Sulfamic acid as energy efficient catalyst for synthesis of flurophores, 1-H-spiro [isoindoline-1,2′-quinazoline]-3,4′(3′H)-diones

Article abstract of DOI:10.1007/s12039-016-1047-7

An energy efficient synthesis of 1-H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′ H)-diones has been expediently accomplished by a reaction of isatin(s) / cyclic ketone and anthranilamide in ethanol at ambient temprature. Excellent yields of the products in short time duration, operational simplicity, and simple work-up procedure are the attractive features of the present protocol. Synthesized 1-H-spiro[isoindoline-1,2′-quinazoline]-3,4′(3′ H)-diones were found to be fluorescent with absorption in UV region (302, 362 nm) and emission in visible region (413-436 nm) with Stokes shift of 44-72 nm.

Full text of DOI:10.1007/s12039-016-1047-7

c
J. Chem. Sci. Vol. 128, No. 4, April 2016, pp. 657–662. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1047-7
Sulfamic acid as energy efficient catalyst for synthesis of flurophores,
1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones
MANSING M MANE and DATTAPRASAD M PORE∗
Department of Chemistry, Shivaji University, Kolhapur 416 004, India
e-mail: p_dattaprasad@rediffmail.com
MS received 15 September 2015; revised 5 January 2016; accepted 7 January 2016
Abstract. An energy efficient synthesis of 1-H-spiro[isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones has
been expediently accomplished by a reaction of isatin(s) / cyclic ketone and anthranilamide in ethanol at
ambient temprature. Excellent yields of the products in short time duration, operational simplicity, and simple
work-up procedure are the attractive features of the present protocol. Synthesized 1-H-spiro[isoindoline-1,2ꢁ-
quinazoline]-3,4ꢁ(3ꢁH)-diones were found to be fluorescent with absorption in UV region (302, 362 nm) and
emission in visible region (413-436 nm) with Stokes shift of 44-72 nm.
Keywords. Cyclo-condensation; energy efficient synthesis; fluorescence spectroscopy; spiro compounds.
method for the synthesis of 1-H-spiro[isoindoline-1,2ꢁ-
quinazoline]-3,4ꢁ(3ꢁH)-diones is highly desirable.
Sulfamic acid (SA, H2NSO3H) is a solid inorganic
acid with mild acidity. The properties like nonvolatile,
noncorrosive, stable, low-cost, easy commercial avail-
ability, etc., have triggered their use as catalyst of choice
in number of organic transformations.38–41 In recent
years, we have reported SA as an effective catalyst for
the synthesis of 1,2,4-triazole-3-thiones, spiroindolo-
quinoxaline, and substituted-5-deazaoxaflavins.42–44 Our
earlier experience with SA and interest in the synthe-
sis of heterocycles, prompted us to explore SA for the
synthesis of 1-H-spiro[indoline-3,2ꢁ-quinazoline]-2,4-
(3-H)-diones. In the current work, we disclose an effi-
cient methodology for synthesis of 1-H-spiro [indoline-
3,2ꢁ-quinazoline]-2,4-(3-H)-diones by ring closure of
anthranilamide with a carbonyl derivative in the pres-
ence of catalytic amount of sulfamic acid in ethanol
media at room temperature (scheme 1).
1. Introduction
Environmental and economic concerns have recently
directed strong attention towards achieving synthesis
of useful pharmacophores under eco-benign conditions.
Quinazolinones have emerged as important structural
motifs due to their wide biological and pharmaceutical
activities, such as analgesic, anticancer, antifertility, anti-
bacterial, diuretic, and herbicide activities.1–7 On the
other hand, spiro-oxindole framework is found to be the
core structure in many pharmacological agents and nat-
ural alkaloids.8 In particular, 3-substituted indolin-2-one
derivatives have received extensive biological scrutiny.9–12
Recently, extensive and versatile pharmacological pro-
pertieshave been reported for some isatin-derived spiro-
2,3-dihydroquinazolinones13–15 (figure 1). In this context,
the synthesis of spiro[isoindoline-1,2ꢁ-quinazoline]-3,
4ꢁ(3ꢁH)-dione is of prime importance.
In contrast to the widely studied 2,3-dihydroquina-
zolinones,16–29 sporadic literature is available30–34
for the synthesis of 1-H-spiro[isoindoline-1,2ꢁ-
quinazoline]-3,4ꢁ(3ꢁH)-diones. They are generally synthe-
sized by multi-component reaction of isatoic anhydride,
amine and carbonyl compounds or two component cy-
clocondensation of anthranilamide with carbonyl com-
pounds. Amongst these two routes, scanty reports
are available for latter which involve reflux condi-
tion using organic asymmetric catalyst CPA,35 KAl
(SO4)2.12H2O (alum)36 and Amberlyst-15 under ultra-
sound irradiation.37 Therefore, an energy efficient
2. Experimental
2.1 Materials and characterization
Various substituted isatins and anthranilamide (Sigma-
Aldrich), sulfamic acid (Spectrochem) were used as
received. Melting points were recorded by open cap-
illary method and are uncorrected. NMR spectra were
recorded on Bruker AC-300/400 (300/400 MHz for 1H
NMR and 75/100 MHz for 13C NMR) spectrometer in
DMSO-d6 using TMS as an internal standard and δ
values are expressed in ppm. Mass spectra were
recorded on SHIMADZU LCMS 2020, UV - Visible
∗For correspondence
657

658
Mansing M Mane and Dattaprasad M Pore
absorption spectra were recorded on Specord 210 plus acids) and AlCl3 were employed for the model reaction
UV Visible-spectrometer and the emission spectrum and results are summarized in table 1. It is evident from
was recorded on a spectrofluorometer- Jasco, Model- table 1 that sulfamic acid is the best catalyst in terms of
F.P-8300 in DMSO solvent with concentration of 0.03 yield of desired product and time required for its forma-
mg/mL and path length 1 cm.
tion. Effect of amount of sulfamic acid was also studied
for model reaction and delightfully, we got the expected
product in excellent yield with 20 mol% of sulfamic
acid within 40 min (scheme 1).
2.2 General procedure for synthesis of 1-H-spiro
[isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones
As desired product gets precipitated from the reac-
tion mixture, isolation was done by simple filtration
after adding cold water. Confirmation of final prod-
uct was done by physical constant (M.P.) and spectral
techniques such as, 1H, 13C NMR, IR and mass spectra.
Comparison of efficiency of SA with that of earlier
reported catalysts for the present transformation is sum-
marized in table 2. The outcome displays outstand-
ing efficacy of SA in terms of time as well as yield.
A plausible mechanism of the reaction is proposed in
scheme 2. Initially, isatin (1) was activated by sulfamic
acid, then the carbonyl unit of the isatin (1ꢁ) undergo
nucleophilic attack by amine of anthranilamide (2) to
To a mixture of isatin(s)/acenaphthoquinone/cyclic ke-
tone(s) (1 mmol) and anthranilamide (1 mmol) in ethanol
(96%, 2 mL), sulfamic acid (0.2 mmol) was added. The
reaction mixture was stirred at ambient temperature for
the time mentioned in table 2 until completion of reac-
tion, as monitored by TLC. After the completion of
reaction, the precipitated products was just filtered. The
confirmation of isolated products was done by spec-
1
tral techniques such as H, 13C NMR, IR and mass
spectrometry.
3. Results and Discussion
Table 1. Optimization of the reaction conditions for syn-
thesis of 1-H-spiro [indoline-3,2ꢁ- quinazoline]-2,4-(3-H)-
diones.
In the initial stages of the present work, screening
of catalysts was carried out for cyclocondensation of
anthranilamide (1 mmol) and isatin (1 mmol) in ethanol
at room temperature to enable optimization of the reac-
tion conditions. Catalysts such as p-TSA, sulfamic
acid, L-proline, EPZ-10, EPZ-G(solid supported Lewis
Catalyst load
(mol%)
Time
Entry
Catalyst
Temp. min Yield %a
1
2
3
4
5
6
7
8
9
L-Proline
p-TSA
EPZ-10
EPZ-G
AlCl3
Sulfamic acid
Sulfamic acid
Sulfamic acid
Sulfamic acid
Sulfamic acid
20
20
20
20
20
20
05
10
15
30
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
60
60
80
80
60
40
50
50
40
40
65
70
43b
38b
62
92
53
60
83
92
R2
H
N
O
O
H
N
O
NH
O
N
NH
O
S
N
N
H
R
R1
10
*Reaction conditions: Isatin (1mmol), anthranilamide (1
mmol), Solvent = 2 mL, 96% ethanol; room temperature;
aIsolated yields; bAs the catalyst is insoluble in alcohol,
extraction of reaction mixture with ethyl acetate was carried
out for isolation of product.
antitumor agent
Potential inhibitor of SIRT1
Figure 1. Some biologically important spiro-2,3-dihydro-
quinoxalinones.
O
O
O
O
NH
SA , R.T.
NH2
O
EtOH
NH
N
+
R
N
NH2
H
H
3
1
2
R
Scheme 1. Efficient synthesis of 1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones.

Synthesis of 1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones
659
produce an imine intermediate 4, which subsequently (entry 9, table 3) were examined under optimized con-
undergoes intramolecular cyclization involving nucle- ditions. Excitingly, corresponding substituted 1-H-spiro
ophilic attack by –CONH2 moiety on –C=N– affording [indoline-3,2ꢁ-quinazoline]-2,4-(3-H)-diones were suc-
the desired product (3) (scheme 2).
cessfully and smoothly obtained, and the results are
Encouraged by the initial success in the synthesis of listed in table 3.
1-H-spiro[indoline-3,2ꢁ-quinazoline]-2,4-(3-H)-diones
Finally, the absorption and fluorescence spectra
and to investigate the general scope and versatility of of synthesized 1-H-spiro[isoindoline-1,2ꢁ-quinazoline]-
current strategy, different substituted isatins (entries 1-7, 3,4ꢁ(3ꢁH)-diones (SIIQ), 3a–j were recorded in DMSO
table 3), acenaphthylene-1,2-dione (entry 10, table 3), solvent (0.03 mg/mL and path length 1 cm) (figure 2).
cyclohexanone (entry 8, table 3) and cyclopentanone The calculated values of the absorption maxima (λmax),
Table 2. Efficiency of SA and comparison with earlier reported catalysts.
Entry
Catalyst
Catalyst load (mol%)
Solvent
Temp.
Time h Yield %a
Ref
1
2
3
KAl(SO4)2. 12H2O
CPA
20
10
20
EtOH
Ethylene dichloride
EtOH
Reflux
30◦C
RT
6
12
0.67
92
56
92
36
35
Sulfamic acid
This work
O
H2N
O
H2NOC
H2N
H2N-SO3H
+
HO
N
N
OH
H
H2N
O
-H2O
O
O
R
R
R
N
2
N
N
H
H
H
1'
4
Intramolecular
Nucleophilic
attack
H2N-SO3H
O
O
O
NH
O
N
R
NH
N
H
H
1
3
R
Scheme 2. Plausible mechanism for the synthesis of 1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones.
Table 3. Sulfamic acid catalyzed synthesis of a wide array of 1-H-spiro[isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones.
Entry
Product
Time min
Yield∗%a
O
O
NH
1
3a
3b
40
92
NH
N
H
O
O
NH
2
30
90
NH
N
H
Me
Me

660
Mansing M Mane and Dattaprasad M Pore
Table 3.
(continued)
Entry
Product
Time min
50
Yield∗%a
86
O
O
NH
3
4
5
6
7
3c
3d
3e
3f
NH
N
H
Br
O
O
NH
60
45
40
40
78
86
76
87
NH
N
H
F
O
O
NH
NH
N
H
Cl
O
O
NH
NH
N
H
Me
O
O
NH
3g
NH
N
H
MeO
O
NH
8
3h
3i
20
25
30
90
85
78
N
H
O
NH
9
N
H
O
O
NH
10
3j
N
H
*Reaction condition: Isatin(s) (1 mmol), anthranilamide (1 mmol), Sulfamic acid 20 mol %, Solvent -2 mL, 96 % ethanol;
room temperature; aIsolated yield.

Synthesis of 1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,4ꢁ(3ꢁH)-diones
661
of substituents have a negligible role in the absorp-
tion spectra, whereas in the emission spectra, con-
siderable Stokes shift was observed (72 nm) for 5-
methoxy substituent (3g). When isatin is replaced by
acenaphthaquinone (3j), intensity of emission spectrum
considerably decreased with Stokes shift of 67 nm,
which may be due to loss of conjugation, while in
the case of 3h, intensity of emission spectra increased
(about eight times) with less Stokes shift of 43 nm.
1
0.8
0.6
0.4
0.2
0
1 (3a)
2 (3b)
3 (3c)
4 (3d)
5 (3e)
6 (3f)
7 (3g)
8 (3h)
A
b
s
o
r
b
a
n
c
e
275
375
475
575
675
Wavelength nm
(a)
UV absorption spectra of 3a-j
4. Conclusions
10000
8000
6000
4000
2000
0
F
l
u
r
o
s
c
e
n
c
e
3a
3b
3c
3d
3e
3f
In conclusion, we have developed an energy efficient
sulfamic acid catalyzed method for the cycloconden-
sation of carbonyl compounds with anthranilamide
leading to 1-H-spiro [isoindoline-1,2ꢁ-quinazoline]-3,
4ꢁ(3ꢁH)-diones. The Synthesized compounds were
found to be flurophores with considerable Stokes shift
of 44-72 nm, even though there is negligible effect
of substituent in absorption and emission spectra. Fur-
ther detailed study will certainly explore the analytical
applications of such spiroquinazolinones. The method
possesses following advantages: (a) inexpensive sul-
famic acid as the catalyst; (b) environment friendly
ethanol as the solvent; (c) high reaction yields; (d) short
time duration; (e) ambient temperature; (f) water as the
only by-product; and (g) wide substrate scope.
A
.
U
.
3g
300
400
500
600
Wavelength nm
(b)
Fluorescence’s spectra of 3a-j
Figure 2. Absorption and emission spectra of SIIQ. (a) UV
absorption spectra of 3a-j and (b) Fluorescence spectra of
3a-j.
Table 4. Photophysical data of the synthesized com-
pounds, 3a-3j in DMSO as solvent.
Absorbance Fluorescence
Stokes
Shift
(ss) nm
Supplementary Information (SI)
Product
code
Maximum
Maximum
(λem) nm
Sr. No.
(λmax) nm
Experimental details, procedures and spectral data viz.,
1
IR, H, 13C NMR and Mass spectra of synthesized
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3j
302, 362
308, 362
304, 362
306,360
306, 362
308, 362
304, 364
346
425
424
422
421
422
421
436
413
348
63
62
60
61
60
59
72
67
44
compounds are provided as supplementary file. Sup-
plementary information is available at www.ias.ac.in/
chemsci.
Acknowledgements
304
Authors DMP and MMM are thankful to UGC, New
Delhi for financial assistance [F. No.42-394/2013
(SR)] and teacher fellowship under FDP [F.No-36-
50/11WRO 30/12/2012], respectively.
*Fluorescence spectra of the synthesized compounds moni-
tored at the excitation wavelength (λmax = 360-365 nm for
3a-3g; concentration = 0.03 mg/mL, path length = 1 cm).
emission maxima (λem), Stokes shift (ss) are listed in
table 4.
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