Sulfamic acid: A mild, efficient, and cost-effective catalyst for synthesis of indoloquinoxalines at ambient temperature

Article abstract of DOI:10.1080/00397911.2014.943345

A simple, cost-effective method for synthesis of indoloquinoxalines from isatin and o-phenylenediamine employing a catalytic amount of sulfamic acid at ambient temperature is reported. Moreover, the method is applicable for a variety of isatins, ninhydrin, 4-hydroxynaphthaquinone, and 1,2-diketones. The key features of the protocol include rapid reactions with good yields, simple workup procedure, and easy isolation of products.

Full text of DOI:10.1080/00397911.2014.943345

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Sulfamic Acid: A Mild, Efficient, and
Cost-Effective Catalyst for Synthesis
of Indoloquinoxalines at Ambient
Temperature
a
a
a
Pravin G. Hegade , Mansing M. Mane , Jayavant D. Patil
&
a
Dattaprasad M. Pore
a
Department of Chemistry , Shivaji University , Kolhapur , India
Accepted author version posted online: 08 Aug 2014.Published
online: 26 Sep 2014.
To cite this article: Pravin G. Hegade , Mansing M. Mane , Jayavant D. Patil & Dattaprasad
M. Pore (2014): Sulfamic Acid: A Mild, Efficient, and Cost-Effective Catalyst for Synthesis of
Indoloquinoxalines at Ambient Temperature, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.943345
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1
Synthetic Communications , 0: 1–8, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.943345
SULFAMIC ACID: A MILD, EFFICIENT, AND
COST-EFFECTIVE CATALYST FOR SYNTHESIS OF
INDOLOQUINOXALINES AT AMBIENT TEMPERATURE
Pravin G. Hegade, Mansing M. Mane, Jayavant D. Patil, and
Dattaprasad M. Pore
Department of Chemistry, Shivaji University, Kolhapur, India
GRAPHICAL ABSTRACT
Abstract A simple, cost-effective method for synthesis of indoloquinoxalines from isatin
and o-phenylenediamine employing a catalytic amount of sulfamic acid at ambient tempera-
ture is reported. Moreover, the method is applicable for a variety of isatins, ninhydrin,
4-hydroxynaphthaquinone, and 1,2-diketones. The key features of the protocol include rapid
reactions with good yields, simple workup procedure, and easy isolation of products.
Keywords Cost-effective; 1,2-diaminobenzene; indoloquinoxalines; isatins; sulfamic acid
INTRODUCTION
Heterocycles play an important role in the design and discovery of new
[
1]
compounds for pharmaceutical applications. Among the important classes of
bioactive heterocycles, quinoxalines have attracted the attention of synthetic organic
chemists as they are a frequently occurring framework in a number of biologically
[
2]
[3]
active natural products such as izumiphenazine C and echinomycin (Fig. 1),
[
4]
many pharmaceuticals, and agrochemicals. They have also found applications in
[
dyes, as efficient electroluminescent materials, as organic semiconductors, as
5]
[6]
[7]
[8]
[9]
dehydroannulenes, and in chemically controllable switches. Recent reviews on
the biological activities of indoles and quinoxalines highlight their medicinal impor-
10]
tance. Certainly the interest in their synthesis stems from their antibacterial, anti-
viral, anthelmintic, anti-inflammatory, kinase inhibitory, and anticancer activity;
for example, NCG555879-01 acts as BRCA1 inhibitor. Additionally, antibiotics such
as echinomycin and actinomycin have quinoxaline backbones.
[
[
11]
[
3a,12]
Received March 29, 2014.
Address correspondence to Dattaprasad M. Pore, Department of Chemistry, Shivaji University,
Kolhapur 416 004, India. E-mail: p_dattaprasad@rediffmail.com
1

2
P. G. HEGADE ET AL.
Figure 1. Biologically important quinoxalines.
[
13]
Hence, different synthetic methods have been reported,
and there is a
demand for development of ecofriendly methods for synthesis of quinoxalines.
Among various classes of quinoxalines, synthesis of indoloquinoxalines from isatins
[14]
possessing electron-withdrawing groups is a challenge because of the possibility of
0
0
formation of 3-(2 -amino-5 -substituted)-quinoxaline-2(1H)-ones via opening of the
isatin ring instead of classical 6H-indolo[2,3-b]quinoxalines. There are sporadic
reports available for synthesis of indoloquinoxalines employing catalytic amounts
[
13a]
[14]
of tetrabutylammonium bromide (TBAB)
and excess glacial acetic acid.
However, these methods are performed at elevated temperatures. Therefore, an
environmentally benign procedure for synthesis of indoloquinoxalines from o-pheny-
lenediamine and a variety of isatins at ambient temperature is highly desirable.
A commercially available sulfamic acid (NH SO H, SA) is a nonhygroscopic,
2
3
white crystalline Bronsted acid available at low cost with high stability and outstand-
[
15]
ing physical properties.
substitute for conventional acidic catalytic materials because of its ease of setup,
Recently, it has been shown that SA has potential as a
[
mild conditions, rapid reaction, selectivity, good yields, good purity of products,
16]
[17]
and low cost.
The most important feature of SA is its solubility in water, which
could facilitate easy separation and isolation of products just by filtration when
products are sparingly soluble or insoluble in organic solvents. The interesting
properties of SA spurred us to investigate its catalytic potential for the synthesis
of biorelevant heterocycles.
In continuation of our work in the development of efficient methodologies for
[
18]
[18h]
synthesis of heterocycles
sulfamic acid–catalyzed synthesis of indoloquinoxalines by reaction of isatin and
,2-diaminobenzene at ambient temperature (Scheme 1).
and our interest in sulfamic acid,
herein we report
1

EFFICIENT SYNTHESIS OF INDOLOQUINOXALINES
3
Scheme 1. Sulfamic acid–catalyzed synthesis of indoloquinoxalines at ambient temperature.
RESULTS AND DISCUSSION
In our initial endeavor to synthesize indoloquinoxalines, a reaction of isatin
and o-phenylene diamine was carried out in ethanol under catalyst-free conditions
at room temperature. However, the reaction did not lead to the formation of the
desired product (Table 1, entry 1). Even though heating conditions were employed,
the reaction did not proceed to completion even after a prolonged time (12 h)
(Table 1, entry 2). To explore suitable reaction conditions, the model reaction was
performed in the presence of various catalysts: p-TSA, sulfamic acid, envirocatalysts
EPZ-10 (clay-supported ZnCl ) and EPZ-G (clay-supported FeCl ), AlCl ,
2
3
3
ꢁ
ꢁ
ꢁ
ꢁ
Gly ꢀ NO3 , Gly ꢀ Cl , Gly ꢀ PF6 , and ½BMIMꢂBF4 . The results are summarized
in Table 1. Among the employed catalysts, sulfamic acid was found to be best cata-
lyst as corresponding indoloquinoxaline was obtained in comparatively good yields
in short times (Table 1, entry 11). The effect of catalyst loading was optimized by
carrying out reaction with 5, 10, 15, 20, and 30 mol% of the catalyst (Table 1, entries
11–15). The result revealed that 20 mol% of sulfamic acid is efficient to carry out
reaction to a synthetically useful degree.
With the optimal reaction conditions in hands, we extended the scope of
reaction by screening a variety of substrates (Table 2). The catalytic system is
Table 1. Optimization of reaction conditions
ꢃ
a
Entry
Catalyst
Catalyst load (mol%)
Temp. ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Catalyst-free
Catalyst-free
p-TSA
00
00
20
20
20
20
20
20
20
20
20
05
10
15
30
RT
Reflux
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
12
12
3
00
20
45
54
Glycine nitrate
EPZ-10
EPZ-G
3
b
3
43
b
3
38
AlCl
Glycine chloride
3
3
62
50
53
40
83
67
71
73
83
3
ꢁ
ꢁ
Glycine PF6
3
1
1
1
1
1
1
0
1
2
3
4
5
½BMIMꢂBF4
3
Sulfamic acid
Sulfamic acid
Sulfamic acid
Sulfamic acid
Sulfamic acid
1
3
3
2
1
Note. Reaction conditions: Isatin (1mmol), o-phenylene diamine (1 mmol), solvent ¼ 10 mL 95% ethanol.
a
Isolated yields.
b
As catalyst is insoluble in water, extraction of reaction mixture with ethyl acetate is carried out for
isolation of product.

4
P. G. HEGADE ET AL.
Table 2. Sulfamic acid–catalyzed synthesis of substituted quinoxalines at ambient temperature
a
Yield (%)
Entry
Product
Time (h)
1
1
83
2
3
4
1.5
95
85
91
2
1.5
5
6
1.5
94
90
1
7
8
1.5
84
86
1
9
1.5
87
(
Continued )

EFFICIENT SYNTHESIS OF INDOLOQUINOXALINES
5
Table 2. Continued
a
Yield (%)
Entry
Product
Time (h)
10
1.5
82
11
1.5
93
12
2
85
Notes.
Reaction
conditions:
Isatin=acenaphthoquinone=2-hydroxynaphthoquinone=ninhydrin
(
1 mmol), o-phenylene diamine (1 mmol), sulfamic acid (20 mol%), ethanol 10 mL; temp. ¼ RT.
a
Isolated yields.
suitable to structurally diverse isatins bearing both electron-deficient and electron-
donating substituents.
The electron-donating substituents on isatin enhanced the rate of reaction and
furnished corresponding products in good yields (Table 2, entries 2, 4, and 5) better
than the electron-withdrawing substituents (Table 2, entries 3 and 7). The note-
worthy feature of the procedure is that the presence of electron-withdrawing sub-
[
14]
stituent on isatin leads to indoloquinoxalines instead of classical quinoxalines.
It was interesting to note that the presence of methyl group at the fourth position
of 1,2-phenylenediamine (Table 2, entries 10, 11, and 12) resulted into two isomeric
products (approx. 60:40) depending on the course of cyclization. This observation
may be attributed to the electron-donating nature of methyl group, which may favor
the nucleophilic character of the 1,2-diamino moiety.
Encouraged by these results to explore the generality of the procedure, we
decided to carry out reactions with ninhydrine=2-hydroxynaphthoquinone=
acenaphthoquinone and o-phenylene diamine (Scheme 2). Interestingly, ninhydrine

6
P. G. HEGADE ET AL.
Scheme 2. Sulfamic acid–catalyzed synthesis of quinoxaline of ninhydrine=2-hydroxynaphthoquinone=
acenaphthoquinone at ambient temperature.
and acenaphthoquinone react smoothly with o-phenylene diamine to yield the
desired product in 90% and 86% yield respectively (Table 2, entries 6 and 8).
Fascinatingly, quinoxaline obtained from 2-hydroxynaphthaquinone also resulted
in good yield (Table 2, entry 9). Results summarized in Table 2 showcase the broad
scope of the method.
CONCLUSION
In summary, sulfamic acid was shown to be an efficient catalyst for the prep-
aration of structurally diverse quinoxalines. The reported protocol offers several
advantages over traditional methods, making it an important contribution under
the umbrella of efficient methodologies for quinoxaline synthesis.
EXPERIMENTAL
1
IR spectra were recorded on an Agilent Cary (IR-630) spectrophotometer. H
1
3
and C NMR spectra were recorded on a Bruker AC (300 MHz and 75 MHz) spec-
trometer in dimethylsulfoxide (DMSO-d ) using tetramethylsilane (TMS) as an
6
internal standard. Mass spectra were recorded on a Shimadzu QP2010 GCMS.
Typical Procedure
A solution of isatin (1 mmol) and o-phenylene diamine (1 mmol) in ethanol
95%, 10 mL) and sulfamic acid (20 mol%) was stirred at ambient temperature for
(
the time mentioned in Table 2, monitored by TLC. After completion of reaction,
product was isolated by filtration and washed it with ethanol, dried to furnish the
desired products in good yields.

EFFICIENT SYNTHESIS OF INDOLOQUINOXALINES
7
FUNDING
D. M. P. is thankful to the University Grant Commision, New Delhi, for finan-
cial assistance [F. No. 42-394=2013 (SR)].
SUPPORTING INFORMATION
1
13
Full experimental details with IR spectra, H and C NMR, and MS spectra
for this article can be accessed on the publisher’s website.
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