One-pot synthesis of imidazo[1,2-c]quinazoline derivatives from nitro-componds reduced by zinc

Article abstract of DOI:10.1002/jhet.189

(Chemical Equation Presented) An efficient, convenient, one-pot synthesis of imidazo[1,2-c]quinazolines was accomplished in good yields via the novel reductive cyclization of 2-(2-nitrophenyl)-1H-imidazole with isothiocyanates mediated by zinc dust.

Full text of DOI:10.1002/jhet.189

September 2009 One-Pot Synthesis of Imidazo[1,2-c]quinazoline Derivatives from
Nitro-Componds Reduced by Zinc
971
Da-Qing Shi,a,b* Shao-Feng Rong,b Guo-Lan Dou,a and Man-Man Wanga
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering, and Materials Science, Soochow University, Suzhou 215123,
People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116,
People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received March 27, 2009
DOI 10.1002/jhet.189
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
An efficient, convenient, one-pot synthesis of imidazo[1,2-c]quinazolines was accomplished in good
yields via the novel reductive cyclization of 2-(2-nitrophenyl)-1H-imidazole with isothiocyanates
mediated by zinc dust.
J. Heterocyclic Chem., 46, 971 (2009).
INTRODUCTION
RESULTS AND DISCUSSION
The quinazolinone skeleton is a building block for the
preparation of natural purine base, alkaloids [1], many
biologically active compounds, and intermediates in or-
ganic synthesis [2]. The quinazoline moiety present in
imidazoquinazolines is responsible for a wide range of
biological activities ranging form anticonvulsants and
antibacterial to antidiabetic agents [3–9].
On the basic of our previous experience, we selected
2-(2-nitro-4,5-methylenedioxyphenyl)-4,5-diphenyl-1H-
imidazole (1a) and phenyl isothiocyanate (2a) as model
substrates to optimize the experimental conditions for
the proposed reductive cyclization reaction (Scheme 1).
The results are summarized in Table 1.
The results obtained from these experiments indicated
that the reaction solvents had a significant influence on
the success of this reaction. No product was obtained
when the solvent was H2O or MeOH. When the solvent
was AcOH, DMF, CH3CN or CHCl3, the yield of the
product was 40–80%. When THF was used as solvent at
refluxing temperature, the products 3a was obtained in
highest yield. To further evaluate the influence of the ra-
tio of 1a: Zn, this reaction was carried out with different
ratio. When the ratio of substrate:Zn was 1:1, 45% yield
of the product was obtained in 20 h, it can be seen that
increasing the catalyst loading increase the yield. When
the ratio of substrate:Zn was 1:5, the yield of the prod-
uct decrease. From the results, it is obvious that the best
ratio is 1:4.
As a consequence, much attention has been paid to the
development of efficient methods for the preparation of
5-amino derivatives of imidazo[1,2-c]quinazoline. The
first method involved treatment of 6-mercaptobenzimida-
zoquinazoline with amines [10] and the second method
involved an aza-wittig reaction of iminophosphoranes
derived from 2-(o-azido)phenylbenzimidazole with iso-
cyanates [11]. Recently, several methods have been
developed for synthesizing this heterocyclic system.
Sharma et al. [12] developed an efficient strategy for the
preparation of imidazoquinazolines, but the use of DBU
and multiple steps limited the method. We developed an
efficient and one-pot synthesis of imidazoquinazolines
from 2-(2-nitrophenyl)-1H-imidazole induced by low-va-
lent titanium reagent [13], but this method required anhy-
drous system. As mentioned in our earlier works, herein,
we reported a convenient protocol for the synthesis of
imidazo[1,2-c]quinazolines in one-pot via the reductive
cyclization of 2-(2-nitrophenyl)-1H-imidazole and iso-
thiocyanates mediated by zinc dust.
Having established an optimal condition for the proto-
col, we performed a more detailed examination of the
substrates. Thus, the behavior of a variety of substrates,
which include different 2-(2-nitrophenyl)-1H-imidazole
as well as different isothiocyanates was examined
(Scheme 2). The results are summarized in Table 2. As
C
V
2009 HeteroCorporation

972
D.-Q. Shi, S.-F. Rong, G.-L. Dou, and M.-M. Wang
Vol 46
Scheme 1
EXPERIMENTAL
THF was untreated. Melting points were determined in open
capillaries and are uncorrected. IR spectra were recorded on a
Varian FT-1000 spectrometer in KBr with absorptions in
.
cmꢀ1 1H NMR was determined on a Varian Inova-400 MHz
or a Varian NMR System 300 MHz spectrometer in DMSO-d6
solution. J values are in Hz. Chemical shifts are expressed in
ppm downfield from internal standard TMS. HRMS data
were obtained using TOF–MS microma GCT-TOF instrument.
X-ray diffraction was recorded on a Mercury Bruker Smart-
1000 CCD diffractometer.
General procedure for the synthesis of 2-(2-nitrophenyl)-
1H-imidazole 1. A solution of benzil (5 mmol) in AcOH was
treated with 2-nitrobenzaldehyde (5 mmol) and NH4OAc
(40 mmol) [12]. The reaction mixture was refluxed for 4 h,
then AcOH was evaporated, and the residue was treated with a
10% aqueous solution of NaHCO3 (pH 8). The mixture was
extracted with EtOAc (2 ꢁ 25 mL), washed with brine
(25 mL), and dried over Na2SO4. The solvent was evaporated
under reduced pressure to give a yellow solid.
General procedure for the synthesis of imidazol[1,2-
c]quinazolines 3. To a solution of 2-(2-nitrophenyl)-1H-imid-
azole (1 mmol) and isothiocyanates (1 mmol) in THF (15
mL), zinc dust (4 mmol) and AcOH (0.5 mL) was added. The
reaction mixture was refluxed for 2 h. After this period, TLC
analysis of the mixture showed the reaction to be completed.
The reaction mixture was quenched with 5% HCl (15 mL) and
extracted with CHCl3 (3 ꢁ 20 mL). The combined extracts
were washed with water (3 ꢁ 20 mL) and dried over anhy-
drous Na2SO4. After evaporation of the solvent under reduced
pressure, the crude product was purified by recrystallization
from acetone.
shown in Table 2, for series of 3, either the aromatic
ring containing electron-withdrawing groups (such as
halides) or electron-donating groups (such as alkyl
group), reacted well to give the corresponding products
3 in good yields under the same reaction conditions. So,
we concluded that no obvious effects from the electronic
or nature of the aromatic ring substrates were observed
in the above reactions.
We propose the possible following mechanism to
account for the reaction. At first step 2-(2-nitro-
phenyl)-1H-imidazole 1 was reduced by Zn/Hþ to 2-
(2-aminophenyl)-1H-imidazole 4, the addition reaction
of reductive product 4 with isothiocyanates 2 to afford
intermediate 5, intermediate 5 was cyclized by the
nucleophilic attack of nitrogen atoms on C¼¼S
group and gave the intermediate 6. Finally the
expected products 3 were afforded by losing of H2S
(Scheme 3).
1
The structures of product 3 were identified by IR, H
NMR, and HRMS. The structure of product 3a was fur-
ther confirmed by X-ray diffraction analysis (Fig. 1).
In conclusion, a series of imidazo[1,2-c]quinazolines
were synthesized by the reaction of 2-(2-nitrophenyl)-
1H-imidazoles and isothiocyanates induced by zinc dust.
This protocol has advantages of accessible materials,
handy manipulation (only one-pot), and isolation of
products via simple recrystallization.
(8,9-Methylenedioxy-2,3-diphenylimidazo[1,2-c]quinazo-
lin-5-yl)phenylamine (3a). This compound was obtained as
solid with mp 215–217ꢂC; IR (KBr) m: 3393, 3059, 2902,
1623, 1598, 1557, 1533, 1466, 1377, 1340, 1271, 1217, 1148,
1036, 941, 864, 824, 750, 706 cmꢀ1 1H NMR (400 MHz,
.
DMSO-d6): 6.19 (s, 2H, OCH2O), 6.78 (s, 1H, NH), 7.00 (t, J
¼ 8.0 Hz, 1H, ArH), 7.15 (s, 1H, ArH), 7.18 (s, 2H, ArH),
7.25–7.31 (m, 5H, ArH), 7.54 (d, J ¼ 7.6 Hz, 2H, ArH), 7.68–
7.72 (m, 2H, ArH), 7.76–7.82 (m, 4H, ArH).
HRMS [Found: m/z 456.1578 (Mþ), Cacld for C29H20N4O2:
M, 456.1586].
(2,3-Diphenylimidazo[1,2-c]quinazolin-5-yl)phenylamine
(3b). This compound was obtained as solid with mp 195–
197ꢂC (ref. 12, 200–201ꢂC); IR (KBr) m: 3340, 1625, 1567,
1597, 1537, 1497, 1477, 1444, 1371, 1331, 1232, 1110, 1027,
Table 1
Optimization for the reductive cyclization reaction.
1
927, 765, 703 cmꢀ1. H NMR (400 MHz, DMSO-d6): 6.89 (s,
Reaction
time (h)
1H, NH), 7.02–7.06 (m, 1H, ArH), 7.21–7.23 (m, 2H, ArH),
7.27–7.33 (m, 5H, ArH), 7.47–7.51 (m, 1H, ArH), 7.56–7.58
(m, 2H, ArH), 7.65–7.85 (m, 7H, ArH), 8.43–8.45 (m, 1H,
ArH).
Entry
Solvent
Ratioa
Yield (%)
1
2
THF
THF
1:2
1:3
1:4
1:5
1:4
1:4
1:4
1:4
1:4
1:4
20
12
1.5
1.5
12
12
2
45
60
86
85
0
3
4
THF
THF
5
6
MeOH
H2O
Scheme 2
0
7
8
AcOH
CH3CN
CHCl3
DMF
50
80
42
73
1.5
2
9
10
1.5
a Ratio of 1a and zinc dust.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
One-Pot Synthesis of Imidazo[1,2-c]Quinazoline Derivatives from
Nitro-Compounds Reduced by Zinc
973
Table 2
Synthesis of imidazo[1,2-c]quinazolines.
Entry
Ar
X
Y
R
Time (h)
Yield (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
C6H5
OCH2O
C6H5
C6H5
C6H5
1.5
2.5
3
2.5
1.5
3
86
80
92
75
83
65
63
81
85
72
H
H
Cl
H
H
H
H
H
H
H
H
H
H
4-CH3C6H4
4-CH3OC6H4
C6H5
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
C6H5
C6H5
C6H5
H
Cl
Cl
H
4
4-CH3C6H4
4-CH3OC6H4
C6H5
C6H5
3-CH3C6H4
3-CH3C6H4
3
1.5
1.5
3j
H
a Isolated yield.
HRMS [Found: m/z 412.1688 (Mþ), Cacld for C28H20N4:
M, 412.1688].
(m, 1H, ArH), 7.56–7.58 (m, 2H, ArH), 7.64 (d, J ¼ 4.0 Hz,
2H, ArH), 7.70–7.84 (m, 5H, ArH), 8.42–8.44 (m, 1H, ArH).
HRMS [Found: m/z 426.1846 (Mþ), Cacld for C29H22N4:
M, 426.1844].
{2,3-Bis(4-methylphenyl)imidazo[1,2-c]quinazolin-5-yl}phe-
nylamine (3c). This compound was obtained as solid with mp
241–243ꢂC; IR (KBr) m: 3387, 3031, 2915, 2857, 1623, 1599,
1565, 1534, 4550, 1498, 1474, 1461, 1353, 1338, 1282, 1185,
4-Chlorophenyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-
yl)amine (3f). This compound was obtained as solid with mp
212–214ꢂC (ref. 13, 208–210ꢂC); IR (KBr) m: 3400, 3054,
1625, 1596, 1566, 1536, 1490, 1472, 1444, 1404, 1332, 1293,
1
1111, 924, 896, 823, 763, 707, 689, 671 cmꢀ1. H NMR (400
MHz, DMSO-d6): 2.27 (s, 3H, CH3), 2.53 (s, 3H, CH3), 6.95
(s, 1H, NH), 7.02–7.05 (m, 1H, ArH), 7.11 (d, J ¼ 8.0 Hz,
2H, ArH),7.21–7.24 (m, 2H, ArH), 7.29–7.33 (m, 2H, ArH),
7.45–7.49 (m, 3H, ArH), 7.53 (d, J ¼ 7.2 Hz, 2H, ArH), 7.62–
7.71 (m, 4H, ArH), 8.41–8.43 (m, 1H, ArH).
HRMS [Found: m/z 440.2008 (Mþ), Cacld for C30H24N4:
M, 440.2001].
1
1088, 830, 802, 757, 709 cmꢀ1. H NMR (400 MHz, DMSO-
d6): 6.92 (s, 1H, NH), 7.21–7.23 (m, 2H, ArH), 7.26–7.52 (m,
5H, ArH), 7.47–7.51 (m, 1H, ArH), 7.56 (d, J ¼ 7.6 Hz, 2H,
ArH), 7.66–7.82 (m, 7H, ArH), 8.44 (d, J ¼ 8.0 Hz, 1H,
ArH).
HRMS [Found: m/z 446.1296 (Mþ), Cacld for
C28H1935ClN4: M, 446.1298].
{9-Chloro-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]quinazo-
lin-5-yl}-p-tolylamine (3d). This compound was obtained as
solid with mp 199–200ꢂC; IR (KBr) m: 3370, 1624, 1610,
1579, 1559, 1533, 1516, 1490, 1473, 1377, 1335, 1289, 1252,
(9-Chloro-2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)phe-
nylamine (3g). This compound was obtained as solid with mp
190–191ꢂC (ref. 13, 182–184ꢂC); IR (KBr) m: 3387, 3058,
1627, 1598, 1559, 1532, 1497, 1472, 1446, 1378, 1336, 1234,
1177, 1073, 1036, 833, 668 cmꢀ1 1H NMR (400 MHz,
.
1
DMSO-d6): 2.25 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 3.93 (s,
3H, OCH3), 6.89 (d, J ¼ 8.4 Hz, 2H, ArH), 6.97 (s, 1H, NH),
7.11–7.16 (m, 4H, ArH), 7.26–7.28 (m, 2H, ArH), 7.49–7.52
(m, 2H, ArH), 7.62–7.65 (m, 2H, ArH), 7.72–7.75 (m, 2H,
ArH), 8.32 (s, 1H, ArH).
HRMS [Found: m/z 520.1665 (Mþ), Cacld for
C31H2535ClN4O2: M, 520.1666].
1071, 1027, 925, 877, 818, 774, 755, 714, 689 cmꢀ1. H NMR
(400 MHz, DMSO-d6): 6.89 (s, 1H, NH), 7.04 (t, J ¼ 7.6 Hz,
1H, ArH), 7.19 (d, J ¼ 8.4 Hz, 2H, ArH), 7.27–7.31 (m, 5H,
ArH), 7.55–7.57 (m, 2H, ArH), 7.61–7.74 (m, 4H, ArH), 7.78
(d, J ¼ 7.2 Hz, 1H, ArH), 7.84 (d, J ¼ 7.2 Hz, 2H, ArH),
8.34 (d, J ¼ 2.4 Hz, 1H, ArH).
HRMS [Found: m/z 446.1296 (Mþ), Cacld for
C28H1935ClN4: M, 446.1298].
(2,3-Diphenylimidazo[1,2-c]quinazolin-5-yl)-p-tolylamine
(3e). This compound was obtained as solid with mp 196–
198ꢂC (ref. 13, 192–194ꢂC); IR (KBr) m: 3400, 3055, 2921,
1630, 1599, 1564, 1543, 1509, 1472, 1378, 1351, 1334, 1240,
1227, 1109, 1026, 924, 831, 814, 778, 760, 712 cmꢀ1 1H
.
NMR (400 MHz, DMSO-d6): 2.24 (s, 3H, CH3), 6.78 (s, 1H,
NH), 7.01 (s, 4H, ArH), 7.26–7.33 (m, 3H, ArH), 7.46–7.48
Scheme 3
Figure 1. X-ray structure of 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

974
D.-Q. Shi, S.-F. Rong, G.-L. Dou, and M.-M. Wang
Vol 46
HRMS [Found: m/z 426.1844 (Mþ), Cacld for C29H22N4:
M, 426.1844].
{9-Chloro-2,3-bis(4-methylphenyl)imidazo[1,2-c]quinazolin-
5-yl}phenylamine (3h). This compound was obtained as solid
with mp 226–227ꢂC. IR (KBr) m: 3387, 2916, 2857, 1626,
1597, 1559, 1530, 1497, 1472, 1450, 1374, 1342, 1246, 1185,
.
1072, 1016, 929, 819, 755, 691 cmꢀ1 1H NMR (400 MHz,
Acknowledgments. We are grateful to the Key Laboratory of
Organic Synthesis of Jiangsu Province for financial support.
DMSO-d6): 2.28 (s, 3H, CH3), 2.53 (s, 3H, CH3), 6.97 (s, 1H,
NH), 7.03–7.08 (m, 1H, ArH), 7.12 (d, J ¼ 8.0 Hz, 2H, ArH),
7.21–7.23 (m, 2H, ArH), 7.31 (t, J ¼ 8.0 Hz, 2H, ArH), 7.46
(d, J ¼ 8.4 Hz, 2H, ArH), 7.54 (d, J ¼ 7.6 Hz, 2H, ArH),
7.63–7.72 (m, 4H, ArH), 8.35 (d, J ¼ 2.4 Hz, 1H, ArH).
HRMS [Found: m/z 474.1609 (Mþ), Cacld for
C30H2335ClN4: M, 474.1611].
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M, 486.2056].
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716, 705 cmꢀ1. H NMR (300 MHz, DMSO-d6): 2.23 (s, 3H,
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ArH), 7.14 (t, J ¼ 7.8 Hz, 1H, ArH), 7.24–7.30 (m, 3H, ArH),
7.42–7.48 (m, 1H, ArH), 7.53–7.56 (m, 2H, ArH), 7.59–7.66
(m, 2H, ArH), 7.69–7.82 (m, 5H, ArH), 8.40 (d, J ¼ 7.5 Hz,
1H, ArH).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet