An efficient synthesis of pyrrolo[1,2-a]quinazoline derivatives in ionic liquid catalyzed by iodine

Article abstract of DOI:10.1002/jhet.1116

A mild, green, and facile method for the synthesis of 2,3,3a,4- tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione derivatives is described in high yields by using ionic liquids as green media. The method involves the reaction of 2-aminobenzamides with 4-oxopentanoic acid or 4-aryl-4-oxo-butanoic acid catalyzed by iodine and has the advantages of mild reaction conditions, high yields, one-pot, operational simplicity, and environmentally benign.

Full text of DOI:10.1002/jhet.1116

May 2014
An Efficient Synthesis of Pyrrolo[1,2-a]quinazoline Derivatives in Ionic
841
Liquid Catalyzed by Iodine
Lian Lu,a Ke Yang,a Mei-Mei Zhang,b and Xiang-Shan Wang
a
*
aSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, People’s Republic of China
bThe Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou Jiangsu
221116, People’s Republic of China
*
E-mail: xswang1974@yahoo.com
Received May 31, 2011
DOI 10.1002/jhet.1116
Published online 26 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
NHR
NR
I2
R'CO(CH2)2CO2H
+
R'
IL, 80 o
C
NH2
N
O
A mild, green, and facile method for the synthesis of 2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione
derivatives is described in high yields by using ionic liquids as green media. The method involves the reaction
of 2-aminobenzamides with 4-oxopentanoic acid or 4-aryl-4-oxo-butanoic acid catalyzed by iodine and has the
advantages of mild reaction conditions, high yields, one-pot, operational simplicity, and environmentally benign.
J. Heterocyclic Chem., 51, 841 (2014).
the synthesis of 2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazo-
line-1,5-dione derivatives in ionic liquids by a one-pot
reaction catalyzed by iodine.
INTRODUCTION
Pyrroloquinazolines are important core structures found in
a variety of natural products and other biologically important
molecules [1]. They often possess a wide range of biological
activities, such as antitumor [2], modulators of chemokine
activity [3], and anti-inflammatory activity [4]. Some of
them may be useful for optimization of thrombin receptor
antagonistic activity [5].
Although a number of useful synthetic procedures to
prepare these compounds have been developed [6], still
several limitations remain. For example, most reported
procedures are several steps, low yields, or in flammable
organic solvents. Moreover, the starting materials are
not often readily available. Thus, a simple, efficient, and
green method to synthesize pyrroloquinazolines would
be attractive.
Room temperature ionic liquids, especially those based
on the 1-N-alkyl-3-methylimidazolium cation, have shown
great promise as attractive alternative to conventional
solvents [7]. The unique property of room temperature
ionic liquids is that they have essentially no vapor pressure,
which makes them optimal replacements for the volatile
organic solvents traditionally used as industrial solvents.
Another nice feature of ionic liquid is its ability to be reused
for many times concerning about green solvent. Therefore,
ionic liquids have made significant contributions to green
chemistry and have been used widely as reaction medium
in organic chemistry [8].
RESULTS AND DISCUSSION
Treatment of 2-aminobenzamides 1 and 4-oxopentanoic
acid 2 in ionic liquid of [BMIm]Br in the presence of 5 mol
% iodine at 80ꢀC resulted in the corresponding 2,3,3a,
4-tetrahydropyrrolo[1,2-a]quinazoline-1,5-dione derivatives
3a-u in high yields (Scheme 1).
By using the conversion of 2-aminobenzamide 1 and
4-oxopentanoic acid 2 as a model, several parameters
were explored as shown in Table 1. 3a was not detected
by TLC in the absence of iodine at 80ꢀC (Table 1,
Entry 1) and was obtained successfully in the presence
of various quantities of the catalyst, reaching a maxi-
mum of 89% yield by using 5 mol% iodine as catalyst
(Table 1, entries 4, 6, and 7). The yield of 3a was also
dependent on temperature (entries 2~5), proceeding
smoothly at 80ꢀC. In addition, different imidazolium
ionic liquids were also tested, and [BMIm]Br appeared
to be the best medium for this transformation (entry
4 vs 8–12).
After reaction completion as monitored by TLC, the
products were isolated by simple filtration after the addi-
tion of a small amount of water to the cooled reaction
mixture. Water in the filtrate was removed by distillation
under reduced pressure, and the [BMIm]Br in the residue
could be reused after being evaporated at 80ꢀC for 4 h in
vacuum. Successive reuse of the recycled ionic liquid of
As a continuation of our research devoted to the devel-
opment of new methods for heterocycles in ionic liquid
and with iodine as catalyst [9], we would like to report
© 2013 HeteroCorporation

842
L. Lu, K. Yang, M.-M. Zhang, and X.-S. Wang
Vol 51
Scheme 1. Reaction of 1 and 4-oxopentanoic acid in ionic liquid.
[BMIm]Br in the model reaction gave high yields of 3a
(88%) even after the fourth cycle.
O
O
R
The optimized conditions were applied for the con-
version of various kinds of 2-aminobenzamides 1 react-
ing with 4-oxopentanoic acid 2 into the corresponding
pyrrolo[1,2-a]quinazoline-1,5-dione analogs 3a-k (Table 2,
entries 1–11). In addition, 4-aryl-4-oxo-butanoic acid
was also selected as reactant to react with 2-aminoben-
zamides in the same reaction conditions; the desired
reaction proceeded well to give polyhydropyrrolo[1,2-a]
quinazolines 3l-u in high yields (Table 2, entries 12–21).
From Table 2, we can conclude that this process can
tolerate both electron-donating (alkyl and alkoxy) and
electron-withdrawing (halogen) substituents on the
aromatic aldehydes in 1(Table 2). In all cases, the reac-
tions proceeded efficiently in ionic liquid at 80ꢀC to
afford the desired products in high yields. All the
compounds were characterized by 1H NMR, IR, and
HRMS, some of them were also characterized by 13C
NMR, and they were all in good agreement with
their structures.
I2
NHR
N
R'CO(CH2)2CO2H
+
R'
IL, 80 o
C
NH2
N
O
1
2
3a-u
Table 1
Synthetic results of 3a under different reaction conditions.a
Entry
Temp./ꢀC
Ionic liquidb
I2 (mol%)
Yield (%)c
1
2
3
4
5
6
7
8
80
r.t.
50
80
100
80
80
80
80
80
80
80
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[EMIm]Br
[PMIm]Br
[EMIm][BF4]
[PMIm][BF4]
[BMIm][BF4]
0
5
5
5
5
10
20
5
5
5
0
trace
82
89
88
89
90
83
85
86
86
89
Consistent with previous suggestions in the literature,6e
we suggest that iodine catalyzes the reaction as a mild
Lewis acid. The proposed mechanism was shown in
Scheme 2. The Schiff base I is formed by condensation 1
with 4-oxopentanoic acid 2. Intramolecular attack on
the iodine-activated Schiff base II then forms the quinazo-
line III, and finally the intermediate III gives 3 by an
intramolecular dehydration.
9
10
11
12
5
5
aReaction condition: 2-mL solvent, 2-aminobenzamide (0.272 g, 2 mmol),
and 4-oxopentanoic acid (0.244 g, 2.1 mmol).
bBMIm = 1-butyl-3-methylimidazolium; EMIm = 1-ethyl-3-methylimida-
zolium; PMIm = 1-propyl-3-methylimidazolium.
cIsolated yields.
Table 2
Synthetic results of 3a–u in ionic liquids.a
Entry
R
R′
Products
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
4
7
6
5
5.5
5.5
5
4
4
6
5
8
8
9
8
6
6
89
86
90
94
92
90
91
93
92
87
92
87
83
87
90
85
84
87
93
92
89
4-MeC6H4
4-FC6H4
Ph
4-MeOC6H4
4-MeOC6H4(CH2)2
4-MeOC6H4CH2
C6H5CH2
C6H5CH2CH2
(Furan-2-yl)methyl
3,4-OCH2OC6H3(CH2)2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
9
10
11
12
13
14
15
16
17
18
19
20
21
4-i-Pr-C6H4
4-MeC6H4
4-MeOC6H4
4-EtC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-i-Pr-C6H4
4-ClC6H4
7
8
6
7
3t
3u
4-EtC6H4
aReaction condition: 2 mL [BMIm]Br, 1 (2 mmol), 2 (2.1 mmol), and iodine (0.025 g, 0.1 mmol), 80ꢀC.
bIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Pyrrolo[1,2-a]quinazoline Derivatives
843
Scheme 2. The possible mechanism for the formation of products 3.
2,3,3a,4-Tetrahydro-3a-methyl-4-p-tolylpyrrolo[1,2-a]
1
quinazoline-1,5-dione (3b). m.p. 244~246ꢀC. H NMR (CDCl3,
O
O
400 MHz): dH 1.75 (s, 3H, CH3), 1.79~1.83 (m, 1H, CH),
2.34~2.40 (m, 4H, CH3 + CH), 2.60~2.64 (m, 2H, CH2),
7.13~7.16 (m, 2H, ArH), 7.27~7.32 (m, 3H, ArH), 7.58~7.63
(m, 1H, ArH), 8.13 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1H, ArH), 8.60
(dd, J = 8.4 Hz, J′ = 0.8 Hz, 1H, ArH). 13C NMR (100 MHz,
DMSO-d6): dC 171.8, 161.1, 137.6, 135.5, 134.4, 133.5, 129.7,
129.6, 128.3, 124.6, 119.7, 119.5, 79.0, 31.2, 29.8, 24.6, 20.6. IR
(KBr): 3028, 2974, 2872, 1720, 1650, 1602, 1513, 1484, 1468,
1385, 1346, 1199, 1140, 813, 766, 698cmÀ1. HRMS (ESI, m/z):
calcd for C19H18N2NaO2 [M+ Na]+ 329.1266, found 329.1251.
4-(4-Fluorophenyl)-2,3,3a,4-tetrahydro-3a-methylpyrrolo
O
NHR
I2
IL
NHR
+
CO2H
N
NH2
HO2C
I
1
2
O
O
N
O
R
NHR
NR
N
-H2O
N
N
H
I2
HO2C
1
[1,2-a]quinazoline-1,5-dione (3c). m.p. 225~227ꢀC. H NMR
O
HO2C
III
(CDCl3, 400 MHz): dH 1.75 (s, 3H, CH3), 1.80~1.86 (m, 1H,
CH), 2.29~2.37 (m, 1H, CH), 2.62~2.65 (m, 2H, CH2), 7.18
(t, J = 8.8 Hz, 2H, ArH), 7.24~7.27 (m, 2H, ArH), 7.29~7.33
(m, 1H, ArH), 7.60~7.64 (m, 1H, ArH), 8.12 (dd, J = 7.6 Hz,
J′ = 1.2 Hz, 1H, ArH), 8.27 (d, J = 8.4 Hz, 1H, ArH). IR (KBr):
3067, 2976, 2931, 1718, 1656, 1602, 1510, 1486, 1397, 1348,
1222, 1155, 1092, 843, 758, 696 cmÀ1. HRMS (ESI, m/z): calcd
for C18H15FN2NaO2 [M+ Na]+ 333.1015, found 333.1011.
3
II
CONCLUSION
In summary, a mild, facile, and environmentally benign
method is developed for the synthesis of pyrrolo[1,2-a]
quinazoline-1,5-dione derivatives in high yields catalyzed
by iodine in ionic liquids. The advantages of this procedure
include mild reaction conditions, high yields, one-pot,
operational simplicity, and environmentally benign.
2,3,3a,4-Tetrahydro-3a-methyl-4-phenylpyrrolo[1,2-a]
quinazoline-1,5-dione (3d).
m.p. 224~225ꢀC, (Lit.6g m.p.
1
223~224ꢀC). H NMR (CDCl3, 400 MHz): dH 1.77 (s, 3H, CH3),
1.80~1.84 (m, 1H, CH), 2.30~2.39 (m, 1H, CH), 2.60~2.64
(m, 2H, CH2), 7.28~7.33 (m, 3H, ArH), 7.41~7.51 (m, 3H, ArH),
7.59~7.64 (m, 1H, ArH), 8.14 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1H,
ArH), 8.27 (dd, J = 8.4 Hz, J′ = 0.8 Hz, 1H, ArH). IR (KBr):
3083, 2971, 2928, 1718, 1659, 1602, 1488, 1465, 1391, 1342,
1194, 1136, 764, 708, 697 cmÀ1. HRMS (ESI, m/z): calcd for
C18H16N2NaO2 [M + Na]+ 315.1109, found 315.1093.
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on a Tensor 27 spectrometer
(Bruker Corporation, Karlsruhe, DE) in KBr pellet. 1H NMR spec-
tra were obtained from a solution in DMSO-d6 with Me4Si as inter-
nal standard by using a Bruker-400 spectrometer. HRMS analyses
were carried out using a Bruker-micro-TOF-Q-MS analyzer.
2,3,3a,4-Tetrahydro-4-(4-methoxyphenyl)-3a-methylpyrrolo
[1,2-a]quinazoline-1,5-dione (3e). m.p. 202~205ꢀC, (Lit.6e m.p.
1
198~200ꢀC). H NMR (CDCl3, 400 MHz): dH 1.74 (s, 3H, CH3),
1.78~1.84 (m, 1H, CH), 2.33~2.41 (m, 1H, CH), 2.60~2.64
(m, 2H, CH2), 3.85 (s, 3H, CH3O), 6.99 (d, J = 9.2 Hz, 2H, ArH),
7.18 (d, J = 8.8 Hz, 2H, ArH), 7.30 (t, J = 7.6 Hz, 1H, ArH),
7.58~7.63 (m, 1H, ArH), 8.13 (d, J = 7.6 Hz, 1H, ArH), 8.26
(d, J = 8.4 Hz, 1H, ArH). IR (KBr): 2970, 2932, 2836, 1717,
1652, 1601, 1514, 1487, 1468, 1398, 1347, 1303, 1251, 1176,
1038, 767, 696 cmÀ1. HRMS (ESI, m/z): calcd for C19H18N2NaO3
[M+ Na]+ 345.1215, found 345.1200.
General procedure for the synthesis of 2,3,3a,4-tetrahy-
dropyrrolo[1,2-a]quinazoline-1,5-dione derivatives 3.
A
dry 50-mL flask was charged with 2-aminobenzamides 1
(2.0 mmol), 4-oxopentanoic acid, or 4-aryl-4-oxo-butanoic acid
2 (2.1 mmol), iodine (0.025 g, 0.1 mmol), and ionic liquid of
[BMIm]Br (2 mL). The reaction mixture was stirred at 80ꢀC for
4–9 h, and then a small amount of water (5 mL) was added to
the mixture, and the generated yellow solid was filtered off.
The water in the filtrate was removed by distillation under
reduced pressure, and the ionic liquid in the residue could be
reusable by being evaporated at 80ꢀC for 4 h at vacuum. The
crude yellow products were washed with water, purified by
recrystallization from 95% EtOH, and then dried at 80ꢀC for
2 h under vacuum to give 3.
2,3,3a,4-Tetrahydro-3a-methylpyrrolo[1,2-a]quinazoline-1,5-
dione (3a). m.p. 184~186ꢀC, (Lit.6f m.p. 181~182ꢀC). 1H NMR
(CDCl3, 400MHz): dH 1.58 (s, 3H, CH3), 2.36~2.40 (m, 2H, CH2),
2.69~2.73 (m, 2H, CH2), 7.29 (t, J = 7.6 Hz, 1H, ArH), 7.58~7.62
(m, 2H, NH + ArH), 8.07 (d, J = 7.6 Hz, 1H, ArH), 8.16
(d, J = 8.4 Hz, 1H, ArH). IR (KBr): 3174, 3057, 2965, 2925,
1719, 1681, 1603, 1492, 1446, 1386, 1352, 1211, 1153, 791,
759, 617cmÀ1. HRMS (ESI, m/z): calcd for C12H12N2NaO2
[M + Na]+ 239.0796, found 239.0790.
4-(4-Methoxyphenethyl)-2,3,3a,4-tetrahydro-3a-methylpyrrolo
1
[1,2-a]quinazoline-1,5-dione (3f). m.p. 159~160ꢀC; H NMR
(DMSO-d6, 400 MHz): dH 1.41 (s, 3H, CH3), 2.27~2.47
(m, 3H, CH2 + CH), 2.68~2.96 (m, 3H, CH + CH2), 3.25~3.33
(m, 1H, CH), 3.71~3.78 (m, 4H, CH3O + CH), 6.89
(d, J = 8.8 Hz, 2H, ArH), 7.20 (d, J = 8.4 Hz, 2H, ArH), 7.31 (t,
J = 7.6 Hz, 1H, ArH), 7.62 (t, J = 7.6 Hz, 1H, ArH), 7.97
(d, J = 7.6 Hz, 1H, ArH), 8.19 (d, J = 8.4 Hz, 1H, ArH). IR
(KBr): 2994, 2963, 2929, 2834, 1704, 1646, 1613, 1587, 1512,
1488, 1438, 1402, 1340, 1307, 1247, 1162, 1041, 978, 819,
770, 695 cmÀ1. HRMS (ESI, m/z): calcd for C21H22N2NaO3
[M + Na]+ 373.1548, found 373.1539.
4-(4-Methoxybenzyl)-2,3,3a,4-tetrahydro-3a-methylpyrrolo
[1,2-a]quinazoline-1,5-dione (3g). m.p. 139~141ꢀC. 1H NMR
(CDCl3, 400 MHz): dH 1.45 (s, 3H, CH3), 2.18~2.23 (m, 1H,
CH), 2.44~2.63 (m, 3H, CH2 + CH), 3.79 (s, 3H, CH3O), 4.30
(d, J = 15.6 Hz, 1H, CH), 5.14 (d, J = 15.2 Hz, 1H, CH), 6.85 (d,
J = 8.8 Hz, 1H, ArH), 7.23~7.31 (m, 3H, ArH), 7.56~7.59 (m,
1H, ArH), 8.15 (d, J = 8.0 Hz, 1H, ArH), 8.26 (d, J = 8.4 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

844
L. Lu, K. Yang, M.-M. Zhang, and X.-S. Wang
Vol 51
1H, ArH). IR (KBr): 3074, 2976, 2954, 2835, 1714, 1650, 1601,
1515, 1487, 1469, 1434, 1403, 1362, 1341, 1246, 1200, 1178,
1036, 959, 825, 759, 696 cmÀ1. HRMS (ESI, m/z): calcd for
C20H20N2NaO3 [M + Na]+ 359.1372, found 359.1373.
7.56~7.60 (m, 1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 8.00
(d, J = 8.0 Hz, 1H, ArH). IR (KBr, n, cmÀ1): 3031, 2927, 1720,
1664, 1604, 1489, 1468, 145, 1396, 1377, 1350, 1321, 1311,
1225, 770, 730, 698. HRMS (ESI, m/z): calcd for C25H23N2O2
[M+ H]+ 383.1760, found 383.1776.
4-Benzyl-2,3,3a,4-tetrahydro-3a-methylpyrrolo[1,2-a]
quinazoline-1,5-dione (3h).
m.p. 102~103ꢀC. 1H NMR
4-Benzyl-2,3,3a,4-tetrahydro-3a-(4-methoxyphenyl)pyrrolo
[1,2-a]quinazoline-1,5-dione (3n). m.p. 210~212ꢀC; 1H NMR
(DMSO-d6, 400 MHz): dH 2.37~2.45 (m, 1H, CH), 2.51~2.54
(m, 1H, CH), 2.61~2.67 (m, 1H, CH), 2.81~2.89 (m, 1H, CH),
3.69 (s, 3H, OCH3), 4.51 (d, J = 16.4 Hz, 1H, CH), 5.55
(d, J = 16.0 Hz, 1H, CH), 6.88 (d, J = 8.8 Hz, 2H, ArH), 7.18 (d,
J = 8.8 Hz, 2H, ArH), 7.24~7.33 (m, 6H, ArH), 7.56~7.60
(m, 1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 7.98
(d, J = 8.4 Hz, 1H, ArH). IR (KBr, n, cmÀ1): 3065, 2953,
2928, 1733, 1658, 1604, 1581, 1512, 1489, 1468, 1430,
1396, 1371, 1345, 1309, 1254, 1222, 1210, 1180, 1029, 834,
766, 730, 698, 623. HRMS (ESI, m/z): calcd for C25H23N2O3
[M + H]+ 399.1709, found 399.1715.
(CDCl3, 400 MHz): dH 1.48 (s, 3H, CH3), 2.17~2.22 (m, 1H,
CH), 2.38~2.65 (m, 3H, CH2 + CH), 4.30 (d, J = 15.6Hz, 1H,
CH), 5.25 (d, J = 15.6 Hz, 1H, CH), 7.24~7.34 (m, 6H, ArH), 7.58
(t, J = 8.4 Hz, 1H, ArH), 8.16 (d, J = 7.6 Hz, 1H, ArH), 8.27
(d, J = 8.0 Hz, 1H, ArH). IR (KBr): 3046, 2983, 2934, 1729,
1643, 1600, 1487, 1471, 1410, 1367, 1342, 1220, 1208, 1164, 761,
743, 703, 627 cmÀ1. HRMS (ESI, m/z): calcd for C19H18N2NaO2
[M+ Na]+ 329.1266, found 329.1248.
2,3,3a,4-Tetrahydro-3a-methyl-4-phenethylpyrrolo[1,2-a]
quinazoline-1,5-dione (3i).
m.p. 161~163ꢀC; 1H NMR
(CDCl3, 400 MHz): dH 1.44 (s, 3H, CH3), 2.11~2.19 (m, 2H,
CH2), 2.44~2.57 (m, 2H, CH2), 2.96~3.00 (m, 1H, CH),
3.10~3.20 (m, 2H, CH2), 3.99~4.07 (m, 1H, CH), 7.22~7.34
(m, 6H, ArH), 7.55~7.59 (m, 1H, ArH), 8.12 (dd, J = 7.6 Hz,
J′ = 1.2 Hz, 1H, ArH), 8.26 (dd, J = 8.0 Hz, J′ = 0.4 Hz, 1H,
ArH). IR (KBr): 3027, 2973, 2934, 1692, 1651, 1602, 1488,
4-Benzyl-3a-(4-ethylphenyl)-2,3,3a,4-tetrahydropyrrolo[1,2-
a]quinazoline-1,5-dione (3o).
m.p. 128~129ꢀC; 1H NMR
(DMSO-d6, 400 MHz): dH 1.10 (t, J = 7.6 Hz, 3H, CH3),
2.38~2.56 (m, 4H, 2CH2), 2.64~2.67 (m, 1H, CH), 2.82~2.91
(m, 1H, CH), 4.54 (d, J = 16.4 Hz, 1H, CH), 5.57 (d, J = 16.4Hz,
1H, CH), 7.15~7.37 (m, 10H, ArH), 7.56~7.60 (m, 1H, ArH),
7.70 (d, J = 7.6 Hz, 1H, ArH), 7.99 (d, J = 7.6 Hz, 1H, ArH). IR
(KBr, n, cmÀ1): 2964, 2931, 1712, 1655, 1604, 1487, 1470, 1430,
1397, 1365, 1338, 1315, 1221, 1209, 1192, 835, 759, 708. HRMS
(ESI, m/z): calcd for C26H25N2O2 [M+ H]+ 397.1916, found
397.1915.
1471, 1407, 1369, 1346, 1218, 1167, 1121, 1005, 762, 697cmÀ1
.
HRMS (ESI, m/z): calcd for C20H20N2NaO2 [M + Na]+ 343.1422,
found 343.1408.
4-((Furan-2-yl)methyl)-2,3,3a,4-tetrahydro-3a-methylpyrrolo
1
[1,2-a]quinazoline-1,5-dione (3j). m.p. 187~189ꢀC; H NMR
(DMSO-d6, 400 MHz): dH 1.33 (s, 3H, CH3), 2.42~2.51
(m, 3H, CH2 + CH), 2.76~2.81 (m, 1H, CH), 4.73 (q, J = 16.0 Hz,
2H, CH2), 6.37~6.41 (m, 2H, ArH), 7.31 (t, J = 7.6 Hz, 1H, ArH),
7.59~7.65 (m, 2H, ArH), 7.96 (d, J = 7.6 Hz, 1H, ArH), 8.20
(d, J = 8.4 Hz, 1H, ArH). IR (KBr): 3107, 2973, 2829, 1716,
1657, 1600, 1486, 1468, 1422, 1396, 1360, 1330, 1307, 1218,
1160, 1024, 936, 874, 828, 767, 758cmÀ1. HRMS (ESI, m/z):
calcd for C17H16N2NaO3 [M+ Na]+ 319.1059, found 319.1067.
4-((3,4-Methylenedioxophenyl)ethyl)-2,3,3a,4-tetrahydro-
4-Benzyl-3a-(4-chlorophenyl)-2,3,3a,4-tetrahydropyrrolo
[1,2-a]quinazoline-1,5-dione (3p).
m.p. 200~202ꢀC; 1H
NMR (DMSO-d6, 400 MHz): dH 2.37~2.45 (m, 1H, CH),
2.54~2.57 (m, 1H, CH), 2.64~2.69 (m, 1H, CH), 2.83~2.87
(m, 1H, CH), 4.57 (d, J = 16.4 Hz, 1H, CH), 5.80 (d, J = 16.0Hz,
1H, CH), 7.25~7.38 (m, 8H, ArH), 7.41 (d, J = 8.4 Hz, 2H, ArH),
7.58~7.62 (m, 1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 7.97
(d, J = 8.0 Hz, 1H, ArH). IR (KBr, n, cmÀ1): 3063, 2983, 2954,
2913, 1722, 1652, 1602, 1487, 1470, 1454, 1433, 1393, 1364,
1311, 1250, 1210, 1096, 1009, 878, 839, 762, 731, 711, 685.
HRMS (ESI, m/z): calcd for C24H19ClN2O2Na [M+ Na]+
425.1033, found 425.1060.
4-(4-Methoxybenzyl)-2,3,3a,4-tetrahydro-3a-p-tolylpyrrolo
[1,2-a]quinazoline-1,5-dione (3q). m.p. 167~169ꢀC; 1H NMR
(DMSO-d6, 400MHz): dH 2.21 (s, 3H, CH3), 2.36~2.43 (m, 1H,
CH), 2.47~2.54 (m, 1H, CH), 2.67~2.73 (m, 1H, CH), 2.81~2.89
(m, 1H, CH), 3.72 (s, 3H, OCH3), 4.42 (d, J = 16.0 Hz, 1H, CH),
5.52 (d, J = 16.0 Hz, 1H, CH), 6.91 (d, J = 8.4 Hz, 2H, ArH),
7.12~7.15 (m, 4H, ArH), 7.23~7.26 (m, 3H, ArH), 7.55~7.58
(m, 1H, ArH), 7.86 (d, J = 7.6 Hz, 1H, ArH), 7.95
(d, J = 8.0Hz, 1H, ArH). IR (KBr, n, cmÀ1): 3029, 3001, 2921,
1707, 1650, 1603, 1514, 1486, 1469, 1396, 1362, 1338, 1293,
1250, 1216, 1206, 1181, 1135, 1033, 809, 762. HRMS (ESI, m/z):
calcd for C26H25N2O3 [M + H]+ 413.1865, found 413.1875.
4-(4-Methoxybenzyl)-2,3,3a,4-tetrahydro-3a-(4-methoxyphenyl)
pyrrolo[1,2-a]quinazoline-1,5-dione (3r). m.p. 183~184ꢀC; 1H
NMR (DMSO-d6, 400 MHz): dH 2.35~2.42 (m, 1H, CH),
2.48~2.55 (m, 1H, CH), 2.65~2.73 (m, 1H, CH), 2.80~2.89
(m, 1H, CH), 3.68 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.41 (d,
J = 16.0 Hz, 1H, CH), 5.49 (d, J = 16.0 Hz, 1H, CH), 6.87
(d, J = 8.8 Hz, 2H, ArH), 6.91 (d, J = 8.4 Hz, 2H, ArH), 7.16 (d,
J = 8.8Hz, 2H, ArH), 7.23~7.27 (m, 3H, ArH), 7.55~7.59 (m,
1H, ArH), 7.87 (d, J = 7.6 Hz, 1H, ArH), 7.95 (d, J = 8.0 Hz, 1H,
3a-methylpyrrolo[1,2-a]quinazoline-1,5-dione (3k).
m.p.
1
174~175ꢀC; H NMR (CDCl3, 400 MHz): dH 1.44 (s, 3H, CH3),
2.19~2.29 (m, 2H, CH2), 2.52~2.64 (m, 2H, CH2), 2.83~2.91 (m,
1H, CH), 3.06~3.15 (m, 2H, CH2), 3.91~3.98 (m, 1H, CH), 5.94
(s, 2H, CH2), 6.69~6.77 (m, 3H, ArH), 7.26~7.30 (m, 1H, ArH),
7.54~7.58 (m, 1H, ArH), 8.11 (d, J = 7.6 Hz, 1H, ArH), 8.26
(d, J = 8.4 Hz, 1H, ArH). IR (KBr, n, cmÀ1): 2990, 2962, 2900,
1719, 1639, 1601, 1486, 1471, 1444, 1406, 1347, 1247, 1205,
1188, 1039, 928, 795, 760, 699. HRMS (ESI, m/z): Calcd for
C21H20N2O4 [M + Na]+ 387.1321, found 387.1335.
4-Benzyl-2,3,3a,4-tetrahydro-3a-(4-isopropylphenyl)pyrrolo
1
[1,2-a]quinazoline-1,5-dione (3l). m.p. 199~201ꢀC; H NMR
(CDCl3, 400 MHz): dH 1.18 (d, J = 6.8 Hz, 6H, 2CH3), 2.43~2.55
(m, 2H, CH2), 2.74~2.87 (m, 3H, CH2 + CH), 4.24 (d, J = 16.0Hz,
1H, CH), 5.88 (d, J = 16.0Hz, 1H, CH), 7.11~7.16 (m, 4H, ArH),
7.20~7.34 (m, 6H, ArH), 7.49~7.53 (m, 1H, ArH), 8.06~8.10
(m, 2H, ArH). IR (KBr, n, cmÀ1): 2958, 2918, 2867, 1722, 1656,
1602, 1487, 1469, 1426, 1397, 1365, 1343, 1300, 1252, 1223,
1194, 1056, 983, 881, 832, 763, 732, 707, 627. HRMS (ESI, m/z):
calcd for C27H27N2O2 [M + H]+ 411.2073, found 411.2065.
4-Benzyl-2,3,3a,4-tetrahydro-3a-p-tolylpyrrolo[1,2-a]
1
quinazoline-1,5-dione (3m). m.p. 236~238ꢀC; H NMR
(DMSO-d6, 400 MHz): dH 2.23 (s, 3H, CH3), 2.34~2.45 (m, 2H,
CH2), 2.63~2.71 (m, 1H, CH), 2.82~2.91 (m, 1H, CH), 4.54 (d,
J = 16.4Hz, 1H, CH), 5.58 (d, J = 16.4 Hz, 1H, CH), 7.15~9.19
(m, 4H, ArH), 7.23~7.27 (m, 2H, ArH), 7.28~7.33 (m, 4H, ArH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Pyrrolo[1,2-a]quinazoline Derivatives
845
ArH). IR (KBr, n, cmÀ1): 3063, 2949, 2930, 1725, 1664, 1605,
1584, 1513, 1489, 1467, 1395, 1370, 1349, 1303, 1253, 1221,
1178, 1123, 1035, 828, 812, 773, 699. HRMS (ESI, m/z): calcd
for C26H25N2O4 [M+ H]+ 429.1814, found 429.1811.
Acknowledgment. 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
Institutions, and the Qing Lan Project (08QLT001, 10QLD008) of
Jiangsu Education Committee for financial support.
4-(4-Methoxybenzyl)-2,3,3a,4-tetrahydro-3a-(4-isopropylphenyl)
pyrrolo[1,2-a]quinazoline-1,5-dione (3s). m.p. 188~190ꢀC;
1H NMR (DMSO-d6, 400 MHz): dH 1.20 (d, J = 6.8 Hz, 6H,
2CH3), 2.37~2.44 (m, 1H, CH), 2.53~2.55 (m, 1H, CH),
2.66~2.71 (m, 1H, CH), 2.79~2.86 (m, 2H, 2CH), 3.72 (s, 3H,
OCH3), 4.43 (d, J = 16.0 Hz, 1H, CH), 5.51 (d, J = 16.0 Hz, 1H,
CH), 6.90 (d, J = 8.8 Hz, 2H, ArH), 7.16~7.27 (m, 7H, ArH),
7.56~7.59 (m, 1H, ArH), 7.88 (d, J = 7.6 Hz, 1H, ArH), 7.98
(d, J = 8.0 Hz, 1H, ArH),. 13C NMR (DMSO-d6, 100 MHz):
23.5, 29.7, 31.9, 32.8, 46.7, 55.0, 82.2, 112.7, 113.9, 120.4,
120.5, 125.0, 126.8, 127.8, 127.9, 130.4, 133.3, 135.6,
139.6, 148.7, 158.2, 162.7, 172.4. IR (KBr, n, cmÀ1):
2960,2916, 1722, 1652, 1604, 1512, 1487, 1468, 1430,
1395, 1662, 1341, 1292, 1248, 1217, 1180, 1031, 836, 807,
764. HRMS (ESI, m/z): calcd for C28H28N2O3Na [M + Na]+
463.1998, found 468.2001.
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4-(4-Methoxybenzyl)-3a-(4-chlorophenyl)-2,3,3a,4-tetra-
hydropyrrolo[1,2-a]quinazoline-1,5-dione (3t). m.p. 182~184ꢀC;
1H NMR (DMSO-d6, 400 MHz): dH 2.34~2.42 (m, 1H, CH),
2.53~2.57 (m, 1H, CH), 2.69~2.77 (m, 1H, CH), 2.82~2.88
(m, 1H, CH), 3.72 (s, 3H, OCH3), 4.47 (d, J = 16.0 Hz, 1H,
CH), 5.52 (d, J = 16.0Hz, 1H, CH), 6.91 (d, J = 8.8 Hz, 2H, ArH),
7.23~7.30 (m, 5H, ArH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 7.59 (t,
J = 7.6Hz, 1H, ArH), 7.88 (d, J = 7.6 Hz, 1H, ArH), 7.94
(d, J = 8.0 Hz, 1H, ArH). IR (KBr, n, cmÀ1): 3074, 2963, 2921,
1720, 1658, 1604, 1514, 1487, 1470, 1432, 1327, 1307, 1289,
1249, 1220, 1177, 1094, 1010, 879, 841, 824, 800, 758,
683. HRMS (ESI, m/z): calcd for C25H22ClN2O3 [M + H]+
433.1319, found 433.1339.
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4-(4-Methoxybenzyl)-3a-(4-ethylphenyl)-2,3,3a,4-tetrahydro-
1
pyrrolo[1,2-a]quinazoline-1,5-dione (3u). m.p. 160~162ꢀC; H
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NMR (DMSO-d6, 400 MHz): dH 1.09 (t, J = 7.2 Hz, 3H,
CH3), 2.38~2.44 (m, 1H, CH), 2.49~2.55 (m, 3H, CH2 + CH),
2.66~2.72 (m, 1H, CH), 2.82~2.86 (m, 1H, CH), 3.72 (s, 3H,
OCH3), 4.43 (d, J = 16.0 Hz, 1H, CH), 5.20 (d, J = 16.0 Hz,
1H, CH), 6.91 (d, J = 8.4 Hz, 2H, ArH), 7.14~7.19 (m, 4H,
ArH), 7.23~7.26 (m, 3H, ArH), 7.57 (t, J = 7.6 Hz, 1H, ArH),
7.87 (d, J = 8.0 Hz, 1H, ArH), 7.97 (d, J = 8.0 Hz, 1H,
ArH). IR (KBr, n, cmÀ1): 2965, 2929, 2906, 1725, 1655,
1605, 1513, 1487, 1467, 1391, 1362, 1339, 1316, 1293,
1246, 1218, 1181, 1025, 987, 908, 840, 830, 809, 761, 704.
HRMS (ESI, m/z): calcd for C27H27N2O3 [M + H]+ 427.2022,
found 427.2031.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet