Metal-free synthesis of benzimidazo[1,2-c]quinazolin-6-ones with indole and benzenediamine oxidized by I2/TBHP

Article abstract of DOI:10.1016/j.tet.2019.02.022

A variety of benzimidazo[1,2-c]quinazolin-6-ones derivatives can be accessed in moderate to good yields under simple and metal-free reaction conditions using indoles and o-benzenediamines oxidized by iodine and TBHP. This procedure works in reasonable yields for different indoles as well as o-benzenediamines thus may provide a good synthesis of quinazolinones. A TBHP oxidized ring expansion reaction mechanism that explains the synthesis of benzimidazo[1,2-c]quinazolin-6-ones were reported.

Full text of DOI:10.1016/j.tet.2019.02.022

Accepted Manuscript
Metal-free synthesis of benzimidazo[1,2-c]quinazolin-6-ones with indole and
benzenediamine oxidized by I /TBHP
2
Zhen Dai, Songhua Li, Yunyi Li, Lei Feng, Chen Ma
PII:
S0040-4020(19)30171-1
https://doi.org/10.1016/j.tet.2019.02.022
TET 30145
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 December 2018
Revised Date: 1 February 2019
Accepted Date: 8 February 2019
Please cite this article as: Dai Z, Li S, Li Y, Feng L, Ma C, Metal-free synthesis of
benzimidazo[1,2-c]quinazolin-6-ones with indole and benzenediamine oxidized by I /TBHP, Tetrahedron
2
(2019), doi: https://doi.org/10.1016/j.tet.2019.02.022.
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Metal-free Synthesis of Benzimidazo[1,2-c]quinazolin-6-ones with Indole and
Benzenediamine Oxidized by I2/TBHP
Zhen Daia , Songhua Li a , Yunyi Li a , Lei Feng *a, b and Chen Ma *a, b
a. School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P R China.
b. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, P. R. China. E-mail:
chenma@sdu.edu.cn
A variety of benzimidazo[1,2-c]quinazoline derivatives can be accessed in moderate to good yields under
simple and metal-free reaction conditions using indoles and o-benzenediamines oxidized by iodine and
TBHP. A TBHP oxidized ring expansion reaction mechanism that explains the synthesis of
benzimidazo[1,2-c]quinazolines was reported.

1
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Tetrahedron
journal homepage: www.elsevier.com
Metal-free Synthesis of Benzimidazo[1,2-c]quinazolin-6-ones with Indole and
Benzenediamine Oxidized by I2/TBHP
Zhen Daia , Songhua Li a , Yunyi Li a , Lei Feng *a, b and Chen Ma *a, b
a.School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P R China.
b. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, P. R. China. E-mail: chenma@sdu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A variety of benzimidazo[1,2-c]quinazolin-6-ones derivatives can be accessed in moderate to
good yields under simple and metal-free reaction conditions using indoles and o-
benzenediamines oxidized by iodine and TBHP. This procedure works in reasonable yields
for different indoles as well as o-benzenediamines thus may provide a good synthesis of
quinazolinones. A TBHP oxidized ring expansion reaction mechanism that explains the
synthesis of benzimidazo[1,2-c]quinazolin-6-ones were reported.
Available online
Keywords:
Metal-free
.
Oxidation
Indoles
Iodines
TBHP
Benzimidazo[1,2-c]quinazolin-6-ones
1. Introduction
serotonic receptor anatgonismthat selectively antagonized the α1
adrenoceptor. Also compounds with the similar structure such
-
4
Benzimidazole and quinazolinone derivatives exist widely in
natural products. They are important heterocycles with diverse
range of biological and medical activities such as antidiabetic,
analgesic, antiviral, chemotherapeutic, antifungal, anti-parasitic
anti-inflammatory, antihypertensive, anti-HIV, bronco-dilatory
and anti-allergic. 1 Also in the early literatures, benzimidazo[1,2-
c]quicnazoline and its derivatives have shown potential activities
in pharmaceuticals. For example, they showed antihypertonic,
antirheumatic, antianaphylactic, anti-asthmatic, tranquilizing,
as
2-[[4-(2-methoxyphenyl)-piperazin-1-yl]methyl]-2,3-dihy-
droimidazo[1,2-c]-quinazolin-5(6H)-one (3) and 3-[[4-(2-
methoxyphenyl)piperazin-1-yl]methyl]-2,3-dihydroimidazo[1,2-
c]-quinazolin-5(6H)-one (4) that selectively antagonized the α-1
adrenoceptor.
5
On this basis, we speculated that benzo-
H)-one and its derivatives had
[
4,5]imidazo[1,2-c]quinazolin-
6(5
potential biological and medical activities.
2
neurostimulating, and benzodiazepine binding activities.
(Scheme 1).
O
CF3
O
N
N
N
N
N
N
N
H
O
N
O
H
SGB-1534
CGS-1761
O
O
N
N
N
N
N
N
N
N
N
O
N
H
O
H
Scheme 2 Preparation of benzimidazo[1,2-c]quinazolin-6-ones
2
1
There have been some literatures that reported the methods for
Scheme 1 Example of benzimidazo[1,2-c]quinazoline-6-ones.
6
preparation of benzimidazo[1,2-c]quinazolin-6-ones.
Zhao
For example, CGS-1761 was thought to have weak anxiolytic
3
reported a synthesis of pyridoimidazoles through transition-
metal-catalyzed or hypervalent-iodine-mediated C-H/N-H cross-
profiles.
The SGB-1534 has been found to have
-adrenoceptor and
antihypertensive activities mediated via
α

2
Tetrahedron
coupling of N-arylamidines (Scheme 2a). 7 In the other report, a
that the yield of reaction was uninfluenced by the electronic
ACCEPTED MANUSCRIPT
synthesis of quinazolines via the reductive cyclization by low-
valent titanium reagent was proposed (Scheme 2b). Based on
effect of the substituents on the indoles.
5
the early literatures, an operationally
simple and generally
applicable strategy to access a variety of benzimidazo[1,2-
c]quinazolin-6-ones with indoles and o-benzenediamines
mediated by I2/TBHP was reported (Scheme 2c).
2. Results and discussion
Our study was initiated by the reaction of N-methyl-indoles (0.5
o
mmol) in DMSO at 90 C in the presence of I2 and TBHP (2.5
mmol). After 24 hours, o-benzenediamine was added, and the
reaction lasted for 30 min. The product could be obtained in 90%
yield (Table 1, entry 1). In our design, the reaction would give
quinoxaline, but finally 5-methylbenzo-[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4a) was obtained. The structure was
1
determined by H NMR, 13C NMR and XRD (see supporting
information). When the reaction was mediated by other iodine
sources such as KI and NH4I, the yield of 4a was decreased
(Table 1, entries 3-4). Then we changed the oxidants, reaction
temperatures, solvents and other reaction conditions (more details
are shown in Supporting Information), no better results were
revealed (Table 1 entries 5-13).
Table 1. Reaction Optimizationa.
Entry
1
Iodine(mmol)
I2 (0.6)
Oxidant (mmol)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
BPO (2.5)
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
90
2
NH4I (0.6)
KI (0.6)
I2 (0.6)
40
3
36
4
44
5
I2 (0.6)
Na2S2 (2.5)
(NH4)2S2O8 (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
TBHP (2.5)
Trace
84
Scheme 3 Substrate scope of indoles and o-benzenediamines (All reactions were
carried out by adding 0.5 mmol 1, 0.6 mmol I2 and 2.5 mmol TBHP to 6 ml DMSO
at 90 oC, stirring for 24 hours, followed by adding 0.34 mmol 2 at 90 oC and
stirring for 30 min).
6
I2 (0.6)
7
I2 (0.6)
30
8
I2 (0.6)
Toluene
54
It was worth noting that indoles proceeded smoothly in this
reaction and provided the higher yields of the products than N-
methyl-indoles (4g-4i). Steric hindrance also played an important
role in this reaction. 4-Chloro-1-methyl-1H-indole (4j-4l)
showed lower yields than 5-chloro-1-methyl-1H-indole (4c, 4o
and 4s). Electron-donating groups and electron-withdrawing
groups on the o-benzenediamines were tolerated. Intriguingly, o-
benzenediamines with electron-donating groups (4m-4q) gave
better yields than those with electron-withdrawing groups (4r-
4v). Monosubstituted substituted o-benzenediamines (4x-4z) also
9
I2 (0.6)
1,4-dioxane trace
10
11
12
13
I2 (0.6)
DMSO
DMSO
DMSO
DMSO
40c
66d
64e
88f
I2 (0.6)
I2 (0.6)
I2 (0.6)
a All reactions were carried out using 0.5 mmol 1a in the solvent (5 ml) by first
adding I2 (0.6 mmol) and TBHP (2.5 mmol) at the 90 oC and stirring for 24 h,
followed by adding 3a (0.34 mol) and stirring until reaction finished. b Isolated
c
o
d
yield. Changed the temperature to 120 C after added o-benzenediamine.
Reaction time of step 2 is 10 min. e Reaction proceeded in nitrogen. f Reaction
proceeded well.
In order to better understand the mechanism of this reaction,
several control experiments were performed in Scheme 4. Isatin
2a was used under standard conditions, and a slightly high yield
of 4a was obtained, which indicated that isatin was an
intermediate in the reaction. A faster reaction rate was received
when acetic acid was added in, which showed that hydrogen ion
influenced the reaction. One control experiment was conducted
with TBHP as the only oxidant and a slightly high yield of 4a was
obtain, which showed that TBHP was crucial for the second step.
proceeded in oxygen.
With the optimal reaction conditions in hand, we investigated
the scope of the reaction by using different indoles and o-
benzenediamines (Scheme 3). Generally, N-methyl-indoles
bearing electron-donating groups gave similar yields with those
bearing electron-withdrawing groups (4b-4d, 4e-4f). It showed

3
Then the 2a reacted in the reaction condition without any oxidant,
Subsequently, intramolecular nucleophilic reaction of II
ACCEPTED MANUSCRIPT
and no product 4a was obtained. It was shown that oxidant
played an important role in the reaction process. When isatoic
anhydride 2b was subjected to the reaction under the standard
conditions, and no product was obtained. The result proved that
isatin wasn’t oxidized and the oxidant showed effect on other
process. When aniline 3b was used in the standard conditions and
a trance amount of compound 5a was obtained. It was indicated
that nucleophilic reaction occurred with o-benzenediamine and
isatin. Finally, the 2a reacted for 2 minutes under the same
reaction condition Scheme (a). We found that the less yield of
product 4a was obtained and intermediate I was detected by
crude HRMs.
afforded the intermediate III. The nitrogen atom attack to ketone
and provides intermediate IV. Finally, along with intramolecular
condensation reaction, the desired product 4a was obtained.
3. Conclusions
In conclusion, we have found that benzimidazo[1,2-c]-
quinazolin-6(5H)-ones could be synthesized with indoles 1 and
o-benzenediamines 2 oxidized by I2 and TBHP. This procedure
worked in reasonable yields for different indoles as well as o-
benzenediamines and thus might provide a convenient and metal-
free synthesis of quinazolinone derivatives.
4. Experimental
4.1. General Information:
N-methyl-1H-indoles were prepared according to literature
procedures. Other reagents were purchased from commercial
suppliers and used without further purification. All reactions
were carried out in air and using undistilled solvent, without any
precautions to exclude air and moisture. All reactions were
monitored by thin-layer chromatography (TLC). Chromatograms
were visualized by fluorescence quenching with UV light at 254
1
nm and 365 nm. H NMR spectra were recorded in CDCl3 or d6-
DMSO on a Bruker Avance 300 spectrometer at 400 MHz and
500 MHz, and tetramethylsilane (TMS) served as internal
standard. 13C NMR spectra were run in the same instrument at
101 MHz, and 126 MHz. HRMS was recorded on a commercial
apparatus (ESI Source).
4.2. Preparation of N-methyl-1H-indoles:
To a solution of indole (1.17 g, 10 mmol) and potassium
hydroxide (2.8 g, 50 mmol) in anhydrous DMF (20 ml) was
added iodomethane (2.13 g, 15 mmol). The reaction mixture was
stirred at room temperature for 2 h. Then H2O was added to the
mixture. The water layer was extracted with EtOAc (50 ml × 3).
The organic layer was combined and dried over Na2SO4. After
filtration and evaporation, the residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate 8/1) to afford N-
methyl-1H-indole (1.24 g, 94%).
Scheme 4 Control experiments
4.3.General Procedure for the Reaction:
8
Based on the above result and the literatures, a proposed
N-methyl indole (0.5 mmol), DMSO (5 ml) were added into
reaction tube and stirred at 90 C. Then the I2 (0.6 mmol) and
TBHP (2.5 mmol) were added into the reaction tube. After 24
hours the o-benzenediamine (0.34 mmol) was added into the
reaction mechanism for the formation of benzimidazo[1,2-c]-
quinazoline derivatives is illustrated in Scheme 5. First, indole 1a
was oxidized to the isatin 2a. Then nucleophilic reaction
occurred with compound 2a and o-benzenediamines and
intermediate I was generated. Baeyer-Villiger oxidation was
occurred on the intermediate I and generated intermediate II.
o
mixture. The reaction was stopped until the -benzenediamine
o
was completetly consumed as monitored by TLC analysis. After
the completion of reaction, 5% Na2S2O3 solution (30 mL) was
added to the mixture. The mixture was extracted with EtOAc
(3×20 ml) and the organic layer was dried by Na2SO4. Then the
crude product was purified by silica gel chromatography
(petroleum ether/ethyl acetate/ dichloromethane 3/1/1).
4.4. Characterization of Benzimidazo[1,2-c]quinazoline.
4.4.1.5-Methylbenzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-one
(4a)
o
1
Yield = 90%; white solid. Mp: 160-161 C. H NMR (400 MHz,
Scheme 5 Proposed reaction mechanism
CDCl3) δ 8.57 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 7.90
(d, J = 8.0 Hz, 1H), 7.65 (t, 1H), 7.52 (m, 4H), 3.19 (s, 3H).; 13
C
NMR (101 MHz, CDCl3) δ 147.0, 146.7, 143.5, 138.0, 132.4,

4
Tetrahedron
131.2, 125.7, 125.6, 124.3, 123.9, 119.3, 115.5, 114.5, 113.2,
MHz, d6-DMSO) δ 148.1, 146.9, 144.0, 137.6, 132.7, 131.1,
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30.5. 19F NMR (376 MHz, CDCl3) δ -103.76, -218.54. HRMS
(ESI) calcd for C15H11N3O [(M + H)+]: 250.0975; found,
250.0975.
125.5, 124.9, 124.1, 123.8, 119.6, 116.4, 115.2, 112.3. HRMS
(ESI) calcd for C14H9N3O [(M +H)+]: 236.0818; found, 236.0815.
4.4.2.
6(5H)-one (4b)
3-Fluoro-5-methylbenzo[4,5]imidazo[1,2-c]quinazolin-
4.4.8. 2-Methoxybenzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-one
(4h)
o
1
o
1
Yield = 61%; white solid. Mp: 188-190 C. H NMR (400 MHz,
Yield = 75%, white solid. Mp: 292-294 C. H NMR (400 MHz,
d6-DMSO) δ 11.83 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.84 (d, J =
7.6 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.49-7.24 (m, 4H), 3.86 (s,
3H).; 13C NMR (101 MHz, d6-DMSO) δ 155.7, 148.0, 146.6,
143.9, 131.6, 131.2, 125.5, 124.1, 121.6, 119.6, 118.0, 115.3,
112.8, 106.3, 56.1. HRMS (ESI) calcd for C15H11N3O2 [(M
+H)+]: 266.0924; found, 266.0918.
CDCl3) δ 8.52 (dd, J = 8.8, 6.4 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H),
7.85 (d, J = 7.6 Hz, 1H), 7.50-7.40 (m, 2H), 7.11-6.99 (m, 2H)
3.72 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 166.3 (d, JC, F
=
1
3
253 Hz, 1C), 146.9, 146.0, 143.7, 139.8 (d, JC, F = 10 Hz, 1C),
3
131.0, 127.9 (d, JC, F = 10 Hz, 1C), 125.6, 124.3, 119.3, 115.3,
111.7 (d, 2JC, F = 23 Hz, 1C), 109.8 (d, 4JC, F = 3 Hz, 1C), 102.2 (d,
2JC, F = 28 Hz, 1C), 30.7. HRMS (ESI) calcd for C15H10FN3O [(M
+H)+]: 268.0881; found, 268.0888.
4.4.9.
1-Chlorobenzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-one
(4i)
4.4.3.
6(5H)-one (4c)
3-Chloro-5-methylbenzo[4,5]imidazo[1,2-c]quinazolin-
o
Yield = 68%, white solid. Mp: >300 C. 1H NMR (400 MHz, d6-
DMSO) δ 12.09 (s, 1H), 8.39 (dd, J = 7.2, 1.6 Hz, 1H), 7.91 (d, J
= 8.0 Hz, 1H), 7.58 (t, 1H), 7.49-7.34 (m, 5H).; 13C NMR (101
MHz, d6-DMSO) δ 146.5, 146.0, 143.8, 139.7, 132.4, 131.6,
130.4, 126.0, 125.6, 124.8, 120.1, 115.3, 115.3, 110.4. HRMS
(ESI) calcd for C14H8ClN3O [(M +H)+]: 270.0429; found,
270.0423.
o
1
Yield = 57%, white solid. Mp: 223-224 C. H NMR (400 MHz,
CDCl3) δ 8.44 (dd, J = 8.4, 5.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H),
7.50-7.26 (m, 4H), 3.73 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ
146.7, 145.9, 143.7, 138.8, 138.4, 131.1, 126.8, 125.7, 124.5,
124.2, 119.4, 115.4, 114.7, 111.8, 30.6. HRMS (ESI) calcd for
C15H10ClN3O [(M +H)+]: 284.0585; found, 284.0588.
4.4.10. 1-Chloro-5-methylbenzo[4,5]imidazo[1,2-c]quinazolin-
6(5H)-one (4j)
4.4.4.
6(5H)-one (4d)
3-Bromo-5-methylbenzo[4,5]imidazo[1,2-c]quinazolin-
o
1
Yield = 49%, white solid. Mp: 238-240 C. H NMR (500
MHz, CDCl3) δ 8.50 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8.0 Hz,
1H), 7.53-7.22 (m, 5H), 3.77 (s, 34H).; 13C NMR (126 MHz,
CDCl3) δ 146.6, 144.4, 143.6, 139.7, 133.5, 131.1, 130.4, 126.6,
125.5, 124.9, 120.3, 115.4, 113.1, 111.8, 31.3. HRMS (ESI)
calcd for C15H10ClN3O [(M + Na)+]: 306.0405; fond, 306.0412.
Yield = 64%, white solid. Mp: 221-223 C. 1H NMR (400 MHz,
CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.85
(dd, J = 1.2, 6.8 Hz, 1H), 7.50-7.41 (m, 4H), 3.73 (s, 3H).; 13C
NMR (101 MHz, CDCl3) δ 146.6, 145.9, 143.5, 138.8, 131.1,
127.1, 126.8, 126.7, 125.7, 124.6, 119.4, 117.6, 115.4, 112.1,
30.6. HRMS (ESI) calcd for C15H10BrN3O [(M +H)+]: 328.0080;
found, 328.0088.
o
4.4.11.
1-Chloro-5,9,10-trimethylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4k)
o
1
Yield = 49%, white solid. Mp: 243-245 C. H NMR (500
MHz, CDCl3) δ 8.20 (s, 1H), 7.73 (s, 1H), 7.41-7.35 (m, 2H),
7.19 (dd, J = 8.0, 1.0 Hz, 1H), 3.74 (s, 3H), 2.43 (d, J = 6.0 Hz,
6H).; 13C NMR (126 MHz, CDCl3) δ 146.6, 143.5, 142.1, 139.5,
134.6, 134.4, 133.1, 130.6, 128.7, 126.4, 120.2, 115.3, 112.9,
111.9, 31.2, 20.6, 20.5. HRMS (ESI) calcd for C17H14ClN3O [(M
+ H)+]: 312.0898; found, 312.0907.
4.4.5. 3,5-Dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-
one (4e)
o
1
Yield = 80%, white solid. Mp: 269-271 C. H NMR (500 MHz,
CDCl3) δ 8.47 (dd, J = 9.5, 8.0 Hz, 2H), 7.88(d, J = 8.0 Hz, 1H),
7.51-7.42 (m, 2H), 7.20 (d, J = 8.0, 1H), 7.09 (s, 1H), 3.76 (s,
3H), 2.48 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 147.1, 146.9,
143.5, 138.0, 131.1, 125.5, 125.5, 125.1, 124.0, 119.1, 115.4,
114.8, 110.6, 30.4, 22.3. HRMS (ESI) calcd for C16H13N3O [(M
+H)+]: 264.1131; found, 264.1138.
4.4.12. 1-Chloro-9,10-difluoro-5-methylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4l)
o
1
Yield = 56%, white solid. Mp: 266-268 C. H NMR (400
3N3O [(M +H)+]: 264.1131; found, 264.1138.
MHz, CDCl3) δ 8.38 (dd, J = 10.0, 7.9 Hz, 1H), 7.81 (dd, J =
10.0, 7.9 Hz, 1H), 7.59-7.49 (m, 2H), 7.34 (d, J = 8.0 Hz, 1H),
1
4.4.6. 2-Methoxy-5-methylbenzo[4,5]imidazo[1,2-c]quinazolin-
6(5H)-one (4f)
3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 151.0 (dd, JC, F
=
18, 249 Hz, 1C), 150.2 (dd, 1JC, F = 17, 249 Hz, 1C), 146.3, 145.8
2
(d, 3JC, F = 3 Hz, 1C) 139.7, 133.6, 131.6, 127.0, 125.8 (d, JC, F
=
o
2
Yield = 61%, white solid. Mp: 233-235 C. 1H NMR (500 MHz,
11 Hz, 1C), 113.3, 111.6, 107.8 (d, JC, F = 20 Hz, 1C), 104.1 (d,
2JC, F = 24 Hz, 1C), 31.5. 19F NMR (376 MHz, CDCl3) δ -137.65~
-137.91 (m, 2F). HRMS (ESI) calcd for C15H8ClF2N3O [(M +
H)+]: 320.0397; found, 320.0402.
CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.88
(d, J = 8.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.26-7.16 (m, 2H), 3.94
(s, 3H), 3.74 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 156.0,
146.8, 146.6, 143.6, 132.0, 131.3, 125.5, 124.2, 121.3, 119.2,
116.0, 115.5, 113.8, 106.7, 56.0, 30.5. HRMS (ESI) calcd for
C16H13N3O2 [(M +H)+]: 280.1081; found, 280.1122.
4.4.13.
5,9,10-Trimethylbenzo[4,5]imidazo[1,2-c]quinazolin-
6(5H)-one (4m)
o
1
Yield = 64%, white solid. Mp: 221-223 C. H NMR (400
MHz, CDCl3) δ 8.53 (dd, J = 7.6, 1.2 Hz, 1H), 8.23 (s, 1H), 7.63-
7.26 (m, 4H), 3.77 (s, 3H), 2.44 (d, J = 6.4 Hz, 6H).; 13C NMR
(400 MHz, CDCl3) δ 147.1, 145.9, 142.1, 137.8, 134.6, 133.6,
131.9, 129.6, 125.5, 123.7, 119.4, 115.4, 114.4, 113.5, 30.4, 20.6.
4.4.7. Benzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-one (4g)
o
Yield = 84%, white solid. Mp: >300 C. 1H NMR (400 MHz, d6-
DMSO) δ 11.97 (s, 1H), 8.38 (dd, J = 10.0, 8.0 Hz, 2H), 7.88 (d,
J = 7.6 Hz, 1H), 7.68 (t, 1H), 7.52-7.36 (m, 4H).; 13C NMR (101

5
1
HRMS (ESI) calcd for C17H16N3O [(M + H)+]: 278.1288; found,
278.1300.
3.79.; 13C NMR (101 MHz, CDCl3) δ 149.9 (d, JC, F = 260 Hz,
ACCEPTED MANUSCRIPT
1C), 148.6 (d, 1JC, F = 217 Hz, 1C), 139.4 (d, JC, F = 10 Hz, 1C),
3
138.9 (d, 3JC, F = 11 Hz, 1C), 126.8, 126.5 (d, JC, F = 12 Hz, 1C),
3
2
2
4.4.14.
3-Fluoro-5,9,10-trimethylbenzo[4,5]imidazo[1,2-
124.6, 114.9, 111.5, 107.1 (d, JC, F = 20 Hz, 1C), 104.1 (d, JC, F
= 24 Hz, 1C), 30.8. 19F NMR (376 MHz, CDCl3) δ -137.56~-
138.24(m, 2F). HRMS (ESI) calcd for C15H8ClF2N3O [(M +
H)+]: 320.397; found, 320.0402
c]quinazolin-6(5H)-one (4n)
o
1
Yield = 69%, white solid. Mp: 252-254 C. H NMR (400
MHz, CDCl3) δ 8.49 (dd, J = 8.8, 6.4 Hz, 1H), 8.16 (s, 1H), 7.58
(s, 1H), 7.09-6.97 (m, 2H), 3.71 (s, 3H), 2.43 (d, J = 7.6 Hz,
6H).; 13C NMR (101 MHz, CDCl3) δ 166.1 (d, JC, F = 253 Hz,
4.4.20. 3-Bromo-9,10-difluoro-5-methylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4t)
1
3
1C), 146.9, 145.3, 142.0, 139.5 (d, JC, F = 11 Hz, 1C), 134.7,
133.7, 129.3, 127.7 (d, 3JC, F = 10 Hz, 1C), 119.3, 115.3, 111.6 (d,
2JC, F = 23 Hz, 1C), 111.3, 109.9 (d, 4JC, F = 2.2 Hz, 1C), 102.1 (d,
2JC, F = 28 Hz, 1C), 30.6, 20.5. 19F NMR (376 MHz, CDCl3) δ -
104.53 (s, 1F). HRMS (ESI) calcd for C17H14FN3O [(M + H)+]:
296.1194; found, 296.1203.
Yield = 77%, white solid. Mp: >300 C. H NMR (500 MHz,
CDCl3) δ 8.41 (d, J = 6.8 Hz, 1H), 8.34 (dd, J = 6.0, 8.0 Hz, 1H),
7.68 (dd, J = 5.6, 8.0 Hz, 1H), 7.58-7.57 (m, 2H), 3.80 (s, 3H).;
o
1
13C NMR (126 MHz, CDCl3) δ 149.3 (dd, JC, F = 16, 243 Hz,
1
1
1C), 148.2 (dd, JC, F = 15, 236 Hz, 1C), 147.3, 140.2, 139.2 (d,
3JC, F = 9 Hz, 1C), 138.8, 130.6, 127.5, 127.2, 126.9, 117.9, 111.8,
2
2
4.4.15.
3-Chloro-5,9,10-trimethylbenzo[4,5]imidazo[1,2-
107.1 (d, JC, F = 21 Hz, 1C), 104.1 (d, JC, F = 25 Hz, 1C), 30.8.
19F NMR (376 MHz, CDCl3) δ -137.87~-138.64 (m, 2F). HRMS
(ESI) calcd for C15H8BrF2N3O [(M +H)+]: 363.9892; found,
363.9898.
c]quinazolin-6(5H)-one (4o)
o
1
Yield = 71%, whitesolid. Mp: 267-279 C. H NMR (400
MHz, CDCl3) δ 8.40 (d, J = 8.4, 1H), 8.15 (s, 1H), 7.58(s, 1H),
7.32-7.26 (m, 2H), 3.72 (s, 3H), 2.43 (d, J = 7.6, 6H).; 13C NMR
(101 MHz, CDCl3) δ 146.7, 145.1, 142.1, 138.6, 137.9, 134.9,
133.9, 129.4, 126.5, 124.0, 119.4, 115.3, 114.6, 112.0, 30.5, 20.6,
20.5. HRMS (ESI) calcd for C17H14ClN3O [(M + H)+]: 312.0898;
found, 312.0901.
4.4.21.
9,10-Difluoro-3,5-dimethylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4u)
o
1
Yield = 73%, white solid. Mp: 279-281 C. H NMR (400
MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 7.2, 10.0
Hz, 1H), 7.65 (dd, J = 7.2, 10.0 Hz, 1H), 7.24-7.18 (m, 2H), 3.79
(s, 3H), 2.55 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 150.8 (dd,
4.4.16.
3-Bromo-5,9,10-trimethylbenzo[4,5]imidazo[1,2-
1
c]quinazolin-6(5H)-one (4p)
1JC, F = 24, 258 Hz, 1C), 149.5 (dd, JC, F = 26, 246 Hz, 1C),
o
1
3
Yield = 83%, white solid. Mp: 286-288 C. H NMR (400
MHz, CDCl3) δ 8.38 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 7.61 (s,
1H), 7.50-7.46 (m, 2H), 3.74 (s, 3H), 2.44 (d, J = 7.2 Hz, 6H).;
13C NMR (101 MHz, CDCl3) δ 146.7, 145.1, 141.8, 138.7, 135.0,
134.1, 129.4, 127.0, 126.7, 126.3, 119.4, 117.6, 115.4, 112.3,
30.6, 29.7, 20.6. HRMS (ESI) calcd for C17H14BrN3O [(M + H)+]:
356.0393; found, 356.0397.
143.8, 138.0, 128.8, 126.5, 125.5 (d, JC, F = 12 Hz, 1C), 115.0,
2
2
110.7, 106.8 (d, JC, F = 20 Hz, 1C), 104.0 (d, JC, F = 24 Hz, 1C),
30.5, 29.7, 23.9, 22.4. 19F NMR (376 MHz, CDCl3) δ -138.26(d,
2F). HRMS (ESI) calcd for C16H11F2N3O [(M + H)+]: 300.0943;
found, 300.0964.
4.4.22.
9,10-Difluoro-2-methoxy-5-methylbenzo[4,5]
imidazo[1,2-c]quinazolin-6(5H)-one (4v)
o
1
4.4.17.
2-Methoxy-5,9,10-trimethylbenzo[4,5]imidazo[1,2-
Yield = 42%, white solid. Mp: 249-251 C. H NMR (500
MHz, CDCl3) δ 8.35 (dd, J = 10.0, 6.0 Hz, 1H), 7.93 (d, J = 2.5
Hz, 1H), 7.66 (dd, J = 10.0, 7.5 Hz, 1H), 7.32-7.26 (m, 2H), 3.94
(s, 3H), 3.79 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 156.2,
c]quinazolin-6(5H)-one (4q)
o
1
Yield = 56%, White solid. Mp: 242-245 C. H NMR (500
MHz, CDCl3) δ 8.21 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.22-7.13
(m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 2.43 (d, J = 7.0 Hz, 3H).; 13C
NMR (126 MHz, CDCl3) δ 155.9, 146.8, 145.8, 134.7, 133.7,
131.9, 129.6, 121.0, 119.2, 115.9, 115.5, 113.9, 106.6, 56.0, 30.5,
20.6, 20.6. HRMS (ESI) calcd for C18H17N3O2 [(M +H)+]:
308.1394; found, 308.1400.
1
1
150.7 (dd, JC, F = 15, 246 Hz, 1C), 149.4 (d, JC, F = 15, 246 Hz,
4
3
1C), 148.0 (d, JC, F = 3 Hz, 1C), 146.4, 139.3 (d, JC, F = 11 Hz,
3
1C), 132.1, 126.6 (d, JC, F = 12 Hz, 1C), 121.7, 116.2, 113.6,
2
2
106.8 (d, JC, F = 20Hz, 1C), 106.7, 104.1 (d, JC, F = 25 Hz, 1C),
56.0, 30.7. 19F NMR (376 MHz, CDCl3) δ -137.82 (d, 2F).
HRMS (ESI) calcd for C16H11F2N3O2 [(M + H)+]: 316.0892;
found, 316.0891.
4.4.18.
3,9,10-Trifluoro-5-methylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4r)
Yield = 70%, white solid. Mp: 241-242 C. H-NMR (400
o
1
4.4.23 5-methylpyrido[3',2':4,5]imidazo[1,2-c]quinazolin-6(5H)-
one (4w)
MHz, CDCl3) δ 8.54 (dd, J = 8.6, 6.4 Hz, 1H), 8.32 (dd, J = 9.6,
o
1
7.4 Hz, 1H), 7.65 (dd, J = 10.2, 7.0 Hz, 1H), 7.18-7.07(m, 2H),
Yield= 68%, white solid. Mp: >300 C. H NMR (500 MHz,
CDCl3) δ 8.75 (m, 2H), 8.71 (dd, J = 1.5, 8.0 Hz, 1H), 7.76 (m,
1H), 7.49 (m, 3H), 3.84 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
156.1, 148.9, 147.6, 146.7, 138.2, 133.3, 126.8, 124.3, 123.5,
119.2, 114.6, 113.0, 30.6. HRMS (ESI) calcd for C14H10N4O [(M
+ H)+]: 251.0927; found, 251.0930
1
3.78 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 166.6 (d, JC, F
=
254 Hz, 1C), 151.0 (dd, 1JC, F = 15, 246 Hz, 1C), 149.7 (dd, JC, F
1
=15, 246 Hz, 1C), 147.4, 146.6, 139.8 (d, 3JC, F = 11 Hz, 1C),
139.3 (d, 3JC, F = 11 Hz, 1C), 128.0 (d, JC, F = 10 Hz, 1C), 126.2,
3
2
4
112.2 (d, JC, F = 23 Hz, 1C), 109.5 (d, JC, F = 2 Hz, 1C), 107.0
(d, 3JC, F = 20 Hz, 1C), 104.0 (d, 3JC, F = 24 Hz, 1C), 102.4 (d, 3JC,
= 28 Hz, 1C), 30.8. 19F NMR (376 MHz, CDCl3) δ -103.03 (s,
F
1F), -137.97~-138.85(m, 2F). HRMS (ESI) calcd for C15H8F3N3O
4.4.24. 5,10-dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6(5H)-
one (4x)
[(M + H)+]: 304.0692; found, 304.0694.
1
Yield = 59%, white solid. Mp: 219-221 oC. H NMR (400 MHz,
4.4.19. 3-Chloro-9,10-difluoro-5-methylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4s)
CDCl3) δ 8.53 (dd, J = 1.5, 9.5 Hz, 1H), 8.32 (d, J = 10.5 Hz,
1H), 7.65 (s, 1H), 7.63 (m, 1H), 7.38 (m, 3H), 3.76 (s, 3H),
2.54 (s, 3H) 13C NMR (101 MHz, CDCl3) δ 147.0, 146.7,
144.0, 137.9, 135.5, 132.1, 129.2, 125.7, 125.6, 123.7,
o
1
Yield = 68%, white solid. Mp: 293-295 C H NMR (400
MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 10.0, 7.6
Hz, 1H), 7.67 (dd, J = 10.0, 7.8 Hz, 1H), 7.42-7.40 (m, 2H),

6
Tetrahedron
Kumar, A.; Rajput, C. S.; Eur. J. Med. Chem. 2009, 44, 83-90. (h)
119.2, 114.8, 114.4, 113.4, 30.4, 21.9, 21.8. HRMS (ESI)
ACCEPTED MANUSCRIPT
calcd for C16H13N3O [(M+H)+]: 264.3013; found, 264.3020.
Alexandre, F.; Berecibar, A.; Wrigglesworth, R.; Besson, T.
Tetrahedron 2003, 59, 1413-1419. (i) Alagarsamy, V.; Giridhar, R.;
.
Yadav, M. R.; Revathi, R.; Ruckmani, K.; Clercq, E. D. Indian J.
Pharm. Sci. 2006, 68, 532-535. (j) Jindal, D. P.; Bhatti, R. S.;
Ahlawat, S.; Gupta, R.; Eur. J. Med. Chem, 2002, 37, 419-425. (k)
Sircar, J. C.; Capiris, T.; Kesten, S. J.; Herzig, D. J.; J. Med.
4.4.25.
2-methoxy-5,10-dimethylbenzo[4,5]imidazo[1,2-
c]quinazolin-6(5H)-one (4y
)
Yield = 38% white solid. Mp: 175-177 oC. 1H NMR (400
MHz, CDCl3) δ 8.36 (m, 1H), 8.00 (m, 1H), 7.76 (m, 1H),
7.33 (m, 3H), 3.96 (s, 3H), 3.77 (s, 3H), 2.55 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 156.1, 146.8, 132.2, 127.1,
125.8, 121.4, 119.0, 118.7, 116.0, 115.5, 115.0, 107.0,
106.9, 56.1, 30.6, 21.9. HRMS (ESI) calcd for C17H15N3O2
[(M+H)+]:294.3273; found, 294.3281.
Chem. 1981, 24, 735-742.
2. Francis, J. E.; Cash, W. D.; Barbaz, W. D.; Bernard, P. S.; Lovell,
R. A.; Mazzenga, G. C.; Friedmann, R. C.; Hyun, J. L.;
Braunwalder, A. F.; Loo, P. S.; Bennett, D. A.; J. Med. Chem
.
1991, 34, 281-290. (b) Gineinah, M. M.; Ismaiel, A. M.; El-
Kerdawy, M. M.; J. Het. Chem. 1990, 27, 723-726. (c) Liu, K. C.;
Hu, M. K.; Arch Pharm (Weinheim) 1986, 319, 188-189. (d)
Vostrova, L. N.; Voronina, T. A.; Karaseva, T. L.; Gernega, S. A.;
4.4.26.
]quinazolin-6(5
Yield = 65% white solid. Mp: 136-138 oC. 1H NMR (400
MHz, CDCl3) δ 8.38 (d, = 7.2 Hz, 1H), 8.22 (d, = 8.0 Hz,
1H), 7.73 (d, = 7.2 Hz, 1H), 7.62 (d, = 10.7 Hz, 1H),
7.44 (d, = 7.6 Hz, 1H), 7.25 (d, = 7.6 Hz, 1H), 3.68 (s,
10-chloro-5-methylbenzo[4,5]imidazo[1,2-
Ivanov,É. I.; Kirichenko, A. M.; Totrova, M. Y.; Pharm. Chem. J
.
1986, 20, 404-406. (e) Lamazz, C.; Léonce, S.; Pfeiffer, B.; Renard,
P.; Guillaumet, G.; Rees, C. W.; Besson, T.; Med. Chem. Lett.
2000, 10, 2183-2185.
c
H
)-one (4z
)
J
J
3. Francis, J. E.; Cash, W. D.; Barbaz, B. S.; Bernard, P. S.; Lovell, R.
A.; Mazzenga, G. C.; Friedmann, R. C.; Hyun, J. L.; Braunwalder,
J
J
J
J
A. F.; Loo, P. S.; Bennett, D. A.; J. Med. Chem
4. Chern, J. W.; Tao, P.; Ten, M. H.; Lu, G. Y.; Shiau, C. Y.; Lai, Y.
J.; Chein, S. L.; Chan, C. H.; J. Med. Chem 1993, 36, 2196-2207.
5. Zhao, X.; Shi, D. Q.; J. Heterocyclic. Chem 2010, 47 524-527.
6. (a) Zaitsev, B. E.; Avvakumova, V. V.; Ryabov, M. A.;
Tsyrul’nikova, N. V.; Nokel, A.Y.; Russ. J. Gen. Chem 2008, 78,
. 1991. 34. 281-290.
3H); 13C NMR (101 MHz, CDCl3) δ 147.0, 146.6, 146.3,
138.0, 135.6, 134.6, 132.3, 129.2, 127.0, 125.8, 123.8, 119.2,
118.8, 115.4, 114.8, 114.5. HRMS (ESI) calcd for
C15H10ClN3O [(M+H)+]: 284.7194 found, 284.7196.
.
.
,
.
5. Acknowledgements
1579-1585. (b) Molina, P.; Alajarin, M.; Vidal, A.; Tetrahedron
Lett. 1988, 29, 3849-3852. (c) Molina, P.; Alajarin, M.; Vidal, A.;
Tetrahedron. 1989, 45, 4263-4286. (d) Langer, P.; Bodtke, A.;
We are grateful to the National Science Foundation of China (No.
21572117) and the State Key Laboratory of Natural and
Biomimetic Drugs of Peking University (No. K20180205) for
financial support of this research.
Tetrahedron Lett
Wen, M.; Shen, H. Y.; Jin, J. Z.; Zhang, P. F.; Ind. Eng. Chem.
Res. 2016, 55 3177–3181. (f) Ambethkar, S.; Kalaiselvi, M.;
Ramamoorthy, J.; Padmini, V.; ACS Omega 2018, 3, 5021−5028
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C. Angew. Chem. Int. Ed 2017, 56, 587 –590.
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,
,
.
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6. Notes and references
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