Indium Trichloride (InCl3) Catalyzed Synthesis of Fused 7-Azaindole Derivatives Using Domino Knoevenagel-Michael Reaction

Article abstract of DOI:10.1002/jccs.201500540

An efficient and high yielding methodology developed for the synthesis of fused 7-azaindole derivatives via one pot multicomponent assembly process of cyclic 1,3-dicarbonyls with substituted aldehydes and 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile. The transformation occurs via domino Knoevenagel- Michael reaction followed by intramolecular cyclization in the presence of catalytic amount of InCl₃ (10 mol%). Mild reaction conditions, easy isolation of products, and good to excellent yields in a shorter period of time are the silent features of present methodology. Structures of all the newly prepared compounds have been corroborated by various spectroscopic methods.

Full text of DOI:10.1002/jccs.201500540

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Indium Trichloride (InCl3) Catalyzed Synthesis of Fused 7-Azaindole Derivatives Using
Domino Knoevenagel-Michael Reaction
Sakharam B. Dongare,a Hemant V. Chavan,a,b* Datta N. Surwase,a Pravin S. Bhale,a
Yoginath B. Mulea and Babasaheb P. Bandgara*
aSchool of Chemical Sciences, Solapur University, Solapur-413 255, Maharashtra, India
bDepartment of Chemistry, A.S.P. College, Devrukh, Dist-Ratnagiri-415 804, Maharashtra, India
(Received: Dec. 31, 2015; Accepted: Feb. 16, 2016; Published Online: Apr. 5, 2016; DOI: 10.1002/jccs.201500540)
An efficient and high yielding methodology developed for the synthesis of fused 7-azaindole derivatives
via one pot multicomponent assembly process of cyclic 1,3-dicarbonyls with substituted aldehydes and
5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile. The transformation occurs via domino Knoevenagel-
Michael reaction followed by intramolecular cyclization in the presence of catalytic amount of InCl3 (10
mol%). Mild reaction conditions, easy isolation of products, and good to excellent yields in a shorter pe-
riod of time are the silent features of present methodology. Structures of all the newly prepared com-
pounds have been corroborated by various spectroscopic methods.
Keywords: Indium trichloride; Fused 7-azaindoles; Knoevenagel condensation; Michael addition;
Domino reaction.
INTRODUCTION
Improvement in atom economy, avoidance of toxic
agents12 and agrochemicals.13. The introduction of a basic
nitrogen in benzene ring of indole molecule leads to aza-
indoles, bioisosters of the indoles show improved physico-
chemical properties for various biological targets such as
kinase inhibitors,14 inhibitors of microtubule dynamics,
anti-cancer agents,15 CNS disorders,16 PDE-4 inhibitors,17
CRTh2 receptor antagonists,18 nicotinic agonists,19 anti-
viral,20 cardiovascular agents,21 etc. In addition, azaindole
possess applications in material science, as 7-azaindole and
its variety of derivatives are excellent blue emmitors for or-
ganic light emmiting light diodes. 7-azaindole have rich
co-ordination chemistry with main group elements, transi-
tion metal ions because of bidentate nature and they shows
phosphorescence, luminescence properties as well.22
Our group is dedicated for the development of envi-
ronmentally benign synthetic methodologies for small
heterocycles possessing interesting biological activities.23
In this regard, we would like to report a facile, one-pot,
multi-component assembly process for the synthesis of
fused 7-azaindole derivatives.
reagents, solvents and minimization of wastes are the ulti-
mate aims in modern synthetic organic chemistry. In this
regard, development of multi-component assembly pro-
cesses consisting of multiple bond forming steps in one pot
could satisfy above principles. Furthermore, a simple, eco-
logically and economically viable synthesis of complex
molecules with reduced number of steps could be achieved
by multi-component assembly processes technique.1
Recently synthetic utility of Indium trichloride (InCl3)
in organic transformations2 has received great attention for
the construction of complex heterocycles which involves
C-C and C-X (heteroatom) bond formations using multiple
components. Furthermore, InCl3 has been used in various
transformations such as Strecker reaction,3 Mannich reac-
tion,4 Pechmann condensation,5 amino Diels-Alder, Friedel-
Craft’s reductive acylation,6 condensation of silyl enol
ethers, Mukaiyama aldol reactions,7 Biginelli reaction,8
etc. In addition, InCl3 has been used in the synthesis of a va-
riety of nitrogen containing biologically active hetero-
cyclic compounds.9 More recently, InCl3 has been used in
reductive coupling of nitroaniline with 1,2-diketones for
the synthesis of quinoxaline10 and diastereoselective syn-
thesis of indenothiepines and indenodithiocines.11
RESULTS AND DISCUSSION
Our initial investigation was started with the reaction
of dimedone (1), 4-chlorobenzaldehyde (2) and 5-amino-
1-tert-butyl-1H-pyrrole-3-carbonitrile (3) to give dihydro-
7-azaindole (4) as a model reaction. The reaction condi-
tions were optimized systematically by changing one pa-
Indole is one of the important heterocyclic scaffolds
present in a variety of natural products, pharmaceutical
* Corresponding author. Email: hemantchavan.sus@rediffmail.com
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Dongare et al.
rameter and keeping others constant. The neat reaction was
attempted without any catalyst in ethanol; however the de-
sired product was not obtained even after 12 h. Further-
more, the introduction of bases such as triethyl amine,
pyridine, piperidine, pyrrolidine, diammonium hydrogen
phosphate, DBU, DMAP, etc. did not improve the situa-
tion. This clearly indicated that the reaction required acidic
condition to progress. In order to find the suitable acid to
catalyze the reaction, various acids such as PTSA, AlCl3,
ZnCl2, H3PW12O40, FeCl3, InCl3 were screened in catalytic
amounts in ethanol under reflux conditions (Table 1). The
excellent yield (90%) for the formation of product 4a was
observed under reflux condition (Table 1, entry 6), how-
ever only traces of product 4a was detected when the same
reaction was carried at RT (Table 1, entry 9). Subsequently,
the solvent effect was studied by using solvents such as
methanol, acetonitrile, THF, etc. The results summarized in
Table 1 clearly show that ethanol is the best solvent for this
transformation amongst the solvents screened. 10 mol% of
InCl3 was found to be optimum for the reaction to go for
completion, however > 10% InCl3 led to diminished yields
of product (Table 1, entry 7) and < 10% InCl3 led to the re-
duced yield of the product (Table 1, entry 8). From all re-
sults summarized in Table 1, InCl3 was found to be the best
catalyst for this particular transformation. In order to gen-
eralize the method, a wide range of substrates were used for
the construction of fused 7-azaindole derivatives. When
the substituted aldehydes 2a-k were reacted individually
with 1a and 3 under the optimized conditions described
above afforded a variety of fused 7-azaindole derivatives
4a-k. Remarkably, the nature of aromatic substituent (elec-
tron withdrawing or electron donating) did not show any
considerable impact on yield. The non-aromatic ring B was
converted into the aromatic ring to get the aromatized
tricyclic fused 7-azaindole scaffold. The aromatization of
ring B of compounds 4a-k was studied by using different
oxidizing agents, such as m-CPBA, H2O2, Ceric Ammo-
nium Nitrate (CAN), 4,5-dichloro-3,6-dioxocyclohexa-
1,4-diene-1,2-dicarbonitrile (DDQ), etc. DDQ in ace-
tonitrile was found to be the best aromatizing agent with
90% yield (Scheme 1).
The scope expanded by applying the methodology for
the synthesis of indeno-pyridine derivatives. The indeno-
pyridine motif is reported to have extensive biological ac-
tivities like cytotoxic agent,24 antidepressant,25 antihyper
lipoproteinemia and antiarteio-sclerosis26 and used in
neurogenerative diseases.27 We envisioned our methodol-
ogy by replacing dimedone 1a with Indane-1,3-dione 1b
(Scheme 2). Interestingly, we could isolated directly the
aromatized products instead of dihydro compounds in ex-
cellent yields (Table 2), presumably due to the most stable
aromatic structures.
Table 1. Optimization of reaction conditions
Yields (4) (%)a,b
Entry
Catalyst
(mol%)
Time
(h)
MeOH EtOH MeCN THF
1
2
3
4
5
6
7
8
9
10
PTSA.H2O(10%)
AlCl3(10%)
ZnCl2(10%)
H3PW12O40(10%)
FeCl3(10%)
InCl3(10%)
8
8
50
48
51
56
34
70
72
65
65
38
48
65
55
90
90
78
53
56
45
60
50
76
68
61
50
52
36
45
25
60
64
54
8
On the basis of our results with respect to this particu-
lar transformation, a proposed mechanism for the forma-
tion of fused 7-azaindoles is depicted in Scheme 3. The first
step involves Knoevenagel condensation between cyclic
1,3-dicarbonyls and aromatic aldehydes to give adduct 8a28
which acts as a Michael acceptor. The adduct 8a instantly
undergoes Michael type addition with amino pyrrole 3 to
yield intermediate 9a which may exist in another tauto-
meric form. Finally, intramolecular cyclization of 9a fol-
lowed by dehydration leads to the formation of non-
8
8
2.5
2.5
2.5
InCl3(20%)
InCl3(05%)
InCl3(10%)c
12 Trace Trace Trace Trace
12 -- -- -- --
No Catalyst
a The reaction was performed with dimedone 1 (1 mmol), 4-
chlorobenzaldehyde 2a (1 mmol) and 5-amino-1-tert-butyl-1H-
pyrrole-3-carbonitrile 3 (1 mmol), Catalyst, reflux; b Isolated
yields; c Room Temperature.
Reaction of dimedone 1a with aldehyde 2 and aminopyrrole 3 in the presence of InCl3
Scheme 1
324
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CHEMICAL SOCIETY
Synthesis of Fused 7-Azaindole Derivatives
Reaction of Indane-1,3-dione 1b with 2 and 3 in presence of InCl3 catalyst
Scheme 2
Table 3. Synthesis of fused 7-azaindole derivatives using indane-
1,3-dione
Table 2. Synthesis of fused 7-azaindole derivatives
Products (Yield %)a-c
Yieldsa-c (%)
Comp-
ound
Entry
Compound
Aldehyde
Entry
Aldehyde
Non
Aromatized
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
4-ClC6H4
3-OHC6H4
95
93
96
91
90
91
90
88
95
aromatized (4)
(5)
1
2
3
4
5
4a, 5a
4b, 5b
4-ClC6H4
90
93
91
89
92
94
93
95
92
96
3,4,5-(MeO)3C6H2
3,4-(O-CH2-O)C6H3
2,4-(Cl)2C6H3
4-MeO-3-FC6H3
4-(CN)C6H4
4-MeOC6H4
4c, 5c 3-MeO-4-OHC6H3
4d, 5d 3,4,5-(MeO)3C6H2
4e, 5e
3,4-
6g
6h
6i
(O-CH2-O)C6H3
2,4-(Cl)2C6H3
Thiophene
6
4f, 5f
90
88
89
86
87
90
91
90
92
93
94
90
2,4-(F)2C6H3
7
4g, 5g 4-MeO-3-FC6H3
a The reaction was performed on 1 mmol scale with each reactant
with 10 mol% catalyst InCl3 in EtOH; b EOR was monitored by
TLC analysis; c Yields of isolated products.
8
4h, 5h
4i, 5i
4-CNC6H4
Thiophene
Furan
9
10
11
4j, 5j
4k, 5k
2,4-(F)2C6H3
a The reaction was performed on 1 mmol scale with 10 mol%
catalyst-InCl3 in EtOH (5 ml) and aromatization in CH3CN with
DDQ as an oxidant; b End of Reaction (EOR) was monitored by
TLC analysis; c Yields of isolated products.
CONCLUSIONS
We have demonstrated a simple, efficient and rapid
route for the synthesis of wide range of fused 7-azaindole
derivatives via one pot multi-component assembly process.
Simple practical operation, high yields with pure products
from just filtration and short reaction time are the silent fea-
tures of this methodology. It is noteworthy that this domino
transformation results in the formation of three new bonds
(two C-C, and one C-N) in a single operation. Further in-
vestigations of methodology for various active methylene
compounds are under consideration in our group.
aromatized product 4. DDQ dehydrogenates to give aro-
matic fused 7-azaindoles whereas in other case of indane-
1,3-dione spontaneous oxidation takes place to give the
most stable aromatic products.
Plausible reaction pathway for transforma-
tion into product
Scheme 3
EXPERIMENTAL
Materials and methods: All melting points (MP) were de-
1
termined with open capillary method and are uncorrected. H
NMR and 13C NMR spectra were recorded on a Brucker spec-
trometer at 400 MHz and 100 MHz, respectively. The solvent was
either CDCl3 or DMSO-d6 or mixture of both solvents depending
on the solubility. TMS was used as an internal standard. Chemical
shifts are reported in ppm values. Coupling constants J are re-
ported in Hz. Mass spectra were performed on a Mass Spectrome-
ter (Thermo) API instrument. FT-IR spectra were recorded on
Bruckers instruments with direct or KBr pellets method in the
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range of 600-4000 cm-1. The reaction was monitored by TLC and
UV light and/or iodine vapour were used for the detection of com-
pounds. All chemicals or reagents used for synthesis were com-
mercially available, were of AR grade, and were used as received
from freshly opened containers. 5-amino-1-tert-butyl-1H-pyr-
role-3-carbonitrile synthesized as per literature precedent.29
General procedure for the synthesis of compound (4a-
k): In a typical experiment, a mixture of dimedone (1 eq.), the
p-chlorobenzaldehyde (1 eq.) and 5-amino-1-tert-butyl-pyrrole-
3-carbonitrile (1 eq.) was refluxed in ethanol (5 ml) with indium
trichloride (10 mol%) as a catalyst for 2.5 h. After consumption of
all precursors as indicated by TLC (eluent: n-hexane/ethyl ace-
tate; 6:4), the reaction mixture were cooled to room temperature,
and the precipitated product was collected by filtration. The pro-
duct was washed with cold ethanol to afford the pure products.
General procedure for the synthesis of compound (5a-
k): In a typical experiment, a mixture of the corresponding
dihydropyridine 4 (1 eq.) and 4,5-dichloro-3,6-dioxocyclohexa-
1,4-diene-1,2-dicarbonitrile (DDQ) (1.2 eq.) was stirred in
acetonitrile (3 ml) for 4 h at room temperature. After completion
of reaction indicated by TLC, the reaction mixture diluted with 10
ml of water and precipitated product was filtered off and washed
with water (5 ml x 2). The crude product was purified by re-
crystallization in aqueous ethanol.
229-231 °C, IR (KBr, cm-1): 3306, 2954, 2221, 1595, 1524, 1498,
1
1431, 1392, 1333, 1249, 1226, 1188, 1117, 1028, 847, 802; H
NMR (300 MHz, DMSO-d6) d = 0.94 (s, 3H, -CH3), 1.04 (s, 3H,
-CH3), 1.58 (s, 9H, t-Bu), 1.98 (d, 1H, J = 16.1 Hz, gem-CH2CO),
2.19 (d, 1H, J = 16.1 Hz, gem-CH2CO), 2.54 (d, 1H, J = 17.0 Hz,
gem-CH2) 2.70 (d, 1H, J = 17.0 Hz, gem-CH2), 3.69 (s, 3H,
-OCH3), 4.96 (s, 1H, Ar-CH) 6.78 (d, 2H, J = 8.7 Hz, Ar-H), 7.04
(d, 2H, J = 8.7 Hz, Ar-H), 7.30 (s, 1H, Pyrrole-CH), 8.60 (s, 1H,
-NH); MS (ESI): 404 (M + 1). 1-tert-butyl-4-(4-hydroxy-3-
methoxyphenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1
H-pyrrolo[2,3-b]quinoline-3-carbonitrile (4c): Yield 91%, off
white solid, mp. 214-215 °C, IR (KBr, cm-1): 3536, 3290, 2220,
1597, 1575, 1526, 1500, 1385, 1332, 1265, 1232, 1189, 1027,
753; 1H NMR (300 MHz, DMSO-d6) d = 1.00 (s, 3H, -CH3), 1.06
(s, 3H, -CH3), 1.57 (s, 9H, t-Bu), 2.01 (d, 1H, J = 16.1 Hz,
gem-CH2CO), 2.21 (d, 1H, J = 16.1 Hz, gem-CH2CO) 2.55 (d,
1H, J = 16 Hz, gem-CH2CO), 2.72 (d, 1H, J = 16 Hz, gem-CH2),
3.71 (s, 3H, -OCH3), 4.93 (s, 1H, Ar-CH), 6.48 (d, 1H, J = 8.1 Hz,
Ar-H), 6.61 (d, 1H, J = 8.1 Hz, Ar-H), 6.77 (s, 1H, Ar-H), 7.30 (s,
1H, Pyrrole-CH), 8.57 (s, 1H, -OH), 8.63 (s, 1H, -NH); MS (ESI):
420 (M
+ 1). 1-tert-butyl-7,7-dimethyl-5-oxo-4-(3,4,5-
trimethoxyphenyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]
quinoline-3-carbonitrile (4d): Yield 89%, cream white solid,
mp. 262-264 °C, IR (KBr, cm-1): 3305, 2954, 2220, 1595, 1524,
1
1496, 1430, 1395, 1333, 1249, 1182, 1117, 1025, 847, 800; H
General procedure for the synthesis of compound (6a-i):
In a typical experiment, a mixture of 1,3-indanedione (1 eq.), the
corresponding aldehyde 2 (1 eq.) and 5-amino-1-tert-butyl-
pyrrole-3-carbonitrile (1 eq.) refluxed in ethanol (5 ml) with In-
dium trichloride (10 mol%) as catalyst for 2.5 h. After end of reac-
tion as indicated by TLC (eluent: n-hexane/ethyl acetate 6:4) re-
action mixture were cooled to room temperature and the precipi-
tated product was collected, washed with cold ethanol to afford
the pure products.
NMR (400 MHz, DMSO-d6) d = 0.9 (s, 3H, -CH3), 1.03 (s, 3H,
-CH3), 1.57 (s, 9H, -t-Bu), 1.96-2.50 (m, 2H, -CH2CO), 2.54-2.72
(m, 2H, -CH2), 3.59 (s, 3H, -OCH3), 3.69 (s, 3H, 2x-OCH3), 4.95
(s, 1H, Ar-CH), 6.44 (s, 2H, Ar-H), 7.31 (s, 1H, Pyrrole-CH), 8.66
(s, 1H, -NH); MS (ESI): 464 (M + 1). 4-(benzo[d][1,3]dioxol-
5-yl)-1-tert-butyl-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-
1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (4e): Yield 92%,
off white solid, mp. 182-184 °C; IR (KBr, cm-1): 3310, 2950,
2232, 1598, 1530, 1498, 1430, 1392, 1250, 1226, 1184, 1118,
1028, 845, 802; 1H NMR (400 MHz, DMSO-d6) d = 0.93 (s, 3H,
-CH3), 1.03 (s, 3H, -CH3), 1.57 (s, 9H, t-Bu), 1.96-2.20 (m, 2H,
-CH2CO), 2.54-2.71 (m, 2H, -CH2), 4.93 (s, 1H, Ar-CH), 5.91 (s,
2H, -OCH2O), 6.58-6.63 (m, 2H, Ar-H), 6.73-6.75 (m, 1H, Ar-H),
7.31 (s, 1H, Pyrrole-CH), 8.63 (s, 1H, -NH); MS (ESI): 418 (M +
1). 1-tert-butyl-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-4,
5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile
(4f): Yield 90%, off white solid, mp. 270-272 °C, IR (KBr, cm-1):
3330, 2228, 1632, 1618, 1525, 1508, 1380, 1195, 1016, 850, 772,
655; 1H NMR (400 MHz, DMSO-d6) d = 0.92 (s, 3H, -CH3), 1.03
(s, 3H, -CH3), 1.57 (s, 9H, t-Bu), 1.91-2.18 (m, 2H, -CH2CO),
2.54-2.68 (m, 2H, -CH2), 5.40 (s, 1H, Ar-CH), 7.18 (d, 1H, J = 8
Hz, Ar-H), 7.27-7.29 (m, 2H, Ar-H, Pyrrole-CH), 7.39 (d, 1H, J =
Spectral data of synthesized compounds
1-tert-butyl-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-4,5,
6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile
(4a): Yield 90%, off white solid, mp. 239-241 °C, IR (KBr, cm-1):
3330, 2216, 1638, 1617, 1525, 1503, 1380, 1334, 1192, 1013,
1
850, 770, 650; HNMR (300 MHz, DMSO-d6) d = 0.94 (s, 3H
-CH3), 1.05 (s, 3H, CH3), 1.60 (s, 9H, t-Bu), 2.00 (d, 1H, J = 16.1
Hz, gem-CH2CO), 2.20 (d, 1H, J = 16.1 Hz, gem-CH2CO), 2.55
(d, 1H, J = 17.0 Hz, gem-CH2), 2.72 (d, 1H, J = 17.0 Hz,
gem-CH2), 5.04 (s, 1H, Ar-CH), 7.16 (d, 2H, J = 7.9 Hz, Ar-H),
7.24-7.37 (m, 3H, Ar-H, Pyrrole-CH), 8.69 (s, 1H, -NH); MS
(ESI): 409 (M + 1). 1-tert-butyl-4-(4-methoxyphenyl)-7,7-
dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quin-
oline-3-carbonitrile (4b): Yield 93%, off white solid, mp.
326
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Fused 7-Azaindole Derivatives
2 Hz, Ar-H), 8.68 (1H, s, -NH); 13C NMR (75 MHz, CDCl3) d =
27.94 (C(CH3)2), 29.62 (C(CH3)3), 32.27 (C(CH3)2), 35.02 (CH-
Ar) 41.07 (CH2C = C), 50.63 (CH2C = O), 57.57 (C(CH3)3), 87.78
(CN), 106.29 (C-CN), 106.97 (= C-CO), 116 (= C-C-CN), 123.57
(Ar-CH), 127.35 (Ar-CH), 128.44 (Ar-C), 128.81 (Ar-CH),
131.27 (Ar-C-Cl), 133.20 (Ar-C-Cl), 132.81 (N-CH), 143.78 (C =
C-CO), 151.95 (N-C-NH), 194.36 (C = O); MS (ESI): 442 (M+).
1-tert-butyl-4-(3-fluoro-4-methoxyphenyl)-7,7-dimethyl-5-oxo-
4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-carboni-
trile (4g): Yield 88%, white solid, mp. 151-153 °C; IR (KBr,
cm-1): 3326, 2960, 2230, 1595, 1530, 1496, 1390, 1250, 1226,
1185, 1028, 846, 801; 1H NMR (400 MHz, DMSO-d6) d = 0.92 (s,
3H, CH3), 1.03 (s, 3H, -CH3), 1.57 (s, 9H, t-Bu), 1.97-2.20 (m,
2H, -CH2CO), 2.54-2.71 (m, 2H, -CH2), 3.76 (s, 3H, -OCH3), 4.96
(s, 1H, Ar-CH), 6.82-6.88 (m, 2H, Ar-H,), 6.99-7.03 (m, 1H,
Ar-H), 7.32 (s, 1H, Pyrrole-CH), 8.68 (1H, s, -NH); MS (ESI):
422 (M + 1). 1-tert-butyl-4-(4-cyanophenyl)-7,7-dimethyl-5-
oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-car-
bonitrile (4h): Yield 89%, off white solid, mp. 231-233 °C; IR
(KBr, cm-1): 3335, 2250, 2218, 1630, 1620, 1522, 1380, 1333,
1190, 1015, 852, 774, 648; 1H NMR (400 MHz, DMSO-d6) d =
0.9 (s, 3H, -CH3), 1.03 (s, 3H, -CH3), 1.57 (s, 9H, t-Bu), 1.96-2.20
(m, 2H, -CH2CO), 2.54-2.72 (m, 2H, -CH2), 5.08 (s, 1H, Ar-CH),
7.29-7.34 (m, 3H, Ar-H, Pyrrole-CH), 7.70-7.72 (m, 2H, Ar-H),
8.76 (s, 1H, -NH); MS (ESI): 399 (M + 1). 1-tert-butyl-7,7-
dimethyl-5-oxo-4-(thiophen-2-yl)-4,5,6,7,8,9-hexahydro-1H-
pyrrolo[2,3-b]quinoline-3-carbonitrile (4i): Yield 86%, green-
ish white solid, mp. 161-163 °C; IR (KBr, cm-1): 3320, 2966,
2232, 1598, 1530, 1495; 1H NMR (400 MHz, DMSO-d6): d = 0.92
(s, 3H, -CH3), 1.05 (s, 3H, -CH3), 1.58 (s, 9H, t-Bu), 1.94-2.17 (m,
2H, -CH2CO), 2.53-2.68 (m, 2H, -CH2), 5.02 (s, 1H, Ar-CH),
7.03-7.10 (m, 1H, Thiophene-H), 7.17-7.20 (m, 1H, Thiophene-
H), 7.30 (s, 1H, Pyrrole -CH), 7.51-7.53 (m, 1H, Thiophene-H),
8.63 (1H, s, -NH); MS (ESI): 380 (M + 1). 1-tert-butyl-4-
(furan-2-yl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyr-
rolo[2,3-b]quinoline-3-carbonitrile (4j): Yield 87%, yellowish
white solid, mp. 169-171 °C; IR (KBr, cm-1): 3330, 2962, 2228,
1597, 1535, 1495; 1H NMR (400 MHz, DMSO-d6): d = 0.92 (s,
3H, -CH3), 1.04 (s, 3H, -CH3), 1.52 (s, 9H, t-Bu), 1.92-2.11 (m,
2H, -CH2CO), 2.59-2.66 (m, 2H, -CH2), 5.03 (s, 1H, Ar-CH),
7.11-7.13 (m, 1H, Furan-H), 7.22-7.28(m, 1H, Furan-H), 7.32 (s,
1H, Pyrrole-CH), 7.59-7.62 (m, 1H, Furan-H), 8.65 (1H, s, -NH);
MS (ESI): 364 (M + 1). 1-tert-butyl-4-(4-chlorophenyl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-
3-carbonitrile (5a): Yield 94%, off white solid, mp. 166-168 °C,
IR (KBr, cm-1): 3149, 2962, 2221, 1689, 1574, 1524, 1492, 1395,
1370, 1302, 1257, 1202, 1087, 1015, 812, 749, 626; 1H NMR (400
MHz, CDCl3) d = 1.07 (s, 6H, 2x-CH3), 1.77 (s, 9H, t-Bu), 2.44 (s,
2H, -CH2CO), 3.12 (s, 2H, -CH2), 7.10 (d, 2H, J = 8.5 Hz, Ar-H),
7.37 (d, 2H, J = 8.5 Hz, Ar-H), 7.76 (s, 1H, Pyrrole-CH); MS
(ESI): 406 (M + 1). 1-tert-butyl-4-(4-methoxyphenyl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-
3-carbonitrile (5b): Yield 93%, off white solid, mp. 274-276 °C;
IR (KBr, cm-1): 3120, 2956, 2222, 1681, 1574, 1510, 1465, 1390,
1
1365, 1230, 1205, 1172, 1026, 818, 632; H NMR (400 MHz,
CDCl3) d = 1.06 (s, 6H, 2x-CH3) 1.77 (s, 9H, t-Bu), 2.44 (s, 2H,
-CH2CO), 3.11 (s, 2H, -CH2), 3.79 (s, 3H, -OCH3), 6.93 (d, 2H, J
= 8.7 Hz, Ar-H), 7.10 (d, 2H, J = 8.7 Hz, Ar-H), 7.74 (s, 1H,
Pyrrole-CH); MS (ESI): 402 (M + 1). 1-tert-butyl-4-(4-
hydroxy-3-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (5c): Yield
95%, white solid, mp. 232-234 °C; IR (KBr, cm-1): 3390, 2956,
2220, 1681, 1573, 1513, 1467, 1395, 1254, 1227, 1202, 1032,
768; 1H NMR (400 MHz, CDCl3) d = 1.07 (s, 6H, 2x-CH3) 1.77 (s,
9H, t-Bu), 2.45 (s, 2H, -CH2CO), 3.11 (s, 2H, -CH2), 3.82 (s, 3H,
-OCH3), 5.65 (broad s, 1H, -OH), 6.61-6.66 (m, 1H, Ar-H),
6.71-6.74 (m, 1H, Ar-H), 6.92 (d, 1H, J = 7.9 Hz, Ar-H), 7.75 (s,
1H, Pyrrole-CH); MS (ESI): 418 (M + 1). 1-tert-butyl-7,7-
dimethyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-
1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (5d): Yield 92%,
white solid, mp. 222-224 °C; IR (KBr, cm-1): 3115, 2955, 2220,
1680, 1572, 1511, 1465, 1390, 1365; 1H NMR (400 MHz, CDCl3)
d = 1.06 (s, 6H, 2x-CH3) 1.77 (s, 9H, t-Bu), 2.44 (s, 2H, -CH2CO),
3.11 (s, 2H, -CH2), 3.79 (s, 3H, -OCH3), 3.86 (s, 6H, 2x-OCH3),
6.90 (s, 2H, Ar-H), 7.74 (s, 1H, Pyrrole-CH); MS (ESI): 462 (M +
1). 4-(benzo[d][1,3]dioxol-5-yl)-1-tert-butyl-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-3-carbon-
itrile (5e): Yield 96%, off white solid, mp. 138-140 °C; IR (KBr,
cm-1): 3115, 2960, 2233, 1612, 1535, 1499, 1432, 1390, 1255,
1228, 1121, 1030, 846, 805; 1H NMR (400 MHz, CDCl3) d = 1.15
(s, 3H, -CH3), 1.16 (s, 3H, -CH3), 1.86 (s, 9H, t-Bu), 2.54 (s, 2H,
-CH2CO), 3.20 (s, 2H, -CH2), 5.92 (s, 2H, -OCH2O), 6.04 (d, 1H,
J = 8 Hz, Ar-H), 6.71-6.73 (m, 1H, Ar-H), 6.93-6.95 (m, 1H,
Ar-H), 7.85 (s, 1H, Pyrrole-CH); MS (ESI): 416 (M + 1). 1-tert-
butyl-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (5f): Yield
91%, off white solid, mp. 250-252 °C; IR (KBr, cm-1): 3105,
1
2227, 1634, 1622, 1522, 1381, 1195, 1017, 850, 775, 658; H
NMR (400 MHz, CDCl3) d = 1.16 (s, 6H, 2x-CH3), 1.87 (s, 9H,
t-Bu), 2.49-2.60 (m, 2H, -CH2CO), 3.22 (s, 2H, -CH2), 7.16 (d,
1H, J = 8 Hz, Ar-H), 7.38-7.40 (m, 1H, Ar-H), 7.54 (s, 1H, Ar-H),
7.87 (s, 1H, Pyrrole-CH); 13C NMR (75 MHz, CDCl3) d = 27.91
(C(CH3)2), 28.47(C(CH3)2), 29.13(C(CH3)3), 32.45 (C(CH3)2),
48.12 (CH2C = C), 53.44 (CH2C = O), 59.19 (C(CH3)3), 84.71
J. Chin. Chem. Soc. 2016, 63, 323-330
© 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
327

Article
Dongare et al.
(CN), 113.85 (C-CN), 119.35 (= C-CO), 120.10 (= C-C-CN),
127.00 (Ar-CH), 129.16 (Ar-CH), 130.03 (Ar-CH), 132.95 (Ar-
C-Cl), 134.32 (Ar-C-Cl), 134.70 (Ar-C), 135.72 (Pyrrole-CH),
140.79 (Pyridene-C4), 148.01 (C = C-CO), 158.42 (N-C = N),
197.54 (C = O); MS (ESI): 441 (M + 1). 1-tert-butyl-4-(3-
fluoro-4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (5g): Yield
90%, off white solid, mp. 181-183 °C; IR (KBr, cm-1): 3102,
2958, 2228, 1597, 1530, 1497, 1385, 1252, 1226, 1180, 840, 798;
1H NMR (400 MHz, DMSO-d6) d = 1.08 (s, 6H, 2x-CH3), 1.75 (s,
9H, t-Bu), 2.26-2.39 (m, 2H, -CH2CO), 3.09-3.14 (m, 2H, -CH2),
3.78 (s, 3H, -OCH3), 6.80-6.89 (m, 2H, Ar-H,), 7.12-7.25 (m, 1H,
Ar-H), 7.78 (s, 1H, Pyrrole-CH); MS (ESI): 420 (M + 1). 1-tert-
butyl-4-(4-cyanophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (5h): Yield
92%, off white solid, mp. 182-184 °C; IR (KBr, cm-1): 3123,
2245, 2221, 1629, 1623, 1531, 1378, 1335, 1190, 1017, 852, 778,
93%, yellow solid, mp. 316-318 °C; IR (KBr, cm-1): 3397, 3145,
3069, 3045, 2977, 2915, 2221, 1713, 1587, 1565, 1520, 1503,
1470, 1454, 1384, 1370, 1348, 1336, 1300, 1276, 1226, 1197,
1180, 1117, 1085, 999, 964, 930, 837, 810, 767, 759, 726, 693,
1
666, 660; H NMR (400 MHz, CDCl3): d = 1.87 (s, 9H, t-Bu),
6.87–6.93 (m, 3H, Ar-H), 7.30 (t, 1H, J = 7.7 Hz, Ar-H),
7.48-7.52 (m, 1H, Ar-H), 7.57-7.60 (m, 1H, Ar-H), 7.67-7.73 (m,
1H, Ar-H), 7.88-7.90 (m, 1H, Ar-H), 8.50 (s, 1H, Pyrrole-CH),
9.55 (s, 1H, -OH); MS (ESI): 394 (M + 1). 1-tert-butyl-5-oxo-
4-(3,4,5-trimethoxyphenyl)-1,5-dihydroindeno[1,2-b]pyrrolo
[3,2-e]pyridine-3-carbonitrile (6c): Yield 96%, yellow solid,
mp. 210-212 °C; IR (KBr, cm-1): 3142, 3052, 2994, 2255, 1704,
1608, 1596, 1461; 1H NMR (400 MHz, CDCl3): d = 1.89 (s, 9H,
t-Bu), 3.62 (s, 3H, OCH3), 3.70 (s, 6H, 2xCH3), 6.68 (s, 2H,
Ar-H), 7.36-7.40 (m, 1H, Ar-H), 7.54-7.62 (m, 2H, Ar-H), 7.81 (s,
1H, Pyrrole-CH), 7.88 (m, 1H, Ar-H); MS (ESI): 468 (M + 1).
4-(benzo[d][1,3]dioxol-5-yl)-1-tert-butyl-5-oxo-1,5-dihydroin-
deno[1,2-b]pyrrolo[3,2-e]pyridine-3-carbonitrile (6d):Yield
91%, yellow solid, mp. 215-217 °C; IR (KBr, cm-1): 3144, 3055,
2999, 2256, 1705, 1605, 1590, 1460; 1H NMR (400 MHz, CDCl3)
d = 1.92 (s, 9H, t-Bu), 6.09 (s, 2H, -OCH2O), 6.98-7.05 (m, 3H,
Ar-H), 7.40-7.44 (m, 1H, Ar-H), 7.58-7.67 (m, 2H, Ar-H), 7.83 (s,
1H, Pyrrole-CH). 7.90 (d, 1H, J = 8 Hz, Ar-H); MS (ESI): 422 (M
+ 1). 1-tert-butyl-4-(2,4-dichlorophenyl)-5-oxo-1,5-dihydro-
indeno[1,2-b]pyrrolo[3,2-e]pyridine-3-carbonitrile (6e): Yield
90%, yellow solid, mp. 238-240 °C; IR (KBr, cm-1): 3145, 3050,
2992, 2249, 1710, 1600, 1592, 1465; 1H NMR (400 MHz, CDCl3)
d = 1.93 (s, 9H, t-Bu), 7.32 (d, 1H, J = 8 Hz, Ar-H), 7.41-7.45 (m,
2H, Ar-H), 7.60-7.66 (m, 3H, Ar-H), 7.83 (s, 1H, Pyrrole-CH),
7.93 (d, 1H, J = 8 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) d =
29.28 (C(CH3)3), 59.60 (C(CH3)3), 86.08 (CN), 113.97 (C-CN),
119.56 (= C-C-CN), 120.63 (Pyridine-C-CO), 120.71 (Ar-CH),
123.81 (Ar-CH), 127.00 (Ar-CH), 129.51 (Ar-CH), 129.84
(Ar-C-CO), 130.97 (Ar-CH), 131.27 (Ar-CH), 133.96 (Ar-C-Cl),
134.77 (Ar-CH), 134.98 (Pyrrole-CH), 136.00 (Ar-C-Cl), 136.41
(Ar-C), 138.18 (Pyridine-C4), 143.32 (C = C-CO), 149.43 (N-C =
C-CO), 160.44 (N-C = N), 190.26 (C = O); MS (ESI): 447 (M +
1). 1-tert-butyl-4-(3-fluoro-4-methoxyphenyl)-5-oxo-1,5-di-
hydroindeno[1,2-b]pyrrolo[3,2-e]pyridine-3-carbonitrile
(6f): Yield 91%, yellow solid, mp. 256-258 °C; IR (KBr, cm-1):
3130, 3045, 2990, 2245, 1705, 1605, 1595, 1466; 1H NMR (400
MHz, CDCl3) d = 1.92 (s, 9H, t-Bu), 4.0 (s, 3H, OCH3), 7.12-7.16
(d, 1H, J = 8 Hz, Ar-H), 7.30-7.32 (m, 2H, Ar-H), 7.41-7.45 (t,
1H, J = 8 Hz, Ar-H), 7.59-7.67 (m, 2H), 7.84 (s, 1H, Pyrrole-CH),
7.90 (d, 1H, J = 8 Hz, Ar-H); MS (ESI): 426 (M + 1). 1-tert-
butyl-4-(4-cyanophenyl)-5-oxo-1,5-dihydroindeno[1,2-b]pyr-
rolo[3,2-e]pyridine-3-carbonitrile (6g): Yield 90%, yellow
1
650; H NMR (400 MHz, DMSO-d6) d = 1.13 (s, 6H, 2x-CH3),
1.86 (s, 9H, t-Bu), 2.29 (m, 2H, -CH2CO), 2.87-3.02 (m, 2H,
-CH2), 7.40 (d, 2H, J = 8.5 Hz, Ar-H), 7.84-7.97 (m, 3H, Ar-H,
Pyrrole-CH); MS (ESI): 397 (M+1). 1-tert-butyl-7,7-dimethyl-
5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-
b]quinoline-3-carbonitrile (5i): Yield 93%, gray solid, mp.
172-174 °C; IR (KBr, cm-1): 3124, 3056, 2985, 2245, 1685, 1610,
1595; 1H NMR (400 MHz, CDCl3) d = 1.16 (s, 6H, 2x-CH3), 1.86
(s, 9H, t-Bu), 2.56 (s, 2H, -CH2CO), 3.21 (s, 2H, -CH2), 7.06-7.15
(m, 1H, Thiophene-H), 7.20-7.22 (m, 1H, Thiophene-H), 7.54-
7.56 (m, 1H, Thiophene-H), 7.86 (s, 1H, Pyrrole-CH); MS (ESI):
378 (M + 1). 1-tert-butyl-4-(furan-2-yl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile
(5j): Yield 94%, yellowish white solid, mp. 157-159 °C; IR (KBr,
cm-1): 3144, 3060, 2988, 2248, 1695, 1612, 1597; 1H NMR (400
MHz, CDCl3) d = 1.25 (s, 6H, 2x-CH3), 1.94 (s, 9H, t-Bu), 2.65 (s,
2H, -CH2CO), 3.29 (s, 2H, -CH2), 7.14-7.15 (m, 1H, Furan-H),
7.28-7.31 (m, 1H, Furan-H), 7.63-7.64 (m, 1H, Furan-H), 7.95 (s,
1H, Pyrrole-CH); MS (ESI): 362 (M + 1). 1-tert-butyl-4-
(4-chlorophenyl)-5-oxo-1,5-dihydroindeno[1,2-b]pyrrolo[3,2-e]
pyridine-3-carbonitrile (6a): Yield 95%, yellow solid, mp.
281-283 °C; IR (KBr, cm-1): 3143, 3076, 3028, 2980, 2935, 2878,
2222, 1704, 1667, 1607, 1594, 1574, 1556, 1523, 1486, 1465,
1384, 1370, 1351, 1332, 1294, 1257, 1234, 1198, 1177, 1156,
1115, 1088, 1014, 946, 893, 865, 841, 818, 787, 766, 731, 714,
706, 658, 628; 1H NMR (400 MHz, CDCl3): d = 1.89 (s, 9H, t-Bu),
7.36-7.51 (m, 5H, Ar-H), 7.54-7.62 (m, 2H, Ar-H), 7.80 (s, 1H,
Pyrrole-CH), 7.88 (dd, 1H, J = 8.0, 1.5 Hz, Ar-H); MS (ESI): 412
(M + 1). 1-tert-butyl-4-(3-hydroxyphenyl)-5-oxo-1,5-dihydro-
indeno[1,2-b]pyrrolo[3,2-e]pyridine-3-carbonitrile (6b): Yield
328
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© 2016 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2016, 63, 323-330

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Fused 7-Azaindole Derivatives
solid, mp. 180-182 °C; IR (KBr, cm-1): 3125, 3040, 2996, 2240,
2245, 1708, 1604, 1595, 1465; 1H NMR (400 MHz, CDCl3): d =
1.93 (s, 9H, t-Bu), 7.45 (t, 1H, J = 8 Hz, Ar-H), 7.61-7.66 (m, 4H,
Ar-H), 7.84-7.86 (m, 3H, Ar-H, Pyrrole-CH), 7.93 (d, 1H, J = 8
Hz, Ar-H); MS (ESI): 403 (M + 1). 1-tert-butyl-5-oxo-4-(thio-
phen-2-yl)-1,5-dihydroindeno[1,2-b]pyrrolo[3,2-e]pyridine-3-
carbonitrile (6h): Yield 88%, yellow solid, mp. 284-286 °C; IR
(KBr, cm-1): 3151, 3099, 3083, 3074, 2983, 2968, 2213, 1713,
1606, 1597, 1564, 1527, 1512, 1481, 1466, 1454, 1429, 1387,
1367, 1347, 1293, 1256, 1245, 1202, 1179, 1146, 1113, 1037, 942,
859, 762, 721, 695, 664, 638, 621; 1H NMR (400 MHz, CDCl3) d
= 1.88 (s, 9H, t-Bu), 7.22-7.25 (m, 1H, Ar-H), 7.33-7.41 (m, 2H,
Ar-H), 7.53-7.64 (m, 3H, Ar-H), 7.80 (s, 1H, Pyrrole-CH), 7.85-
7.87 (m, 1H, Ar-H); MS (ESI): 384 (M + 1). 1-tert-butyl-4-(2,4-
difluorophenyl)-5-oxo-1,5-dihydroindeno[1,2-b]pyrrolo[3,2-
e]pyridine-3-carbonitrile (6i): Yield 95%, yellow solid, mp.
265-267 °C; IR (KBr, cm-1): IR (KBr, cm-1): 3150, 3095, 3080,
3071, 2980, 2960, 2215, 1710, 1606, 1592; 1H NMR (400 MHz,
CDCl3) d = 1.93 (s, 9H, t-Bu), 7.04-7.11 (m, 2H, Ar-H), 7.41-7.49
(m, 2H, Ar-H), 7.60-7.64 (t, 1H, J = 8 Hz, Ar-H), 7.66 (d, 1H, J =
8 Hz, Ar-H), 7.84 (s, 1H, Pyrrole-CH), 7.92 (d, 1H, J = 8 Hz,
Ar-H); MS (ESI): 413 (M+).
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Kim, B. H. Org. Biomol. Chem. 2007, 5, 2472-2485; (f) Lee,
J. J.; Kim, J.; Jun, Y. M.; Lee, B. M.; Kim, B. H. Tetrahedron
2009, 65, 8821-8831.
10. Go, A.; Lee, G.; Kim, J.; Bae, S.; Lee, B. M.; Kim, B. H. Tet-
rahedron 2015, 71, 1215-1226.
11. Muthusamy, S.; Sivaguru, M.; Suresh, E. Chem. Commun.
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