I2/CHP-Mediated Oxidative Coupling of 2-Aminobenzamides and Isocyanides: Access to 2-Aminoquinazolinones

Article abstract of DOI:10.1002/ejoc.201600876

An oxidative coupling of 2-aminobenzamides 1 and isocyanides 2 mediated by I₂and cumyl hydroperoxide (CHP) leads to the formation of 2-aminoquinazolinones 3 in moderate to excellent yields. This method provides an efficient approach to 2-aminoq

Full text of DOI:10.1002/ejoc.201600876

A Journal of
Accepted Article
Title: I2/CHP-Mediated Oxidative Coupling of 2-Aminobenzamides and Isocyanides:
Access to 2-Aminoquinazolinones
Authors: Tian-Qi Wei; Pei Xu; Shun-Yi Wang; Shun-Jun Ji
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600876
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600876
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European Journal of Organic Chemistry
10.1002/ejoc.201600876
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
I2/CHP-Mediated Oxidative Coupling of 2-Aminobenzamides and Isocyanides:
Access to 2-Aminoquinazolinones
[a]
[a]
[a]
[a]
Tian-Qi Wei, Pei Xu, Shun-Yi Wang, * and Shun-Jun Ji *
Keywords: 2-aminobenzamides / iodine / isocyanide / 2-aminoquinazolines / metal-free
An I2/cumyl hydroperoxide (CHP)-mediated oxidative
coupling of 2-aminobenzamides 1 and isocyanides 2 to construct 2-
aminoquinazolinones 3 in moderate to excellent yields has been
developed. This method provides an efficient approach to 2-
aminoquinazolinones with high atom economy under metal-free
conditions via two C-N bonds formation, which can be further
transformed to afford benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-
one 4.
(
©
WILEY-VCH Verlag GmbH
& Co. KGaA, 69451
Weinheim, Germany, 2012)
_
___________
[
a]
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science &
Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou, 215123, People’s
Republic of China
Fax: (+)86 512 65880307
E-mail: shunyi@suda.edu.cn; shunjun@suda.edu.cn
http://chemistry.suda.edu.cn/
As for the synthesis of 2-amino-substituted quinazolinones, the
reported methods mainly focus on palladium-catalyzed oxidative
[
7]
isocyanide-insertion reactions and Pd-catalyzed carbonylation
[8]
reactions with carbodiimides (Scheme 1, a, b). Isocyanides are
important and valuable C1 building blocks that have been widely
[
9]
used to construct nitrogen-containing compounds. It is worth
mentioning that intensive efforts have been devoted to the study
[
10]
Supporting information for this article is available on the WWW
under http://www.eurjoc.org/ or from the author.
of palladium-catalyzed reactions involving isocyanides.
However, these methods suffer from limited substrates, harsh
reaction conditions, expensive catalysts and the utilization of toxic
CO, which limit their further applications. Therefore, the
development of an efficient strategy to construct 2-amino-
substituted quinazolinones utilizing inexpensive catalyst under
mild conditions is more desirable. As reported in the literature,
isocyanides could be converted into carbonimidic dihalogens
Introduction
Quinazolinones exist widely in natural products with important
[
1]
biological and pharmacological activities. For example, luotonin
A I shows cytotoxicity against the murine leukemia P-388 cell
(
NCI-H460, MCF-7, and SF-268 cell lines. Nolatrexed III is
used as
thienopyrimidinone derivative IV shows good antimalarial
activity towards chloroquine sensitive(Figure 1). In view the
importance of quinazolinones, various methods for the synthesis
[
11]
[12]
[13]
through the reaction with Br2 , Cl2
or SO Cl , which
2 2
[
2]
IC50 1.8 µg/mL), tryptanthrin II is moderately cytotoxic toward
further reacted with nucleophiles to form heterocycles. Recently,
[
3]
[
11(b)]
Mirza
reported an efficient synthesis of 2-amino-substituted
[
4]
a
drug for the treatment of cancer,
and
quinazolinones under transition metal-free conditions. However,
stoichiometric Br should be used in the transformation.
2
[
5]
Iodine and compounds of iodine-mediated oxidative coupling
reactions are of great importance because they are more
environmentally friendly and less expensive in contrast to
[
1c,6]
of them have been deceloped.
[
14]
transition-metal-catalysed oxidative coupling reactions.
In our
previous work, we have developed an I /cumyl hydroperoxide
2
(
CHP) mediated cross-coupling reaction of isocyanides with
[
15]
amines for the synthesis of carbodiimides (Scheme 1, c).
The
carbonimidic diiodine intermediate was proposed as an active
species in the formation of carbodiimides. Inspired by this，we
herein report an I /CHPmediated oxidative coupling of 2-
2
aminobenzamides with isocyanides to construct various 2-amino
substituted quinazolinones under metal-free conditions.
Figure 1. Representative examples of quinazolinones.
1
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European Journal of Organic Chemistry
10.1002/ejoc.201600876
dimethylformamide. [n] DMSO = dimethyl sulfoxide. [o] Reaction time 2 h. [p] The
o
system was carried out at 80 C
Further screening of different oxidants, such as BPO, CHP,
TBPB, and K S O , showed that CHP was the best oxidant (Table
2
2
8
1
, entries 9−12). Subsequently, various solvents such as 1,4-
dioxane, MeCN, tetrahydrofuran (THF), N,N-dimethylformamide
DMF), and dimethyl sulfoxide (DMSO) were examined, which
(
demonstrated that the reaction proceeded less efficiently
compared to MTBE (Table 1, entries 13–17). To increase the
reaction yields, we further scrutinized the oxidant stoichiometry,
which suggested that 2 equiv. of CHP could achieve a satisfied
result (Table 1, entries 10, 18-19). When the reaction time reduced
to 2 h, 3aa could be obtained in 96% LC yield (Table 1, entry 20).
o
It was found that when the reaction was carried out at 80 C, the
desired product 3aa could be produced in 99% LC yield.
Therefore, the optimum reaction conditions are 10 mol % of I2
and 2 equiv. of CHP as the oxidant in MTBE at 80 °C for 2 h
(
Table 1, entry 21, 99% for 3aa).
Scheme 1. A proposed route to 2-aminoquinazolinones under
metal-free conditions
[a]
Table 2. Substrate scope of reaction
Results and Discussion
Initially, we investigated the model reaction of 2-
aminobenzamide (1a) and tert-butyl isocyanide (2a). To our
delight, 2-aminoquinazolinone 3aa was obtained in 80% LC-yield
by the reaction 1a and 2a utilizing 10 mol % of I and 2 equiv of
2
TBHP (tert-butyl hydroperoxide, 70% in water) in MTBE at 50
o
C (Table 1, entry 1). When the reaction was carried out in the
absence of catalyst, no desired product was observed (Table 1,
entry 2). Other iodo-contaning catalysts such as NIS, KI, and
TBAI led to 3aa were all less efficient compared with I (Table 1,
2
entries 1, 3-5). We also used other halide source catalysts such as
NBS, and NCS that could not promote this reaction (Table 1,
entries 6-7).
[
a]
Table 1. Optimization of reaction conditions
Oxidant
Yield
(%)
Entry
Cat. (mol%)
Solvent
[b]
(
equiv.)
[
c]
[k]
1
2
4
4
5
6
7
8
9
I
2
(10)
-
TBHP (2)
MTBE
80
NR
69
30
NR
NR
NR
8
73
92
12
13
[a] Reaction conditions:compound 1a-j (0.5 mmol), 2a (1.2 equiv, 0.6 mmol), I2 (10
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
-
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
o
[
d]
mol%), CHP (2 equiv) in 3 mL of MTBE at 80 C for 2 h, isolated yields.
NIS (10)
KI (10)
TBAI (10)
NBS (10)
NCS (10)
[
e]
To evaluate the reaction scope, we first tested various substituted
o-aminobenzamides. As shown in Table 2, most of the reactions
proceeded smoothly to afford the desired 2-aminoquinazolinones
products in moderate to excellent yields. The reaction of 2-
aminobenzamide 1a with 2a afforded the desired product 3aa in
92% yield. It should be noted that the reaction of electron-rich
aminobenzamides (Me, OMe) 1b and 1c could lead to 3ba and
3ca in 76% and 92% yields, respectively. When halogen-
substituted 2-aminobenzamides 1d−g were subjected to the
reactions, the desired products 3da−ga were observed in good
yields (78%−85%). However, a heterocyclic o-aminoamide (2-
aminonicotinamide) 1g and 2-amino-N-methylbenzamide 1h
could only offer the desired product 3ga and 3ha in 22% and 32%
yields, respectively. Unfortunately, the reaction of 2-amino-4-
nitrobenzamide 1j only led to the corresponding product 3ja in
trace yield.
[f]
[
g]
I
I
2
I
2
I
2
2
(10)
(10)
(10)
(10)
(10)
[
h]
BPO (2)
CHP (2)
[
i]
1
1
1
0
1
2
[
j]
TBPB (2)
(2)
I
2
2 2 8
K S O
1
,4-
1
3
I
2
(10)
CHP (2)
72
dioxane
MeCN
THF
1
1
1
1
1
1
4
5
6
7
8
9
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
CHP (2)
CHP (2)
CHP (2)
CHP (2)
CHP (1)
CHP (3)
CHP (2)
CHP (2)
24
57
7
16
89
87
96
99
[
l]
[
m]
DMF
n]
DMSO[
MTBE
MTBE
MTBE
MTBE
[o]
2
1
0
[
o,p]
2
[a] Reaction Conditions : 1a (0.5 mmol), 2a (1.2 equiv., 0.6 mmol), catalyst and
oxidant in 3 mL of solvent at 50 oC for 4 h, under air. [b] Yields were determined by
LC-MS analysis using biphenyl as an internal standard. [c] TBHP(70% in H2O). [d]
NIS = N-iodosuccinimide. [e] TBAI = tertabutylammonium iodide. [f] NBS = N-
bromosuccinimide. [g] NCS = N-chlorosuccinimide. [h] BPO = benzoyl peroxide. [i]
CHP = cumene hydroperoxide. [j] TBPB = tert-butylperoxybenzoate. [k] MTBE =
Next, we investigated the scope of isocyanides (Table 3).
Pleasingly, almost all examined substrates underwent clean
conversion to the desired 2-aminoquinazolinones under the
standard conditions. The reactions of tertiary isocyanide 2b
methyl tert-butyl ether. [l] THF
=
terahydrofuran.
[m] DMF = N,N-
(adamantanyl isocyanide) and secondary isocyanide 2c
2
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European Journal of Organic Chemistry
10.1002/ejoc.201600876
(isocyanocyclohexane) could led to the desired products 3ab and
3
ac in 84% and 92% yields, respectively. Unfortunately, primary
aliphatic isocyanide 1d easy decomposed under the established
conditions and only trace product was detected. It is worth noting
that all aromatic isocyanides were suitable for this transformation
(
2e-m). Even if sterically bulky isocyanides such as 2,6-
dimethylphenyl isocyanide (2e), 2,4,6-trimethylphenyl isocyanide
2f ), 2,6-diethylphenyl isocyanide (2g) and 2,6-diisopropylphenyl
isocyanide (2h) were used, the corresponding 3ea, 3fa, 3ga and
ha were obtained in 90-95% yields.
(
3
[
a]
Table 3. The reaction of 1a with other isocyanides.
Scheme 3. Proposed Mechanism.
Conclusions
In summary, we have developed a novel I /CHP-mediated
2
oxidative coupling reaction of readily accessible 2-aminoamides
with isocyanides. This protocol provides a new, atom efficient and
straightforward approach to construct 2-aminoquinazolinones 3
via two C-N bonds formation under metal-free conditions. 2-
Aminoquinazolinones 3 can be further transformed to afford
benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one 4.
[
a] Reaction Conditions: compound 1a (0.5 mmol), 2b-m (1.2 equiv, 0.6 mmol),
o
I2 (10 mol%), CHP (2 equiv) in 3 mL of MTBE at 80 C for 2 h, isolated yields.
To further explore the diversity utility of our above reactions,
we applied the 2-amino substituted quinazolinones in other
transformations. For example, the reaction of 2-((2-
iodophenyl)amino)quinazolin-4(3H)-one 3al catalyzed by CuI
under base conditions easily led to benzo[4,5]imidazo[2,1-
Experimental Section
General Information. All the solvents for routine isolation of
products and chromatography were reagent grade. Flash
chromatography was performed using silica gel (300−400 mesh)
with the indicated solvents. Melting points were recorded on an
Electrothermal digital melting point apparatus and were
uncorrected. IR spectra were recorded on a spectrophotometer
[
16]
b]quinazolin-12(6H)-one 4 in 83% yield (Scheme 2),
which
[
17]
exhibits potent immunosuppressive activity.
1
13
using KBr optics. H NMR and C NMR spectra were recorded
1
13
on a 400 MHz ( H NMR) and 100 MHz ( C NMR) spectrometer
using CDCl3 or DMSO-d6 as solvent and TMS as internal
1
standard. The H NMR data are reported as the chemical shift in
parts per million, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant in hertz, and number of
protons. High resolution mass spectra were obtained using a high
resolution ESI-TOF mass spectrometer.
Scheme 2. Transformation of 2-aminoquinozolinones.
On the basis of the above results, a plausible reaction
mechanism is illustrated in Scheme 3. Isocyanide 2 reacts with
[
11-13, 15, 18]
iodine via 1,1-addition to furnish intermediate I.
The
2-(tert-butylamino)quinazolin-4(3H)-one (3aa). To a mixture of
reaction of I with 2-aminobenzamide 1 affords intermediate II by
dehydrohalogenation. Hydrogen iodide is oxidized by CHP to
furnish iodine and complete the catalytic cycle. Following the
subsequent second time dehydrohalogenation, carbodiimide III
2
-aminobenzamide 1a (0.5 mmol), I2 (0.05 mmol), Cumene
Hydroperoxide (CHP) (80% - 85%) (1 mmol) and isocyanide 2a
0.6 mmol) were added in 3 mL MTBE to test tube. The test tube
(
o
was closed. The reaction mix-ture was stirred at 80 C. When the
reactions were completed(checked by TLC), they were cooled to
room temperature, washed with 10% Na S O Solution(3*15 mL)
(
Scheme 3, path a) or IV (Scheme 3, path b) is formed. After
subsequently intramolecule cycliazation of III or isomerization of
IV, 3 is formed.
2
2
3
and extracted with Ethyl acetate(3*15 mL). The combined organic
layers were dried over Na SO . Removal of solvent followed by
2
4
flash column chromatographic purification afforded 3aa using
petroleum and Ethyl acetate. White solid (99 mg, 92%), m.p.:
o
-1
1
1
53-154 C. IR (neat, ν, cm ): 3378, 3355, 1646, 756. H NMR
(
(
400 MHz, Chloroform-d) δ 8.31 (t, J = 9.3 Hz, 1H), 7.52 – 7.43
m, 2H), 7.41 (s, 1H), 6.97 (t, J = 7.5 Hz, 1H), 5.77 (s, 1H), 1.40
3
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European Journal of Organic Chemistry
10.1002/ejoc.201600876
1
3
(
1
s, 9H) ppm. C NMR (100 MHz, Chloroform-d) δ 153.2 , 142.8 ,
2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (3ia). Pale
o
-1
33.7 , 131.8 , 121.2 , 119.9 , 50.4 , 28.6 ppm. HRMS (ESI) m/z:
Found: 218.1300. Calcd for C H N O : (M+H) 218.1293.
yellow solid (37 mg, 32%), m.p.: 116-118 C. IR (neat, ν, cm ):
+
+
1
3377, 3060, 2957, 1665, 1210, 765. H NMR (400 MHz,
1
2
16
3
Chloroform-d) δ 8.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (ddd, J = 8.4,
7.0, 1.6 Hz, 1H), 7.37 (dd, J = 8.2, 1.1 Hz, 1H), 7.13 (ddd, J = 8.2,
7.0, 1.2 Hz, 1H), 4.35 (s, 1H), 3.47 (s, 3H), 1.56 (s, 9H). C NMR
2
-(tert-butylamino)-7-methylquinazolin-4(3H)-one
(3ba).
-1
o
13
White solid (88 mg, 76%), m.p.: 156-158 C. IR (neat, ν, cm ):
3
1
324, 2928, 1651, 814. H NMR (400 MHz, Chloroform-d) δ 8.19
(100 MHz, CDCl
3
) δ 162.4, 148.3, 147.9, 133.5, 126.4, 124.7,
(s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.80 (d,
121.8, 116.3, 52.2, 28.7, 27.0 ppm. HRMS (ESI) m/z: Found:
1
3
+
+
J = 7.9 Hz, 1H), 5.58 (s, 1H), 2.36 (s, 3H), 1.41 (s, 9H). C NMR
100 MHz, CDCl ) δ 153.2, 145.3, 142.7, 131.5, 122.3, 119.9,
232.1441. Calcd for C13
H N O : (M+H) 232.1450.
18 3
(
3
1
2
17.5, 95.8, 50.4, 28.6, 21.8 ppm. HRMS (ESI) m/z: Found:
2
-(((3s,5s,7s)-adamantan-1-yl)amino)quinazolin-4(3H)-one
+
+
32.1444. Calcd for C H N O : (M+H) 232.1450.
o
1
3
18
3
(3ab). White solid (124 mg, 84%), m.p.: 193-194 C. IR (neat, ν,
-
1
1
cm ): 3324, 2928, 1651, 1523, 814. H NMR (400 MHz, DMSO-
d6) δ 8.33 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.64 (dd, J = 7.8, 1.6
Hz, 1H), 7.57 – 7.47 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.85 (s,
H), 2.02 (s, 3H), 1.94 (d, J = 3.0 Hz, 6H), 1.63 (d, J = 3.0 Hz,
6H). C NMR (100 MHz, DMSO-d ) δ 152.9, 143.0, 133.7, 132.9,
2
-(tert-butylamino)-6-methoxyquinazolin-4(3H)-one
(3ca).
-1
o
White solid (114 mg, 92%), m.p.: 136-136 C. IR (neat, ν, cm ):
3
δ 8.07 (dd, J = 9.2, 2.1 Hz, 1H), 7.07 (dd, J = 9.0, 3.3 Hz, 2H),
6
1
330, 2963, 1656, 1205, 827. H NMR (400 MHz, Chloroform-d)
1
1
3
1
3
6
.93 (s, 1H), 5.32 (s, 1H), 3.77 (s, 3H), 1.39 (s, 9H). C NMR
1
21.6, 120.0, 117.1, 99.9, 50.2, 41.4, 36.0, 28.9 ppm. HRMS (ESI)
+ +
(100 MHz, CDCl ) δ 153.8, 153.5, 136.0, 122.6, 120.6, 116.8,
3
m/z: Found: 296.1759. Calcd for C H N O : (M+H) 296.1763.
1
8
22
3
115.1, 101.0, 55.3, 50.4, 28.7 ppm. HRMS (ESI) m/z: Found:
+
+
2
48.1390. Calcd for C H N O : (M+H) 248.1399.
1
3
18
3
2
2
-(cyclohexylamino)quinazolin-4(3H)-one (3ac). White solid
o
-1
2
-(tert-butylamino)-5-fluoroquinazolin-4(3H)-one (3da). White
(112 mg, 92%), m.p.: 192-193 C. IR (neat, ν, cm ): 3315, 2926,
2860, 1632, 1560, 757. H NMR (400 MHz, DMSO-d ) δ 8.37 (s,
o
-1
1
solid (92 mg, 78%), m.p.: 139-141 C. IR (neat, ν, cm ): 3390,
2
6
1
967, 2930, 1656, 1212, 810. H NMR (400 MHz, Chloroform-d)
1H), 8.13 (d, J = 8.6 Hz, 1H), 7.85 – 7.40 (m, 2H), 7.04 (q, J = 7.9
Hz, 2H), 3.48 (d, J = 10.3 Hz, 1H), 1.66 (td, J = 58.1, 52.4, 12.1
Hz, 5H), 1.24 (dt, J = 41.2, 11.3 Hz, 5H). C NMR (100 MHz,
δ 8.21 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 8.6, 6.7 Hz, 1H), 7.31 (s,
1
3
13
1
H), 6.73 (t, J = 8.5 Hz, 1H), 5.64 (s, 1H), 1.42 (s, 9H). C NMR
(
100 MHz, CDCl ) δ 164.1, 161.6, 152.6, 144.5, 135.3, 135.2,
DMSO-d
6
) δ 153.5, 142.9, 133.8, 132.9, 121.7, 120.0, 117.0,
3
1
14.6, 114.6, 112.9, 107.4, 107.2, 88.4, 88.2, 50.6, 28.5 ppm.
100.1, 47.7, 32.7, 25.2, 24.2 ppm. HRMS (ESI) m/z: Found:
+
+
+
HRMS (ESI) m/z: Found: 236.1192. Calcd for C H FN O :
244.1439. Calcd for C12
H N O : (M+H) 244.1450.
18 3
1
2
15
3
+
(M+H) 236.1199.
2
-((2,6-dimethylphenyl)amino)quinazolin-4(3H)-one
(3ae).
-1
o
2
-(tert-butylamino)-7-chloroquinazolin-4(3H)-one (3ea). White
White solid (126 mg, 95%), m.p.: 187-188 C. IR (neat, ν, cm ):
3
1
o
-1
1
solid (99 mg, 79%), m.p.: 158-159 C. IR ((neat, ν, cm ): 3330,
2
δ 8.49 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H),δ
6
309, 3253, 1644, 756. H NMR (400 MHz, DMSO-d ) δ 8.86 (s,
6
1
967, 2930, 1656, 1212, 810. H NMR (400 MHz, Chloroform-d)
H), 8.46 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.8 Hz),
7.61 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 26.1 Hz, 4H), 2.24 (s, 6H).
1
3
13
.96 (dd, J = 8.4, 2.0 Hz, 1H), 5.63 (s, 1H), 1.41 (s, 9H). C NMR
C NMR (100 MHz, DMSO-d ) δ 152.6, 142.5, 135.4, 134.8,
6
(100 MHz, CDCl ) δ 152.5, 143.8, 140.7, 132.5, 121.5, 119.5,
3
133.9, 133.0, 127.8, 126.2, 122.7, 121.1, 117.1, 18.2 ppm. HRMS
+
+
116.6, 96.5, 50.6, 28.6 ppm. HRMS (ESI) m/z: Found: 252.0898.
(ESI) m/z: Found: 266.1299. Calcd for C H N O : (M+H)
16 16 3
+
+
Calcd for C H ClN O : (M+H) 252.0904.
1
2
15
3
266.1293.
2
-(tert-butylamino)-6-chloroquinazolin-4(3H)-one (3fa) White
2
-(mesitylamino)quinazolin-4(3H)-one (3af). Pale yellow solid
o
-1
solid (106 mg, 85%), m.p.: 171-172 C. IR ((neat, ν, cm ): 3343,
2
Chloroform-d) δ 8.31 (d, J = 9.1 Hz, 1H), 7.62 – 7.34 (m, 2H),
7
MHz, CDCl ) δ 152.7, 141.6, 134.0, 130.7, 126.0, 121.1, 115.9,
9
for C H ClN O : (M+H) 252.0904.
o
-1
(130 mg, 93%), m.p.:191-193 C. IR (neat, ν, cm ): 3329, 2917,
1
988, 2965, 1652, 1555, 1216, 880. H NMR (400 MHz,
1
2
852, 1640, 1539, 1489, 1227, 757. H NMR (400 MHz, DMSO-
d6) δ 8.82 (s, 1H), 8.38 (s, 1H), 8.12 – 8.01 (m, 1H), 7.71 (d, J =
.7 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.88
1
3
.26 (q, J = 5.4 Hz, 1H), 5.54 (s, 1H), 1.40 (s, 9H). C NMR (101
7
13
3
(
s, 2H), 2.23 (s, 3H), 2.19 (s, 6H). C NMR (100 MHz, DMSO-d6)
δ 152.7, 142.5, 135.1, 133.8, 133.0, 132.1, 128.3, 122.5, 120.9,
17.1, 101.5, 20.4, 18.1 ppm. HRMS (ESI) m/z: Found: 280.1447.
9.9, 50.6, 28.6. ppm. HRMS (ESI) m/z: Found: 252.0901. Calcd
+
+
1
2
15
3
1
+
+
Calcd for C H N O : (M+H) 280.1450.
1
7
18
3
6
-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (3ga). White
o
-1
solid (123 mg, 83%), m.p.: 174-175 C. IR (neat, ν, cm ): 3342,
2
Chloroform-d) δ 8.23 (dd, J = 9.1, 2.7 Hz, 1H), 7.78 – 7.46 (m,
2
CDCl ) δ 152.8, 142.0, 136.8, 133.6, 121.3, 115.7, 112.8, 100.4,
5
C H BrN O : (M+H) 296.0398.
1
2-((2,6-diethylphenyl)amino)quinazolin-4(3H)-one
White solid (132 mg, 90%), m.p.: 181-182 C. IR (neat, ν, cm ):
3302, 2967, 2958, 1648, 764, 682. H NMR (400 MHz, DMSO-d )
δ 8.86 (s, 1H), 8.40 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.73 (d, J =
(3ag).
-1
961, 1652, 1552, 1213, 1122, 838, 758, 630. H NMR (400 MHz,
o
1
1
3
6
H), 7.36 (s, 1H), 5.70 (s, 1H), 1.40 (s, 9H). C NMR (100 MHz,
3
7
.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.14 (dt, J = 15.4, 8.0 Hz,
0.6, 28.6 ppm. HRMS (ESI) m/z: Found: 296.0388. Calcd for
1
3
+
+
4H), 2.59 (q, J = 7.6 Hz, 4H), 1.14 (t, J = 7.6 Hz, 6H). C NMR
100 MHz, DMSO-d ) δ 153.3, 142.5, 141.8, 133.9, 133.4, 133.1,
1
2
15
3
(
6
1
27.0, 126.0, 122.6, 120.9, 117.0, 101.5, 24.4, 14.6 ppm. HRMS
2
-(tert-butylamino)pyrido[2,3-d]pyrimidin-4(3H)-one
(3ha).
+
+
(ESI) m/z: Found: 294.1600. Calcd for C H N O : (M+H)
18 20 3
o
-1
White solid (25 mg, 22%), m.p.: 132-134 C. IR (neat, ν, cm ):
3
2
94.1606.
1
213, 2985, 2958, 1680, 750, 670. H NMR (400 MHz,
Chloroform-d) δ 9.15 (s, 1H), 8.38 (dd, J = 5.1, 1.9 Hz, 1H), 7.88
2
-((2,6-diisopropylphenyl)amino)quinazolin-4(3H)-one (3ah).
(
1
1
dd, J = 7.7, 1.9 Hz, 1H), 7.17 (s, 1H), 6.97 (dd, J = 7.7, 5.1 Hz,
o
-1
1
3
White solid (147 mg, 92%), m.p.: 191-193 C. IR (neat, ν, cm ):
3
NMR (400 MHz, DMSO-d ) δ 8.86 (s, 1H, -NH), 8.41 (s, 1H, -
NH), 8.11 (d, J = 8.5 Hz, 1H, -ArH), 7.72 (d, J = 7.8 Hz, 1H, -
ArH), 7.60 (t, J = 8.0 Hz, 1H, ArH), 7.35 – 7.06 (m, 4H), 3.18 (p,
H), 1.44 (s, 9H). C NMR (100 MHz, CDCl ) δ 153.4, 151.4,
3
1
249, 3065, 2962, 1641, 1549, 1236, 1641, 1549, 1236, 754. H
50.0, 141.9, 115.4, 114.2, 94.5, 50.5, 28.5 ppm. HRMS (ESI) m/z:
+
+
6
Found: 219.1236. Calcd for C H N O : (M+H) 219.1246.
11
15
4
1
3
J = 6.9 Hz, 2H), 1.16 (d, J = 6.9 Hz, 12H). C NMR (100 MHz,
4
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600876
DMSO-d ) δ 153.7, 146.4, 142.6, 134.0, 133.0, 131.8, 127.4,
Acknowledgments
6
1
22.9, 122.4, 120.6, 117.0, 101.2, 28.0, 23.9, 23.1 ppm. HRMS
+
+
(ESI) m/z: Found: 322.1911. Calcd for C H N O : (M+H)
20 24 3
We gratefully acknowledge the Natural Science Foundation of China
21372174, 21542015, 21672157), PAPD, and Soochow University for
3
22.1919.
(
financial support, and State and Local Joint Engineering Laboratory for
Novel Functional Polymeric Materials.
2
-((4-methoxyphenyl)amino)quinazolin-4(3H)-one (3ai). Pale
o
-1
_
___________
yellow solid (125 mg, 93%), m.p.: 187-188 C. IR (neat, ν, cm ):
1
3
1
1
7
298, 3276, 1645, 756. H NMR (400 MHz, DMSO-d ) δ 9.21 (s,
[1] a) I. Khan, A. Ibrar, N. Abbas, A. Saeed, Eur. J. Med. Chem. 2014,
6
7
2
6, 193-244; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
014, 57, 10257-10274; c) D. J. Connolly, D. Cusack, T. P. O’Sullivan, P.
H), 8.65 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 7.8 Hz,
H), 7.62 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.16 (t, J =
1
3
J. Guiry, Tetrahedron. 2005, 61, 10153-10202; d) S. B. Mhaske, N. P.
Argade, Tetrahedron. 2006, 62, 9787-9826; e) C. E. Houlden, M. Hutchby,
C. D. Bailey, J. G. Ford, S. N. G. Tyler, M. R. Gagne, ꢀ. C. ꢁloyd-Jones,
.7 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H). C NMR (100
MHz, DMSO-d ) δ 154.8, 152.1, 142.1, 133.9, 133.1, 132.1, 122.7,
1
Found: 268.1078. Calcd for C H N O : (M+H) 268.1086.
6
21.0, 120.1, 117.0, 114.1, 101.6, 55.1 ppm. HRMS (ESI) m/z:
ꢂ. I.
ꢃ
ꢄooker-Milburn, Angew. Chem., Int. Ed. 2009, 48, 1830 -1833.
2] J. S. Yadav, B. V. S. Reddy, Tetrahedron Lett. 2002, 43, 1905-1907.
3] C.-W. Jao, W.-C. Lin, Y.-T. Wu, P.-L. Wu, J. Nat. Prod. 2008, 71,
+ +
1
5
14
3
2
[
[
2
-((3,5-dimethoxyphenyl)amino)quinazolin-4(3H)-one
(3aj).
o
1275-1279.
Pale brown solid (134 mg, 90%), m.p.: 187-188 C. IR (neat, ν,
cm ): 3299, 3246, 1639, 1159, 768, 647. H NMR (400 MHz,
DMSO-d ) δ 9.42 (s, 1H), 8.71 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H),
-
1
1
[4] K. Stuart, J. Tessitore, J. Rudy, N. Clendennin, A. Johnston, Cancer.
1999, 86, 410-414.
6
7
1
1
5
.88 – 7.49 (m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 6.70 (s, 2H), 6.18 (s,
[
5] A. Cohen, P. Suzanne, J. C. Lancelot, P. Verhaeghe, A. Lesnard, L.
1
3
H), 3.72 (s, 6H). C NMR (100 MHz, DMSO-d ) δ 160.6, 151.8,
6
Basmaciyan, S. Hutter, M. Laget, A. Dumetre, L. Paloque, E. Deharo, M.
D. Crozet, P. Rathelot, P. Dallemagne, A. Lorthiois, C. H. Sibley, P.
Vanelle, A. Valentin, D. Mazier, S. Rault, N. Azas, Eur. J. Med. Chem.
41.8, 140.9, 134.0, 133.1, 123.0, 121.1, 116.9, 101.8, 96.5, 94.4,
5.0 ppm. HRMS (ESI) m/z: Found: 298.1191. Calcd for
+
+
2
015, 95, 16-28.
C H N O : (M+H) 298.1192.
1
6
16
3
3
[
6] R. S. Rohokale, U. A. Kshirsagar, Synthesis. 2016, 48, 1253-1268.
2
-((4-chlorophenyl)amino)quinazolin-4(3H)-one (3ak). White
[
7] a) S. Sharma, A. Jain, Tetrahedron Lett. 2014, 55, 6051-6054; b) J. Fei,
o
-1
solid (109 mg, 80%), m.p.: 204-205 C. IR (neat, ν, cm ): 3316,
2
9
M.-F. Lv, W.-B. Yi, C. Cai, Org. Biomol. Chem. 2014, 12, 5766-5772; c)
T. Vlaar, R. C. Cioc, P. Mampuys, B. U. W. Maes, R. V. A. Orru, E.
Ruijter, Angew. Chem., Int. Ed. 2012, 51, 13058-13061.
1
926, 2860, 1632, 1560, 758. H NMR (400 MHz, DMSO-d ) δ
6
.52 (s, 1H), 8.78 (s, 1H), 8.05 (dd, J = 8.5, 3.5 Hz, 1H), 7.76 (dd,
J = 7.8, 1.8 Hz, 1H), 7.69 – 7.60 (m, 1H), 7.56 – 7.46 (m, 2H),
1
3
7
.45 – 7.29 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H). C NMR (100 MHz,
[
8] a) C. Larksarp, H. Alper, J. Org. Chem. 2000, 65, 2773-2777; b) F.
DMSO-d ) δ 151.9, 141.7, 138.2, 134.0, 133.1, 128.7, 125.9,
Zeng, H. Alper, Org. Lett. 2010, 12, 1188-1191.
6
1
2
23.2, 121.4, 119.9, 116.9, 102.3 ppm. HRMS (ESI) m/z: Found:
+
+
72.0583. Calcd for C H ClN O : (M+H) 272.0591.
1
4
11
3
[9] a) S. Sadjadi, M. M. Heravi, Tetrahedron. 2011, 67, 2707-2752; b) J.
Zhu, Eur. J. Org. Chem. 2003, 1133-1144; c) Y. Fang, S. -Y. Wang, X.-B.
Shen, S.-J. Ji, Org. Chem. Front. 2015, 2, 1338-1341; d) E. Ruijter, R.
Scheffelaar, R. V. A. Orru, Angew. Chem.,Int. Ed. 2011, 50, 6234-6246; e)
T.-H. Zhu, T.-Q. Wei, S.-Y. Wang, S.-J. Ji, Org. Chem. Front. 2015, 2,
2
-((2-iodophenyl)amino)quinazolin-4(3H)-one (3al). Brown
o
-1
solid (146 mg, 80%), m.p.:178-179 C. IR (neat, ν, cm ): 3267,
1
3
9
7
064, 1646, 1548, 1015, 758. H NMR (400 MHz, DMSO-d ) δ
6
2
3
2
59-264; f) A. Do¨mling, I. Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168–
210; g) M. Bouma, G. Masson, J.-P. Zhu, J. Org. Chem. 2010, 75, 2748-
751; h) H. Jiang, Y.-Z. Cheng, R.-Z. Wang, Y. Zhang, S.-Y. Yu, Chem.
.43 (s, 1H), 8.63 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.86 (d, J =
.9 Hz, 1H), 7.75 (t, J = 9.6 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.36
(t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz,
Commun. 2014, 50, 6164—6167; i) X.-Y. Sun, S.-Y. Yu, Chin. J. Org.
Chem. 2016, 36, 239-247.
1
3
1
1
H). C NMR (100 MHz, DMSO-d ) δ 152.3, 141.7, 139.5, 139.0,
6
33.9, 133.2, 128.5, 125.8, 124.4, 123.3, 121.9, 117.0, 102.4, 92.5
+
ppm. HRMS (ESI) m/z: Found: 363.9936. Calcd for C H IN O :
1
4
11
3
[
5
10] a) G.-Y.-S. Qiu, Q.-P. Ding, J. Wu, Chem. Soc. Rev. 2013, 42, 5257-
269; b) S. Lang, Chem. Soc. Rev. 2013, 42, 4867-4880; c) J. Wang, S.
+
(M+H) 363.9947.
Luo, J. Li, Q. Zhu, Org. Chem. Front. 2014, 1, 1285–1288; d) P.
Boissarie, Z. Hamilton, S. Lang, J. Murphy, C. Suckling, Org. Lett. 2011,
methyl
(E)-3-(2-((4-oxo-3,4-dihydroquinazolin-2-
1
3, 6256-6259; e) M. Tobisu, S. Y. Imoto, S. Ito, N. Chatani, J. Org.
yl)amino)phenyl)acrylate (3am). Yellow solid (92 mg, 57%),
m.p.:171-172 C. IR (neat, ν, cm ): 3281, 2922, 1710, 1649, 976,
Chem. 2010, 75, 4835-4840; f) B.-F. Liu, Y.-B. Li, M.-Z. Yin, W.-Q. Wu,
H.-F. Jiang, Chem. Commun. 2012, 48, 11446–11448. g) T. Vlaar, E.
Ruijter, B. U. W. Maes, R. V. A. Orru, Angew. Chem., Int. Ed. 2013, 52,
7084-7097.
o
-1
1
7
58, 680. H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 8.5
Hz, 1H), 8.14 – 7.98 (m, 2H), 7.93 (s, 1H), 7.83 (d, J = 8.1 Hz,
H), 7.58 – 7.46 (m, 3H), 7.39 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.6
Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 15.8 Hz, 1H), 3.71
1
[
11] a) F. Jung, C. Delvare, D. Boucherot, A. Hamon, Tetrahedron Letters.
1
3
(s, 3H). C NMR (100 MHz, CDCl ) δ 167.2, 152.2, 141.6, 139.6,
1989, 30, 2375–2378; b) B. Mirza, Tetrahedron Letters. 2016, 57, 146–
147; c) El. L. Kaim, L. Grimaud, P. Patil, Org. Lett. 2011, 13, 1261-1263.
3
1
1
3
35.8, 133.8, 132.0, 130.6, 127.1, 126.6, 124.9, 124.4, 122.3,
20.4, 119.3, 116.8, 100.4, 51.4 ppm. HRMS (ESI) m/z: Found:
22.1187. Calcd for C H N O : (M+H) 322.1192.
[
12] A. G. Ulhe, S. A. Chavan, B. N. Berad, Phosphorus, Sulfur, and
+
+
1
8
16
3
3
Silicon and the Related Elements. 2015, 190, 170-177.
benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (4). White
[13] S. Schann, H. Greney, V. Gasparik, M. Dontenwill, C. Rascente, G.
Lacroix, L. Monassier, V. Bruban, J. Feldman, J. D. Ehrhardt, Bioorg.
Med. Chem. 2012, 20, 4710-4715.
o
-1
solid (59 mg, 83%), m.p.: > 300 C. IR (neat, ν, cm ): 3264, 1720,
1
1
8
=
646, 1227, 757. H NMR (400 MHz, DMSO-d ) δ 11.94 (s, 1H),
6
.32 (dd, J = 21.3, 7.7 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.64 (t, J
7.3 Hz, 1H), 7.53 – 7.31 (m, 4H). C NMR (100 MHz, DMSO-
1
3
[14] a) M.S. Yusubov, V.V. Zhdankin, Resource-Efficient Tech 2015, 1,
49–67; b) D. Liu, A.-W. Lei, Chem. Asian J. 2015, 10, 806-823; c) V. O.
Iaroshenko, S. Dudkin, V. Y. Sosnovskikh, A. Villinger, P. Langer,
Synthesis. 2013, 45, 0971–0977, d) M. Uyanik, K. Lshihara,
ChemCatChem 2012, 4, 177-185; e) Y.-P. Zhu, F.-C. Jia, M.-C. Liu, L.-M.
Wu, Q. Cai, Y. Gao, A.-X. Wu, Org. Lett. 2012, 14, 5378-5381; f) Z.-J.
Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 2013, 15, 5226-5229; g) X. Zhang, M.
d6) δ 147.6, 146.3, 143.5, 137.1, 132.2, 130.6, 124.9, 124.4, 123.6,
1
2
23.3, 119.1, 115.8, 114.7, 111.7 ppm. HRMS (ESI) m/z: Found:
+
+
36.0814. Calcd for C H N O : (M+H) 236.0824.
1
4
9
3
Supporting Information (see footnote on the first page of this article):
5
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600876
Wang, P. Li, L. Wang, Chem. Commun. 2014, 50, 8006–8009; h) J. Zhang,
D. Zhu, C. Yu, C. Wan, Z. Wang, Org. Lett. 2010, 12, 2841–2843.
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15] T.- H. Zhu, S.- Y. Wang, Y.- Q. Tao, S.- J. Ji, Org. Lett. 2015, 17,
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Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
6
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600876
I2/CHP-Mediated
Oxidative Coupling of 2-
Aminobenzamides and
Isocyanides: Access to 2-
Aminoquinazolinones
Tian-Qi Wei, Pei Xu,
Shun-Yi Wang,* and
Shun-Jun Ji*
…
….... Page No. – Page No.
Keywords: 2-
aminobenzamides / iodine
/
isocyanide / 2-
aminoquinazolines /
metal-free
An I / cumyl hydroperoxide(CHP)-mediated oxidative coupling of 2-aminobenzamides 1 and
2
isocyanides 2 to construct 2-aminoquinazolinones 3 in moderate to excellent yields has been
developed. This method provides an efficient approach to 2-aminoquinazolinones with high atom
economy under metal-free conditions via two C-N bonds formation, which can be further transformed
to afford benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one 4.
7
This article is protected by copyright. All rights reserved