An eco-friendly Pictet-Spengler approach to pyrrolo- and indolo[1,2-a]quinoxalines using p-dodecylbenzenesulfonic acid as an efficient Br?nsted acid catalyst

Article abstract of DOI:10.1039/c4ra16651e

A facile and environmentally benign Pictet-Spengler strategy for the synthesis of a series of biologically important pyrrolo- and indolo[1,2-a]quinoxalines has been developed by reacting 1-(2-aminophenyl)-pyrrole or 1-(2-aminophenyl)indoles with a wide range of aromatic aldehydes, acetophenones or isatins in ethanol at ambient temperature using p-dodecylbenzenesulfonic acid (p-DBSA) as an efficient Br?nsted acid-surfactant combined catalyst. This methodology was found to be applicable to generate diverse quinoxaline derivatives in fairly good yields under mild reaction conditions.

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ARTICLE TYPE
An eco-friendly Pictet-Spengler approach to pyrrolo- and indolo[1,2-
a]quinoxalines using p-dodecylbenzenesulfonic acid as an efficient
Brønsted acid catalyst
Amreeta Preetam and Mahendra Nath*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A facile and environmentally benign PictetꢀSpengler strategy for the synthesis of a series of biologically
important pyrroloꢀ and indolo[1,2ꢀa]quinoxalines has been developed by reacting 1ꢀ(2ꢀaminophenyl)ꢀ
pyrrole or 1ꢀ(2ꢀaminophenyl)indoles with a wide range of aromatic aldehydes, acetophenones or isatins in
10 ethanol at ambient temperature using pꢀdodecylbenzenesulfonic acid (pꢀDBSA) as an efficient Brønsted
acid surfactant combined catalyst. This methodology was found to be applicable to generate diverse
quinoxaline derivatives in fairly good yields under mild reaction conditions.
subsequently on oxidation affords pyrrolo[1,2ꢀa]quinoxalines.
Although these reported synthetic strategies are effective, still
they suffer from a number of demerits such as long reaction
times, harsh reaction conditions and use of hazardous organic
50 solvents. Therefore, a search for an efficient, economical,
environment friendly and versatile methodology for the synthesis
of diverse pyrroloꢀ and indolo[1,2ꢀa]quinoxaline scaffolds is
highly desired.
Over the years, the surfactant combined catalysts have been
55 employed as substitute for the toxic catalysts in various
environmentally benign protocols.18 Among these, pꢀ
dodecylbenzenesulfonic acid (pꢀDBSA) has emerged as a cheap,
commercially available, nonꢀhygroscopic, nonꢀvolatile, airꢀstable
and efficient Brønsted acid surfactant combined catalyst for
60 carrying out a variety of useful organic transformations.19 This
intrinsic catalytic efficiency of pꢀDBSA prompted us to
investigate its further ability to catalyze PictetꢀSpengler reaction
for the construction of various pyrrolo[1,2ꢀa]quinoxaline
analogues.
Introduction
Practising the green chemistry concepts for the development of
15 efficient, safe and sustainable synthetic procedures have been
significantly recognised globally in recent years.1 The use of
hazardous solvents and reagents in chemical manufacture is one
of the major factors that contribute towards environmental
pollution. Therefore, a significant attention has been focused for
20 the search of environmentally benign alternatives to these toxic
solvents and consequently, designing of greener methodology for
the construction of various structurally diverse molecules in oneꢀ
pot operation.2
Quinoxaline derivatives are an important class of biologically
25 active nitrogen heterocycles which exhibit a wide range of
pharmacological
profiles.3
In
particular,
pyrrolo[1,2ꢀ
a]quinoxalines substituted at Cꢀ4 position have shown diverse
biological activities such as antiꢀcancer,4 antiꢀmalarial,5 and antiꢀ
proliferative6 activities. Furthermore, these molecules are
30 reported as inhibitors of human protein kinase CK2,7 glucagon
receptor antagonist8 and 5HT3 receptor agonist.9 In addition,
these compounds were also found to be applicable in the
synthesis of GABA benzodiazepine receptor agonist or
antagonist.10 Similarly, indolo[1,2ꢀa]quinoxaline analogues have
35 demonstrated interesting antiꢀfungal activities.11 Due to a wide
range of applications, significant number of synthetic protocols12
have been devised in the past for the preparation of various 4,5ꢀ
65
In the course of our interest to develop ecoꢀfriendly synthetic
methodologies for useful organic transformations,20 we wish to
report herein a convenient and greener practical protocol for the
synthesis of a series of various 4ꢀarylpyrrolo[1,2ꢀa]quinoxalines,
6ꢀarylindolo[1,2ꢀa]quinoxalines,
70 dihydropyrrolo[1,2ꢀa]quinoxalines,
4ꢀarylꢀ4ꢀmethylꢀ4,5ꢀ
5'Hꢀspiro[indolineꢀ3,4'ꢀ
pyrrolo[1,2ꢀa]quinoxalin]ꢀ2ꢀones and 5'Hꢀspiro[indolineꢀ3,6'ꢀ
indolo[1,2ꢀa]quinoxalin]ꢀ2ꢀone derivatives through Pictetꢀ
Spengler condensation cyclization reaction of 1ꢀ(2ꢀ
aminophenyl)pyrrole or 1ꢀ(2ꢀaminophenyl)indoles with aromatic
75 aldehydes, acetophenones or isatins in ethanol using pꢀDBSA as
an efficient Brønsted acid surfactant combined catalyst under
mild reaction conditions. The results are summarized in Tables 1,
2, 3 and 4.
dihydropyrrolo[1,2ꢀa]quinoxalines,13
pyrrolo[1,2ꢀ
a]quinoxalines,14 indolo[1,2ꢀa]quinoxalines15 and their spiro
40 derivatives.16 Among these, PictetꢀSpengler reaction is the most
extensively used approach for the construction of pyrrolo[1,2ꢀ
a]quinoxaline heterocycles.17 According to this protocol, the
reaction proceeds with the initial formation of Schiff’s base
intermediate after the elimination of a water molecule followed
45 by intramolecular cyclization to give dihydro derivative, which
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pꢀDBSA in the synthesis of 4ꢀ phenylpyrrolo[1,2ꢀa]quinoxaline
(3a). Therefore, the 10 mol % pꢀDBSA was selected as an
optimum catalyst load for performing further reactions.
We next examined the effect of other solvents on the rate of
reaction and the results are summarized in tableꢀ1. Best results
obtained when the reaction was carried out in ethanol as solvent
medium (Table 1, entries 1, 2, 4 and 5) while the reaction
proceeded sluggishly in the solvents such as THF, tBuOH,
35 CH3CN, PPG and provided the product 3a in poor to moderate
yields (Table 1, entries 7-10). In addition, when the reaction was
performed in water as a solvent, lower yield (45%) of the product
3a was obtained possibly due to heterogeneous mixture of the
reacting substrates (Table 1, entry 11). To improve the solubility
40 of reacting substrates, a reaction was also carried out in 50%
ethanol in water but the yield of desired product did not increase
significantly (Table 1, entry 12). Furthermore, the formation of
product 3a was also found to be sluggish under solvent free
conditions and only 35% isolated yield was observed (Table 1,
45 entry 13). Based on these observations, ethanol was chosen as a
best solvent to carry out this organic transformation.
Results and discussion
For a facile and ecoꢀfriendly access of a series of pyrroloꢀ and
indolo[1,2ꢀa]quinoxaline scaffolds, initially
performed at room temperature by
a
reaction was
using 1ꢀ(2ꢀ
30
5
aminophenyl)pyrrole and benzaldehyde as model substrates in the
presence of a catalytic amount of DBSA in ethanol for 2 hours
followed by the oxidation in the presence of 1 equivalent of
KMnO4 and the desired product 3a was obtained as white solid in
89% yield (Table 1, entry 1). It is interesting to note that the yield
10 of the product 3a was found to be same even after decreasing the
reaction time from 2 hours to 30 min (Table 1, entry 2). However,
the yield of the reaction was significantly affected by varying the
catalyst load. A significant decrease in the yield of compound 3a
was observed on decreasing the catalyst load from 10 mol % to 5
15 mol % (Table 1, entry 3) whereas, by increasing the amount of pꢀ
DBSA up to 20 mol % did not improve the yield of desired
product significantly (Table 1, entries 1, 4 and 5).
Table 1: Optimization of the reaction conditions for the synthesis of
4-phenylpyrrolo[1,2-a]quinoxaline (3a)a
The catalytic efficiency of pꢀDBSA was also compared with
other acidic catalyst such as PTSA, acetic acid and TFA and it
was observed that the pꢀDBSA is the best suited catalyst for this
50 reaction (Table 1, entries 14ꢀ16). It is noteworthy to mention that
the reaction in the absence of KMnO4 at 25 °C has afforded only
an intermediate, 4,5ꢀdihydroꢀ4ꢀphenylpyrrolo[1,2ꢀa]quinoxaline
in 90% yield. Hence, the optimal conditions for a model reaction
were found to be 10 mol % pꢀDBSA in ethanol followed by the
55 oxidation in the presence of 1 equivalent of KMnO4 at 25 °C
temperature.
Under the optimized conditions, the scope and generality of
this protocol were investigated by treating 1ꢀ(2ꢀ
aminophenyl)pyrrole or 1ꢀ(2ꢀaminophenyl)indoles with a variety
60 of aromatic and heteroaromatic aldehydes at ambient temperature
in ethanol containing 10 mol % pꢀDBSA followed by oxidation in
the presence of 1 equivalent of KMnO4 to afford a series of
pyrroloꢀ and indolo[1,2ꢀa]quinoxaline derivatives (3a-o) in
moderate to good yields (Table 2). In general, the reaction of
65 aromatic aldehydes bearing both electronꢀwithdrawing and
electronꢀdonating substituents on aromatic ring proceeded well
with 1ꢀ(2ꢀaminophenyl)pyrrole and afforded the corresponding
products (3a-f, 3k and 3l) in good to excellent yields (Table 2,
entries 1-6 and 11-12). In contrast, the reaction with heterocyclic
70 aldehydes provided relatively lower yields of the products (3g-j)
(Table 2, entries 7-10). On the other hand, the reaction of 1ꢀ(2ꢀ
aminophenyl)indoles and aromatic aldehydes is found to be
sluggish and provided the corresponding 6ꢀarylindolo[1,2ꢀ
a]quinoxaline products (3m-o) in moderate yields due to the less
75 nucleophilicity of the indole substituted anilines as compared to
the 1ꢀ(2ꢀaminophenyl)pyrrole 21(Table 2, entries 13-15).
CHO
(a) Catalyst, Solvent, 25 °
C
NH2
N
+
N
N
(b) KMnO4, 25 °
C
3a
1a
2a
Entry Catalyst (mol %)
Solvent
Time
(h)b
Yield (%)c
3a
89
1.
2.
pꢀDBSA (10)
pꢀDBSA (10)
pꢀDBSA (5)
pꢀDBSA (15)
pꢀDBSA (20)
pꢀDBSA (0)
pꢀDBSA (10)
pꢀDBSA (10)
pꢀDBSA (10)
pꢀDBSA (10)
pꢀDBSA (10)
pꢀDBSA (10)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
2.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
89
38
3.
4.
90
5.
92
6.
Trace
53
7.
8.
CH3CN
tBuOH
PPG
38
9.
38
10.
11.
12.
33
H2O
45
EtOH:H2O
(1:1)
65
13.
14.
15.
16.
pꢀDBSA (10)
PTSA (10)
ꢀ
0.5
0.5
0.5
0.5
35
68
63
74
EtOH
EtOH
EtOH
CH3COOH (10)
TFA (10)
After chromatographic purification, the isolated products (3a-
o) were fully characterized on the basis of detailed spectral
20 aReagents and conditions: (a) 1ꢀ(2ꢀaminophenyl)pyrrole 1a (1.0 mmol),
benzaldehyde 2a (1.2 mmol), solvent (2.0 ml), 25 °C; (b) KMnO4 (1.0
mmol), 15 min. bTotal reaction time including KMnO4 treatment.
cIsolated yields after column chromatography.
1
analysis including IR, H NMR, 13C NMR and high resolution
80 mass. IR spectrum of compound 3a showed a characteristic
absorption peak at 1599 cmꢀ1 due to the stretching of C=N bond.
In 1H NMR spectrum of compound 3a, one of three pyrrolic
protons was appeared as a multiplet between δ 7.79ꢀ8.06 ppm
along with three phenyl protons where as other two pyrrolic
In contrast, the reaction performed in the absence of catalyst
25 under identical conditions afforded only a trace amount of desired
product 3a (Table 1, entry 6), demonstrating the catalytic role of
2
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protons were found as a doublet at δ 7.00 ppm (J = 4.39 Hz) and
a multiplet between δ 6.88ꢀ6.90 ppm for one proton each,
due to the carbons of the pyrrolic moiety where as a peak at 154.4
ppm corresponds to the imine carbon of quinoxaline ring. The
respectively. Besides these, two sets of the remaining phenyl 10 structure of the compound 3a was further supported by the mass
protons were also observed as a doublet for one proton at δ 7.86
ppm (J = 8.05 Hz) and a multiplet for 5 protons between δ 7.44ꢀ
7.57 ppm, respectively. Additionally, the 13C NMR spectrum
showed the characteristic peaks at 108.7, 114.0 and 114.6 ppm
spectral analysis which showed a [M+H]+ ion peak at m/z
245.1067 for the molecular formula C17H13N2.
5
Table 2: Synthesis of 4-arylpyrrolo[1,2-a]quinoxalines (3a-l), 6-arylindolo[1,2-a]quinoxalines (3m-n), 7-methyl-6-(pyridin-4-yl)indolo[1,2-
15
a]quinoxaline (3o).a
NH2
N
(a) p-DBSA, EtOH , 15 min, 25 °C
N
+
RCHO
2a-m
N
(b) KMnO4, 15 min, 25 °
C
R
R1
R1
3a-o
1a-c
S. No.
1.
Amines
Aldehydes
Products
Yields (%)b
89
2.
90
3.
4.
88
88
5.
6.
75
75
7.
8.
40
62
N
9.
77
80
NH2
10.
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11.
12.
75
82
52
3m
N
N
13.
F
N
N
3n
14.
15.
40
52
aReagents and conditions: (a) Amines 1a-c (1.0 mmol), aldehydes 2a-m (1.2 mmol), pꢀDBSA (0.10 mmol), EtOH (2.0 ml); (b) KMnO4 (1.0 mmol),
bIsolated yields after column chromatography.
Furthermore, the optimized methodology was extended to
Table 3: Synthesis of 4-methyl-4-aryl-4,5-dihydropyrrolo[1,2-
a]quinoxalines (5a-d)a
5
construct
various
4ꢀmethylꢀ4ꢀarylꢀ4,5ꢀdihydropyrrolo[1,2ꢀ
a]quinoxalines in oneꢀpot by reacting 1ꢀ(2ꢀaminophenyl)pyrrole
(1a) with aromatic ketones in 1:1.2 ratio in ethanol at room
temperature using 10 mol % pꢀDBSA (Table 3).
O
NH
NH2
p
-DBSA
N
N
+
To our delight, the desired products (5a-d) were obtained with
EtOH , 30 min, 25
C
R
R
10 good yields of 82ꢀ86% within 30 minutes. As expected, the
reaction proceeded with slightly slow rate in the case of less
reactive aromatic ketones as compared to the aryl aldehydes and
the desired products were obtained in a relatively longer reaction
time. On studying the effect of substituents present in
15 acetophenones on the rate of reaction, it has been observed that
the aromatic ketones having halogen atom at para position affords
the lower yields of the products with decreasing their
electronegativity (Table 3, entry 2 and 3). The best results were
obtained when the reaction of 1a was carried out with 4ꢀ
20 phenylacetophenone possibly due to the extended conjugation of
the additional phenyl ring (Table 3, entry 4). The structures of
compounds (5a-d) were established on the basis of their spectral
data. In the IR spectrum of compound 5a, a characteristic
absorption peak due to NH stretching was appeared at 3367 cmꢀ1.
5a-d
4a-d
1a
S.
No.
Yields
(%)b
Ketones
Products
1.
2.
82
83
1
3.
4.
82
86
25 The H NMR of the product 5a showed a characteristic broad
singlet at δ 4.39 ppm due to NH proton and a singlet at δ 1.90
ppm due to three methyl protons. The three pyrrolic protons
appeared separately as a double doublet at δ 6.05 ppm (J1 = 3.66
Hz and J2 = 1.83 Hz), a triplet at δ 6.33 ppm (J = 3.05 Hz) and a
30 multiplet between δ 7.14ꢀ7.18 ppm, respectively. In the 13C NMR
spectrum, peaks at δ 29.2 and 56.8 ppm were assigned to the
methyl carbon and quaternary carbon of the dihydroquinoxaline
ring, respectively. The high resolution ESIꢀmass spectral analysis
NH
5d
N
aReagents and conditions: Amine 1a (1.0 mmol), ketones 4a-d (1.2
further confirmed the formation of compound 5a by showing the 40 mmol), pꢀDBSA (0.10 mmol), EtOH (2.0 ml), bIsolated yields of products
35 [M+H]+ ion peak at m/z 261.1386 for the molecular formula
(5a-d) after column chromatography.
C18H17N2.
4
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After successful synthesis of
a]quinoxaline and dihydropyrrolo[1,2ꢀa]quinoxaline derivatives
in good yields, we turned our attention towards the synthesis of
a
series of pyrrolo[1,2ꢀ
compound 7a showed characteristic absorption bands at 3313,
3239 and 1721 cmꢀ1 due to stretching of NH and C=O groups,
1
respectively. The H NMR of compound 7a showed two singlets
spiro[indolineꢀ3,4'ꢀpyrrolo[1,2ꢀa]quinoxalin]ꢀ2ꢀone
derivatives
at δ 8.32 and 4.30 ppm due to the presence of NH protons. Two
5
(7a-j) by reacting isatin derivatives either with 1ꢀ(2ꢀ 20 multiplets between δ 7.21ꢀ7.50 ppm and δ 5.60ꢀ5.61 ppm
aminophenyl)pyrrole
or
2ꢀ(1Hꢀindolꢀ1ꢀyl)anilines
under
appeared due to two pyrrolic protons whereas the remaining one
pyrrolic proton appeared as a triplet at δ 6.24 ppm (J = 3.05 Hz).
In addition, the 13C NMR spectrum of 7a showed a characteristic
peak at δ 61.1 ppm which corresponds to quaternary spiroꢀcarbon
optimized reaction conditions. We are delighted to report that the
present ecoꢀfriendly PictetꢀSpengler protocol has also been
successfully extended to prepare a series of spiro derivatives in
10 good to excellent yields (Table 4). As shown in the table 4, this 25 of dihydroquinoxaline ring. High resolution mass data of
reaction proceeded satisfactorily with
a
variety of isatins
compound 7a also supported the assigned structure by showing
[M+H]+ ion peak at m/z 288.1131. Furthermore, the structure of
compound (7d) was finally confirmed by single crystal Xꢀray
analysis (Fig. 1).22
containing both, electron donating as well as electron
withdrawing substituents and provided the target products in
good to excellent yields (79ꢀ87%). The isolated desired products
15 (7a-j) were characterized spectroscopically. IR spectrum of
30
Table 4: Synthesis of 5'H-spiro[indoline-3,4'-pyrrolo[1,2-a]quinoxalin]-2-ones (7a-d), 5'H-spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-ones (7e-
h) and 7'-methyl-5'H-spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-ones (7i-j).a
R
O
NH
NH2
R
p-DBSA, EtOH, 25 °C
N
N
O
+
30 min
N
N
R2
O
R2
R1
R1
1a-c
6a-d
7a-j
S. No.
1.
Amines
Isatins
Products
Yields (%)b
83
2.
3.
4.
84
80
80
5.
6.
82
79
N
O
N
N
7f
H
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7.
8.
80
N
NH2
83
N
NH2
N
O
9.
87
79
7i
NH
N
H
Cl
N
O
N
10.
N
7j
H
aReagents and conditions: Amines 1a-c (1.0 mmol), isatins 6a-d (1.2 mmol), pꢀDBSA (0.10 mmol), EtOH (2.0 ml), b Isolated yields after column
chromatography.
5
The possible mechanistic pathway for the synthesis of pyrroloꢀ
and indolo[1,2ꢀa]quinoxalines is shown in Fig. 2. Probably, the
reaction proceeds via the protonation of the corresponding
carbonyl compounds (aldehydes/ketones/diketones) in the
presence of pꢀDBSA as an Brønsted acid catalyst followed by a
10 nucleophilic attack of pyrrole or indole substituted anilines to
generate an electron deficient iminium ion (III or VII) which
undergoes intramolecular cyclization and deprotonation to afford
desired products 5a-d and 7a-j in good to moderate yields where
as in the case of aldehydes, the reaction initially provided a
15 dihydroꢀpyrroloꢀor indolo[1,2ꢀa]quinoxaline intermediate which
on oxidation in the presence of KMnO4 afforded the desired
products (3a-o) in 40ꢀ90% yields
Fig 1: Xꢀray crystal structure of compound 7d.
20
Fig. 2: Plausible reaction mechanism for the synthesis of pyrroloꢀ and indolo[1,2ꢀa]quinoxalines
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1
1598, 1348, 1096, 852, 751, 727 cmꢀ1; H NMR (400 MHz,
CDCl3): δ (ppm) 8.41 (d, J = 8.79 Hz, 2H, ArH), 8.20 (d, J = 8.79
Hz, 2H, ArH), 8.04ꢀ8.08 (m, 2H, pyrrolic H and ArH), 7.93 (d, J
60 = 8.05 Hz, 1H, ArH), 7.57ꢀ7.61 (m, 1H, ArH), 7.49ꢀ7.53 (m, 1H,
ArH), 6.95ꢀ6.97 (m, 2H, pyrrolic H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 151.8, 148.5, 144.4, 135.8, 130.4, 129.6, 128.3,
127.1, 125.6, 124.7, 123.7, 115.1, 114.4, 113.7, 108.2; HRMS
(ESI, m/z) calcd for C17H12N3O2: 290.0924 [M+H]+, found:
65 290.0924.
Conclusions
In summary, we have developed an energy efficient, facile,
environmentally friendly practical methodology for easy access
5
of
various pyrrolo[1,2ꢀa]quinoxaline, dihydropyrrolo[1,2ꢀ
a]quinoxaline and spiro[indolineꢀ3,4'ꢀpyrrolo[1,2ꢀa]quinoxalin]ꢀ
2ꢀone derivatives via PictetꢀSpengler reaction using pꢀDBSA as
an efficient Brønsted acid catalyst in ethanol at room temperature.
The present synthetic protocol demonstrates many key
10 advantages such as mild reaction conditions, short reaction times,
good to excellent yields of the products and the use of nonꢀ
hazardous solvent medium for the synthesis of these biologically
active nitrogen heterocycles.
4-(Pyridin-4-yl)pyrrolo[1,2-a]quinoxaline (3c). Brown solid,
yield: 136 mg (88%); mp 179ꢀ180 °C; IR (CHCl3) νmax: 2928,
1598, 1407, 1376, 1250, 1039, 824, 753, 729 cmꢀ1; 1H NMR (400
70 MHz, CDCl3): δ (ppm) 8.82ꢀ8.83 (m, 2H, pyridyl H), 8.04ꢀ8.06
(m, 2H, pyridyl H), 7.90ꢀ7.93 (m, 3H, pyrrolic H and ArH), 7.58
(t, J = 7.32 Hz, 1H, ArH), 7.50 (t, J = 7.32 Hz, 1H, ArH), 6.93ꢀ
7.00 (m, 2H, pyrrolic H); 13C NMR (100 MHz, CDCl3): δ (ppm)
151.3, 149.7, 146.0, 135.7, 130.3, 128.3, 127.1, 125.4, 124.5,
75 123.0, 115.0, 114.3, 113.6, 108.1; HRMS (ESI, m/z) calcd for
C16H12N3: 246.1026 [M+H]+, found: 246.1033.
Experimental
15 General: All the chemicals were purchased from SigmaꢀAldrich
and used without further purification. The progress of the reaction
was monitored by thin layer chromatography (TLC) using silica
gel 60 F254 (pre coated aluminium sheets) from Merck. TLC spots
were visualised by UVꢀlight followed by iodine. NMR spectra
20 were obtained in CDCl3 or DMSOꢀd6 on Jeol ECX 400 MHz
NMR spectrometer by using TMS as an internal standard and
chemical shifts are expressed in parts per million (ppm) and
coupling constants (J) are reported in Hertz (Hz). Infrared spectra
were recorded on Perkin Elmer IR spectrometer and absorption
25 maxima (νmax) are given in cmꢀ1. The melting points were
determined in open capillary tubes on Buchi Mꢀ560 melting point
apparatus and are uncorrected. Mass spectra (ESIꢀHRMS) were
recorded on 6530 QTOF LCMS and microTOFꢀQ ll 10262 mass
spectrometer. 2ꢀ(1Hꢀindolꢀ1ꢀyl)aniline and 2ꢀ(3ꢀmethylindolꢀ1ꢀ
30 yl)phenylamine (1b and 1c) were synthesized according to the
literature procedure.23
General procedure for the synthesis of 4-arylpyrrolo[1,2-
a]quinoxalines (3a-l), 6-arylindolo[1,2-a]quinoxalines (3m-n),
7-methyl-6-(pyridin-4-yl)indolo[1,2-a]quinoxaline (3o):
To a well stirred solution of pꢀDBSA (0.1 mmol) in ethanol (2
mL), aromatic aldehyde (1.2 mmol) was added followed by the
addition of 1ꢀ(2ꢀaminophenyl)pyrrole or 2ꢀ(1Hꢀindolꢀ1ꢀyl)aniline
or 2ꢀ(3ꢀmethylindolꢀ1ꢀyl)phenylamine (100 mg, 1.0 mmol). The
reaction mixture was stirred at 25 °C for 15 minutes. After
2-(Pyridin-2-yl)pyrrolo[1,2-a]quinoxaline (3d). Green solid,
yield: 136 mg (88%); mp 106ꢀ108 °C; IR (CHCl3) νmax: 3061,
80 2925, 1583, 1531, 1475, 1441, 1367, 1096, 1037, 812, 756, 743
cmꢀ1; H NMR (400 MHz, CDCl3): δ (ppm) 8.81ꢀ8.82 (m, 1H,
1
pyridyl H), 8.41 (d, J = 8.05 Hz, 1H, pyridyl H), 8.06 (d, J = 8.05
Hz, 1H, pyridyl H), 8.01 (s, 1H, pyridyl H), 7.90 (d, J = 8.05 Hz,
2H, ArH), 7.73 (d, J = 3.66 Hz, 1H, pyrrolic H), 7.40ꢀ7.56 (m,
85 3H, pyrrolic H and ArH), 6.95ꢀ6.97 (m, 1H, pyrrolic H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 156.3, 151.1, 148.8, 136.6,
135.6, 130.2, 127.9, 127.5, 125.0, 124.5, 124.2, 123.3, 114.39,
114.31, 113.6, 110.5; HRMS (ESI, m/z) calcd for C16H12N3:
246.1025 [M+H]+, found: 246.1026.
90
4-(9H-Fluoren-3-yl)pyrrolo[1,2-a]quinoxaline
brown solid, yield: 157 mg (75%); mp 170ꢀ172 °C; IR (CHCl3)
max: 3067, 2925, 1613, 1519, 1477, 1367, 1320, 1216, 1098, 837,
(3e).
Light
35
ν
797, 753, 718 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.20 (s,
95 1H, ArH), 8.04ꢀ8.08 (m, 2H, ArH), 8.00ꢀ8.01 (m, 1H, pyrrolic
H), 7.94 (d, J = 8.05 Hz, 1H, ArH), 7.86ꢀ7.90 (m, 2H, ArH), 7.60
(d, J = 7.32 Hz, 1H, ArH), 7.47ꢀ7.54 (m, 2H, ArH), 7.43 (t, J =
7.32 Hz, 1H, ArH), 7.36 (t, J = 7.32 Hz, 1H, ArH), 7.06ꢀ7.07 (m,
1H, pyrrolic H), 6.90ꢀ6.92 (m, 1H, pyrrolic H), 4.02 (s, 2H, CH2);
100 13C NMR (100 MHz, CDCl3): δ (ppm) 154.4, 143.8, 143.5, 143.2,
141.0, 136.8, 136.2, 130.0, 127.4, 127.2, 127.1, 127.0, 126.7,
125.3, 125.1, 125.0, 120.2, 119.7, 114.5, 113.8, 113.5, 108.7,
36.9; HRMS (ESI, m/z) calcd for C24H17N2: 333.1386 [M+H]+,
found: 333.1387.
40 complete consumption of the starting materials as evident by
TLC, the mixture was treated with KMnO4 (1.0 mmol) and stirred
for additional 15 min at 25 °C. The excess of solvent was then
evaporated and the residue thus obtained was treated with
saturated NaHCO3 solution (20 mL). The product was then
45 extracted with ethyl acetate (10 mL × 3 times). The organic layers
were combined, washed with water (20 mL × 3 times) and brine
solution (20 mL). Finally, the organic layer was dried over
anhydrous sodium sulfate and evaporated under reduced pressure
to dryness. The crude product was purified by column
50 chromatography over silica gel (60ꢀ120 mesh size) using 5ꢀ20%
ethyl acetate in heptane as an eluent to furnish the desired
products (3a-o) in good yields. The characterization data of
known compounds (3a and 3n) were found in good agreement
105 4-(Pyren-2-yl)pyrrolo[1,2-a]quinoxaline (3f). Light brown
solid, yield: 174 mg (75%); mp 218ꢀ220 °C; IR (CHCl3) νmax
:
3041, 1596, 1474, 1418, 1374, 1093, 1036, 847, 754, 716 cmꢀ1;
1H NMR (400 MHz, CDCl3): δ (ppm) 8.31 (s, 2H, ArH), 8.23ꢀ
8.27 (m, 2H, ArH), 8.14ꢀ8.19 (m, 4H, ArH), 7.97ꢀ8.06 (m, 4H,
110 pyrrolic H and ArH), 7.51ꢀ7.63 (m, 2H, ArH), 6.83ꢀ6.85 (m, 1H,
pyrrolic H), 6.54ꢀ6.55 (m, 1H, pyrrolic H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 155.0, 136.2, 132.5, 131.9, 131.2, 130.8, 130.3,
129.3, 128.1, 127.8, 127.7, 127.3, 127.1, 126.8, 126.0, 125.4,
with the reported data 24,25
55 4-(4-Nitrophenyl)pyrrolo[1,2-a]quinoxaline(3b). Yellow solid,
yield: 163 mg (90%); mp 221ꢀ223 °C; IR (CHCl3) νmax: 2927,
.
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125.38, 125.32, 125.0, 124.6, 124.5, 114.5, 114.1, 113.7, 109.2;
2H, ArH), 7.05ꢀ7.07 (m, 2H, ArH), 7.00ꢀ7.01 (m, 1H, pyrrolic
HRMS (ESI, m/z) calcd for C27H17N2: 369.1386 [M+H]+, found: 60 H), 6.88ꢀ6.90 (m, 1H, pyrrolic H), 3.90 (s, 3H, OCH3); 13C NMR
369.1387.
(100 MHz, CDCl3): δ (ppm) 160.9, 153.8, 136.2, 130.9, 130.0,
129.9, 127.1, 126.9, 125.2, 125.1, 114.4, 113.89, 113.83, 113.5,
108.5, 55.3; HRMS (ESI, m/z) calcd for C18H15N2O: 275.1179
[M+H]+, found: 275.1179.
5
4-(1H-Indol-3-yl)pyrrolo[1,2-a]quinoxaline (3g). Light brown
solid, yield: 72 mg (40%); mp 118ꢀ120 °C; IR (CHCl3) νmax
:
3412, 2923, 1644, 1447, 1337, 1239, 1025, 998, 751 cmꢀ1; H
NMR (400 MHz, CDCl3 + DMSOꢀd6): δ(ppm) 10.80 (s, 1H, NH),
7.94ꢀ7.95 (m, 1H, pyrrolic H), 7.48ꢀ7.50 (m, 2H, ArH), 7.30ꢀ7.37
65
1
4-(4-(Trifluoromethyl)phenyl)pyrrolo[1,2-a]quinoxaline (3l).
Brown solid, yield: 161 mg (82%); mp 238ꢀ240 °C; IR (CHCl3)
1
10 (m, 2H, ArH), 6.78ꢀ6.85 (m, 3H, ArH), 6.53ꢀ6.57 (m, 3H,
pyrrolic H and ArH), 6.23 (s, 1H, pyrrolic H); 13C NMR (100
ν
max: 2926, 1609, 1404, 1319, 1095, 1036, 758 cmꢀ1; H NMR
(400 MHz, CDCl3): δ (ppm) 8.13 (d, J = 7.79 Hz, 2H, ArH),
MHz, CDCl3 + DMSOꢀd6): δ (ppm) 149.2, 136.0, 135.4, 128.4, 70 8.04ꢀ8.07 (m, 2H, pyrrolic H and ArH), 7.92 (dd, J1 = 8.24 Hz, J2
126.5, 125.7, 125.67, 125.64, 124.27, 124.20, 121.6, 121.3,
119.8, 113.6, 112.9, 112.8, 111.0, 106.8 ppm; HRMS (ESI, m/z)
15 calcd for C19H14N3: 284.1182 [M+H]+, found: 284.1189.
= 1.37 Hz, 1H, ArH), 7.81 (d, J = 8.24 Hz, 2H, ArH), 7.55ꢀ7.59
(m, 1H, ArH), 7.47ꢀ7.51 (m, 1H, ArH), 6.93ꢀ6.98 (m, 2H,
pyrrolic H); 13C NMR (100 MHz, CDCl3 + DMSOꢀd6): δ (ppm)
2
149.7, 136.4 (d, JCꢀF = 6.71 Hz), 131.5, 129.9, 128.6, 128.2,
3
4
4-(Furan-2-yl)pyrrolo[1,2-a]quinoxaline (3h). Brown solid, 75 125.4 (d, JCꢀF = 5.75 Hz), 125.3, 124.7 (d, JCꢀF = 3.83 Hz),
1
yield: 92 mg (62%); mp 99ꢀ101 °C; IR (CHCl3) νmax: 3140, 2922,
122.7, 122.6 (d, JCꢀF = 280.83 Hz), 119.0, 115.8, 113.9, 112.6;
HRMS (ESI, m/z) calcd for C18H12F3N2: 313.0947 [M+H]+,
found: 313.0952.
1
2851, 1589, 1475, 1364, 1046, 1006, 882, 751 cmꢀ1; H NMR
20 (400 MHz, CDCl3): δ (ppm) 7.98ꢀ8.02 (m, 2H, ArH), 7.85 (d, J =
7.32 Hz, 1H, ArH), 7.71 (s, 1H, ArH), 7.40ꢀ7.50 (m, 4H, pyrrolic
H and furyl H), 6.93 (t, J = 3.36 Hz, 1H, pyrrolic H), 6.64 (br, 80 6-(4-Fluorophenyl)indolo[1,2-a]quinoxaline (3m). Yellow
1H, pyrrolic H); 13C NMR (100 MHz, CDCl3): δ(ppm) 151.9,
144.2, 143.1, 135.4, 129.6, 127.0, 126.7, 125.0, 122.8, 114.2,
25 113.8, 113.3, 112.6, 111.8, 108.1; HRMS (ESI, m/z) calcd for
C15H11N2O: 235.0866 [M+H]+, found: 235.0872.
solid, yield: 77 mg (52%); mp 189ꢀ191 °C; IR (CHCl3) νmax:
2918, 2850, 1617, 1506, 1453, 1330, 1227, 742 cmꢀ1; H NMR
(400 MHz, CDCl3): δ (ppm) 8.53ꢀ8.58 (m, 2H, ArH), 8.07ꢀ8.12
(m, 3H, ArH), 7.98 (d, J = 7.93 Hz, 1H, ArH), 7.67 (t, J = 7.32
85 Hz, 1H, ArH), 7.61 (t, J = 7.32 Hz, 1H, ArH), 7.48ꢀ7.52 (m, 2H,
ArH), 7.30ꢀ7.34 (m, 3H, pyrrolic H and ArH); 13C NMR (100
MHz, CDCl3): δ(ppm) 163.8 (d, 1JCꢀF = 253.04 Hz), 155.0, 136.1,
1
4-(1H-Pyrrol-2-yl)pyrrolo[1,2-a]quinoxaline (3i). Brown solid,
yield: 114 mg (77%); mp 110ꢀ111 °C; IR (CHCl3) νmax: 3434,
30 3064, 1601, 1475, 1415, 1370, 1167, 1072, 1031, 932, 752, 688
cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 10.20 (brs, 1H, NH),
4
134.3 (d, JCꢀF = 2.88 Hz), 133.0, 130.6, 130.5, 130.4, 130.1,
2
3
129.1, 128.9, 128.4, 124.3 (d, JCꢀF = 22.04 Hz), 122.7 (d, JCꢀF
=
7.92ꢀ7.97 (m, 2H, ArH), 7.84 (d, J = 8.54 Hz, 1H, ArH), 7.39ꢀ 90 4.79 Hz), 115.7, 115.5, 114.6, 114.5, 102.3; HRMS (ESI, m/z)
7.47 (m, 2H, pyrrolic H), 7.31 (d, J = 3.66 Hz, 1H, pyrrolic H),
7.18 (d, J = 3.05 Hz, 1H, pyrrolic H), 7.08 (s, 1H, ArH), 6.92ꢀ
35 6.93 (m, 1H, pyrrolic H), 6.42 (t, J = 3.05 Hz, 1H, pyrrolic H);
13C NMR (100 MHz, CDCl3): δ (ppm) 145.7, 144.1, 135.0, 128.4,
126.7, 126.5, 125.2, 123.1, 121.6, 114.6, 114.0, 113.5, 112.4,
110.6, 107.9; HRMS (ESI, m/z) calcd for C15H12N3: 234.1026
[M+H]+, found: 234.1035.
calcd for C21H14FN2: 313.1136 [M+H]+, found: 313.1141.
7-Methyl-6-(pyridin-4-yl)indolo[1,2-a]quinoxaline
(3o).
Orange solid, yield: 72 mg (52%); mp 235ꢀ237 °C; IR (CHCl3)
95
ν
max: 2922, 1597, 1451, 1399, 1211, 831, 745 cmꢀ1; 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.84 (s, 2H, pyridyl H), 8.50 (t, J =
7.93 Hz, 2H, pyridyl H), 7.98ꢀ8.00 (m, 1H, ArH), 7.92 (d, J =
7.93 Hz, 1H, ArH), 7.60ꢀ7.65 (m, 4H, ArH), 7.40ꢀ7.50 (m, 2H,
ArH), 2.11 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ (ppm)
40
4-(Thiophen-2-yl)pyrrolo[1,2-a]quinoxaline (3j). Yellow solid,
yield: 126 mg (80%); mp 116ꢀ117 °C; IR (CHCl3) νmax: 3064, 100 154.7, 149.9, 147.3, 135.2, 132.0, 130.5, 130.3, 130.1, 129.0,
1583, 1524, 1442, 1433, 1365, 1218, 1101, 1067, 852, 754, cmꢀ1;
1H NMR (400 MHz, CDCl3): δ (ppm) 7.96ꢀ8.01 (m, 3H, ArH),
45 7.85 (dd, J1 = 8.05 Hz, J2 = 1.46 Hz, 1H, ArH), 7.55 (dd, J1 =
5.13 Hz, J2 = 1.46 Hz, 1H, thienyl H), 7.42ꢀ7.52 (m, 2H, pyrrolic
125.1, 124.7, 124.0, 123.4, 122.3, 120.8, 114.49, 114.40, 110.5,
11.3; HRMS (ESI, m/z) calcd for C21H16N3: 310.1339 [M+H]+,
found: 310.1345.
H), 7.28 (dd, J1 = 4.39 Hz, J2 = 1.46 Hz, 1H, thienyl H), 7.22 (dd, 105 General procedure for the synthesis of 4-methyl-4-aryl-4,5-
J1 = 5.13 Hz, J2 = 3.66 Hz, 1H, thienyl H), 6.93 (t, J = 3.29 Hz,
1H, pyrrolic H); 13C NMR (100 MHz, CDCl3): δ (ppm) 147.2,
50 142.3, 135.6, 129.8, 128.6, 128.0, 127.7, 127.3, 126.8, 125.2,
123.9, 114.6, 113.9, 113.4, 107.7; HRMS (ESI, m/z) calcd for
C15H11N2S: 251.0637 [M+H]+, found: 251.0638.
dihydropyrrolo[1,2-a]quinoxalines (5a-d):
To a well stirred solution of pꢀDBSA (0.1 mmol) in ethanol (2
mL), aromatic ketone (1.2 mmol) and 1ꢀ(2ꢀaminophenyl)pyrrole
(1.0 mmol) were added successively at 25 °C. The reaction
110 mixture was stirred at same temperature for 30 minutes. After
completion of the reaction, the solvent was evaporated and thus
the residue obtained is treated with saturated NaHCO3 solution (5
mL). Then saturated brine solution (5 mL) was added. The
product was extracted with ethyl acetate (10 mL × 3 times). The
4-(4-Methoxyphenyl)pyrrolo[1,2-a]quinoxaline (3k). White
55 solid, yield: 130 mg (75%); mp 114ꢀ116 °C; IR (CHCl3) νmax
:
2924, 2851, 1606, 1508, 1475, 1368, 1250, 1177, 1031, 834, 755,
1
715 cmꢀ1; H NMR (400 MHz, CDCl3): δ (ppm) 7.98ꢀ8.03 (m, 115 organic layers were combined, washed with water, dried over
4H, pyrrolic H and ArH), 7.87ꢀ7.88 (m, 1H, ArH), 7.45ꢀ7.50 (m,
anhydrous sodium sulfate and evaporated under reduced pressure
8
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DOI: 10.1039/C4RA16651E
to dryness. The crude product was purified by column
product was extracted with ethyl acetate (10 mL×3 times). The
chromatography over silica gel (60ꢀ120 mesh size) using 5ꢀ20% 60 organic layers were combined, washed with water, dried over
ethyl acetate in heptane as an eluent to furnish the desired product
anhydrous sodium sulfate and evaporated under reduced pressure.
The crude product was purified by column chromatography over
silica gel (60ꢀ120 mesh size) using 5ꢀ20% ethyl acetate in
heptane as an eluent to furnish the desired product in good yields.
65 The characterization data of known compound (7a) are matched
in good yields. The spectral data of known compound (5a) are
5
found to be in good agreement with the reported data13a
.
4-(4-Bromophenyl)-4-methyl-4,5-dihydropyrrolo[1,2-
a]quinoxaline (5b). White solid, yield: 178 mg (83%); mp 165ꢀ
166 °C; IR (CHCl3) νmax: 3349, 2980, 1613, 1517, 1482, 1334,
with the reported data 16
.
10 1187, 1077, 778, 746 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm)
7.33ꢀ7.35 (m, 2H, ArH), 7.24ꢀ7.26 (m, 1H, ArH), 7.14ꢀ7.17 (m,
5-Chloro-5'H-spiro[indoline-3,4'-pyrrolo[1,2-a]quinoxalin]-2-
one (7b). Orange solid, yield: 170 mg (84%); mp 116ꢀ118 °C; IR
3H, pyrrolic H and ArH), 6.92ꢀ6.96 (m, 1H, ArH), 6.75ꢀ6.82 (m, 70 (CHCl3) νmax: 3322, 3247, 2926, 2854, 1720, 1617, 1477, 1333,
2H, ArH), 6.33 (t, J = 3.21 Hz, 1H, pyrrolic H), 6.05 (dd, J1 =
3.21 Hz, J2 = 1.37 Hz, 1H, pyrrolic H), 4.33 (s, 1H, NH), 1.87 (s,
15 3H, CH3); 13C NMR (100 MHz, CDCl3): 145.4, 134.7, 132.3,
131.2, 127.5, 125.6, 124.7, 120.8, 119.5, 115.8, 114.6, 114.4,
1196, 822, 753 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.12
(s, 1H, NH), 7.23ꢀ7.38 (m, 4H, pyrrolic H and ArH), 6.88ꢀ6.98
(m, 2H, ArH), 6.63ꢀ6.73 (m, 2H, ArH), 6.26 (t, J = 3.05 Hz, 1H,
pyrrolic H), 5.61ꢀ5.62 (m, 1H, pyrrolic H), 4.32 (s, 1H, NH); 13C
110.0, 104.5, 56.5, 29.0; HRMS (ESI, m/z) calcd for C18H16BrN2: 75 NMR (100 MHz, CDCl3): 178.1, 139.7, 133.8, 131.9, 130.1,
339.0491 [M+H]+, found: 339.0490.
128.4, 126.1, 124.9, 124.8, 124.3, 119.5, 116.0, 115.4, 114.2,
111.8, 110.5, 106.2, 61.4; HRMS (ESI, m/z) calcd for
C18H13ClN3O: 322.0742 [M+H]+, found: 322.0738.
20 4-(4-Iodophenyl)-4-methyl-4,5-dihydropyrrolo[1,2-
a]quinoxaline (5c). White solid, yield: 200 mg (82%); mp 153ꢀ
154 °C; IR (CHCl3) νmax: 3353, 2978, 2930, 1610, 1597, 1515, 80 5-Methyl-5'H-spiro[indoline-3,4'-pyrrolo[1,2-a]quinoxalin]-2-
1482, 1332, 1187, 1073, 746 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.53ꢀ7.55 (m, 2H, ArH), 7.24ꢀ7.26 (m, 1H, ArH), 7.15ꢀ
25 7.16 (m, 1H, pyrrolic H), 7.01ꢀ7.03 (m, 2H, ArH), 6.92ꢀ6.96 (m,
1H, ArH), 6.75ꢀ6.81 (m, 2H, ArH), 6.33 (t, J = 3.05 Hz, 1H,
one (7c). Orange solid, yield: 152 mg (80%); mp 130ꢀ132 °C; IR
(CHCl3) νmax: 3328, 3246, 2924, 1718, 1624, 1508, 1497, 1333,
1
1301, 1207, 1156, 764 cmꢀ1; H NMR (400 MHz, CDCl3): δ
(ppm) 8.04 (s, 1H, NH), 7.36 (d, J = 7.32 Hz, 1H, ArH), 7.20ꢀ
pyrrolic H), 6.04ꢀ6.05 (m, 1H, pyrrolic H), 4.33 (s, 1H, NH), 1.86 85 7.28 (m, 2H, ArH), 7.06 (d, J = 7.93 Hz, 1H, ArH), 6.96 (t, J =
(s, 3H, CH3);13C NMR (100 MHz, CDCl3): 146.2, 137.3, 134.8,
132.3, 127.9, 125.7, 124.8, 119.6, 115.9, 114.7, 114.5, 110.1,
30 104.6, 92.7, 56.7 29.1; HRMS (ESI, m/z) calcd for C18H16IN2:
387.0353 [M+H]+, found: 387.0351.
7.32 Hz, 1H, ArH), 6.87 (t, J = 7.32 Hz, 1H, ArH), 6.66ꢀ6.69 (m,
2H, ArH and pyrrolic H), 6.25 (t, J = 3.05 Hz, 1H, pyrrolic H),
5.62 (d, J = 2.44 Hz, 1H, pyrrolic H), 4.29 (s, 1H, NH), 2.30 (s,
3H, CH3); HRMS (ESI, m/z) calcd for C19H15N3NaO: 324.1107
90 [M+Na]+, found: 324.1114.
4-([1,1'-Biphenyl]-4-yl)-4-methyl-4,5-dihydropyrrolo[1,2-
a]quinoxaline (5d). White solid, yield: 182 mg (86%); mp 158ꢀ
35 159 °C; IR (CHCl3) νmax: 3373, 3029, 2985, 2927, 1612, 1515,
1417, 1334, 1189, 1074, 839, 746, 698 cmꢀ1; 1H NMR (400 MHz,
1-Methyl-5'H-spiro[indoline-3,4'-pyrrolo[1,2-a]quinoxalin]-2-
one (7d). Pale white solid, yield: 152 mg (80%); mp 261ꢀ262 °C;
IR (CHCl3) νmax: 3328, 2928, 1717, 1610, 1517, 1466, 1334,
CDCl3): δ (ppm) 7.47 (d, J = 7.93 Hz, 2H, ArH), 7.42 (d, J = 7.93 95 1091, 737 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.37ꢀ7.45
Hz, 2H, ArH), 7.33ꢀ7.36 (m, 4H, ArH), 7.29ꢀ7.31 (m, 1H, ArH),
7.23ꢀ7.27 (m, 1H, ArH), 7.17ꢀ7.18 (m, 1H, pyrrolic H), 6.91ꢀ6.94
40 (m, 1H, ArH), 6.75ꢀ6.80 (m, 2H, ArH), 6.32ꢀ6.33 (m, 1H,
pyrrolic H), 6.04ꢀ6.07 (m, 1H, pyrrolic H), 4.37 (s, 1H, NH), 1.90
(m, 3H, ArH), 7.28ꢀ7.29 (m, 1H, ArH), 7.13 (t, J = 7.63 Hz, 1H,
ArH) 6.96ꢀ7.00 (m, 1H, ArH), 6.88ꢀ6.91 (m, 2H, ArH), 6.73ꢀ6.75
(m, 1H, pyrrolic H), 6.23 (t, J = 3.05 Hz, 1H, pyrrolic H), 5.56ꢀ
5.57 (m, 1H, pyrrolic H), 4.22 (s, 1H, NH), 3.14 (s, 3H, CH3); 13
C
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3): 145.3, 140.5, 139.6, 100 NMR (100 MHz, CDCl3 + DMSOꢀd6): 175.3, 143.8, 134.2,
135.0, 132.8, 128.6, 127.1, 126.95, 126.90, 126.1, 125.6, 124.7,
119.2, 115.7, 114.6, 114.2, 109.9, 104.5, 56.7, 29.2; HRMS (ESI,
45 m/z) calcd for C24H21N2: 337.1699 [M+H]+, found: 337.1708.
130.0, 129.6, 125.4, 125.3, 125.0, 124.5, 123.1, 119.2, 115.6,
115.1, 114.0, 110.0, 108.1, 105.5, 60.5, 25.9; HRMS (ESI, m/z)
calcd for C19H16N3O: 302.1288 [M+H]+, found: 302.1275.
General procedure for the synthesis of 5'H-spiro[indoline- 105 5'H-spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-one
3,4'-pyrrolo[1,2-a]quinoxalin]-2-ones (7a-d) and 5'H- Orange solid, yield: 132 mg (82%); mp 130ꢀ132 °C; IR (CHCl3)
spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-ones (7e-j):
(7e).
ν
max: 3332, 3193, 1716, 1616, 1508, 1452, 1321, 1198, 735 cmꢀ1;
50
To a well stirred solution of pꢀDBSA (0.1 mmol) in ethanol (2
1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (s, 1H, NH), 8.07 (d, J
= 8.54 Hz, 1H, ArH), 7.98 (dd, J1 = 7.32 Hz, J2 = 1.83 Hz, 1H,
mL), isatin derivative (1.2 mmol), and 1ꢀ(2ꢀaminophenyl)pyrrole
or
2ꢀ(1Hꢀindolꢀ1ꢀyl)aniline
or
2ꢀ(3ꢀmethylindolꢀ1ꢀ 110 ArH), 7.51 (d, J = 7.93 Hz, 1H, ArH), 7.41ꢀ7.45 (m, 1H, ArH),
yl)phenylamine (1.0 mmol) were added at 25 °C. The reaction
mixture was stirred at same temperature for the 30 minutes. After
55 complete consumption of the starting materials as shown by TLC,
the reaction mixture was then evaporated and the residue thus
7.24ꢀ7.33 (m, 2H, ArH), 7.16 (t, J = 7.93 Hz, 1H, ArH), 7.05ꢀ
7.09 (m, 2H, ArH), 7.00ꢀ7.04 (m, 1H, ArH), 6.83 (dd, J1 = 7.32
Hz, J2 = 1.83 Hz, 1H, ArH), 6.76 (d, J= 7.93 Hz, 1H, ArH), 6.00
(s, 1H, pyrrolic H), 4.35 (s, 1H, NH); 13C NMR (100 MHz,
obtained was treated with saturated NaHCO3 solution (5 mL) 115 CDCl3): 177.4, 141.1, 138.5, 134.8, 130.3, 129.6, 129.3, 127.1,
followed by the addition of saturated brine solution (5 mL). The
125.8, 124.1, 123.3, 123.1, 121.3, 121.0, 120.1, 116.2, 116.1,
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DOI: 10.1039/C4RA16651E
112.6, 112.1, 110.8, 100.7, 61.6; HRMS (ESI, m/z) calcd for
C22H15N3NaO: 360.1107 [M+Na]+, found: 360.1115.
1,7'-Dimethyl-5'H-spiro[indoline-3,6'-indolo[1,2-
60 a]quinoxalin]-2-one (7j). Orange solid, yield: 129 mg (79%); mp
88ꢀ90 °C; IR (CHCl3) νmax: 3315, 3053, 2922, 1717, 1610, 1492,
1455, 1363, 1093, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.24 (d, J = 8.70, 1H, ArH), 8.16 (d, J = 7.79 Hz, 1H,
ArH), 7.69ꢀ7.78 (m, 2H, ArH), 7.59 (t, J = 7.73 Hz, 1H, ArH),
1-Methyl-5'H-spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-
one (7f). Orange solid, yield: 132 mg (79%); mp 200ꢀ202 °C; IR
(CHCl3) νmax: 3356, 2934, 1715, 1611, 1472, 1342, 1238, 1095,
5
762, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (d, J = 65 7.49ꢀ7.53 (m, 1H, ArH), 7.43ꢀ7.46 (m, 1H, ArH), 7.36ꢀ7.39 (m,
8.54 Hz, 1H, ArH), 7.97ꢀ7.99 (m, 1H, ArH), 7.50 (d, J = 7.32 Hz,
1H, ArH), 7.38ꢀ7.46 (m, 2H, ArH), 7.25ꢀ7.32 (m, 1H, ArH), 7.13
10 (t, J = 7.93 Hz, 2H, ArH), 7.04ꢀ7.07 (m, 2H, ArH), 6.91 (d, J =
1H, ArH), 7.27ꢀ7.31 (m, 1H, ArH), 7.19ꢀ7.24 (m, 1H, ArH), 7.13
(d, J = 7.79 Hz, 1H, ArH), 7.03 (d, J = 7.79 Hz, 1H, ArH), 4.47
(s, 1H, NH), 3.44 (s, 3H, CH3) 3.40 (s, 3H, CH3); 13C NMR (100
MHz, CDCl3): 174.3, 151.2, 143.3, 138.2, 134.0, 130.2, 129.4,
7.93 Hz, 1H, ArH), 6.84ꢀ6.86 (m, 1H, ArH), 5.97 (s, 1H, pyrrolic
H), 4.13 (s, 1H, NH), 3.14 (s, 3H, CH3); 13C NMR (100 MHz, 70 127.2, 125.3, 123.5, 123.3, 123.0, 120.4, 120.3, 118.9, 116.1,
CDCl3): 174.6, 151.2, 143.9, 138.2, 134.9, 130.4, 129.2, 127.4,
125.7, 124.0, 123.3, 123.0, 121.1, 120.9, 120.3, 116.4, 116.0,
15 112.0, 109.7, 108.4, 100.2, 61.0, 26.1; HRMS (ESI, m/z) calcd
for C23H18N3O: 352.1444 [M+H]+, found: 352.1439.
116.0, 112.0, 109.8, 108.5, 108.3, 61.5, 26.2, 8.1; HRMS (ESI,
m/z) calcd for C24H19N3NaO 388.1420 [M+Na]+, found:
388.1426
Acknowledgments
5-Methyl-5'H-spiro[indoline-3,6'-indolo[1,2-a]quinoxalin]-2-
one (7g). Orange solid, yield: 134 mg (80%); mp 155ꢀ157 °C; IR
20 (CHCl3) νmax: 3343, 3248, 1719, 1625, 1490, 1454, 1324, 1300,
1198, 745 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.08 (d, J
= 8.54 Hz, 1H, ArH), 7.99 (dd, J1 = 7.32 Hz, J2 = 1.83 Hz, 1H,
ArH), 7.88 (s, 1H, NH), 7.52 (d, J = 7.32 Hz, 1H, ArH), 7.28ꢀ
7.32 (m, 1H, ArH), 7.14ꢀ7.17 (m, 2H, ArH), 7.02ꢀ7.09 (m, 3H,
25 ArH), 6.82ꢀ6.84 (m, 1H, ArH), 6.69 (d, J = 7.93 Hz, 1H, ArH),
75 This work is supported by University of Delhi, India under the
scheme to strengthen R&D Doctoral Research Programme. We
are thankful to Central Instrumentation Facility, University of
Delhi, India for providing NMR, mass and single crystal Xꢀray
data. Amreeta Preetam is grateful to CSIR, New Delhi, India for
80 providing SRF.
6.01 (s, 1H, pyrrolic H), 4.30 (s, 1H, NH), 2.29 (s, 3H, CH3); 13
C
Notes and references
NMR (100 MHz, CDCl3): 177.4, 138.7, 134.9, 134.7, 134.6,
132.8, 130.6, 129.7, 129.3, 127.1, 126.3, 124.1, 123.0, 121.2,
121.0, 120.0, 116.2, 116.0, 112.2, 110.5, 100.6, 61.7, 21.0;
30 HRMS (ESI, m/z) calcd for C23H18N3O: 352.1444 [M+H]+,
found: 352.1454.
Department of Chemistry, University of Delhi, Delhi, 110 007, India.
Fax: + 91 11 27666605; E-mail: mnath@chemistry.du.ac.in.
† Electronic Supplementary Information (ESI) available: 1H and 13
85 NMR spectra of the synthesized products
C
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1
1616, 1455, 1384, 1322, 1235, 736 cmꢀ1; H NMR (400 MHz,
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8.54 Hz, 1H, ArH), 7.95 (d, J = 7.32 Hz, 1H, ArH), 7.58 (d, J =
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55 129.1, 127.0, 123.6, 123.3, 123.2, 120.5, 120.2, 119.1, 116.0,
115.9, 112.6, 112.2, 110.8, 109.0, 62.0, 8.2; HRMS (ESI, m/z)
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