Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinazoline-3a-carboxylic acid derivatives in ionic liquids

Article abstract of DOI:10.1007/s11164-012-0845-x

The iodine-catalyzed reaction of 2-aminobenzamide and 2-oxopentanedioic acid in ionic liquids is described in this paper. It gave 1,5-dioxo-1,2,3,3a,4, 5-hexahydropyrrolo[1,2-a]quinazoline-3a-carboxylic acid derivatives in high yields. One of their struct

Full text of DOI:10.1007/s11164-012-0845-x

Res Chem Intermed
DOI 10.1007/s11164-012-0845-x
Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinazoline-
3a-carboxylic acid derivatives in ionic liquids
•
•
•
Mei-Mei Zhang Lian Lu Yu-Jing Zhou
Xiang-Shan Wang
Received: 29 July 2012 / Accepted: 30 September 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract The iodine-catalyzed reaction of 2-aminobenzamide and 2-oxopentanedioic
acid in ionic liquids is described in this paper. It gave 1,5-dioxo-1,2,3,3a,4,5-hexahy-
dropyrrolo[1,2-a]quinazoline-3a-carboxylic acid derivatives in high yields. One of their
structures was confirmed by X-ray diffraction analysis.
Keywords Pyrroloquinazoline ꢀ 2-aminobenzamide ꢀ Ionic liquid ꢀ Iodine ꢀ
Synthesis
Introduction
Pyrroloquinazoline and its derivatives are important heterocycles found in a variety
of biological molecules. It is reported that they possess a wide range of biologic
activities, for example, antitumor [1–3] and anti-inflammatory activity [4]. In
addition, some of them are used as thrombin receptor antagonists [5–7] and
modulators of chemokine [8]. Therefore, much attention has been devoted to the
synthesis of these active heterocyclic compounds both in organic synthesis and in
pharmaceutical chemistry. In general, they could be achieved by a three-component
reaction of isatoic anhydride, amine, and 2-formylbenzoic acid [9], or coupling
cyclization of 2-aminobenzamide with 3-butynoic acid catalyzed by platinum salt
[10, 11], or reduction reaction of 2-nitrobenzamide with c-ketonic acid or
M.-M. Zhang
The Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province,
Jiangsu Normal University, Xuzhou 221116, Jiangsu, People’s Republic of China
L. Lu ꢀ Y.-J. Zhou ꢀ X.-S. Wang (&)
School 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
e-mail: xswang1974@yahoo.com
123

M.-M. Zhang et al.
halogenated ketone in the presence of SnCl2 [12, 13], or condensation cyclization of
2-aminobenzamide with c-ketone acid ester [14].
Although these reported reactions [9–14] have developed some useful synthetic
procedures, several limitations still remain. For example, most of the procedures
involve several steps, or low yields, or metal catalysts, or inorganic solvents. Thus,
simple, efficient, and green methods to synthesize pyrroloquinazoline would be
attractive.
Ionic liquid containing catalytic iodine is a green system, because the ionic
liquids have attracted increasing interest in the context of green chemistry in the
past few years for a large number of organic transformations [15, 16]. In addition,
iodine is also a novel and green Lewis metal-free catalyst for many organic
reactions in recent years [17]. As a continuation of our research devoted to prepare
heterocycles in ionic liquid and with iodine-catalyzed reaction [18, 19], we would
like to report the synthesis of pyrrolo[1,2-a]quinazoline-3a-carboxylic acid
derivatives in ionic liquids. This method involves the reaction of 2-aminobenza-
mides with 2-oxopentanedioic acid catalyzed by iodine.
Results and discussion
The treatment of 2-aminobenzamides 1a–l and 2-oxopentanedioic acid 2 in ionic
liquid of [BMIm]Br in the presence of 5 mol% iodine at 80 °C resulted in the
corresponding 1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-car-
boxylic acid derivatives 3a–l in high yields (Scheme 1).
Using the conversion of 2-aminobenzamide 1a and 2-oxopentanedioic acid 2 as a
model reaction, several parameters, such as Lewis acids, catalyst amount, reaction
temperature, and ionic liquids, were explored as shown in Table 1. 3a was obtained
successfully in the presence of various quantities of the catalyst, reaching a
maximum of 86 % yield, using 5 mol% iodine as a catalyst (Table 1, entry 4).
Different imidazolium ionic liquids and Lewis acids were also tested, and the
iodine-[BMIm]Br system appeared to be the best medium for this transformation.
First of all, these optimized conditions were applied for the conversion of various
kinds of 2-aminobenzamides 1a–l into the corresponding pyrrolo[1,2-a]quinazoline-
3a-carboxylic acid analogs (Table 2, entries 1–12). Entries 1–12 demonstrate that
the reactions also tolerate significant functionalization of the 2-aminobenzamides 1;
both electron-donating (such as alkyl and alkoxyl group) and electron-withdrawing
O
O
O
NHR'
IL
I2
O
NR'
CO2H
R
CO2H
R
+
NH2
OH
N
O
1a-l
2
3a-l
Scheme 1 The reaction of 2-aminobenzamides and 2-oxopentanedioic acid
123

Iodine-catalyzed synthesis
Table 1 Synthetic results of 3a
under different reaction
conditions
Entry
T/ °C
Ionic liquid
Cat. (mol%)
Yield (%)a
1
2
80
r.t.
50
80
100
80
80
80
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]
[BMIm]Br
[BMIm]Br
[BMIm]Br
I2(0)
0
I2(5)
Trace
80
3
I2(5)
4
I2(5)
86
5
I2(5)
86
Reaction conditions: ionic
liquids (2.0 mL),
6
I2(1)
78
7
I2(10)
I2(5)
86
2-aminobenzamide (0.272 g,
2.0 mmol), 2 (0.292 g,
2.0 mmol)
8
82
9
I2(5)
82
BMIm 1-butyl-3-
10
11
12
13
14
15
I2(5)
85
methylimidazolium, EMIm
1-ethyl-3-methylimidazolium,
PMIm 1-propyl-3-
methylimidazolium
a
Isolated yields
I2(5)
84
I2(5)
82
CuI(5)
ZnCl2(5)
Yb(OTf)3(5)
Trace
Trace
79
Bold value indicates the best
reaction condition
(such as halide) groups can be accommodated, and aliphatic groups can all be
generated. They all reacted well to provide a library of pyrrolo[1,2-a]quinazoline
derivatives 3a–l (Table 2). All the structures of the products were characterized by
1H NMR, IR, and HRMS, and their data were in good agreement with the
preconceived structures. Of which, the structure of 3a was further confirmed by
X-ray diffraction analysis, indicating that there are two independent molecules in a
unit and one of them is shown in Fig. 1.
The X-ray diffraction analysis indicates that the center pyrimidine ring is slightly
distorted, and adopts a skew-boat confirmation: the atoms of C1, C6, C7, and N2 are
coplanar, with the atoms of N1 and C8 deviating from the defined plane by 0.235(2)
˚
and 0.691(2) A, respectively. The adjacent pyrrole ring adopts a typical envelope
confirmation, the atom of C9 deviates from the defined plane (including atoms of
˚
C8, C10, C11, and N2) by 0.278(3) A. It makes a dihedral angle of 30.8(1)8 to the
pyrimidine ring. The latter is nearly parallel to the benzene ring, forming a dihedral
angle of 1.5(3)8.
The typical N–HꢀꢀꢀO and O–HꢀꢀꢀO hydrogen bonds (Table 3) are presented in the
crystal structure. They link the adjacent molecules forming polymers along the a-
axis (Fig. 2).
According to the structure of product 3, we hypothesize that the subsequent
condensation, cyclization, and intra-molecular dehydration reactions may take
place. The possible reaction mechanism is outlined in Scheme 2.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
1
were recorded on a Tensor 27 spectrometer in KBr pellet. H NMR spectra were
123

M.-M. Zhang et al.
Table 2 The reaction time and
yields of the products 3a–l
Entry
R
R0
Product Time (h) Yields (%)
1
2
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
6
8
86
82
89
79
85
80
88
92
90
86
90
87
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-i-PrC6H4
3
8
4
5
5
9
6
3-Cl-4-FC6H3 3f
10
8
7
C6H5
3g
3h
3i
8
H
4-n-BuC6H4
8
Reaction conditions:
2-aminobenzamides 1
(2.0 mmol), 2 (0.307 g,
2.1 mmol), iodine (0.025 g,
0.1 mmol), [BMIm]Br
(2.0 mL), 80 °C
9
H
C6H5CH2
6
10
11
12
5-Br
5-Me
5-Cl
H
H
3j
6
3k
8
C6H5CH2CH2 3l
6
Fig. 1 The crystal structure of product 3a
obtained from a solution in DMSO-d6 or CDCl3 with Me4Si as the internal standard
using a Bruker 400 spectrometer. HRMS analyses were carried out using a Bruker
micrOTOF-Q MS analyzer.
General procedure for the synthesis of pyrrolo[1,2-a]quinazoline-3a-carboxylic
acid derivatives 3
A dry 50-mL flask was charged with 2-aminobenzamides 1 (2.0 mmol),
2-oxopentanedioic acid 2 (0.307 g, 2.1 mmol), iodine (0.025 g, 0.1 mmol), and
ionic liquid of [BMIm]Br (2.0 mL). The reaction mixture was stirred at 80 °C for
5–10 h. Then, a small amount of water (5 mL) was added to the mixture, and the
123

Iodine-catalyzed synthesis
˚
Table 3 The data of hydrogen bonds in 3a (A and 8)
˚
˚
˚
Entry D–HꢀꢀꢀA
d(D–H, A) d(HꢀꢀꢀA, A) d(DꢀꢀꢀA, A) \(DHA, 8) Symmetry code
1
2
3
4
O2–H2ꢀꢀꢀO1 0.879(10)
1.654(10)
1.793(10)
1.955(10)
1.967(10)
2.5298(15)
2.6533(15)
2.8345(17)
2.8349(16)
174(3)
175(3)
x, -y ? 3/2, z ? 1/2
x, -y ? 1/2, z-1/2
x, -y ? 3/2, z-1/2
-x ? 1, -y ? 1, -z
O7–H7ꢀꢀꢀO8 0.862(10)
N1–H1ꢀꢀꢀO3 0.889(9)
N3–H3ꢀꢀꢀO5 0.875(9)
170.1(16)
171.3(16)
Fig. 2 The molecular packing diagram for 3a
O
O
N
R
O
R
N
H
N
I2
H
+
HO2C
COOH
NH2
HOOC
CH2CH2COOH
O
4
1
2
O
O
R
R
R
N
N
N
-H2O
COOH
H
COOH
N
N
H
N
I2
HOOC
CH2CH2COOH
HOOC
O
6
3
5
Scheme 2 The possible reaction mechanism for the formation of 3
123

M.-M. Zhang et al.
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 80 °C for 4 h in a vacuum. The crude yellow
products were washed with water and purified by recrystallization from 95 % EtOH,
then dried at 80 °C for 2 h under vacuum to give 3.
1,5-Dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-carboxylic acid
(3a): M.p. 266 * 268 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.32 * 2.38
(m, 1H, CH), 2.46 * 2.51 (m, 1H, CH), 2.65 * 2.70 (m, 2H, CH2), 7.27 * 7.31
(m, 1H, ArH), 7.60 * 7.64 (m, 1H, ArH), 7.88 (d, J = 7.6 Hz, 1H, ArH), 8.15
(d, J = 8.0 Hz, 1H, ArH), 9.35 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz): dC
29.0, 29.7, 75.5, 118.7, 119.4, 124.7, 127.8, 133.4, 136.1, 161.8, 172.3, 172.5. IR
(KBr): m 3349, 3160, 3,054, 2,918, 1,706, 1,671, 1,605, 1,579, 1,486, 1,468, 1,393,
1,366, 1,328, 1,290, 1277, 1227, 1208, 1169, 1157, 1075, 1035, 814, 793, 764 cm-1
HRMS (ESI, m/z): calcd. for C12H9N2O4 [M - H]- 245.0563, found 245.0562.
.
1,5-Dioxo-4-(p-tolyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-car-
boxylic acid (3b): M.p. 166 * 168 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.16 * 2.21 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.53 * 2.70 (m, 2H, CH2),
7.26 * 7.32 (m, 4H, ArH), 7.34 (d, J = 7.6 Hz, 1H, ArH), 7.65 * 7.69 (m, 1H,
ArH), 7.93 * 7.95 (m, 1H, ArH), 8.26 (d, J = 8.4 Hz, 1H, ArH). IR (KBr): m 3008,
2927, 1731, 1711, 1654, 1604, 1582, 1512, 1487, 1470, 1397, 1352, 1299, 1286,
1265, 1238, 1218, 1198, 1173, 1148, 1106, 1073, 808, 756, 703 cm-1. HRMS (ESI,
m/z): calcd. for C19H16N2O4Na [M ? Na]? 359.1008, found 359.1034.
4-(4-Methoxyphenyl)-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazo
line-3a-carboxylic acid (3c): M.p. 255 * 257 °C; 1H NMR (DMSO-d6, 400 MHz):
dH 2.12 * 2.22 (m, 2H, CH2), 2.60 * 2.70 (m, 2H, CH2), 3.80 (s, 3H, OCH3), 7.02
(d, J = 8.8 Hz, 2H, ArH), 7.31 * 7.37 (m, 3H, ArH), 7.65 * 7.69 (m, 1H, ArH),
7.93 * 7.95 (m, 1H, ArH), 8.26 (d, J = 8.4 Hz, 1H, ArH). 13C NMR (DMSO-d6,
100 MHz): dC 27.8, 30.3, 55.9, 80.4, 114.2, 118.2, 119.8, 124.9, 128.4, 129.5, 130.5,
133.6, 135.8, 158.7, 161.8, 171.8, 172.5. IR (KBr): m 3000, 2980, 2939, 1723, 1656,
1603, 1585, 1509, 1486, 1469, 1443, 1399, 1351, 1298, 1272, 1248, 1237, 1214,
1204, 1181, 1169, 1148, 1073, 1049, 1029, 879, 836, 820, 793, 767, 720 cm-1
.
HRMS (ESI, m/z): calcd. for C19H16N2O5Na [M ? Na]? 375.0957, found
375.0977.
4-(4-Fluorophenyl)-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-
1
3a-carboxylic acid (3d): M.p. 243 * 245 °C; H NMR (DMSO-d6, 400 MHz): dH
2.18 * 2.23 (m, 2H, CH2), 2.58 * 2.70 (m, 2H, CH2), 7.31 * 7.36 (m, 3H, ArH),
7.48 * 7.52 (m, 2H, ArH), 7.66 * 7.71 (m, 1H, ArH), 7.93 * 7.96 (m, 1H, ArH),
8.27 (d, J = 8.4 Hz, 1H, ArH). IR (KBr): m 2974, 2938, 2900, 1648, 1610, 1572,
1511, 1497, 1481, 1471, 1439, 1387, 1358, 1337, 1241, 1216, 1196, 1177, 1146,
1133, 1120, 1109, 1045, 1027, 808, 754 cm-1. HRMS (ESI, m/z): calcd. for
C18H13FN2O4Na [M ? Na]? 363.0757, found 363.0770.
4-(4-i-Propylphenyl)-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazo-
line-3a-carboxylic acid (3e): M.p. 147 * 148 °C; 1H NMR (DMSO-d6, 400 MHz):
dH 1.24 (d, J = 6.8 Hz, 6H, 2CH3), 2.17 * 2.21 (m, 2H, CH2), 2.58 * 2.72 (m,
2H, CH2), 2.91 * 3.00 (m, 1H, CH), 7.32 * 7.37 (m, 5H, ArH), 7.66 * 7.69 (m,
1H, ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH), 8.27 (d, J = 8.4 Hz, 1H, ArH). IR (KBr):
123

Iodine-catalyzed synthesis
m 2962, 2873, 1710, 1646, 1604, 1508, 1488, 1470, 1398, 1348, 1290, 1270, 1237,
1220, 1205, 1147, 1121, 1096, 1076, 1057, 1040, 1025, 884, 826, 757 cm-1. HRMS
(ESI, m/z): calcd. for C21H20N2O4Na [M ? Na]? 387.1321, found 387.1352.
4-(3-Chloro-4-fluorophenyl)-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]qui-
nazoline-3a-carboxylic acid (3f): M.p. 181 * 183 °C; 1H NMR (DMSO-d6,
400 MHz): dH 2.19 * 2.30 (m, 2H, CH2), 2.59 * 2.71 (m, 2H, CH2), 7.35 (t,
J = 7.6 Hz, 1H, ArH), 7.50 * 7.59 (m, 2H, ArH), 7.68 * 7.74 (m, 2H, ArH), 7.94
(d, J = 7.6 Hz, 1H, ArH), 8.27 (d, J = 8.4 Hz, 1H, ArH). IR (KBr): m 3051, 1708,
1670, 1603, 1503, 1469, 1388, 1348, 1300, 1265, 1218, 1197, 1177, 1147, 1136,
1060, 1040, 828, 812, 760 cm-1. HRMS (ESI, m/z): calcd. for C18H11ClFN2O4
[M - H]- 373.0392, found 373.0410.
1,5-Dioxo-4-phenyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-car-
boxylic acid (3g): M.p. 234 * 235 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.13 * 2.24 (m, 2H, CH2), 2.63 * 2.71 (m, 2H, CH2), 7.33 * 7.36 (m, 1H, ArH),
7.37 * 7.39 (m, 3H, ArH), 7.42 * 7.47 (m, 2H, ArH), 7.66 * 7.71 (m, 1H, ArH),
7.95 (d, J = 6.8 Hz, 1H, ArH), 8.27 (d, J = 8.0 Hz, 1H, ArH). 13C NMR (DMSO-
d6, 100 MHz): dC 27.8, 30.3, 80.3, 112.7, 112.8, 118.2, 119.7, 124.9, 128.0, 129.1,
133.8, 135.7, 137.0, 161.6, 171.8, 172.5. IR (KBr): m 3076, 2963, 2938, 1723, 1655,
1601, 1575, 1491, 1469, 1453, 1400, 1349, 1303, 1274, 1238, 1214, 1203, 1184,
1160, 1122, 1100, 1073, 1032, 884, 766, 755 cm-1. HRMS (ESI, m/z): calcd. for
C18H13N2O4 [M - H]- 321.0876, found 321.0916.
4-(4-n-Butylphenyl)-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazo-
line-3a-carboxylic acid (3h): M.p. 212 * 213 °C; 1H NMR (DMSO-d6, 400 MHz):
dH 0.92 (t, J = 7.2 Hz, 3H, CH3), 1.29 * 1.37 (m, 2H, CH2), 1.55 * 1.63 (m, 2H,
CH2), 2.17 * 2.22 (m, 2H, CH2), 2.61 * 2.64 (m, 3H, CH ? CH2), 2.67 * 2.72
(m, 1H, CH), 7.28 * 7.32 (m, 4H, ArH), 7.35 (d, J = 7.6 Hz, 1H, ArH),
7.66 * 7.69 (m, 1H, ArH), 7.94 (d, J = 8.0 Hz, 1H, ArH), 8.26 (d, J = 8.0 Hz,
1H, ArH). IR (KBr): m 3089, 3052, 2962, 2933, 2857, 1736, 1724, 1635, 1623, 1579,
1511, 1488, 1470, 1402, 1352, 1309, 1241, 1216, 1201, 1178, 1151, 1067, 1024,
882, 825, 792, 767, 709 cm-1. HRMS (ESI, m/z): calcd. for C22H21N2O4 [M - H]-
377.1502, found 377.1515.
4-Benzyl-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-carbox-
ylic acid (3i): M.p. 156 * 158 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.26 * 2.35 (m, 2H, CH2), 2.59 * 2.65 (m, 1H, CH), 2.69 * 2.70 (m, 1H,
CH), 4.36 (d, J = 16.4 Hz, 1H, CH), 5.23 (d, J = 16.4 Hz, 1H, CH), 7.13 * 7.19
(m, 1H, ArH), 7.23 * 7.27 (m, 1H, ArH), 7.32 * 7.35 (m, 4H, ArH), 7.66 (t,
J = 7.6 Hz, 1H, ArH), 7.96 (d, J = 7.6 Hz, 1H, ArH), 8.30 (d, J = 8.4 Hz, 1H,
ArH). IR (KBr): m 3062, 3029, 2978, 2929, 1739, 1660, 1601, 1488, 1468, 1454,
1441, 1371, 1336, 1316, 1304, 1265, 1231, 1193, 1148, 1078, 1027, 977, 789, 740,
717, 701 cm-1. HRMS (ESI, m/z): calcd. for C19H15N2O4 [M - H]- 355.1032,
found 355.1064.
7-Bromo-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-carbox-
ylic acid (3j): m.p. 281 * 283 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.30 * 2.38 (m, 1H, CH), 2.65 * 2.73 (m, 3H, CH ? CH2), 7.81 * 7.83 (m,
1H, ArH), 7.94 * 7.95 (m, 1H, ArH), 8.13 (d, J = 8.8 Hz, 1H, ArH), 9.53 (s, 1H,
NH). IR (KBr): m 3247, 3177, 3068, 2913, 1720, 1685, 1597, 1483, 1433, 1365,
123

M.-M. Zhang et al.
1337, 1274, 1235, 1196, 1162, 1106, 1072, 1029, 824, 782, 752, 722 cm-1. HRMS
(ESI, m/z): calcd. for C12H8BrN2O4 [M - H]- 322.9668, found 322.9666.
7-Methyl-1,5-dioxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-carbox-
1
ylic acid (3k): M.p. 288 * 289 °C; H NMR (DMSO-d6, 400 MHz): dH 2.33 (s,
3H, CH3), 2.36 * 2.37 (m, 1H, CH), 2.64 * 2.69 (m, 3H, CH ? CH2), 7.43 (d,
J = 7.2 Hz, 1H, ArH), 7.68 (s, 1H, ArH), 8.03 (d, J = 8.0 Hz, 1H, ArH), 9.28 (s,
1H, NH). IR (KBr): m 3277, 3093, 2956, 2922, 1733, 1642, 1613, 1574, 1495, 1460,
1424, 1337, 1290, 1275, 1240, 1212, 1198, 1163, 1149, 1129, 1094, 1071, 1041,
1008, 851, 788, 742 cm-1. HRMS (ESI, m/z): calcd. for C13H11N2O4 [M - H]-
259.0719, found 259.0736.
7-Chloro-1,2,3,3a,4,5-hexahydro-1,5-dioxopyrrolo[1,2-a]quinazoline-3a-carbox-
ylic acid (3l): M.p. 272 * 273 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.33 * 2.39 (m, 1H, CH), 2.66 * 2.69 (m, 3H, CH ? CH2), 7.68 * 7.71 (m,
1H, ArH), 7.82 * 7.83 (m, 1H, ArH), 8.19 (d, J = 8.8 Hz, 1H, ArH), 9.53 (s, 1H,
NH). IR (KBr): m 3330, 3244, 3070, 2989, 2921, 1743, 1731, 1623, 1601, 1493,
1476, 1437, 1417, 1385, 1363, 1338, 1307, 1287, 1273, 1235, 1197, 1165, 1107,
1076, 1030, 842, 827, 783, 755, 723 cm-1. HRMS (ESI, m/z): calcd. for
C12H8ClN2O4 [M - H]- 279.0173, found 279.0176.
Conclusion
In conclusion, we found a mild and green method for the synthesis of 1,5-dioxo-
1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinazoline-3a-carboxylic acid derivatives
catalyzed by iodine in ionic liquid. The novelty of this procedure is in using
simple reactants to construct two fused heterocycles at the same time. In addition,
the features of this procedure also include mild reaction conditions, high yields,
operational simplicity, and the use of a metal-free catalyst.
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 Institutions,
Qing-Lan Project (10QLD008), and College Industrialization Project (JHB2012-31) of Jiangsu Province
for the financial support.
References
1. P. Barraja, V. Spano, P. Diana, A. Carbone, G. Cirrincione, Tetrahedron Lett. 50, 5389 (2009)
2. D.-J. Baek, Yakhak Hoechi 50, 278 (2006)
3. S. Sarno, M. Ruzzene, P. Frascella, M.A. Pagano, F. Meggio, A. Zambon, M. Mazzorana, G. Di
Maira, V. Lucchini, L.A. Pinna, Mol. Cell. Biochem. 274, 69 (2005)
4. I. Rioja, M.C. Terencio, A. Ubeda, P. Molina, A. Tarraga, A. Gonzalez-Tejero, M.J. Alcaraz, Eur.
J. Pharmacol. 434, 177 (2002)
5. A. Dixit, S.K. Kashaw, S. Gaur, A.K. Saxena, Bioorg. Med. Chem. 12, 3591 (2004)
6. B.E. Maryanoff, H.-C. Zhang, D.F. McComsey, PCT Int. Appl. WO 2002068425 A1 6 Sept, Chem.
Abstr. 137, 216956 (2002)
7. H.-S. Ahn, C. Foster, G. Boykow, A. Stamford, M. Manna, M. Graziano, Biochem. Pharmacol. 60,
1425 (2000)
8. R. Anderskewitz, H. Dollinger, C. Heine, P.A.J. Pouzet, F. Birke, T. Bouyssou, PCT Int. Appl. WO
2004072074 A1 26 Aug, Chem. Abstr. 141, 225527 (2004)
123

Iodine-catalyzed synthesis
9. K.S. Kumar, P.M. Kumar, K.A. Kumar, M. Sreenivasulu, A.A. Jafar, D. Rambabu, G.R. Krishna,
C.M. Reddy, R. Kapavarapu, K. Shivakumar, K.K. Priya, K.V.L. Parsa, M. Pal, Chem. Commun. 47,
5010 (2011)
10. N.T. Patil, R.D. Kavthe, V.S. Raut, V.S. Shinde, B. Sridhar, J. Org. Chem. 75, 1277 (2010)
11. E.G. Feng, Y. Zhou, D.Y. Zhang, L. Zhang, H.F. Sun, H.L. Jiang, H. Liu, J. Org. Chem. 75, 3274
(2010)
12. M.M. Wang, G.L. Dou, D.Q. Shi, J. Comb. Chem. 12, 582 (2010)
13. X. Zhao, D.-Q. Shi, J. Heterocycl. Chem. 48, 634 (2011)
14. R.T. Iminov, A.V. Tverdokhlebov, A.A. Tolmachev, Y.M. Volovenko, S.V. Shishkina, O.V.
Shishkin, Tetrahedron 65, 8582 (2009)
15. M.A.P. Martins, C.P. Frizzo, D.N. Moreira, N. Zanatta, H.G. Bonacorso, Chem. Rev. 108, 2015
(2008)
16. J. Dupont, R.F. de Souza, P.A.Z. Suarez, Chem. Rev. 102, 3667 (2002)
17. M. Jereb, D. Vrazic, M. Zupan, Tetrahedron 67, 1355 (2011)
18. X.S. Wang, J. Sheng, L. Lu, K. Yang, Y.L. Li, J. Comb. Chem. 196, 1011 (2011)
19. X.S. Wang, K. Yang, J. Zhou, S.J. Tu, J. Comb. Chem. 12, 417 (2010)
123