Efficient and convenient synthesis of spiroindolinone-quinazolines induced by stannous chloride

Article abstract of DOI:10.1016/j.tet.2011.09.130

An efficient, convenient, one-pot synthesis of 1′H-spiro[indoline-3, 2′-quinazoline]-2,4′(3′H)-dione derivatives was accomplished in good yields via the novel reductive cyclization of 2-nitrobenzamides and isatins mediated by SnCl₂·2H₂O system. A variety of substrates can participate in the process with good yields, making this methodology have broad applicability. The structure of compound 3c has been confirmed by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tet.2011.09.130

Tetrahedron 67 (2011) 9342e9346
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient and convenient synthesis of spiroindolinone-quinazolines induced
by stannous chloride
*
Yu Hu, Man-Man Wang, Hui Chen, Da-Qing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
An efficient, convenient, one-pot synthesis of 10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-dione de-
rivatives was accomplished in good yields via the novel reductive cyclization of 2-nitrobenzamides and
isatins mediated by SnCl2$2H2O system. A variety of substrates can participate in the process with good
yields, making this methodology have broad applicability. The structure of compound 3c has been
confirmed by X-ray diffraction analysis.
Article history:
Received 30 June 2011
Received in revised form 21 September 2011
Accepted 27 September 2011
Available online 5 October 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Quinazoline
Spirooxindole derivatives
Synthesis
Stannous chloride
1. Introduction
isatin. However this method required special catalyst and long
reaction time. Recently Mohammadi et al.13 also reported the syn-
2,3-Dihydroquinazoline-4(3H)-ones and spirooxindole de-
rivatives are important classes of heterocyclic compounds. It has
been reported that 2,3-dihydroquinazolin-4(3H)-ones possess
a broad spectrum of biological and pharmaceutical activities, such
as analgesic, antitumor, diuretic, and herbicide activities.1 In addi-
tion, these compounds can easily be oxidized to quinazolin-4(3H)-
one analogues,2 which also include important pharmacologically
active compounds.3 Several methods have been reported for the
synthesis of 2,3-dihydroquinazolinones.4e6
The indole core represents an interesting pharmacophore, which
displays the feature of biological and pharmacological properties.
Furthermore, the 30-spirooxindoles formed by sharing of the
30-carbon atom have been of interest to organic chemists because
spirooxindole derivatives are characterized by interesting biological
properties.7 For instances, Spirotryprostain A and B, which have
been isolated from the fermentation broth of Aspergillus fumigatus,
have been identified as novel inhibitors of microtubule assembly.8
Derivatives of spirooxindole exhibit a range of biological proper-
ties, including antimicrobial, antitumoral, antibiotic agents, and
inhibitors of human NK-1 receptor.9 Oxa and azaspiro derivatives
are well-known,9e11 but the preparation of corresponding quina-
zolinone analogues has been reported byonly very few workers. e.g.,
List et al.12 reported the synthesis of 10H-spiro-[indoline-3,20-qui-
nazoline]-2,40(30H)-dione by reaction of 2-aminobenzamide with
thesis of the same compounds via a three-component cyclo-
condensation of isatoic anhydride, isatins, and amines using
KAl(SO4)2$12H2O as catalyst. In recent years, our interest has been
focused on the usage of SnCl2 reagent. We have previously reported
the synthesis of 2-aryl-2H-indazoles,14 1-hydroxyquinazolinones,15
quinoxaline derivatives,16 imidazo[1,2-c]quinazoline-5(6H)-thi-
one,17 imidazo[1,2-c]quinazolin-5(6H)-one,17 and pyrrolo[1,2-a]
quinazoline,18 respectively, mediated by SnCl2 reagent. As part of our
interest in the synthesis of spiroheterocyclic compounds,19 we re-
port herein the synthesis of 10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione derivatives via the novel reductive cyclization of 2-
nitrobenzamides with isatins mediated by SnCl2$2H2O system.
2. Results and discussion
In
a
preliminary study, the reaction of 4-chloro-2-
nitrobenzamide 1a with isatin 2a was chosen as model reaction
to optimize the reaction conditions (Scheme 1). The results are
summarized in Table 1.
As shown in Table 1, we first examined the effect of different
organic solvents (entries 1e4) and concluded that ethanol was the
best solvent for this reaction. Then, we also briefly examined the
effect of different temperatures and ratio of 1a/SnCl2$2H2O. The
results showed that at refluxing temperature the reaction preceded
smoothly in high yield. To further evaluate the influence of the ratio
of 1a/SnCl2$2H2O, the reaction was carried out in ethanol using
a 1:1 to 1:5 ratio of 1a/SnCl2$2H2O (entries 5, 6, 4, 7, 8), leading to
* Corresponding author. E-mail address: dqshi@263.net (D.-Q. Shi).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.09.130

Y. Hu et al. / Tetrahedron 67 (2011) 9342e9346
9343
As shown in Table 2, we were pleased to find that the method
was applicable to a broad substrate scope on both substituted 2-
nitrobenzamides and isatins. It can be seen that this protocol can
be applied not only to the 2-nitrobenzamides with electron-
withdrawing groups (such as halide and trifluoromethyl groups)
or electron-donating groups (such as alkyl groups) but also to N-
substituted-2-nitrobenzamides under the same conditions, which
highlighted the wide scope of this reaction. Meanwhile, it was
particularly noteworthy that the effects of different isatins were
also investigated. 4-Substituted and 5-substituted isatins can also
give moderate to good yields.
Scheme 1. Model reaction.
Table 1
Optimization of temperature, ratio, and solvents in the synthesis of 3a
Encouraged by these results, we then focused our attention on
the reaction of bis(2-nitrobenzamides) 4 with isatins 2. To our
delight, the desired product bis(spiroindolinone-quinazoline) 5
was obtained (Scheme 2).
As expected, when the isatin 2 was replaced by acenaphthylene-
1,2-dione 6, another series of 10H,2H-spiro[acenaphthylene-1,20-
quinazoline]-2,40(30H)-dione 7 were obtained under the same re-
action conditions. The results are summarized in Table 3.
Entry
Solvent
Ratioa
Temperature (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
CH3OH
THF
1:3
1:3
1:3
1:3
1:1
1:2
1:4
1:5
1:4
1:4
1:4
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
50
44
57
71
23
45
83
80
30
55
68
CHCl3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
9
10
11
40
60
Table 3
Synthesis of 7 from 2-nitrobenzamides 1 and acenaphthylene-1,2-diones 6
a
Ratio of 1a and SnCl2$2H2O system.
Isolated yields.
b
3a in 23%, 45%, 71%, 83%, and 80% yields, respectively. We con-
cluded the best ratio of 1a/SnCl2$2H2O was 1:4.
With the optimized conditions in hand, we then performed the
reaction of a variety of 2-nitrobenzamides 1 and isatins 2 via
SnCl2$2H2O system. The results are summarized in Table 2.
Entry
X
Y
R
Products
Isolated yield (%)
1
2
3
4
5
6
Cl
H
H
H
H
H
H
H
CH3
H
H
H
7a
7b
7c
7d
7e
7f
80
73
78
83
69
82
Table 2
4-FC6H4
H
H
4-BrC6H4
C6H5CH2
Synthesis of spiroindolinone-quinazoline derivatives 3
H
Similarly, it can be seen that either 2-nitrobenzamides or N-
substituted ones were well tolerated. They all reacted well with
acenaphthylene-1,2-diones under the optimized conditions, and
the corresponding products were obtained in moderate yields. No
remarkable electronic effects on the reaction were observed.
Although the detailed mechanism of the above reaction has not
been clarified yet, the formation of spiroindolinone-quinazoline
derivatives 3 can be explained by a possible mechanism presented
in Scheme 3. In the initial step, 2-nitrobenzamides 1 was reduced by
tin(II) chloride to 2-aminobenzamide A and Sn(II) was oxidated to
Sn(IV). The 2-aminobenzamide A then reacted with isatins 2 with
the aid of Sn(IV) or excess Sn(II) to give the intermediate B. Finally,
products 3 were formed by attack of the amino group onto the
central carbon atom of the imine mediated by Sn(IV) or excess Sn(II).
All the structures of products 3, 5, and 7 were characterized by
IR, 1H NMR, 13C NMR, and HRMS spectra. The structure of 3c was
further confirmed by X-ray diffraction analysis. The molecular
structure of the product 3c is shown in Fig. 1.
Entry
X
Y
R
R1
Products
Isolated
yield (%)
1
2
3
4
5
6
7
8
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
CH3
CH3
H
H
H
H
4-Cl
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
83
85
82
91
86
72
81
86
85
82
75
86
82
84
87
82
4-FC6H4
4-FC6H4
H
4-CH3C6H4
3-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
H
5-Br
4-Br
5-Cl
5-Br
4-Br
4-Br
4-Cl
4-Br
4-Cl
4-Br
H
9
10
11
12
13
14
15
16
H
H
H
4-CH3C6H4
H
Scheme 2. Synthesis of compounds 5 from bis(2-nitrobenzamides) 4 and isatins 2.

9344
Y. Hu et al. / Tetrahedron 67 (2011) 9342e9346
SnCl2$2H2O (4 mmol) in EtOH (5 mL) was stirred at reflux for
3e5 h. After this period, the TLC analysis of the mixture showed the
reaction to be completed. The mixture was quenched with 3% HCl
(10 mL) and filtered to yield a crude product, which was purified by
recrystallization from 95% ethanol and DMF.
4.2.1. 70-Chloro-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-dione
(3a). Yellow powder; mp: >300 ꢀC. IR (KBr)
n: 3309, 3207, 3073,
2831, 1729, 1668, 1612, 1475, 1394, 1296, 1206, 1079, 915, 764,
663 cmꢁ1. 1H NMR (300 MHz, DMSO-d6): dH 6.62 (s, 1H, ArH), 6.69
(dd, J1¼8.4 Hz, 1H, J2¼1.8 Hz, ArH), 6.85 (d, J¼7.5 Hz, 1H, ArH), 7.06
(t, J¼7.5 Hz, 1H, ArH), 7.33 (t, J¼7.5 Hz, 1H, ArH), 7.48 (d, J¼7.2 Hz,
1H, ArH), 7.55 (d, J¼5.1 Hz, 1H, ArH), 7.59 (s, 1H, NH), 8.46 (s, 1H,
NH), 10.35 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 71.6, 110.9,
113.6,114.0,117.8, 123.1, 126.2, 129.4, 129.5, 131.8, 138.5, 142.8, 148.6,
163.9, 176.5. HRMS found: m/z 300.0559 (MþH), calcd for
C15H11N3O325Cl: MþH, 300.0540.
Scheme 3. Proposed reaction mechanism.
4.2.2. 70-Chloro-30-(4-fluorophenyl)-10H-spiro[indoline-3,20-quina-
zoline]-2,40(30H)-dione (3b). Yellow powder; mp: >300 ꢀC. IR (KBr)
n
: 3265, 3169, 2998, 2809, 1739, 1625, 1506, 1357, 1225, 1084, 936,
847, 755, 682 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH 6.69e6.80
.
(m, 3H, ArH), 6.98e7.21 (m, 6H, ArH), 7.62e7.68 (m, 2H, ArH), 7.94
(s, 1H, NH), 10.54 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 77.0,
111.0, 113.8, 113.9, 116.1, 116.4, 118.4, 123.0, 127.1, 127.3, 130.1, 131.8,
134.5, 139.0, 142.3, 147.9, 160.0, 163.6, 175.8. HRMS found: m/z
393.0679 (Mþ), calcd for C21H13N3O2F35Cl: M, 393.0680.
4.2.3. 4,70-Dichloro-30-(4-fluorophenyl)-10H-spiro[indoline-3,20-qui-
nazoline]-2,40(30H)-dione (3c). Yellow powder; mp: >300 ꢀC. IR
(KBr)
n
: 3260, 2927, 2850, 1744, 1644, 1513, 1352, 1228, 1175, 1088,
923, 835, 770, 619 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6): dH
6.65e6.68 (m, 2H, ArH), 6.75 (d, J¼8.4 Hz, 1H, ArH), 7.02 (d,
J¼8.4 Hz, 1H, ArH), 7.07e7.15 (m, 4H, ArH), 7.24 (t, J¼8.0 Hz, 1H,
ArH), 7.65 (d, J¼8.4 Hz, 1H, ArH), 8.06 (s, 1H, NH), 10.83 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 77.8, 110.1, 112.2, 113.3, 116.2, 116.5,
117.9, 123.9, 124.0, 130.1, 131.1, 131.2, 132.3, 133.6, 133.8, 139.2, 144.1,
Fig. 1. The crystal structure of compound 3c.
3. Conclusion
147.6, 160.2, 162.8, 174.9. HRMS found: m/z 427.0282 (Mþ), calcd for
35
C21
H Cl2FN3O2: M, 427.0291.
12
In conclusion, a series of 10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-diones and 10H,2H-spiro[acenaphthylene-1,20-quinazo-
line]-2,40(30H)-diones were synthesized by the reaction of 2-
nitrobenzamides with isatins and acenaphthylene-1,2-diones, re-
spectively, mediated by SnCl2$2H2O system. A variety of substrates
can participate in the process with moderate to good yields. Our
protocol is characterized by (i) faster reaction times, (ii) accessible
materials and handy manipulation (only one pot), and (iii) isolation
of products via simple recrystallization to give higher purities.
4.2.4. 60-Chloro-10H-spiro[indoline-3,20-quinazoline]-2,40(30H)-dione
(3d). Yellow powder; mp: 276e278 ꢀC. IR (KBr):
: 3299, 3194, 3078,
n
2832, 1726, 1665, 1650, 1511, 1475, 1393, 1293, 1207, 1108, 895, 826,
760, 664 cmꢁ1. 1H NMR (300 MHz, DMSO-d6): dH 6.62 (d, J¼8.7 Hz,
1H, ArH), 6.84 (d, J¼7.8 Hz, 1H, ArH), 7.04 (t, J¼7.5 Hz, 1H, ArH), 7.25
(dd, J1¼8.7 Hz, J2¼2.4 Hz,1H, ArH), 7.32 (t, J¼7.8 Hz,1H, ArH), 7.48 (s,
1H, NH), 7.50 (t, J¼2.7 Hz, 2H, ArH), 8.53 (s,1H, NH),10.33 (s,1H, NH).
13C NMR (75 MHz, DMSO-d6): dC 71.5,110.9,116.4,116.5,121.5,123.1,
126.2, 126.6, 129.5, 131.7, 133.7, 142.8, 146.3, 163.6, 176.5. HRMS
found: m/z 299.0464 (Mþ), calcd for C15H10N3O325Cl: M, 299.0462.
4. Experimental section
4.1. General
4.2.5. 5-Bromo-60-chloro-30-p-tolyl-10H-spiro[indoline-3,20-quinazo-
line]-2,40(30H)-dione (3e). Yellow powder; mp: 294e297 ꢀC. IR
Melting points were determined in open capillaries and un-
corrected. IR spectrawere recorded on a Varian F-1000 spectrometer
in KBr pellet. 1H NMR and 13C NMR spectra were obtained from
a solution in DMSO-d6 with Me4Si as internal standard using Varian
Invoa-400 MHz or Invoa-300 MHz spectrometer. HRMS analyses
were carried out using TOF-MS or GCT-TOF instrument. X-ray crys-
tallographic analysis was performed with a Rigaku Mercury CCD/
AFC diffractometer.
(KBr):
n
: 3243, 3080, 2924, 2860, 1737, 1639, 1509, 1355, 1249, 1182,
1094, 882, 818, 692, 532 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6): dH
6.63 (d, J¼8.4 Hz, 1H, ArH), 6.73 (d, J¼8.4 Hz, 1H, ArH), 6.92 (d,
J¼7.6 Hz, 2H, ArH), 7.06 (d, J¼7.6 Hz, 2H, ArH), 7.35e7.37 (m, 2H,
ArH), 7.60 (s,1H, ArH), 7.81 (s,1H, ArH), 7.86 (s,1H, NH),10.60 (s,1H,
NH). 13C NMR (75 MHz, DMSO-d6): dC 21.2, 76.9, 113.0, 114.5, 116.5,
116.8, 122.2, 127.2, 129.6, 129.8, 130.1, 134.0, 134.2, 134.4, 135.5,
138.1, 141.7, 145.3, 163.1, 175.7. HRMS found: m/z 467.0044 (Mþ),
79
calcd for C22
H
Br35ClN3O2: M, 467.0036.
15
4.2. General procedure for the synthesis of 4, 5, and 7
4.2.6. 4-Bromo-60-chloro-30-m-tolyl-10H-spiro[indoline-3,20-quina-
A solution of 2-nitrobenzamides 1 or bis(2-nitrobenzamides) 4
(1 mmol), isatins 2 or acenaphthylene-1,2-diones 6 (1 mmol), and
zoline]-2,40(30H)-dione (3f). Yellow powder; mp: 282e284 ꢀC. IR
(KBr) n: 3239, 2998, 2921, 2876, 1734, 1669, 1632, 1521, 1445, 1351,

Y. Hu et al. / Tetrahedron 67 (2011) 9342e9346
9345
1181, 1098, 903, 817, 695, 533 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 2.17 (s, 3H, CH3), 6.66 (d, J¼7.2 Hz, 1H, ArH), 6.69 (d, J¼8.8 Hz,1H,
ArH), 6.88 (d, J¼7.6 Hz, 1H, ArH), 6.93 (s, 1H, ArH), 7.04 (d, J¼7.6 Hz,
1H, ArH), 7.10e7.18 (m, 3H, ArH), 7.34 (dd, J1¼8.8 Hz, J2¼2.8 Hz, 1H,
ArH), 7.57 (s, 1H, ArH), 7.93 (s, 1H, NH), 10.74 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): dC 21.4, 78.5, 110.5, 114.4, 116.2, 121.3, 121.4,
126.0, 127.0, 127.1, 129.2, 129.6, 129.8, 133.5, 133.9, 134.3, 137.6,
138.7, 144.6, 145.6, 163.0, 175.2. HRMS found: m/z 467.0028 (Mþ),
calcd for C22H15N3O325Cl79Br: M, 467.0036.
78.0, 110.0, 113.6, 114.2, 117.8, 123.9, 124.9, 128.1, 128.9, 129.9, 132.4,
133.2, 134.5, 135.6, 138.1, 144.3, 146.7, 163.7, 175.4. HRMS found: m/z
389.0917 (Mþ), calcd for C22H16N3O325Cl: M, 389.0931.
4.2.12. 4-Bromo-30-p-tolyl-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (3l). Yellow powder; mp: 278e280 ꢀC. IR (KBr)
n:
3344, 3040, 2921,1751, 1621,1510,1486, 1368,1266,1169, 1025, 934,
806, 744, 613 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 2.20 (s, 3H,
CH3), 6.64 (d, J¼8.0 Hz, 2H, ArH), 6.69 (t, J¼7.6 Hz, 1H, ArH), 6.98 (d,
J¼8.4 Hz, 2H, ArH), 7.04 (d, J¼8.4 Hz, 2H, ArH), 7.09e7.16 (m, 2H,
ArH), 7.28 (t, J¼7.6 Hz, 1H, ArH), 7.63 (d, J¼7.2 Hz, 1H, ArH), 7.67 (s,
1H, NH), 10.64 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 21.1,
78.5, 110.3, 113.1, 114.0, 117.5, 121.3, 126.4, 126.9, 128.0, 129.0, 129.8,
133.2,134.4,135.4,137.9,144.4,146.6,163.5,175.4. HRMS found: m/z
433.0424 (Mþ), calcd for C22H16N3O729Br: M, 433.0426.
4.2.7. 5-Chloro-30-(4-chlorophenyl)-10H-spiro[indoline-3,20-quinazo-
line]-2,40(30H)-dione (3g). Yellow powder; mp: 268e270 ꢀC. IR
(KBr)
n
: 3326, 3280, 3103, 2838, 2718, 1737, 1647, 1483, 1355, 1275,
1185, 1091, 870, 813, 634 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6): dH
6.70 (d, J¼8.4 Hz, 2H, ArH), 6.78 (t, J¼7.6 Hz, 1H, ArH), 7.08 (d,
J¼8.4 Hz, 2H, ArH), 7.25 (dd, J1¼8.4 Hz, J2¼2.0 Hz, 1H, ArH),
7.31e7.36 (m, 3H, ArH), 7.67 (d, J¼7.6 Hz, 1H, ArH), 7.73 (d, J¼2.4 Hz,
1H, ArH), 7.74 (s, 1H, NH), 10.64 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 77.0, 112.4, 114.8, 118.6, 126.9, 127.2, 128.1, 129.4,
129.5,131.6,131.8,132.0, 133.0,134.6, 137.4,141.2, 146.4, 164.0,175.7.
HRMS found: m/z 409.0396 (Mþ), calcd for C21H13N3O235Cl2: M,
409.0385.
4.2.13. 4-Chloro-60-methyl-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (3m). Yellow powder; mp: 287e289 ꢀC. IR (KBr)
n:
3237, 3018, 2921, 1743, 1647, 1523, 1449, 1370, 1253, 1172, 1095, 918,
819, 782, 656 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 2.19 (s, 3H,
CH3), 6.48 (d, J¼8.4 Hz, 1H, ArH), 6.80 (d, J¼7.6 Hz, 1H, ArH), 7.04 (d,
J¼8.0 Hz, 2H, ArH), 7.16 (s, 1H, ArH), 7.32 (t, J¼8.0 Hz, 1H, ArH), 7.40
(s, 1H, NH), 8.32 (s, 1H, NH), 10.52 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 20.7, 72.5, 109.7, 113.7, 114.1, 123.7, 125.9, 126.3, 127.4,
132.3, 132.8, 134.7, 144.6, 145.0, 164.0, 175.9. HRMS found: m/z
313.0620 (Mþ), calcd for C16H12N3O235Cl2: M, 313.0618.
4.2.8. 5-Bromo-30-(4-chlorophenyl)-10H-spiro[indoline-3,20-quinazo-
line]-2,40(30H)-dione (3h). Yellow powder; mp: 256e258 ꢀC. IR
(KBr)
n
: 3326, 3267, 3091, 2832, 1737, 1658, 1484, 1355, 1276, 1186,
1092, 870, 813, 758, 660 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6): dH
6.65 (d, J¼8.4 Hz, 1H, ArH), 6.71 (d, J¼8.0 Hz, 1H, ArH), 6.78 (t,
J¼7.2 Hz, 1H, ArH), 7.07 (d, J¼8.0 Hz, 2H, ArH), 7.31e7.39 (m, 4H,
ArH), 7.68 (d, J¼7.6 Hz, 1H, ArH), 7.71 (s, 1H, ArH), 7.80 (s, 1H, NH),
10.60 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 77.0, 113.0, 114.5,
114.9, 118.7, 128.2, 129.6, 129.9, 130.0, 131.8, 131.9, 133.1, 134.5, 134.7,
4.2.14. 4-Bromo-60-methyl-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (3n). Yellow powder; mp: 278e280 ꢀC. IR (KBr)
n:
3238, 3023, 2922,1742, 1645,1525,1447,1372,1258,1171,1095, 912,
816, 656 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 2.18 (s, 3H, CH3),
6.48 (d, J¼8.0 Hz, 1H, ArH), 6.83 (d, J¼7.6 Hz, 1H, ArH), 7.03 (d,
J¼8.4 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 7.18e7.24 (m, 2H, ArH), 7.39 (s,
1H, NH), 8.27 (s, 1H, NH), 10.47 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 20.7, 73.2, 110.2, 113.6, 114.1, 120.9, 125.8, 126.8, 127.4,
127.8, 133.0, 134.7, 145.0, 145.1, 164.0, 176.0. HRMS found: m/z
357.0110 (Mþ), calcd for C16H12N3O729Br: M, 357.0113.
137.5, 141.7, 146.5, 164.1, 175.7. HRMS found: m/z 452.9876 (Mþ),
79
calcd for C21
H
Br35ClN3O2: M, 452.9880.
13
4.2.9. 4-Bromo-30-(4-chlorophenyl)-10H-spiro[indoline-3,20-quinazo-
line]-2,40(30H)-dione (3i). Yellow powder; mp: 280e282 ꢀC. IR (KBr)
n
: 3344, 3060, 2930, 1751, 1615, 1507, 1487, 1448, 1362, 1266, 1175,
1090, 817, 778, 613, 516 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH
.
4.2.15. 70-(Trifluoromethyl)-10H-spiro[indoline-3,20-quinazoline]-
6.64e6.73 (m, 3H, ArH), 7.08e7.17 (m, 4H, ArH), 7.28e7.31 (m, 1H,
ArH), 7.35 (t, J¼7.6 Hz, 2H, ArH), 7.64 (t, J¼6.4 Hz, 1H, ArH), 7.74 (d,
J¼6.4 Hz, 1H, NH), 10.72 (d, J¼6.4 Hz, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): dC 78.2, 110.1, 112.6, 113.9, 117.4, 121.0, 125.5, 126.7, 127.7,
129.1, 130.8, 132.9, 133.2, 134.4, 136.6, 144.2, 146.4, 163.3, 174.9.
HRMS found: m/z 452.9870 (Mþ), calcd for C21H13N3O325Cl79Br: M,
452.9880.
2,40(30H)-dione (3o). Yellow powder; mp: 264e266 ꢀC. IR (KBr)
n:
3297, 3195, 3078, 2832,1724,1664,1650,1518,1476,1394,1293,1209,
1108, 896, 826, 760, 670 cmꢁ1 1H NMR (300 MHz, DMSO-d6): dH
.
6.86e6.89 (m, 2H, ArH), 6.96e6.99 (m, 1H, ArH), 7.08 (t, J¼0.66 Hz,
1H, ArH), 7.34 (t, J¼5.4 Hz,1H, ArH), 7.51 (t, J¼5.7 Hz,1H, ArH), 7.71 (s,
1H, NH), 7.77e7.80 (m,1H, ArH), 8.65 (s,1H, NH),10.39 (s,1H, NH).13C
NMR (100 MHz, DMSO-d6): dc 76.0, 115.5, 115.6, 118.6, 122.7, 127.8,
130.9, 133.4, 133.8, 136.5, 147.5, 152.4, 168.1, 181.0. HRMS found: m/z
334.0812 (MþH)þ, calcd for C16H11F3N3 O2: MþH, 334.0804].
4.2.10. 4-Bromo-30-(4-fluorophenyl)-10H-spiro[indoline-3,20-quina-
zoline]-2,40(30H)-dione (3j). Yellow powder; mp: >300 ꢀC. IR (KBr)
n
: 3356, 3280, 2926, 1751, 1626, 1513, 1445, 1368, 1164, 1090, 934,
4.2.16. 30-(4-Methylphenyl)-70-(trifluoromethyl)-10H-spiro[indoline-
823, 746, 698 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH 6.65e6.68
.
3,20-quinazoline]-2,40(30H)-dione
(3p). Yellow powder; mp:
(m, 2H, ArH), 6.71 (d, J¼7.6 Hz,1H, ArH), 7.11e7.18 (m, 6H, ArH), 7.30
(t, J¼8.0 Hz, 1H, ArH), 7.64 (d, J¼7.6 Hz, 1H, ArH), 7.73 (s, 1H, NH),
10.71 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dH 78.6, 110.4, 112.8,
114.1, 116.1, 116.4, 117.6, 121.2, 126.0, 127.0, 128.0, 131.3, 131.4, 133.4,
134.2, 134.6, 144.4, 146.7, 160.1, 163.6, 175.2. HRMS found: m/z
437.1072 (Mþ), calcd for C21H13N3O2 F79Br: M, 437.0175.
>300 ꢀC. IR (KBr)
n: 3311, 3210, 3073, 2834, 1727, 1669, 1612, 1470,
1395,1213,1077, 925, 665, 771 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
dH 2.18 (s, 3H, CH3), 6.66 (s, 1H, ArH), 6.88e7.02 (m, 6H, ArH), 7.17 (s,
1H, ArH), 7.35 (d, J¼7.2 Hz, 1H, ArH), 7.58 (s, 1H, ArH), 7.85 (s, 1H,
NH), 7.94e8.03 (m, 1H, ArH), 10.52 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): dC 25.9, 81.5, 115.7, 119.0, 180.7, 167.9, 151.7, 147.1, 142.9,
142.5, 140.3, 140.1, 138.6, 136.5, 134.6, 134.1, 131.9, 127.7, 127.5, 126.4,
122.9, 122.6, 193.2. HRMS found: m/z 424.1267 (MþH)þ, calcd for
C23H17F2N2O2: MþH, 424.1274.
4.2.11. 4-Chloro-30-p-tolyl-10H-spiro[indoline-3,20-quinazoline]-
2,40(30H)-dione (3k). Yellow powder; mp: 296e298 ꢀC. IR (KBr)
n:
3338, 3043, 2927, 1751, 1624,1513, 1485, 1448, 1374, 1272, 1175, 939,
815, 744, 695, 516 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 2.18 (s,
3H, CH3), 6.62 (t, J¼10.0 Hz, 2H, ArH), 6.69 (t, J¼7.6 Hz, 1H, ArH),
6.93e6.98 (m, 3H, ArH), 7.03 (d, J¼7.6 Hz, 2H, ArH), 7.18 (t, J¼8.0 Hz,
1H, ArH), 7.27 (t, J¼7.6 Hz, 1H, ArH), 7.63 (d, J¼8.0 Hz, 1H, ArH), 7.68
(s, 1H, NH), 10.66 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 21.2,
4.2.17. Compound 5. Yellow powder; mp: 237e239 ꢀC. IR (KBr)
n:
3258, 3108, 2935, 1735, 1611, 1476, 1320, 1185, 1081, 923, 850, 755,
683 cmꢁ1. 1H NMR (400 MHz, DMSO-d6): dH 1.27e1.52 (m, 2H, CH2),
2.31e2.38 (m, 2H, CH2), 3.01e3.14 (m, 2H, CH2), 6.60 (s, 2H, ArH),
6.73 (d, J¼8.0 Hz, 2H, ArH), 6.92 (d, J¼7.6 Hz, 2H, ArH), 7.05 (t,

9346
Y. Hu et al. / Tetrahedron 67 (2011) 9342e9346
J¼7.6 Hz, 2H, ArH), 7.33e7.39 (m, 4H, ArH), 7.58 (d, J¼8.4 Hz, 2H,
ArH), 7.61 (s, 2H, 2ꢂNH), 10.58 (s, 2H, 2ꢂNH). 13C NMR (75 MHz,
DMSO-d6): dC 28.5, 41.5, 75.9, 111.5, 113.5, 113.9, 118.2, 123.3, 126.5,
127.1, 129.7, 132.2, 138.4, 142.8, 147.4, 163.7, 175.6. HRMS found: m/z
639.1311 (MþH), calcd for C33H24N6O345Cl2: MþH, 639.1314.
124.2, 127.4, 128.3, 128.8, 129.6, 129.8, 130.4, 132.1, 132.3, 133.4,
134.7,135.9,136.2,138.2,141.5,146.5,164.2, 200.7. HRMS found: m/z
454.0315 (Mþ), calcd for C25H15N2O729Br: M, 454.0317.
4.2.23. 30-Benzyl-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-
2,40(30H)-dione (7f). Yellow powder; mp: 163e165 ꢀC. IR (KBr)
n:
4.2.18. 70-Chloro-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-
3250, 3074, 3029, 2967, 1734, 1621, 1573, 1516, 1433, 1260, 1158,
2,40(30H)-dione (7a). Yellow powder; mp: 249e251 ꢀC. IR (KBr)
n
:
1076, 868, 834, 698, 548 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH
.
3350, 3259, 2930, 2876, 1899, 1720, 1675, 1598, 1487, 1337, 1203,
4.27 (d, J¼15.6 Hz, 1H, CH), 4.41 (d, J¼15.6 Hz, 1H, CH), 6.58 (t,
J¼6.8 Hz, 3H, ArH), 6.80 (t, J¼7.6 Hz, 1H, ArH), 6.92 (t, J¼7.6 Hz, 2H,
ArH), 7.00 (t, J¼7.6 Hz, 1H, ArH), 7.28 (t, J¼8.4 Hz, 1H, ArH), 7.63 (s,
1H, NH), 7.70e7.75 (m, 2H, ArH), 7.75e7.80 (m, 3H, ArH), 8.14 (dd,
J1¼7.2 Hz, J2¼1.6 Hz, 1H, ArH), 8.33 (d, J¼7.6 Hz, 1H, ArH). 13C NMR
(75 MHz, DMSO-d6): dC 46.6, 78.6, 114.5, 115.5, 118.6, 123.3, 123.7,
127.4, 127.6, 128.1, 128.3, 128.5, 129.0, 129.4, 129.6, 130.6, 133.0,
134.2, 135.3, 137.9, 141.8, 146.5, 164.6, 200.4. HRMS found: m/z
390.1374 (Mþ), calcd for C26H18N2O2: M, 390.1368].
1101, 931, 868, 673, 545 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH
.
6.59 (d, J¼2.0 Hz, 1H, ArH), 6.75 (dd, J1¼8.4 Hz, J2¼2.0 Hz, 1H, ArH),
7.66 (d, J¼8.4 Hz, 1H, ArH), 7.73 (s, 1H, NH), 7.85 (t, J¼7.6 Hz, 1H,
ArH), 7.86e7.89 (m, 1H, ArH), 7.90e7.93 (m, 1H, ArH), 8.03 (d,
J¼6.8 Hz, 1H, ArH), 8.16 (d, J¼8.0 Hz, 1H, ArH), 8.39 (d, J¼8.4 Hz, 1H,
ArH), 8.61 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): dC 74.6, 113.5,
114.0,118.1,122.6,123.6,127.3,128.7,129.7,129.9,130.0,130.6,133.0,
138.0, 138.7, 141.6, 148.4, 163.6, 200.8. HRMS found: m/z 334.0516
(Mþ), calcd for C19H11N2O325Cl: M, 334.0509.
Acknowledgements
4.2.19. 30-(4-Fluorophenyl)-10H,2H-spiro[acenaphthylene-1,20-quina-
zoline]-2,40(30H)-dione (7b). Yellow powder; mp: >300 ꢀC. IR (KBr)
We acknowledge the financial support from the Foundation of
the Natural Science Foundation of China (No. 21072144), the Major
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049), A Project
Funded by the Priority Academic Project Development of Jiangsu
Higher Education Institutions and the Foundation of Key Laboratory
of Organic Synthesis of Jiangsu Province (No. JSK0812).
n
: 3338, 3290, 3068, 2998, 1737, 1644, 1507, 1485, 1351, 1255, 1158,
1067, 885, 829, 741, 661, 528 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 6.66 (d, J¼8.0 Hz, 1H, ArH), 6.81 (t, J¼8.0 Hz, 1H, ArH), 6.88 (t,
J¼8.4 Hz, 2H, ArH), 6.95 (s, 2H, ArHþNH), 7.33 (t, J¼8.4 Hz,1H, ArH),
7.70e7.76 (m, 2H, ArH), 7.83 (t, J¼7.6 Hz, 2H, ArH), 7.99 (d, J¼7.6 Hz,
2H, ArH), 8.02 (d, J¼2.4 Hz, 1H, ArH), 8.27 (d, J¼8.4 Hz, 1H, ArH). 13C
NMR (75 MHz, DMSO-d6): dC 79.9, 114.6, 115.1, 115.8, 116.1, 118.6,
123.4, 124.1, 127.2, 128.2, 128.7, 129.4, 129.6, 130.2, 131.9, 132.0,
133.1, 133.2, 134.5, 134.9, 135.9, 141.3, 146.5, 164.3, 200.8. HRMS
found: m/z 394.1120 (Mþ), calcd for C25H15N2O2F: M, 394.1118.
References and notes
1. (a) Hour, M.; Huang, L.; Kuo, S.; Xia, Y.; Bastow, K.; Nakanishi, Y.; Hamel, E.; Lee,
K. J. Med. Chem. 2000, 43, 4479e4487; (b) Kacker, I. K.; Zaheer, S. H. J. Indian
Chem. Soc. 1951, 28, 344e348.
2. Abdel-Jalil, R. J.; Volter, W.; Saeed, M. Tetrahedron Lett. 2004, 45, 3475e3476.
3. (a) Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.; Traber, J. E. J. Med.
Chem. 1994, 19, 381e383; (b) Sharma, S. D.; Kaur, V. Synthesis 1989, 677e680;
(c) Liu, J. F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.;
Brown, M. Tetrahedron Lett. 2005, 46, 1241e1244.
4. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.; Palermo, S.; Webster, W.
J. Org. Chem. 1969, 34, 887e892.
5. Su, W.; Yang, B. Aust. J. Chem. 2002, 55, 695e697.
6. Shi, D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H. Tetrahedron Lett. 2003,
44, 3199e3201.
7. (a) Joshi, K. C.; Chand, P. Pharmazie 1982, 37, 1e12; (b) Da-Silva, J. F. M.; Garden,
S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273e324; (c) Abdel-Rahman, A. H.;
Keshk, E. M.; Hanna, M. A.; El-Bady, S. M. Bioorg. Med. Chem. 2006, 12,
2483e2488; (d) Kobayashi, J.; Tsuda, M.; Agemi, K.; Shigemori, H.; Ishibashi, M.;
Sasaki, T.; Mikami, Y. Tetrahedron 1991, 47, 6617e6622; (e) James, D. M.; Kunze,
H. B.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 1137e1140.
8. (a) Usui, T.; Kondoh, M.; Cui, C. B.; Mayumi, T.; Osada, H. Biochem. J. 1998, 333,
543e548; (b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832e835; (c)
Hiton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639e2641.
9. (a) Okita, T.; Isobe, M. Tetrahedron 1994, 50, 11143e11152; (b) Rosenmond, P.;
Hosseini-Merescht, M.; Bub, C. Liebigs Ann. Chem. 1994, 2, 151e152; (c) Kornet,
M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892e898.
10. (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.;
Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J.
Am. Chem. Soc. 2005, 127, 10130e10131; (b) Chen, C.; Li, X.; Neumann, C. S.; Lo,
M. M.-C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2005, 44, 2249e2252; (c) Bella,
M.; Kobbelgaard, S.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670e3671.
11. Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org. Chem. 2006, 71, 2346e2351.
12. Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130,
15786e15787.
4.2.20. 60-Methyl-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-
2,40(30H)-dione (7c). Yellow powder; mp: 258e260 ꢀC. IR (KBr)
n
:
3387, 3188, 2918, 1720, 1649, 1604, 1502, 1351, 1252, 1186, 1064, 897,
829, 741, 548 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH 2.23 (s, 3H,
.
CH3), 6.49 (d, J¼8.0 Hz, 1H, ArH), 7.07 (dd, J1¼8.0 Hz, J2¼3.2 Hz, 1H,
ArH), 7.28 (s, 1H, ArH), 7.49 (s, 1H, NH), 7.81e7.86 (m, 2H, ArH), 7.89
(t, J¼7.6 Hz,1H, ArH), 8.00 (d, J¼6.8 Hz,1H, ArH), 8.13 (dd, J1¼7.2 Hz,
J2¼1.6 Hz, 1H, ArH), 8.36 (d, J¼8.0 Hz, 1H, ArH), 8.44 (s, 1H, NH). 13
C
NMR (75 MHz, DMSO-d6): dC 20.8, 74.7, 114.5, 115.1, 122.3, 123.2,
126.7, 127.0, 127.7, 129.2, 129.8, 129.9, 130.6, 132.8, 134.9, 138.7,
141.4, 145.1, 164.6, 201.1. HRMS (ESI) found: m/z 315.1128, calcd for
C20H15N2O2: [MþH]þ, 315.1134.
4.2.21. 10H,2H-Spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-di-
one (7d). Yellow powder; mp: 238e240 ꢀC. IR (KBr)
n
: 3384, 3248,
3040, 2927, 1732, 1658, 1607, 1521, 1493, 1368, 1339, 1147, 1090, 840,
786, 669, 548 cmꢁ1 1H NMR (400 MHz, DMSO-d6): dH 6.57 (d,
.
J¼8.0 Hz, 1H, ArH), 6.72 (t, J¼7.6 Hz, 1H, ArH), 7.24 (t, J¼8.4 Hz, 1H,
ArH), 7.46 (s, 1H, NH), 7.67 (d, J¼8.0 Hz, 1H, ArH), 7.71e7.91 (m, 3H,
ArH), 8.00 (d, J¼6.8 Hz, 1H, ArH), 8.14 (d, J¼8.0 Hz, 1H, ArH), 8.37 (d,
J¼8.0 Hz, 1H, ArH), 8.49 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
dC 74.7, 114.4, 115.0, 118.1, 122.4, 123.3, 127.1, 127.7, 129.0, 129.8,
129.9, 130.6, 132.8, 134.2, 138.6, 141.5, 147.3, 164.4, 201.0. HRMS
found: m/z 300.0891 (Mþ), calcd for C19H12N2O2: M, 300.0899.
13. Mohammadi, A. A.; Dabiri, M.; Qaraat, H. Tetrahedron 2009, 65, 3804e3808.
14. Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J. W.; Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J.
Synlett 2007, 2509e2512.
15. Shi, D. Q.; Dou, G. L.; Zhou, Y. Synthesis 2008, 2000e2007.
16. Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J. W.; Li, X. Y. J. Heterocycl. Chem. 2008, 45,
1797e1801.
17. Wang, M. M.; Dou, G. L.; Shi, D. Q. J. Heterocycl. Chem. 2009, 46, 1364e1368.
18. Wang, M. M.; Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2010, 12, 582e586.
19. (a) Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S. J. J. Comb. Chem. 2010, 12,
231e237; (b) Liu, H.; Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2010, 12, 292e294; (c)
Chen, H.; Shi, D. Q. J. Comb. Chem. 2010, 12, 571e576; (d) Liu, H.; Dou, G. L.; Shi,
D. Q. J. Comb. Chem. 2010, 12, 633e637; (e) Chen, H.; Shi, D. Q. Tetrahedron 2011,
67, 5686e5692.
4.2.22. 30-(4-Bromophenyl)-10H,2H-spiro[acenaphthylene-1,20-qui-
nazoline]-2,40(30H)-dione (7e). Yellow powder; mp: 257e259 ꢀC. IR
(KBr) n: 3236, 3097, 2938, 1723, 1661, 1601, 1527, 1487, 1246, 1186,
1098, 894, 834, 755, 656, 519 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
dH 6.66 (d, J¼8.4 Hz,1H, ArH), 6.81 (t, J¼7.6 Hz, 1H, ArH), 6.88 (s, 2H,
ArHþNH), 7.26 (d, J¼8.0 Hz, 2H, ArH), 7.33 (t, J¼7.6 Hz, 1H, ArH),
7.70e7.76 (m, 2H, ArH), 7.84 (t, J¼8.0 Hz, 2H, ArH), 7.95 (d, J¼4.8 Hz,
1H, ArH), 8.01 (d, J¼8.4 Hz, 2H, ArH), 8.28 (d, J¼8.0 Hz, 1H, ArH). 13C
NMR (75 MHz, DMSO-d6): dC 79.8, 114.7, 115.2, 118.8, 121.3, 123.7,