An efficient and convenient protocol for the synthesis of novel 1′H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione derivatives

Article abstract of DOI:10.1007/s00706-008-0040-3

An efficient and direct procedure for the synthesis of novel spiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione derivatives is described. The process employs a condensation reaction of 2-aminobenzamides and isatins in the presence of a catalytic amount o

Full text of DOI:10.1007/s00706-008-0040-3

Monatsh Chem (2009) 140:401–404
DOI 10.1007/s00706-008-0040-3
ORIGINAL PAPER
An efficient and convenient protocol for the synthesis of novel
10H-spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione derivatives
M. Dabiri Æ Ali A. Mohammadi Æ Hassan Qaraat
Received: 27 June 2008 / Accepted: 7 July 2008 / Published online: 3 September 2008
Ó Springer-Verlag 2008
Abstract An efficient and direct procedure for the syn-
thesis of novel spiro[isoindoline-1,20-quinazoline]-3,40
(30H)-dione derivatives is described. The process employs
a condensation reaction of 2-aminobenzamides and isatins
in the presence of a catalytic amount of KAl(SO4)2.12H2O
(alum) in ethanol under reflux.
isolated from the marine bryozoan Amathia convoluta, was
found to show potent activity in the differentiation of HL-
60 human promyelocytic leukemia cells [16]. The synthetic
precursors to this type of alkaloid are also isatin derivatives
[17].
Oxindole derivatives have been prepared by the reaction
of isatins with aromatics in triflic acid [18], the reaction of
isatins with diphenyl urea and AlCl3 [19], the reaction of
isatins with barbituric acid [20], and by other routes [21,
22].
Keywords Quinazoline ꢀ 2-aminobenzamides ꢀ
Isatin ꢀ KAl(SO4)2.12H2O (alum) ꢀ Microwave irradiation
Introduction
Results and discussion
2,3-Dihydroquinazoline-4(3H)-ones and oxindole deriva-
tives are an important class of heterocyclic compounds.
2,3-Dihydroquinazolin-4(3H)-ones possess a broad spec-
trum of biological and pharmaceutical activities, such as
analgesic [1], antitumor [2], anticancer [3], diuretic [4], and
herbicidal activities [5]. In addition, these compounds can
easily be oxidized to their quinazolin-4(3H)-one analogs
[6], which also include important pharmacologically active
compounds [7, 8]. Several methods have been reported for
the synthesis of 2,3-dihydroquinazolinones [8–13].
Very recently, we have reported the preparation of 2,3-
dihydroquinazoline-4(3H)-ones [23] and oxindoles [24].
Along these lines, we designed the synthesis of 10H-
spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione. To this
end, the use of a KAl(SO4)2.12H2O (alum), which is rel-
atively nontoxic and inexpensive, is the focus of our study
[25–28]. In the course of our research on the applications of
KAl(SO4)2.12H2O in organic reactions, we have found that
alum is an effective promoter in the preparation of 10H-
spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione.
Oxindoles are useful as antibacterial, antiinflammatory
[14] and laxative agents [15]. Furthermore, these hetero-
cycle compounds have recently been isolated from plants.
For example, the marine alkaloid convolutamydine A,
The 2-aminobenzamides 3a–g necessary for this inves-
tigation were prepared according to [29]; their physical
properties were in accordance with those described in [30].
When a mixture of 2-amino-N-phenylbenzamide (3a)
and isatin (4a) in ethanol was stirred at reflux in the
presence of a catalytic amount of alum, the reaction was
completed within 7 h (until 4a disappeared, as shown by
TLC analysis). Workup of the reaction mixture prepared 5a
in 91% yield (Scheme 1).
M. Dabiri (&) ꢀ A. A. Mohammadi (&) ꢀ H. Qaraat
Department of Chemistry, Faculty of Science,
Shahid Beheshti University, P.O. Box 19395-4716,
Tehran, Iran
e-mail: m-dabiri@sbu.ac.ir
Encouraged by this success, we extended this reaction of
2-aminobenzamides 3b–g with a range of other isatins 4a
A. A. Mohammadi
e-mail: a-mohammadi@sbu.ac.ir
123

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M. Dabiri et al.
10H-Spiro[indoline-3,20-quinazoline]-2,40(30H)-dione (5a,
C22H18N2S)
O
R1
O
O
N
O
R1
R2
Cream powder; mp 261–263 °C dec.; IR (KBr) m = 3,491
(NH), 3,227(NH), 2,964, 1,725 (C=O), 1,642 (C=O), 1,614,
1,526 cm-1; 1H NMR (DMSO-d6) d = 6.60 (d, 1H, J = 8.0,
ArH), 6.68(t, 1H, J = 7.4, ArH), 6.84 (d, 1H, J = 7.7, ArH),
7.05 (t, 1H, J = 7.4, ArH), 7.22 (t, 1H, J = 7.2, ArH), 7.28
(s, 1H, NH), 7.33 (t, 1H, J = 7.8, ArH), 7.47 (d, 1H, J = 7.3,
ArH), 7.59 (d, 1H, J = 7.4, ArH), 8.36 (s, 1H, NH), 10.30 (s,
1H, NH) ppm; 13C NMR (DMSO-d6) d = 71.41, 110.53,
114.31, 114.76, 117.61, 122.73, 125.81, 127.30, 129.89,
131.26, 133.75, 142.58, 147.28, 164.40, and 176.47 ppm;
MS: m/z (%) = 265 (M+, 25), 263 (50), 237 (100), 119
(95), 92 (60), 63 (35), 50 (30), 39 (40); anal. calcd. for
C15H11N3O2: C, 67.92; H, 4.18; N, 15.84; found: C, 67.80;
H, 4.11; N, 15.73.
N
Alum /EtOH
N
H
NH
H
O
+
Reflux
NH2
N
H
R2
R1
H
Ph
R2
H
Br
R1
H
Ph
R2
H
H
H
H
H
H
H
Br
3a
3b
3c
3d
3e
3f
4a
4b
5a
5b
5c
5d
5e
5f
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
p-ClC6H4
PhCH2
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
p-ClC6H4
3g
5g
5h
PhCH2
p-CH3C6H4
Scheme 1
and b under similar conditions, furnishing the respective
10H-spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione
5b–h with good yields. The optimized results are summa-
rized in Scheme 1. All products were characterized by their
1H, 13C NMR, IR and MS spectral data.
30-Phenyl-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-
dione (5b, C21H15N3O2)
Yellow powder; mp 251–253 °C dec.; IR (KBr) m = 3,428
(NH), 3,265 (NH), 2,916, 1,727 (C=O), 1,642 (C=O),
In conclusion, a novel and efficient method for the
condensation of 2-aminobenzamides with isatin derivatives
into 10H-spiro[isoindoline-1,20-quinazoline]-3,40(30H)-di-
ones was developed. The novelty and synthetic usefulness
of this methodology was demonstrated by the efficient
synthesis of some novel and interesting dihydroquinazo-
line-4(3H)-ones or oxindoles.
1,616 cm-1
;
1H NMR (DMSO-d6) d = 6.63 (d, 1H,
J = 7.7, ArH), 6.70–6.78 (m, 2H, ArH), 6.92 (t, 1H,
J = 7.4, ArH), 6.98 (d, 2H, J = 7.0, ArH), 7.12–7.23 (m,
4H, ArH), 7.30 (t, 1H, J = 7.0, ArH), 7.53 (d, 1H, J = 7.3,
ArH), 7.63 (s, 1H, NH), 7.66 (d, 1H, J = 7.0, ArH), 10.42
(s, 1H, NH) ppm; 13C NMR d (DMSO-d6) d = 76.85,
110.57, 114.57, 115.04, 118.17, 122.59, 126.96, 127.75,
127.90, 128.10, 129.11, 129.74, 131.29, 134.16, 138.55,
142.12, 146.58, 164.08, and 175.96 ppm; MS: m/z
(%) = 341 (M+, 5), 313 (100), 269 (15), 249 (15), 221
(25), 194 (25), 167 (15), 120 (60), 92 (30), 77 (80), 63 (35),
51 (50), 39 (40); anal. calcd. for C21H15N3O2: C, 73.89; H,
4.43; N, 12.31; found: C, 73.80; H, 4.32; N, 12.25.
Experimental
Melting points were obtained in open capillary tubes and
were measured on an Electrothermal (Southend, UK) 9200
apparatus. Mass spectra were recorded on a Shimadzu
(Tokyo, Japan) QP 1100 BX mass spectrometer. The IR
spectra were recorded on KBr pellets on a Shimadzu IR-
470 spectrophotometer. 1H and 13C NMR spectra were
determined on a Bruker (Rheinstetten, Germany) 300 DRX
Avance instrument at 300 and 75 MHz. Elemental analysis
for C, H and N were performed using a Heraus (Banau,
Germany) CHN rapid analyzer.
30-p-Tolyl-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-
dione (5c, C22H17N3O2)
Cream powder; mp 271–273 °C dec.; IR (KBr) m = 3,420
(NH), 3,258 (NH), 2,964, 1,708 (C=O), 1,644 (C=O),
1
1,613, 1,503 cm-1; H NMR (DMSO-d6) d = 2.17 (s, 3H,
CH3), 6.63–6.77 (m, 3H, ArH), 6.85 (d, 2H, J = 8.2,
ArH), 6.93 (d, 2H, J = 7.5, ArH), 6.99 (d, 2H, J = 8.2,
ArH), 7.15 (t, 1H, J = 7.2, ArH), 7.29 (t, 1H, J = 7.0,
ArH), 7.53 (d, 1H, J = 7.3, ArH), 7.60 (s, 1H, NH), 7.64
(d, 1H, J = 7.0, ArH), 10.40 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6) d = 21.00, 76.86, 110.59, 114.51, 115.04,
118.09, 122.60, 126.90, 127.88, 127.96, 129.65, 131.26,
134.08, 135.91, 137.30, 142.10, 146.56, 164.12, and
175.96 ppm; MS: m/z (%) = 355 (M+, 5), 353 (15), 327
(100), 249 (15), 235 (25), 208 (25), 120 (50), 91 (35), 77
(20), 65 (45), 51 (30), 39 (30); anal. calcd. for
C22H17N3O2: C, 74.35; H, 4.82; N, 11.82; found: C,
74.24; H, 4.73; N, 11.74.
General procedure for preparation of 10H-
spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione
A mixture of 1 mmol 3, 1 mmol isatin 4, 0.4 g alum and
5 cm3 EtOH in a 20 cm3 flask was stirred at reflux for the
time period indicated in Scheme 1. After the reaction had
completed (monitored by TLC, ethyl acetate/n-hexane,
1/1), EtOH was removed under reduced pressure, 25 cm3
H2O was added to the reaction mixture, the resulting solid
was separated by filtration and recrystallized from ethanol
to afford pure product.
123

Protocol for the synthesis of novel 10H-spiro[isoindoline-1,20-quinazoline]-3,40(30H)-dione derivatives
403
30-(4-Methoxyphenyl)-10H-spiro[indoline-3,20-quinazo-
line]-2,40(30H)-dione (5d, C22H17N3O3)
30-Benzyl-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-
dione (5g, C22H17N3O2)
Cream powder; mp 269–271 °C dec.; IR (KBr)
m = 3,426 (NH), 3,287(NH), 2,964, 1,726 (C=O), 1,638
Cream powder; mp 190–192 °C dec.; IR (KBr) m = 3,480
(NH), 3,329 (NH), 2,924, 1,729 (C=O), 1,623 (C=O)
;
1,610 cm-1 1H NMR (DMSO-d6) d = 4.15–4.52 (d,d,
(C=O), 1,612, 1,510 cm-1
;
1H NMR (DMSO-d6)
d = 3.64 (s, 3H, OCH3), 6.67–6.75 (m, 5H, ArH),
6.89–9.91 (m, 3H, ArH), 7.16–7.29 (m, 2H, ArH), 7.55
(s, 1H, NH), 7.59–7.68 (m, 2H, ArH), 10.40 (s, 1H, NH)
ppm; 13C NMR (DMSO-d6) d = 55.54, 77.03, 110.59,
114.23, 114.50, 115.01, 118.09, 122.63, 126.85, 127.92,
128.08, 131.02, 131.23, 134.08, 142.08, 146.59, 158.61,
164.27, and 175.97 ppm; MS: m/z (%) = 371 (M+, 5),
369 (15), 343 (100), 328 (90), 249 (35), 221 (25), 192
(25), 120 (40), 91 (45), 77 (60), 65 (45), 51 (45), 39
(50); anal. calcd. for C22H17N3O3: C, 71.15; H, 4.61; N,
11.31; found: C, 71.06; H, 4.53; N, 11.20.
J = 15.3, 2H, CH2), 6.67 (d, 1H, J = 7.9, ArH), 6.76 (t, 1H,
J = 7.4, ArH), 6.81 (d, 1H, J = 7.6, ArH), 6.90–6.92 (m,
3H, ArH), 7.14–7.16 (t, 2H, ArH), 7.24–7.34 (m, 3H, ArH),
7.48 (s, 1H, NH), 7.73 (d, 1H, J = 7.5, ArH), 10.36 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6) d = 46.31, 75.54, 110.91,
114.41, 115.06, 118.12, 122.41, 126.71, 126.76, 127.27,
127.82, 127.87, 128.24, 131.73, 133.86, 137.83, 142.97,
146.47, 164.53, and 175.47 ppm; MS: m/z (%) = 355 (M+,
5), 353 (20), 327 (100), 249 (20), 235 (25), 208 (25), 120
(50), 91 (30), 77 (30), 65 (35), 51 (20), 39 (35); anal. calcd.
for C22H17N3O2: C, 74.35; H, 4.82; N, 11.82; found: C,
74.23; H, 4.71; N, 11.70.
30-(4-Bromophenyl)-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (5e, C21H14BrN3O2)
5-Bromo-30-p-tolyl-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (5h, C22H16BrN3O2)
Yellow powder; mp 213–215 °C dec.; IR (KBr) m = 3,429
(NH), 3,252 (NH), 2,964, 1,725 (C=O), 1,642 (C=O),
Yellow powder; mp 150–152 °C dec.; IR (KBr) m = 3,450
(NH), 3,236 (NH), 1,736 (C=O), 1,645 (C=O), 1,613,
1
1,614 cm-1; H NMR (DMSO-d6) d = 6.67-6.79 (m, 3H,
1
ArH), 6.93-6.97 (m, 3H, ArH), 7.16 (t, 1H, J = 7.6, ArH),
7.31 (t, 1H, J = 7.2, ArH), 7.41 (d, 2H, J = 8.4, ArH), 7.56
(d, 1H, J = 7.3, ArH), 7.67 (s, 1H, NH), 7.69 (d, 1H,
J = 7.0, ArH), 10.47 (s, 1H, NH) ppm; 13C NMR (DMSO-
d6) d = 76.81, 110.74, 114.65, 114.75, 118.25, 120.71,
121.24, 126.97, 127.46, 127.93, 131.53, 131.99, 132.21,
134.34, 137.91, 142.13, 146.59, 164.08, and 175.77 ppm;
MS: m/z (%) = 419 (M+, 5), 391 (100), 301 (15), 272 (15),
249 (35), 221 (15), 194 (25), 171 (35), 155 (20), 120 (90),
92 (45), 77 (60), 63 (65), 51 (65), 39 (55); anal. calcd. for
C21H14BrN3O2: C, 60.02; H, 3.36; N, 10.00; found: C,
59.03; H, 3.26; N, 9.89.
1,512 cm-1; H NMR (DMSO-d6) d = 2.08 (s, 3H, CH3),
6.60 (d, 1H, J = 8.2, ArH), 6.67 (d, 1H, J = 7.7, ArH),6.74
(t, 1H, ArH),6.89 (d, 2H, J = 6.7, ArH), 7.03 (d, 1H,
J = 7.8, ArH), 7.28–7.35 (m, 2H, ArH), 7.65 (m, 2H, ArH),
7.76 (s, 1H, NH), 10.55 (s, 1H, NH) ppm; 13C NMR d
(DMSO-d6) d = 21.03, 76.87, 112.66, 114.17, 114.54,
114.98, 118.34, 127.94, 129.68, 129.81, 130.15, 134.03,
134.21, 135.69, 137.61, 141.44, 146.27, 163.91, and
175.64 ppm; MS: m/z (%) = 434 (M+, 10), 405 (95),
327 (25), 286 (35), 250 (15), 209 (15), 192 (25), 166 (25),
146 (20), 120 (100), 91 (85), 77 (60), 65 (95), 51 (60), 39
(70); anal. calcd. for C22H16BrN3O2: C, 60.84; H, 3.71; N,
9.68; found: C, 60.74; H, 3.62; N, 9.57.
30-(4-Chlorophenyl)-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (5f, C21H14ClN3O2)
Acknowledgments We gratefully acknowledge financial support
from the Research Council of Shahid Beheshti University.
Yellow powder; mp 264–266 °C dec.; IR (KBr)
m = 3,427 (NH), 3,337 (NH), 2,964, 1,739 (C=O),
1,643 (C=O), 1,608, 1,491 cm-1 1H NMR (DMSO-d6)
;
d = 6.66–6.78 (m, 3H, ArH), 6.92–7.02 (m, 3H, ArH),
7.16 (t, 1H, J = 7.5, ArH), 7.28–7.33 (m, 3H, ArH), 7.56
(d, 1H, J = 7.3, ArH), 7.63(d, 1H, J = 7.3, ArH), 7.66 (s,
1H, NH), 10.46 (s, 1H, NH) ppm; 13C NMR (DMSO-d6)
d = 76.86, 110.73, 114.65, 114.76, 118.24, 122.75,
126.98, 127.47, 127.93, 129.25, 131.52, 131.66, 132.66,
134.34, 137.47, 142.14, 146.60, 164.13, and 175.79 ppm;
MS: m/z (%) = 375 (M+, 5), 347 (100), 249 (35), 228
(15), 192 (25), 166 (25), 120 (70), 92 (35), 75 (60), 63
(65), 51 (60), 39 (60); anal. calcd. for C21H14ClN3O2: C,
67.12; H, 3.75; N, 11.18; found: C, 67.01; H, 3.76; N,
11.09.
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