H-[1,3,4]thiadiazino-[2,3-b]quinazolin-6-one,
4-amino-2-phenyl-3a,4-dihydro-2H-thiazolo[3,2-a]quinazoline-1,5-
with the substituent bonded to the N-3 position11 while N-1
substituted structures were rarely reported.12 Consequently, new
and efficient methodologies for construction of 1-aryl-2-thioxo-
2,3-dihydroquinazolin-4(1H)-ones are still desirable.
Metal catalyzed cross-coupling reactions of N-central nucleo-
philes and aryl halides have been demonstrated to be a powerful
tool in the formation of aryl C–N bonds.13–15 Recently, one-pot
strategies for the synthesis of various useful heterocyclic com-
pounds based on the copper-catalyzed C–X (X = N, O, and S) bond
formation have been studied.16–18 For example, benzimidazoles
could be efficiently formed via aryl amination/condensative cycli-
zation processes.16a–c Also, intermolecular addition/intramolecular
C–N, or C–O, or C–S coupling protocols for the formation of indo-
les,16h–l benzofurans,17b and benzothiazoles18d–g have been dis-
closed, respectively. To the best of our knowledge, there is no
report on the formation of 2-thioxo-2,3-dihydroquinazolin-
4(1H)-ones via a one-pot copper-catalyzed coupling process. Here-
in we report an efficient one-pot cascade reaction to synthesize
2-thioxo-2,3-dihydroquinazolin-4(1H)-ones: ortho-bromobenzam-
ide would undergo the intermolecular addition/intramolecular C–
N coupling process with isothiocyanate in the Cu(I)-ligand-base
system. Our proposed approach is summarized in Scheme 1. In
the presence of a proper base, the nucleophilic nitrogen of ortho-
bromobenzamide 1 would attack the carbon atom of NCS on isoth-
iocyanatobenzene 2 and intermediate 4 could be formed (step a).
In the presence of a proper copper(I) catalyst and ligand, 4 might
convert into the product 3 via an intramolecular C–N coupling
(step b). In the latter step, the nitrogen atom would take priority
over sulfur atom in the assaulting action.
dione,
and
2-phenyl-[1,3,4]thiadiazino[2,3-b]quinazoline-3,6
(2H,4H)-dione.5 General methods for the preparation of these use-
ful structural motifs include condensing the anthranilic acid with
isothiocyanates,6 reaction of aminobenzamide with carbon disul-
fide,7 reaction of 2-methoxycarbonyl phenylisothiocyanate with
amine,8 reaction of nitrobenzamide with isothiocyanates,9 and
reaction of isatoic anhydride with isothiocyanates.10 Although
some of these synthetic methods are very useful, most of them
are associated with one or the other limitations, such as involving
two or more steps, use of toxic chemicals, for example, thiophos-
gene, employment of harsh reaction conditions, long reaction time,
low reaction yields, and the low availability of starting materials.
Furthermore, most of the methods provide thioxo-quinazolines
⇑
Corresponding author. Tel.: +86 10 62782695.
E-mail address: cjxi@tsinghua.edu.cn (C. Xi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.010

232
F. Wang et al. / Tetrahedron Letters 52 (2011) 231–235
O
reaction also showed a significant dependence on temperature.
O
R1
R1
When the reaction was treated at 80 °C, the reaction did not pro-
ceed (entry 15). When the reaction mixture was warmed to
100 °C, the desired product was formed in 60% yield (entry 14).
It is noteworthy that without using CuI, the reaction proceeded
in less than 10% yield (entry 16). CuBr also gave product in 69%
yield (entry 18).
To confirm the structure of the product, colorless single crystals
of 3a suitable for X-ray diffraction analysis were obtained by
recrystallization in dichloromethane/n-hexane (5/1) at room tem-
perature. The structure of 3a in Figure 1 clearly shows the forma-
tion of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one skeleton, in
which the nitrogen ring was formed.
On the basis of these results, the optimal condition involved the
following parameters: CuI as precatalyst, Cs2CO3 as base, N,N0-
dimethylethane-1,2-diamine as ligand, and toluene as solvent,
with reaction temperature at 120 °C. Under these optimized condi-
tions, a study on the substrate scope was carried out and the re-
sults are summarized in Table 2.
In order to investigate the scope and the generality of this
method, we varied the isothiocyanates, in which several kinds
of substituent are linked to the benzene ring. To our delight,
the reaction could proceed mostly under the optimized conditions
(entries 1–5). When isothiocyanatocyclohexane 2f was treated
with ortho-bromobenzamide 1a under the similar conditions,
the desired product was not observed rather 1,3-dic-
yclohexylthiourea 5a was obtained (entry 6). This may be attrib-
uted to self-condensation under the condition.19 The reaction of
ortho-bromobenzamide with p-methyl substituent 1b could per-
form successfully (entries 7–8). When 4-F-ortho-bromobenzamide
1c was used as the substrate, the yield of product was excellent
regardless of electron-donating or electron-withdrawing group
linked to the isothiocyanates (entries 10–13). It might be attrib-
uted to the strong electron-withdrawing effect of fluoro atom,
which greatly enhanced the acidity of the amide proton. It is
noteworthy that the reaction of 4,5-dimehoxyl-ortho-bromobenz-
amide 1d with isothiocyanate 2a did not afford the desired prod-
uct, only the corresponding thiourea derivative 6a and 6b were
found (entries 14–15). Furthermore, the reaction of 5-methoxyl
ortho-bromobenzamide 1e and 4-methoxyl ortho-bromobenzam-
ide 1f with isothiocyanate 2a did not afford the desired product,
respectively, only the corresponding thiourea derivative 6a was
found (entries 16–17). It may be that the strong electron-donat-
ing group blocked the reaction.
Copper(I)/L, Base
Solvent
NH
NH2
SCN Ar
+
N
Ar
S
Br
B-
2
3
1
a
O
b
R1
NH
S
BH
N
Ar
Br
4
Scheme 1. Proposed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-
ones via intermolecular addition/intramolecular C–N coupling.
In our preliminary experiments, ortho-bromobenzamide 1a
and isothiocyanate 2a were chosen as model substrates. The reac-
tion was originally examined in toluene with CuI (10 mol %) as
precatalyst, Cs2CO3 as base at 120 °C to screen ligand (Table 1).
To our delight, among the three ligands examined, N,N0-dimethy-
lethane-1,2-diamine (DMEDA) L1 gave an excellent result (entry
1). 1,10-Phenanthroline L2 and L-proline L3 also afforded satisfy-
ing results (entries 2–3). In the absence of ligand, the reaction can
also proceed in 38% yield under the reaction conditions (entry 4).
Next, the applicability of other bases and solvents was also eval-
uated. Clearly, Cs2CO3 proved to be superior to tBuONa, DBU,
K3PO4, and K2CO3 (entry 1, entries 5–8). DABCO and AcONa
proved to be inefficient (entries 9–10). The reaction also showed
a solvent dependence. Except toluene, other solvents, such as
DMF, 1,4-dioxane, and DMSO proved to be appropriate and the
product was formed in moderate yield (entries 11–13). The
Table 1
Optimization of the reaction conditions for the formation of 3aa
O
O
10 mol% [Cu], 20 mol% L
Base, solvent, temp
NH
NH2
SCN Ph
+
N
S
Br
3a Ph
2a
1a
Entry
[Cat]
Base
Ligand
Solvent
Yielde (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
15c
16
17d
18
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
Cul
—
Cs2C03
Cs2C03
Cs2C03
Cs2C03
tBuONa
DBU
L1
L2
L3
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
82
72
65
38
58
70
53
48
Trace
NR
67
74
57
60
NR
10
62
69
In summary, we have developed a novel, concise, and efficient
one-pot synthetic method to synthesize 2-thioxo-2,3-dihydroqui-
nazolin-4(1H)-one using CuI as precatalyst. Various 2-thioxo-2,3-
dihydroquinazolin-4(1H)-ones, which might be potentially appli-
cable in the pharmaceutical and biochemical area, were conve-
niently synthesized in moderate to excellent yields.
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
K3P04
K2C03
DABCO
AcONa
Cs2C03
Cs2C03
Cs2C03
Cs2C03
Cs2C03
Cs2C03
Cs2C03
Cs2CQ3
1,4-Dioxane
DMSO
Toluene
Toluene
Toluene
Toluene
Toluene
Cul
CuBr
a
Unless otherwise noted, all the reactions were performed in sealed tube with 1a
(0.5 mmol), 2a (0.75 mmol), cat (10 mol %), ligand (20 mol %), base (1 mmol) in
2 mL solvent for 24 h.
b
The temperature was 100 °C.
The temperature was 80 °C.
c
d
The reaction time was 12 h.
e
The yields were evaluated by 1H NMR of crude product with CH2Cl2 as internal
standard.
Figure 1. The structure of 3a.

F. Wang et al. / Tetrahedron Letters 52 (2011) 231–235
233
Table 2
CuI-catalyzed one-pot synthesis of 1-aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-onesa
O
O
R1
R1
CuI (10 mol %),
DMEDA (20 mol %)
NH
NH2
SCN R2
+
Cs2CO3, Toluene
120 oC, 24 h
N
S
Br
R2
3
2
1
Entry
ortho-Bromobenzamide
Isothiocyanate
Product
Yieldb (%)
O
NCS
O
N
NH2
NH
3a
1
80
78
82
67
Br
1a
S
2a
NCS
O
N
NH
S
3b
2
3
4
1a
1a
1a
Me
2b
Me
O
NCS
Me
NH
3c
N
S
Me
2c
NCS
O
N
NH
S
S
3d
OMe
2d
OMe
O
NCS
NH
N
3e
5
1a
1a
85
Cl
2e
Cl
S
NCS
NH NH
6
7
78
75
5a
2f
O
O
N
NH
NH2
2a
Me
Br
Me
Me
S
3f
1b
O
NH
N
S
3g
8
1b
2b
72
Me
(continued on next page)

234
F. Wang et al. / Tetrahedron Letters 52 (2011) 231–235
Table 2 (continued)
Entry
ortho-Bromobenzamide
Isothiocyanate
Product
Yieldb (%)
O
O
N
NH2
NH
9
10
11
12
2a
2b
2c
2d
85
F
Br
F
S
3h
1c
O
N
NH
F
S
1c
86
87
82
3i
Me
O
NH
F
F
N
S
Me
3j
O
N
NH
S
3k
1c
OMe
O
NH
F
N
S
3l
13
1c
2e
90
Cl
O
S
MeO
MeO
NH2
N
H
N
H
14
15
2a
2c
84
62
6a
Br
1d
S
N
H
N
H
1d
Me
Me
6b
O
MeO
NH2
NH2
16
2a
2a
6a
70
65
Br
O
1e
17
6a
MeO
Br
1f
a
Unless otherwise noted, all the reactions were performed in sealed tube with 1 (0.5 mmol), 2 (0.75 mmol), CuI (10 mol %), DMEDA (20 mol %), Cs2CO3 (1 mmol) in 2 ml
toluene for 24 h.
b
Isolated yields.

F. Wang et al. / Tetrahedron Letters 52 (2011) 231–235
235
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Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, 1H, 13C NMR spectra and MS data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.010.
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