CuI-catalyzed C-N bond formation and cleavage for the synthesis of benzimidazo[1,2- a ]quinazoline derivatives

Article abstract of DOI:10.1021/jo5007398

A copper(I)-catalyzed domino reaction of N-(2-benzimidazolyl)-2- aminobenzamide and 2-halogenated benzaldehyde has been studied. The procedure is based on a sequential CuI-catalyzed Ullmann reaction (C-N bond formation) and two bond cleavage reactions and provides an efficient strategy for the synthesis of benzimidazo[1,2-a]quinazolines catalyzed by CuI/l-proline.

Full text of DOI:10.1021/jo5007398

Note
pubs.acs.org/joc
CuI-Catalyzed C−N Bond Formation and Cleavage for the Synthesis
of Benzimidazo[1,2‑a]quinazoline Derivatives
Chao Li, Wen-Ting Zhang, and Xiang-Shan Wang*
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal
University, Xuzhou, Jiangsu 221116, P. R. China
S
* Supporting Information
ABSTRACT: A copper(I)-catalyzed domino reaction of N-(2-
benzimidazolyl)-2-aminobenzamide and 2-halogenated benzaldehyde
has been studied. The procedure is based on a sequential CuI-
catalyzed Ullmann reaction (C−N bond formation) and two bond
cleavage reactions and provides an efficient strategy for the synthesis
of benzimidazo[1,2-a]quinazolines catalyzed by CuI/L-proline.
uinazolines are an important class of heterocyclic
to the syntheses of these potentially active fused heterocycles.11
However, it should be noted that they are usually benzimidazo-
[2,1-b]quinazoline, benzimidazo[1,2-c]quinazoline, or
benzimidazo[1,2-b]quinazoline but seldomly benzimidazo[1,2-
a]quinazoline.12
Q compounds which have attracted considerable attention
due to their diverse anticancer activities.1 A well-known
example is terazosin (Figure 1, left), which is an α-1-selective
It is well-known that transition metals, such as Cu, Fe, and
Pd, are efficient catalysts to promote the C−N bond
formation13 (Ullmann reaction) and C−N bond cleavage.14
We previously reported that CuBr could catalyze the Ullmann-
type reaction of 2-amino-N′-arylbenzohydrazide and o-
halogenated benzaldehyde to synthesize 5-arylindazolo[3,2-
b]quinazolin-7(5H)-ones in high yields.15 Therefore, in order
to obtain the desired fused heterocyle of 5H-benzo[4,5]-
imidazo[1,2-a] quinazolino[3,2-c]quinazolin-17(5aH)-one, the
reaction of N-(2-benzimidazolyl)-2-aminobenzamide 1a and 2-
bromobenzaldehyde 2a was carried out in the presence of CuI/
L-proline (Scheme 1). However, to our surprise, it unexpectedly
gave benzimidazo[1,2-a]quinazoline 3a with two C−N bond-
cleavage reactions. Herein, we report the synthesis of
benzimidazo[1,2-a]quinazoline derivatives via a Ullmann-type
N-arylation reaction catalyzed by CuI/L-proline.
The reaction of N-(2-benzimidazolyl)-2-aminobenzamide 1a
with 2-bromobenzaldehyde 2a was used as a model reaction to
optimize reaction conditions (Scheme 1), and the results are
summarized in Table 1. Initially, the reaction in toluene in the
presence of CuCl (5 mol %) and K2CO3 (2 equiv) could afford
the desired product 3a in 51% yield. Adding the ligand of L-
proline (10 mol %), the yield increased to 62%. Further
investigation of various catalysts, CuI was found to be more
effective than other Cu(I) species, and the reaction yield
increased to 66% when CuI was employed (entries 2−4).
Figure 1. Drugs containing quinazoline or benzimidazole.
adrenoceptor blocking agent and is able to reduce a bladder
outlet obstruction without affecting bladder contractility.2
Therefore, it is a very good drug on the market used for the
treatment of symptomatic benign prostatic hyperplasia in
recent years.
In addition, benzimidazoles are also useful heterocyclic
molecules, and the potential therapeutic applications of their
derivatives include antimicrobial,3 antitumor,4 and antibacterial
activities.5 They are also used as inhibitors of PI3-kinase6 and
the potent antistaphylococcal agents with dual inhibitory
mechanisms against DNA gyrase.7 The most noteworthy is
pantoprazole (Figure 1, right), and it is used for short-term
treatment of erosion and ulceration of the esophagus caused by
gastroesophageal reflux disease.8
The benzimidazoquinazoline moiety contains both quinazo-
line and benzimidazole heterocyclic skeletons, and it has been
reported that its derivatives are potent immunosuppressors in
doses as low as 0.1 mg/kg.9 They have also recently been found
to present promising antitumor activity serving to intercalate
DNA, thereby effectively truncating proliferation of human
tumor cell lines.10 Therefore, much attention has been devoted
Received: March 31, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5007398 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Model Reaction
a
Table 1. Synthesis of 3a under Different Reaction
Conditions
Table 2. Synthetic Results for the Products 3
a
b
time
(h)
yield
b
entry
X
R1
R2
R3
products
(%)
entry catalyst
solvent
ligand
base
yield (%)
c
c
1
Br
Br
Br
Br
Br
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
18
16
18
16
20
16
16
14
16
26
14
20
76
1
CuCl
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
Et3N
51
62
60
66
56
47
58
71
65
67
63
64
76
52
65
c
c
c
c
c
c
c
c
2
CH3
Cl
H
H
81
2
L-proline
c
3
H
74
3
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
PPh3
4
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
3b
3c
3d
3e
3f
78
80
68
79
82
81
72
75
76
4
5
H
5
d
6
H
6
7
Br
Br
Br
Br
Cl
Br
H
7
8
H
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
H
3g
3h
3i
9
CH3CN
THF
10
11
12
H
3-OCH3
3-CF3
10
11
12
13
14
15
c
H
DMF
H
2,3-
(OCH3)2
3j
benzene
dioxane
dioxane
dioxane
13
14
15
16
Br
H
H
H
H
H
2,3-
OCH2O
3k
3l
24
24
19
20
67
66
75
82
Me2NCH2CO2H
Br 9,10-
Me2
H
a
Reagents and conditions: 1a (0.252 g, 1.0 mmol), 2a (0.185 g, 1.0
mmol), solvent (10 mL), base (2.0 mmol), catalyst (5 mol %), ligand
(10 mol %), reflux. Isolated yields. 100 °C. NaHCO3 (4 mmol).
Br 9,10-
Me2
2-Cl
3m
b
c
d
d
Br
H
2-thienyl
3n
a
Reagents and conditions: 1 (1.0 mmol), CuI (10 mg, 0.05 mmol), L-
proline (12 mg, 0.1 mmol), Cs2CO3 (652 mg, 2.0 mmol), dioxane (10
Several bases such as Na2CO3, NaHCO3, Et3N, and Cs2CO3
were examined, and Cs2CO3 was found to give the best result
(entries 4−8). Subsequently, different solvents including THF,
CH3CN, DMF, benzene, and dioxane were also evaluated, and
a 76% yield was obtained when dioxane was used as a solvent
(entry 13). In addition, lower yields were observed if other
ligands were loaded (entries 14 and 15).
b
c
mL). Isolated yields. The corresponding 2-aminobenzoic acids were
d
isolated in 56%, 62%, and 52% yields, respectively. 3-Bromothio-
phene-2-carbaldehyde was used as o-halogenated benzaldehyde.
phene-2-carbaldehyde was used as a reactant (Table 2, entry
1
16). All of the products were characterized by H NMR, 13C
With these optimized conditions in hand, we surveyed the
substrate scope of N-(2-benzimidazolyl)-2-aminobenzamides
and o-halogenated benzaldehydes (Scheme 2, Table 2, entries
1−15). It can be observed that the process tolerates both
electron-donating and electron-withdrawing substituents in the
benzaldehydes. In all cases, the reactions proceeded efficiently
at reflux under mild conditions to afford the corresponding
products (3a−m) in good yields. The benzo[4,5]imidazo[1,2-
a]thieno[2,3-e]pyrimidine 3n was obtained when 3-bromothio-
NMR, IR, and HRMS, and the structure of 3a was confirmed
by X-ray diffraction analysis.
We propose that four subsequent steps are involved in the
formation of 3, namely cyclization to dihydroquinazolinone 4
catalyzed by CuI, Ullmann reaction to 5H-benzo[4,5]imidazo-
[1,2-a]quinazolino[3,2-c]quinazolin-17(5aH)-one 5 in the
presence of CuI/L-proline, and then cleavage of amide bond
(Cs2CO3 and H2O) in 5 occurs along with the ring-opening to
6. At last, 6 takes place the second C−N bond-cleavage reaction
in the presence of base (Cs2CO3) to give final product 3. The
key step is the C−N coupling in Ullmann reaction catalyzed by
CuI/L-proline, and using L-proline as a ligand for copper(I) has
been well reported by Zhao and Ma’ groups.16 The plausible
reaction mechanism is outlined in Scheme 3.
Scheme 2. Synthetic Route of 3
In order to get more insight into the mechanism, the model
reaction of 1a and 2a was treated with CuI in the absence of
Cs2CO3, and the reaction formed the compound 4 in 86% yield
at reflux (Scheme 4).
B
dx.doi.org/10.1021/jo5007398 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. Possible Reaction Mechanism
sequential CuI-catalyzed Ullmann N-arylation (C−N bond
formation) and two C−N bond-cleavage reactions.
Scheme 4. Model Reaction in the Absence of Cs2CO3
EXPERIMENTAL SECTION
■
General Procedure for the Syntheses of Benzimidazo[1,2-
a]quinazoline Derivatives 3. N-(2-Benzimidazolyl)-2-aminobenza-
mide (1.0 mmol), o-halogenated benzaldehyde (1.0 mmol), L-proline
(12 mg, 0.1 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (2.0 mmol, 652
mg), and dioxane (10 mL) were added into a 25 mL flask. The
reaction mixture was stirred at reflux for 14−24 h before reaching
completion, which was monitored by TLC. The product 3 was purified
by column chromatography using ethyl acetate and petroleum ether
(1:1) as eluent.
In addition, the 2-aminobenzoic acid was isolated in 56%
yield from the residue of the reaction. These data all supported
the proposed four-step mechanism.
In our continued study, the Cu-catalyzed control experiment
between 1H-benzo[d]imidazol-2-amine and 2-bromobenzalde-
hyde was tested at the same reaction. However, the desired
product of 3a was not detected by TLC with (E)-N-(2-
bromobenzylidene)-1H-benzo[d]imidazol-2-amine 7 being ob-
tained as the main product in 53% yield (Scheme 5); perhaps
Benzo[4,5]imidazo[1,2-a]quinazoline (3a). Yield: 76% (166 mg).
Pale yellow solid. Mp: 228−230 °C. 1H NMR (DMSO-d6, 400 MHz):
δH 7.53−7.59 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.97 (dd, J = 7.2 Hz, J′
= 2.0 Hz, 1H), 8.06−8.10 (m, 1H), 8.28 (dd, J = 8.0 Hz, J′ = 1.6 Hz,
1H), 8.64−8.66 (m, 1H), 8.76 (d, J = 8.8 Hz, 1H), 9.36 (s, 1H). 13C
NMR (DMSO-d6, 100 MHz): δC 115.1, 115.6, 118.6, 120.5, 123.7,
125.1, 125.4, 129.1, 130.8, 135.7, 137.2, 143.5, 150.2, 159.7. IR (KBr):
ν 3072, 3046, 3017, 1608, 1551, 1521, 1483, 1471, 1451, 1393, 1341,
1327, 1258, 1245, 1226, 1197, 1155, 1129, 1050, 1016, 953, 839, 765,
746, 703 cm−1. HRMS (TOF, ESI, m/z): calcd for C14H10N3 [M +
H]+ 220.0875, found 220.0876.
Scheme 5. Control Experiment
2-Chlorobenzo[4,5]imidazo[1,2-a]quinazoline (3b). Yield: 78%
1
(197 mg). Pale yellow solid. Mp: 241−242 °C. H NMR (DMSO-d6,
400 MHz): δH 7.55−7.63 (m, 2H), 7.78 (dd, J = 8.4 Hz, J′= 2.0 Hz,
1H), 7.98 (dd, J = 7.2 Hz, J′= 2.0 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H),
8.72−8.74 (m, 2H), 9.38 (s, 1H). 13C NMR (DMSO-d6, 100 MHz):
δC 115.1, 115.2, 117.4, 120.6, 124.0, 125.4, 125.8, 129.0, 132.5, 138.0,
140.4, 143.6, 150.1, 159.0. IR (KBr): ν 3070, 3037, 2978, 2924, 1611,
1591, 1528, 1481, 1454, 1423, 1397, 1337, 1310, 1275, 1254, 1221,
1184, 1087, 1041, 1010, 957, 842, 819, 762, 726 cm−1. HRMS (TOF,
ESI, m/z): calcd for C14H8ClN3Na [M + Na]+ 276.0304, found
276.0299.
the (E)-configuration prevented the further Ullmann reaction.
This result indicated that this C−N bond cleavage reaction was
a good and efficient method toward the synthesis of
benzimidazo[1,2-a]quinazolines, in which the simple materials
were hard to realize.
CONCLUSION
■
3-Chlorobenzo[4,5]imidazo[1,2-a]quinazoline (3c). Yield: 80%
1
In conclusion, we found a novel and efficient method for the
synthesis of benzimidazo[1,2-a]quinazoline derivatives using
CuI/L-proline as a catalyst. The interesting reaction includes a
(202 mg). Pale yellow solid. Mp: 225−227 °C. H NMR (DMSO-
d6, 400 MHz): δH 7.56−7.62 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 8.08
(dd, J = 8.8 Hz, J′= 1.6 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.64 (d, J =
C
dx.doi.org/10.1021/jo5007398 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.6 Hz, 1H), 8.81 (d, J = 9.2 Hz, 1H), 9.35 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz): δC 115.1, 117.8, 119.8, 120.7, 124.0, 125.3,
129.0, 129.1, 129.8, 135.1, 135.9, 143.5, 149.9, 158.6. IR (KBr): ν
3069, 3059, 3023, 2948, 1653, 1634, 1622, 1606, 1590, 1544, 1530,
1455, 1417, 1375, 1327, 1257, 1243, 1208, 1197, 1084, 1008, 955, 832,
821, 815, 762, 732 cm−1. HRMS (TOF, ESI, m/z): calcd for
C14H8ClN3Na [M + Na]+ 276.0304, found 276.0294.
MHz): δC 115.2, 117.0, 118.4, 120.8, 124.3, 125.2 (q, JF−C = 32.9 Hz),
125.6, 128.3, 128.4, 129.2, 131.3, 139.4, 143.6, 150.1, 159.4. IR (KBr):
ν 3087, 3060, 1649, 1628, 1613, 1592, 1567, 1533, 1479, 1455, 1430,
1388, 1347, 1321, 1248, 1203, 1167, 1151, 1115, 1075, 957, 939, 834,
819, 767, 737 cm−1. HRMS (TOF, ESI, m/z): calcd for C15H8F3N3Na
[M + Na]+ 310.0568, found 310.0558.
2,3-Dimethoxybenzo[4,5]imidazo[1,2-a]quinazoline (3j). Yield:
76% (212 mg). Pale yellow solid. Mp: 222−225 °C. 1H NMR
(DMSO-d6, 400 MHz): δH 3.92 (s, 3H), 4.17 (s, 3H), 7.47−7.56 (m,
2H), 7.73 (s, 1H), 7.83 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.49 (d, J =
8.0 Hz, 1H), 9.13 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 56.4,
56.7, 96.9, 109.1, 112.5, 113.2, 121.1, 122.6, 124.8, 128.5, 133.9, 143.9,
146.8, 150.3, 155.4, 156.5. IR (KBr): ν 3051, 3037, 2984, 2937, 2829,
1616, 1598, 1555, 1529, 1455, 1395, 1283, 1251, 1200, 1159, 1142,
1115, 1048, 1011, 990, 961, 873, 856, 797, 761, 724 cm−1. HRMS
(TOF, ESI, m/z): calcd for C16H13N3O2Na [M + Na]+ 302.0905,
found 302.0905.
4-Chlorobenzo[4,5]imidazo[1,2-a]quinazoline (3d). Yield: 68%
1
(172 mg). Pale yellow solid. Mp: 266−267 °C. H NMR (DMSO-d6,
400 MHz): δH 7.58−7.65 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 8.02 (dd,
J = 7.2 Hz, J′= 2.0 Hz, 1H), 8.06−8.10 (m, 1H), 8.02 (dd, J = 7.2 Hz,
J′= 2.0 Hz, 1H), 8.82 (d, J = 8.4 Hz, 1H), 9.57 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz): δC 115.2, 115.4, 115.7, 120.8, 124.1, 125.5,
126.1, 129.1, 134.0, 136.2, 138.8, 143.8, 149.9, 155.1. IR (KBr): ν
3100, 3068, 3052, 3033, 1599, 1585, 1547, 1526, 1482, 1447, 1393,
1337, 1303, 1263, 1213, 1192, 1158, 1012, 973, 883, 841, 783, 760,
742 cm−1. HRMS (TOF, ESI, m/z): calcd for C14H8ClN3Na [M +
Na]+ 276.0304, found 276.0298.
Benzo[4,5]imidazo[1,2-a][1,3]dioxolo[4,5-g]quinazoline (3k).
1
2-Fluorobenzo[4,5]imidazo[1,2-a]quinazoline (3e). Yield: 79%
Yield: 67% (176 mg). Pale yellow solid. Mp: 283−285 °C. H NMR
1
(187 mg). Pale yellow solid. Mp: 272−275 °C; H NMR (DMSO-
(DMSO-d6, 400 MHz): δH 6.37 (s, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.57
(t, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 8.36 (s,
1H), 8.71 (d, J = 8.4 Hz, 1H), 9.15 (s, 1H). 13C NMR (DMSO-d6, 100
MHz): δC 96.2, 103.4, 103.7, 107.4, 113.8, 115.3, 120.1, 122.9, 123.8,
125.1, 135.0, 143.6, 145.5, 154.6, 157.6. IR (KBr): ν 3089, 3066, 3007,
2976, 2914, 1654, 1628, 1568, 1529, 1503, 1474, 1454, 1419, 1401,
1312, 1278, 1266, 1233, 1225, 1169, 1120, 1104, 1043, 944, 842, 828,
818, 767, 750 cm−1. HRMS (TOF, ESI, m/z): calcd for C15H9N3O2Na
[M + Na]+ 286.0592, found 286.0588.
d6, 400 MHz): δH 7.52−7.60 (m, 3H), 7.95 (d, J = 7.6 Hz, 1H), 8.39
(dd, J = 8.4 Hz, J′ = 6.4 Hz, 1H), 8.53 (d, J = 9.2 Hz, 1H), 8.69 (d, J =
8.0 Hz, 1H), 9.34 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 102.7
(d, JF−C = 27.2 Hz), 113.7 (d, JF−C = 23.3 Hz), 115.1, 115.8 (d, JF−C
=
1.9 Hz), 120.5, 123.8, 125.3, 129.0, 133.9 (d, JF−C = 11.3 Hz), 138.7 (d,
JF−C = 12.7 Hz), 143.6, 150.1, 158.9, 166.2 (d, JF−C = 252.5 Hz). IR
(KBr): ν 3099, 3074, 2987, 2946, 1625, 1596, 1556, 1536, 1492, 1455,
1435, 1402, 1348, 1269, 1247, 1223, 1167, 1110, 1049, 965, 931, 858,
843, 761, 740 cm−1. HRMS (TOF, ESI, m/z): calcd for C14H8FN3Na
[M + Na]+ 260.0600, found 260.0602.
9,10-Dimethylbenzo[4,5]imidazo[1,2-a]quinazoline (3l). Yield:
66% (163 mg). Pale yellow solid. Mp: 255−257 °C. 1H NMR
(CDCl3, 400 MHz): δH 2.43 (s, 3H), 2.50 (s, 3H), 7.66−7.69 (m,
1H), 7.72 (s, 1H), 8.06−8.10 (m, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.44
(s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 9.13 (s, 1H). 13C NMR ((CDCl3,
100 MHz): δC 20.6, 21.1, 113.8, 114.7, 118.5, 121.1, 124.3, 129.1,
129.8, 133.0, 134.3, 135.1, 137.6, 142.4, 145.6, 157.3. IR (KBr): ν
3079, 3046, 3026, 2970, 2918, 2849, 1720, 1609, 1552, 1524, 1466,
1389, 1326, 1254, 1228, 1198, 1158, 1093, 1044, 1023, 1004, 991, 969,
860, 817, 766, 749 cm−1. HRMS (TOF, ESI, m/z): calcd for C16H14N3
[M + H]+ 248.1182, found 248.1192.
3-Fluorobenzo[4,5]imidazo[1,2-a]quinazoline (3f). Yield: 82%
1
(194 mg). Pale yellow solid. Mp: 223−225 °C. H NMR (DMSO-
d6, 400 MHz): δH 7.53−7.60 (m, 2H), 7.91−7.98 (m, 2H), 8.17 (dd, J
= 8.0 Hz, J′ = 2.4 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.81 (dd, J = 8.8
Hz, J′ = 4.0 Hz, 1H), 9.33 (s, 1H). 13C NMR (DMSO-d6, 100 MHz):
δC 114.9, 115.7 (d, JF−C = 22.9 Hz), 118.1 (d, JF−C = 8.0 Hz), 119.8 (d,
JF−C = 8.3 Hz), 120.7, 123.3 (d, JF−C = 24.1 Hz), 123.9, 125.2, 129.1,
134.1 (d, JF−C = 1.8 Hz), 143.5, 150.0, 158.5 (d, JF−C = 242.5 Hz),
158.7. IR (KBr): ν 3050, 3024, 1556, 1525, 1476, 1454, 1428, 1387,
1343, 1262, 1253, 1194, 1143, 1031, 970, 929, 858, 827, 816, 761, 734
cm−1. HRMS (TOF, ESI, m/z): calcd for C14H8FN3Na [M + Na]+
260.0600, found 260.0587.
2-Chloro-9,10-dimethylbenzo[4,5]imidazo[1,2-a]quinazoline
1
(3m). Yield: 75% (211 mg). Pale yellow solid. Mp: 249−251 °C. H
NMR (CDCl3, 400 MHz): δH 2.51 (s, 3H), 2.58 (s, 3H), 7.88 (s, 1H),
7.93 (dd, J = 8.8 Hz, J′= 2.4 Hz, 1H), 8.02 (s, 1H), 8.03 (d, J = 2.4 Hz,
1H), 8.44 (d, J = 8.8 Hz, 1H), 9.06 (s, 1H). 13C NMR (CDCl3, 100
MHz): δC 20.6, 21.1, 113.6, 116.1, 119.4, 121.3, 127.4, 128.8, 129.7,
133.5, 134.2, 134.6, 135.9, 142.4, 149.3, 155.9. IR (KBr): ν 3044, 2920,
2861, 1612, 1586, 1533, 1455, 1380, 1324, 1303, 1248, 1211, 1159,
1127, 1098, 1024, 999, 950, 877, 863, 815, 756 cm−1. HRMS (TOF,
ESI, m/z): calcd for C16H13ClN3 [M + H]+ 282.0793, found 282.0801.
Benzo[4,5]imidazo[1,2-a]thieno[2,3-e]pyrimidine (3n). Yield: 82%
4-Fluorobenzo[4,5]imidazo[1,2-a]quinazoline (3g). Yield: 81%
(192 mg). Pale yellow solid. Mp: 249−251 °C. H NMR (DMSO-
1
d6, 400 MHz): δH 7.53−7.64 (m, 3H), 8.01 (d, J = 8.0 Hz, 1H), 8.10−
8.15 (m, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 7.6 Hz, 1H), 9.50
(s, 1H). 13C NMR (CDCl3, 100 MHz): δC 108.6 (d, JF−C = 16.8 Hz),
110.5 (d, JF−C = 22.7 Hz), 110.6, 113.7, 121.5, 123.9, 125.3, 129.0,
135.7 (d, JF−C = 10.1 Hz), 138.5 (d, JF−C = 4.7 Hz), 143.8, 149.8, 151.6
(d, JF−C = 6.8 Hz), 160.5 (d, JF−C = 257.4 Hz). IR (KBr): ν 3100, 3076,
3053, 1628, 1614, 1590, 1548, 1529, 1485, 1465, 1455, 1341, 1272,
1265, 1251, 1224, 1202, 1156, 1125, 1065, 886, 863, 835, 786, 763,
744 cm−1. HRMS (TOF, ESI, m/z): calcd for C14H9FN3 [M + H]+
238.0775, found 238.0782.
1
(185 mg). Pale yellow solid. Mp: 202−203 °C. H NMR (DMSO-d6,
400 MHz): δH 7.49−7.53 (m, 1H), 7.57−7.61 (m, 1H), 7.95 (d, J =
8.0 Hz, 1H), 8.53 (d, J = 4.8 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.65
(d, J = 4.8 Hz, 1H), 9.43 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δC
114.1, 116.9, 119.9, 120.3, 122.6, 125.5, 127.7, 139.1, 141.9, 143.4,
150.3, 151.3. IR (KBr): ν 3096, 3074, 2963, 2948, 1655, 1612, 1573,
1530, 1487, 1460, 1440, 1418, 1373, 1308, 1267, 1252, 1222, 1203,
1158, 1128, 1092, 1063, 1009, 888, 861, 833, 764, 730 cm−1. HRMS
(TOF, ESI, m/z): calcd for C12H7N3SNa [M + Na]+ 248.0258, found
248.0251.
3-Methoxybenzo[4,5]imidazo[1,2-a]quinazoline (3h). Yield: 72%
1
(179 mg). Pale yellow solid. Mp: 222−224 °C. H NMR (DMSO-d6,
400 MHz): δH 3.92 (s, 3H), 7.49−7.56 (m, 2H), 8.17 (dd, J = 8.8 Hz,
J′ = 2.8 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.93−7.95 (m, 1H), 8.57 (d,
J = 7.6 Hz, 1H), 8.65 (d, J = 9.2 Hz, 1H), 9.28 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz): δC 56.4, 112.2, 114.8, 117.0, 119.7, 120.5,
123.4, 124.1, 124.9, 129.0, 131.8, 143.5, 150.0, 156.4, 159.0. IR (KBr):
ν 3054, 3031, 3007, 2982, 2946, 1620, 1597, 1557, 1522, 1481, 1467,
1453, 1421, 1388, 1378, 1353, 1265, 1252, 1199, 1189, 1040, 1016,
955, 898, 798, 763, 728 cm−1. HRMS (TOF, ESI, m/z): calcd for
C15H11N3ONa [M + Na]+ 272.0800, found 272.0782.
General Procedure for the Syntheses of 3-(1H-Benzo[d]-
imidazol-2-yl)-2-(2-bromophenyl)-2,3-dihydroquinazolin-
4(1H)-one (4). N-(2-Benzimidazolyl)-2-aminobenzamide (1.0 mmol),
2-bormobenzaldehyde (1.0 mmol), CuI (10 mg, 0.05 mmol), and
dioxane (10 mL) were added into a 25 mL flask. The reaction mixture
was stirred at reflux for 6 h before reaching completion, which was
monitored by TLC. The solid was filtered off, the filtrate was cooled to
room temperature, and product 4 was obtained in 86% yield by
filtration.
3-(Trifluoromethyl)benzo[4,5]imidazo[1,2-a]quinazoline (3i).
1
Yield: 75% (215 mg). Pale yellow solid. Mp: >300 °C. H NMR
(DMSO-d6, 400 MHz): δH 7.61−7.64 (m, 2H), 8.01−8.03 (m, 1H),
8.17 (dd, J = 8.8 Hz, J′ = 2.0 Hz, 1H), 8.68−8.71 (m, 1H), 8.81 (s,
1H), 8.98 (d, J = 9.2 Hz, 1H), 9.50 (s, 1H). 13C NMR (DMSO-d6, 100
D
dx.doi.org/10.1021/jo5007398 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3-(1H-Benzo[d]imidazol-2-yl)-2-(2-bromophenyl)-2,3-dihydroqui-
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nazolin-4(1H)-one (4). Yield: 86% (360 mg). Pale yellow solid. Mp:
1
228−229 °C. H NMR (DMSO-d6, 400 MHz): δH 6.83−6.87 (m,
1H), 6.89 (d, J = 7.6 Hz, 1H), 7.07−7.13 (m, 2H), 7.14−7.17 (m,
1H), 7.20−7.26 (m, 2H), 7.35−7.39 (m, 1H), 7.41−7.43 (m, 1H),
7.48 (d, J = 4.4 Hz, 1H), 7.54−7.56 (m, 1H), 7.69−7.72 (m, 1H), 7.91
(d, J = 4.4 Hz, 1H), 7.94 (dd, J = 8.0 Hz, J′= 1.2 Hz, 1H), 12.61 (s,
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119.0, 122.0, 122.1, 122.3, 126.3, 127.7, 128.3, 128.6, 130.9, 133.6,
134.2, 135.7, 139.0, 140.1, 145.8, 146.7, 162.8.
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* Supporting Information
1
13
Copies of H NMR and C NMR spectra for compounds
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(CIF). This material is available free of charge via the Internet
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AUTHOR INFORMATION
Corresponding Author
*E-mail: xswang1974@yahoo.com.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science foundation of
China (20802061), a Project Funded by the Priority Academic
Program Development of Jiangsu Higher Education Institu-
tions, Qing Lan Project (10QLD008), and College Industrial-
ization Project (JHB2012-31) of Jiangsu Province for financial
support.
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