Synthesis of four series of quinoline-based heterocycles by reacting 2-chloroquinoline-3-carbonitriles with various types of isocyanides

Article abstract of DOI:10.1002/aoc.5024

Four distinct sets of functionalized quinolines were synthesized by reacting 2-chloroquinoline-3-carbonitriles with various types of isocyanides under appropriate conditions. The palladium-catalysed reaction of less hindered aliphatic and aromatic isocyan

Full text of DOI:10.1002/aoc.5024

Received: 9 March 2019
DOI: 10.1002/aoc.5024
Revised: 9 May 2019
Accepted: 11 May 2019
F U L L P A P E R
Synthesis of four series of quinoline‐based heterocycles by
reacting 2‐chloroquinoline‐3‐carbonitriles with various
types of isocyanides
Zahra Tanbakouchian1 | Mohammad Ali Zolfigol1
Morteza Shiri3
| Behrouz Notash2 | Maryam Ranjbar3 |
1 Faculty of Chemistry, Bu‐Ali Sina
University, Hamedan 6517838683, Iran
Four distinct sets of functionalized quinolines were synthesized by reacting
2‐chloroquinoline‐3‐carbonitriles with various types of isocyanides under
appropriate conditions. The palladium‐catalysed reaction of less hindered
aliphatic and aromatic isocyanides with 2‐chloroquinoline‐3‐carbonitriles
yielded 2‐alkyl(aryl)‐1‐imino‐1H‐pyrrolo[3,4‐b]quinolin‐3(2H)‐one derivatives;
however, the catalysed reaction of more hindered isocyanides such as
tert‐butyl isocyanide produced the corresponding 3‐cyanoquinoline‐2‐
carboxamides. Interestingly, chloroquinoline‐3‐carbonitriles reacted with ethyl
isocyanoacetate in the presence of Cs2CO3 to generate imidazo[1,5‐a]quinoline
derivatives; notably, tosylmethyl isocyanide under the same conditions formed
unprecedented 2‐tosyl‐3‐cyanoquinolines.
2 Department of Chemistry, Shahid
Beheshti University, G. C. Evin, Tehran
1983963113, Iran
3 Department of Chemistry, Faculty of
Physics and Chemistry, Alzahra
University, Vanak, Tehran 1993893973,
Iran
Correspondence
Mohammad Ali Zolfigol, Faculty of
Chemistry, Bu‐Ali Sina University,
Hamedan 6517838683, Iran.
Email: zolfi@basu.ac.ir
Morteza Shiri, Department of Chemistry,
Faculty of Physics and Chemistry, Alzahra
University, Vanak, Tehran 1993893973,
Iran.
KEYWORDS
C–C bond formation, isocyanides, palladium, TosMIC, tosylquinolines
Email: mshiri@alzahra.ac.ir
Funding information
Iran National Science Foundation (INSF)
1 | INTRODUCTION
reported Pd‐catalysed isocyanide insertion into the
C–SMe bond of 2‐(methylthio)thiophene‐3‐carbonitriles,
The nucleophilicity and electrophilicity of isocyanides
have made them powerful reagents for synthesizing
nitrogen‐containing heterocycles. Despite significant
efforts in isocyanide chemistry in recent decades,[1]
reports of isocyanide insertion or cyclization reactions
with various nucleophiles, which involve their
addition to adjacent electrophilic functional groups,
are rare. Recent examples are tandem Pd‐catalysed
carboxamidation and hydroamidation for synthesizing
isoindolin‐1‐ones2a and the reaction of α‐acyl ketene
dithioacetals involving C–S bond activation/isocyanide
insertion/hydration to produce 5‐hydroxy‐α,β‐unsaturated
γ‐lactams2b via intramolecular cyclization. Vahabi et al.
followed by amidation and cyclization in acidic media to
form thieno[2,3‐c]pyrroles via a two‐step method.3a In
the presence of Pd, 2‐chloroquinoline‐3‐carbaldehydes
reacted with isocyanides to afford pyrrolo[3,4‐b]quinolinyl
derivatives.3b
To the best of our knowledge, there are few recent
reports regarding the synthesis of 5‐imino‐1‐alkyl‐1H‐
pyrrol‐2(5H)‐ones. For instance, 5‐imino‐6‐methyl‐5H‐
pyrrolo[3,4‐b]pyridin‐7(6H)‐ones were the side products
of
a
ring contraction reaction of 7‐methyl‐1,7‐
naphthylidinium iodide with liquid ammonia/potassium
permanganate.[4] In 1984, the synthesis of aza analogues
of 1‐iminoisoindoline‐3‐ones from ethyl‐2‐cyanobenzoate
Appl Organometal Chem. 2019;e5024.
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TANBAKOUCHIAN ET AL.
was reported.[5] Biological effects are exhibited by 5‐
imino‐1‐alkyl‐1H‐pyrrol‐2(5H)‐ones. Cyclohexylglycine‐
based matrix metalloproteinase (MMP) inhibitors were
synthesized; they exhibited selective inhibition for five
enzymes of the MMP family. The potential of an inhibitor
depends on the nature of the substituent binding interac-
tions.[6] A β‐carboline derivative (I) inhibits MMP‐2 and
can form a covalent bond with blood proteins via its reac-
tive maleimide group (Figure 1).[7]
Sulfones have attractive moieties and exhibit biological
activity.[8] Sulfonyl halides,[9] sulfonyl hydrazides,[10]
sulfinic acid[11] and sodium sulfinate[12] are commonly
known sulfonyl reagents. In the literature, p‐tosylmethyl
isocyanide (TosMIC) is widely used as a 1,3‐dipolar
reagent in cycloaddition reactions with double and triple
bonds. Recently, a few reports have focused on the use of
TosMIC as a sulfonyl precursor. Further, the I2‐catalysed
syntheses of vinyl and allyl sulfones from olefins and
alkynes with TosMIC have been reported.[13] Similarly,
studies of the Ag‐catalysed reactions of propargylic
alcohols with E‐vinylsulfones[14] or benzoheteroles[15]
with TosMIC have been published. Additionally,
stereoselective syntheses of E‐vinylsulfones from alkynes
and TosMIC that are catalysed with magnetically recover-
able Cu0/Fe3O4 are among recent publications.[16] In
these studies, while there are no reports of the direct
sulfonation of aromatic compounds with TosMIC, the
triple bond transformed to sulfone products. Notably, 2‐
chloroquinolines have been mainly used as starting mate-
rials for synthesizing quinoline derivatives.[17]
10 mol% of palladium acetate, with 2 equiv. of Cs2CO3,
in 1,4‐dioxane as solvent at 100°C as a model reaction.
Product 3a was isolated in 67% yield. This interesting
result encouraged us to optimize the reaction conditions.
Various solvents, bases, palladium sources and reaction
temperatures were tested to optimize the reaction time
and product yield. Employing solvents such as CH3CN,
EtOH, 1,4‐dioxane, dimethylsulfoxide (DMSO) and
dimethylformamide (DMF) indicated that the best result
is achieved using DMF, which afforded complete conver-
sion to the desired product 3a (Table 1, entries 1–5).
However, the results with DMSO and DMF were not
significantly different; as such, DMSO was selected as it
is safer. Reducing the amount of catalyst to 5 mol%
decreased the product yield (Table 1, entry 6). Adding
Ph3P as a ligand did not influence the yield (Table 1,
entry 7). Using a base significantly affected the reaction
completion. Therefore, the efficiencies of various bases
were evaluated (Table 1, entries 10–13). The reaction
was completed using KOtBu and K2CO3 but with a long
reaction time (Table 1, entries 10 and 11). Using Et3N
and pyridine did not afford the desired product. Decreasing
the amount of Cs2CO3 to 1.5 equiv. did not change the yield
TABLE 1 Optimization of reaction conditions for synthesis of 3aa
Time Yield (%)b
Entry Catalyst Base
Solvent
(h)
1
Pd(OAc)2 Cs2CO3 1,4‐Dioxanec
Pd(OAc)2 Cs2CO3 CH3CNc
Pd(OAc)2 Cs2CO3 EtOHc
Pd(OAc)2 Cs2CO3 DMF
Pd(OAc)2 Cs2CO3 DMSO
Pd(OAc)2 Cs2CO3 DMSO
Pd(OAc)2 Cs2CO3 DMSO
8
8
89
50
55
92
91
28
91
88
90
85
90
0
2
Herein, continuing our investigations of quinoline
18
chemistry,3b,
we report the functionalization of
3
7
quinoline‐3‐carbonitriles with isocyanides under various
reaction conditions. The nitrile group is important
because it is easily converted to amines, tetrazoles, acids,
ketones, guanidines, amidines and other structural units
with useful pharmacophores.
4
1
5
1
6d
7e
8
7
1
PdCl2
Cs2CO3 DMSO
7
9f
10
11
12
13
14
Pd(OAc)2 Cs2CO3 DMSO
1
2 | RESULTS AND DISCUSSION
Pd(OAc)2 KOt‐Bu DMSO
2
Pd(OAc)2 K2CO3
Pd(OAc)2 Et3N
DMSO
—
7
Our primary research interest is the rational design and
synthesis of novel bioactive quinolines. Thus, we report
the treatment of 2‐chloroquinoline‐3‐carbonitrile (1a)
and cyclohexyl isocyanide (2a) in the presence of
24
24
24
Pd(OAc)2 Pyridine
—
0
None
Cs2CO3 DMSO
0
aAll reactions were carried out using 1a (1 mmol), 2a (1.1 mmol), catalyst
(10 mol%), base (2 equiv.) and solvent +10% (v/v) H2O (5.0 ml) at 100°C
unless otherwise noted.
bIsolated yields.
cAt reflux temperature of the solvent.
d5 mol% of Pd(OAc)2 was used.
e20 mol% of Ph3P was used.
f1.5 equiv. of Cs2CO3 was used.
FIGURE 1 Structure of β‐carboline derivative of I

TANBAKOUCHIAN ET AL.
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FIGURE 2 Synthesis of various 2‐
alkyl(aryl)‐1‐imino‐1H‐pyrrolo[3,4‐b]
quinolin‐3(2H)‐ones (3a–i) and N‐(t‐
butyl)‐3‐cyanoquinoline‐2‐carboxamides
(4a–d)
of 3a (Table 1, entry 9). Finally, the control experiment
indicated that the desired product could not be afforded
without the Pd catalyst (Table 1, entry 14). Therefore,
Pd(OAc)2 (10 mol%) with Cs2CO3 (1.5 equiv.) at 100°C
were selected as the optimized conditions based on cost,
reaction time and yield (Table 1, entry 9).
This result prompted us to optimize these reaction
conditions. This is the first report regarding the prepara-
tion of aromatic sulfone compounds using TosMIC as a
sulfonyl agent via aromatic nucleophilic substitution.[15]
TABLE 2 Optimization of reaction conditions for synthesis of 6aa
To investigate the generality, scope and limitations of
the reaction, various 2‐chloroquinoline‐3‐carbonitriles
(1) possessing a variety of substituents were examined
under the optimized reaction conditions (Figure 2). The
behaviour of cyclohexyl, n‐butyl and phenyl isocyanides
was the same. However, with t‐butyl isocyanide, the reac-
tion stopped at amide formation to generate 4, which
probably occurred owing to steric hindrance; no cycliza-
tion occurred even after 24 h. Further, the effects of
various substituents on 1 such as Me, OMe and Cl were
explored. Lower yields and longer reaction times were
observed with OMe substituents (Figure 2). Moreover,
we extended our method using 2‐chloronicotinonitrile
and 2‐chlorobenzo[h]quinoline‐3‐carbonitrile as starting
materials under the optimized conditions to afford 3e,
3f and 3i (Figure 2). However, the reactions of 2‐
Entry Base
Catalyst Solvent Time (h) Yield (%)b
1
Cs2CO3 Pd(OAc)2 DMF
4
4
92
90
92
85
30
—
80
90
—
—
—
—
2
Cs2CO3 PdCl2
DMF
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOtBu
DABCO
Pyridine
—
—
—
—
—
—
—
—
—
I2
DMF
DMSO
EtOHc
4
4
4
5
24
6
Toluene 24
7
DMF
DMF
DMF
DMF
24
7
8
9
24
10
11
12
24
DMSOd 24
DMSOe 24
—
I2
chlorobenzonitrile,
5‐chloro‐1‐phenyl‐1H‐pyrazole‐4‐
carbonitrile and 1‐bromo‐2‐naphthonitrile failed to afford
the corresponding products.
aAll reactions were carried out using 1a (1 mmol), 5 (1.2 mmol), catalyst
(10 mol %), base (2.0 mmol) and solvent (5.0 ml) and stirred for 4 h at
100°C unless otherwise noted.
bIsolated yield.
cReflux.
dRoom temperature.
e120°C.
Next, TosMIC (5) was investigated through its reaction
with 1a under the optimum reaction conditions specified
above. Surprisingly, we obtained 2‐tosylquinoline‐3‐
carbonitrile (6a), in which TosMIC reacted as the sulfonyl
reagent (Scheme 1).
SCHEME 1 Reaction of 1a with
TosMIC

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TANBAKOUCHIAN ET AL.
for this conversion (Table 2, entries 3–6). Base screening
indicated no product formation with DABCO or
pyridine and lower yields with KOtBu and K2CO3
(Table 2, entries 7–10). No product was formed in the
presence of 1 equiv. of molecular iodine (Table 2, entries
11 and 12).
Using these optimized conditions (Table 2, entry 3),
various
2‐chloroquinoline‐3‐carbonitriles
and
2‐
chloronicotinonitrile were converted to the correspond-
ing 2‐tosylquinoline‐3‐carbonitriles (Figure 3, 6a–f).
A single‐crystal X‐ray structural analysis of 6b
confirmed its structure (Figure 4, and Supporting
information).[19]
We extended this reaction to ethyl isocyanoacetate
(7) and 1a, which, surprisingly, formed ethyl 4‐
cyanoimidazo[1,5‐a]quinoline‐3‐carboxylate (8a) in 91%
yield (Scheme 2). Other quinolines participated to form
the corresponding compounds (8b and 8c), to be quanti-
fied (Scheme 2).
The proposed reaction mechanism for the formation
of 3 and 4, shown in Scheme 3, was initiated by
the oxidative addition of 1 to the Pd catalyst to give
intermediate I. Inserting isocyanide into the C–Pd
bond provided intermediate II. The base‐mediated
replacement of OH− by Cl− in complex II followed by
reductive elimination resulted in III and a Pd(0) spe-
cies.[20] Finally, tautomerizing III formed 4 or base‐
promoted nucleophilic addition to the adjacent nitrile
afforded 3.
FIGURE
tosylpyridine‐3‐carbonitrile (6f)
3
2‐Tosylquinoline‐3‐carbonitriles (6a–e) and 2‐
Interestingly, using Pd(OAc)2, PdCl2 or omitting these
did not affect the yield of 6a (Table 2, entries 1–3).
Solvent screening showed that DMF is more efficient
The generation of various types of Ts components
by decomposing TosMIC has been reported.[13–15,21]
Therefore, Ts− was generated from TosMIC in the
presence of base and then reacted with
1 via
nucleophilic aromatic substitution at the 2‐position to
afford the desired product 6 (Scheme 4). Utilization of
TosMIC as sulfonyl source has been reported by Liu
et al. for the synthesis of sulfonyl benzoheterocycles,
sulfonated via a nucleophilic aliphatic substitution
mechanism.[15]
A plausible mechanism for synthesizing 8 involves
the nucleophilic addition of intermediate IV to imine
(N═C─Cl) followed by Cl− elimination to furnish VI
(Scheme 5).[22] Finally, base‐promoted proton removal
from VI followed by cyclization afforded 8.
FIGURE 4 X‐ray crystal structure of 6b
SCHEME 2 Reaction of 1 with ethyl
isocyanoacetate

TANBAKOUCHIAN ET AL.
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sulfonylation of 2‐chloroquinoline‐3‐carbonitrile. Further-
more, chloroquinoline‐3‐carbonitriles reacted with ethyl
isocyanoacetate in the presence of Cs2CO3 to yield
imidazo[1,5‐a]quinoline derivatives. All these products
were synthesised in practical conditions with short
reaction times and high yields. The proposed work
may provide novel and promising insights into the
course of rational design and the synthesis of novel
bioactive quinolines.
4 | EXPERIMENTAL
4.1 | General
The solvents and chemicals were purchased from Merck
and Aldrich. Unless otherwise mentioned they were
used without any further purification. Melting points
were obtained with an Electrothermal 9100 apparatus
and are uncorrected. Infrared (IR) spectra were recorded
with a Shimadzu IR‐435 spectrometer. NMR spectra were
recorded with a Bruker AVANCE spectrometer (400 MHz
for 1H, 100 MHz for 13C) in DMSO‐d6 and CDCl3 as
solvent. Tetramethylsilane was used as internal standard.
Elemental analysis was carried out with a Leco CHNS
model 932.
SCHEME 3 Plausible mechanism for synthesis of 3 and 4
SCHEME 4 Tosylation of quinolines and pyridine 1
4.2 | Typical procedure for synthesis of
2‐cyclohexyl‐1‐imino‐1H‐pyrrolo[3,4‐b]
quinolin‐3(2H)‐one (3a)
A mixture of 1 (188 mg, 1.0 mmol), Pd(OAc)2 (22 mg,
0.1 mmol), Cs2CO3 (488 mg, 1.5 mmol) and cyclohexyl
isocyanide (131 mg, 1.2 mmol) in DMSO + 10% (v/v)
H2O (5.0 ml) was heated at 100°C for 1 h. After completion
of the reaction (progress was monitored by TLC) the
reaction mixture was cooled to room temperature
and extracted with dichloromethane and brine. The
organic layer was concentrated, purified with trituration
with diethyl ether or column chromatography (EtOAc–n‐
hexane, 1:2) and washed to afford the desired product 3a.
SCHEME 5 Plausible mechanism for formation of 8
3 | CONCLUSIONS
The reactions of 2‐chloroquinoline‐3‐carbonitriles
with isocyanides under various conditions, which pro-
duced four types of quinoline derivatives, have been
described. 2‐Chloroquinoline‐3‐carbonitriles reacted with
isocyanides in the presence of Pd to produce imino‐1H‐
pyrrolo[3,4‐b]quinolin‐3(2H)‐one derivatives. This reac-
tion included the insertion of non‐bulky isocyanides in
C–Cl bonds, hydration and nucleophilic attack of amide
nitrogen to the adjacent electrophile CN group facilitated
by Cs2CO3. However, under the same conditions
tert‐butyl isocyanide produced the corresponding 3‐
cyanoquinoline‐2‐carboxamide. Interestingly, the use
of TosMIC in the presence of Cs2CO3 yielded the
4.2.1 | 2‐Cyclohexyl‐1‐imino‐1,2‐dihydro‐
3H‐pyrrolo[3,4‐b]quinolin‐3‐one (3a)
Yield: 0.251 g (90%); white solid; m.p. 184–186°C. FT‐IR
(KBr, νmax, cm−1): 3277, 2926, 2852, 1724, 1649. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.18–1.41 (m, 3H),
1.72 (m, 3H), 1.86 (m, 2H), 2.35 (m, 2H), 4.41 (m, 1H),
7.83 (t, J = 7.6 Hz, 1H), 7.99 (t, J = 7.2 Hz 1H), 8.19 (d,
J = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 9.12 (s, 1H),
10.32 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ,

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TANBAKOUCHIAN ET AL.
ppm): 25.6, 26.2, 29.4, 51.2, 122.7, 128.9, 129.4, 130.2,
130.7, 131.9, 132.4, 149.8, 150.0, 156.9, 165.6. Anal. calcd
for C17H17N3O (%): C, 73.10; H, 6.13; N, 15.04. Found
(%): C, 72.98; H, 6.11; N, 15.13.
4.2.5 | 2‐Cyclohexyl‐3‐iminoisoindolin‐1‐
one (3e)
Yield: 0.208 g (91%); white solid; m.p. 150–152°C. IR
(neat, νmax, cm−1): 3229, 2925, 2862, 1733, 1651. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.23–1.40 (m, 3H),
1.76 (m, 3H), 1.87 (m, 2H), 2.27 (m, 2H), 3.81 (m, 1H),
7.82 (m, 1H), 8.47 (t, J = 8.0, 1H), 8.89 (dd, J = 4.0 Hz,
8.0 Hz, 1H), 10.42 (s, NH, 1H). 13C NMR (101 MHz,
DMSO‐d6, δ, ppm): 22.8, 26.2, 32.0, 68.5, 121.3, 129.1,
131.2, 132.6, 150.0, 154.0, 168.3. Anal. calcd for
C13H15N3O (%): C, 68.10; H, 6.59; N, 18.33. Found (%):
C, 68.18; H, 6.71; N, 18.19.
4.2.2 | 2‐Cyclohexyl‐1‐imino‐5‐methyl‐1H‐
pyrrolo[3,4‐b]quinolin‐3(2H)‐one (3b)
Yield: 0.266 g (91%); white solid; m.p. 194–196°C. FT‐IR
(KBr, νmax, cm−1): 3272, 2929, 2860, 1726, 1646. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.18–1.41 (m, 3H),
1.72 (m, 3H), 1.86 (m, 2H), 2.38 (m, 2H), 2.81 (s, 3H),
4.42 (m, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.99 (t,
J = 7.2 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 9.25 (s, 1H),
10.29 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ,
ppm): 18.4, 24.9, 26.1, 29.4, 55.4, 123.2, 127.3, 129.1,
130.1, 132.4, 135.0, 136.6, 148.5, 148.6, 150.7, 157.5,
167.2. Anal. calcd for C18H19N3O (%): C, 73.69; H, 6.53;
N, 14.32. Found (%): C, 73.48; H, 6.71; N, 14.19.
4.2.6 | 9‐Cyclohexyl‐8‐imino‐8,9‐dihydro‐
10H‐benzo[h]pyrrolo[3,4‐b]quinolin‐10‐one
(3f)
Yield: 0.292 g (89%); white solid; m.p. 145–147°C. IR
(neat, νmax, cm−1): 3272, 2929, 2860, 1726, 1646. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.24 (m, 1H), 1.38
(m, 2H), 1.77 (m, 3H), 1.87 (m, 2H), 2.39 (m, 2H), 4.44
(m, 1H), 7.89 (m, 2H), 8.02 (d, J = 8.8 Hz, 1H), 8.16
(m, 2H), 9.14 (s, 1H), 9.28 (dd, J = 3.6 Hz, 6.0 Hz, 1H),
10.41(s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6,
δ, ppm): 25.6, 26.2, 29.6, 51.2, 124.0, 125.0, 126.7, 127.9,
128.4, 128.8, 130.1, 130.3, 131.3, 131.5, 134.4, 148.5,
148.6, 157.1, 165.9. Anal. calcd for C21H19N3O (%):
C, 76.57; H, 5.81; N, 12.76. Found (%): C, 76.48; H, 5.71;
N, 12.49.
4.2.3 | 2‐Cyclohexyl‐1‐imino‐7‐methyl‐1,2‐
dihydro‐3H‐pyrrolo[3,4‐b]quinolin‐3‐one
(3c)
Yield: 0.257 g (88%); white solid; m.p. 210–212°C. IR
(KBr, νmax, cm−1): 3272, 2929, 2860, 1726, 1646. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.21–1.41 (m, 3H),
1.71 (m, 3H), 1.86 (m, 2H), 2.36 (m, 2H), 2.59 (s,3H),
4.40 (m, 1H), 7.82 (dd, J = 2.0, 8.8 Hz, 1H), 7.95 (s, 1H),
8.18 (d, J = 8.4 Hz, 1H), 9.01 (s, 1H), 10.31 (s, NH, 1H).
13C NMR (101 MHz, DMSO‐d6, δ, ppm): 21.6, 25.5, 26.2,
29.4, 51.1, 122.8, 128.8, 128.9, 130.4, 131.1, 134.6, 139.5,
148.3, 157.0, 165.7. Anal. calcd for C18H19N3O (%):
C, 73.69; H, 6.53; N, 14.32. Found (%): C, 73.47; H, 6.71;
N, 14.19.
4.2.7 | 1‐Imino‐7‐methyl‐2‐phenyl‐1H‐
pyrrolo[3,4‐b]quinolin‐3(2H)‐one (3g)
Yield: 0.266 g (93%); pale yellow powder; m.p. 107–109°C.
FT‐IR (KBr, νmax, cm−1): 3272, 2929, 2860, 1726, 1646. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 2.52 (s, 3H), 7.11 (m,
3H), 7.22 (m, 1H), 7.32 (m, 1H), 7.82 (t, J = 10.0 Hz, 1H),
8.11 (t, J = 1.2 Hz, 2H), 8.19 (d, J = 1.2 Hz, 2H), 8.95 (s,
1H), 11.44 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6,
δ, ppm): 21.8, 106.3, 116.3, 120.4, 122.0, 129.1, 129.7,
130.0, 130.4, 134.4, 139.2, 139.4, 150.0, 159.3, 167.0. Anal.
calcd for C18H13N3O (%): C, 75.25; H, 4.56; N, 14.63.
Found (%): C, 75.17; H, 4.62; N, 14.77.
4.2.4 | 2‐Cyclohexyl‐1‐imino‐7‐methoxy‐
1H‐pyrrolo[3,4‐b]quinolin‐3(2H)‐one (3d)
Yield: 0.256 g (83%); white solid; m.p. 204–206°C. FT‐IR
(KBr, νmax, cm−1): 3272, 2929, 2860, 1726, 1646. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.03–1.15 (m, 5H),
1.62 (m, 3H), 1.88 (m, 2H), 3.83 (m, 1H), 3.97 (s, 3H),
7.58 (d, J = 3.6 Hz, 1H), 7.69 (dd, J = 4.0 Hz, 12.4 Hz,
1H), 8.20 (d, J = 12.4 Hz, 1H), 8.69 (d, J = 11.2 Hz, 1H),
10.53 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ,
ppm): 24.9, 25.3, 32.6, 56.4, 63.6, 106.4, 126.7, 128.7,
131.3, 144.5, 147.8.0, 157.1, 159.8, 162.3. Anal. calcd for
C18H19N3O2 (%): C, 69.88; H, 6.19; N, 13.58. Found (%):
C, 69.74; H, 6.08; N, 13.43.
4.2.8 | 2‐Butyl‐1‐imino‐1,2‐dihydro‐3H‐
pyrrolo[3,4‐b]quinolin‐3‐one (3h)
Yield: 0.232 g (92%); white solid; m.p. 149–152°C. FT‐IR
(KBr, νmax, cm−1): 3272, 2951, 1728, 1649. 1H NMR
(400 MHz, DMSO‐d6, δ, ppm): 0.94 (t, J = 7.4 Hz, 3H),

TANBAKOUCHIAN ET AL.
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1.35 (m, 2H), 1.69 (m, 2H), 3.84 (t, J = 9.0 Hz, 2H), 7.83 (t,
J = 7.2 Hz, 1H), 7.99 (t, J = 7.2 Hz, 1H), 8.19 (d,
J = 8.0 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 9.12 (s, 1H),
10.28 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ,
ppm): 14.1, 20.1, 30.2, 38.3, 123.0, 128.8, 129.4, 130.3,
130.8, 131.9, 132.4, 149.6, 150.2, 156.9, 165.7. Anal. calcd
for C15H15N3O (%): C,71.13; H, 5.97; N, 16.59. Found
(%): C, 71.28; H, 5.71; N, 16.38.
4.2.12 | N‐(tert‐butyl)‐3‐cyano‐6‐
methoxyquinoline‐2‐carboxamide (4c)
Yield: 0.223 g (79%); white solid; m.p. 180–182°C. FT‐IR
(KBr, νmax, cm−1): 3375, 2972, 2925, 2227, 1679, 1517.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.47 (s, 9H),
3.96 (s, 3H) 7.54 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.8,
9.6 Hz 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.25 (s, 1H), 9.00
(s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm):
28.8, 51.3, 56.4, 104.4, 106.3, 117.5, 126.7, 128.6, 131.2,
142.4, 144.7, 147.8, 159.8, 162.4. Anal. calcd for
C16H17N3O2 (%): C,67.73; H, 6.05; N, 14.83. Found (%):
C, 67.48; H, 6.11; N, 14.88.
4.2.9 | 9‐Butyl‐8‐imino‐8,9‐dihydro‐10H‐
benzo[h]pyrrolo[3,4‐b]quinolin‐10‐one (3i)
Yield: 0.266 g (88%); white solid; m.p. 200–202°C. FT‐IR
(KBr, νmax, cm−1): 3274, 2952, 1733, 1653. 1H NMR
(400 MHz, DMSO‐d6, δ, ppm): 0.97 (t, J = 7.2 Hz, 3H),
1.40 (m, 2H), 1.72 (m, 2H), 3.89 (t, J = 7.2 Hz, 2H), 7.89
(m, 2H), 8.03 (d, J = 8.8 Hz 1H), 8.17 (d, J = 8.4 Hz,
2H), 9.14 (d, J = 2.0 Hz, 1H), 9.29 (m, 1H), 10.38 (s,
NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 14.2,
20.1, 30.4, 38.4, 124.2, 124.9, 126.7, 127.8, 128.4, 128.8,
130.1, 130.4, 131.3, 131.5, 134.4, 148.4, 148.9, 157.0,
166.0. Anal. calcd for C19H17N3O (%): C, 75.23; H, 5.65;
N, 13.85. Found (%): C, 75.48; H, 5.71; N, 13.69.
4.2.13 | N‐(tert‐butyl)‐6‐chloro‐3‐
cyanoquinoline‐2‐carboxamide (4d)
Yield: 0.246 g (86%); white solid; m.p. 135–137°C. FT‐IR
(KBr, νmax, cm−1): 3391, 2960, 2923, 2854, 2221, 1741,
1
1527. H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.47 (s,
9H), 8.08 (dd, J = 2.4, 9.2 Hz, 1H), 8.26 (d, J = 8.8 Hz
1H), 8.31 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 9.19 (s, NH,
1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 28.7, 51.4,
105.2, 117.0, 127.6, 127.7, 131.8, 134.4, 134.5, 145.0,
145.8, 151.1, 162.4 ppm. Anal. calcd for C15H14ClN3O
(%): C, 62.61; H, 4.90; N, 14.60. Found (%): C, 62.49; H,
5.01; N, 14.49.
4.2.10 | N‐(tert‐butyl)‐3‐cyanoquinoline‐2‐
carboxamide (4a)
Yield: 0.225 g (89%); white solid; m.p. 130–132°C. FT‐IR
(KBr, νmax, cm−1): 3355, 3059, 2962, 2923, 2854, 2221,
1684, 1524. H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.48
4.3 | Typical procedure for synthesis of
2‐tosylquinoline‐3‐carbonitrile (6a or 8a)
1
(s, 9H), 7.87 (t, J = 7.4 Hz, 1H), 8.06 (t, J = 7.2 Hz, 1H),
8.20 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4, 1H), 8.36 (s,
1H), 9.25 (s, NH, 1H). 13C NMR (101 MHz, DMSO‐d6, δ,
ppm): 28.8, 51.5, 104.2, 109.3, 117.3, 127.0, 129.0, 129.7,
130.0, 134.2, 146.4, 146.6, 150.7, 162.6. Anal. calcd for
C15H15N3O (%): C,71.13; H, 5.97; N, 16.59. Found (%):
C, 71.28; H, 5.71; N, 16.38.
A mixture of 1a (188 mg, 1.0 mmol), Cs2CO3 (650 mg,
2.0 mmol) and TosMIC (5; 234 mg, 1.2 mmol) or ethyl
isocyanoacetate (7; 140 mg, 1.2 mmol) was added to
DMF (5.0 ml) in a reaction flask. Reaction was heated
at 100°C for the appropriate time. After completion
of the reaction (progress monitored by TLC) the
mixture was cooled to room temperature and extracted
with dichloromethane and brine. Organic layer was
concentrated and purified with column chromatography
(EtOAc–n‐hexane, 1:2) to afford the desired product
6a or 8a.
4.2.11 | N‐(tert‐butyl)‐3‐cyano‐6‐
methylquinoline‐2‐carboxamide (4b)
Yield: 0.234 g (88%); white solid; m.p. 157–159°C. FT‐IR
(KBr, νmax, cm−1): 3374, 2969, 2924, 2225, 1680, 1522.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.49 (s, 9H),
2.80 (s, 3H), 7.75 (t, J = 7.6 Hz, 1H), 7.92 (d, J = 6.8 Hz,
1H), 8.00 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 9.19 (s, NH,
1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 17.5, 28.7,
51.3, 103.9, 117.4, 126.8, 127.2, 129.9, 134.1, 137.5, 145.1,
146.9, 149.0, 162.3. Anal. calcd for C16H17N3O (%):
C, 71.89; H, 6.41; N, 15.72. Found (%): C, 71.77; H, 6.71;
N, 15.59.
4.3.1 | 2‐Tosylquinoline‐3‐carbonitrile (6a)
Yield: 0.283 g (92%); white solid; m.p. 200–202°C. FT‐IR
(KBr, νmax, cm−1): 2922, 2229, 1619, 1544, 1458, 1323.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.45 (s, 3H),
7.54 (d, J = 8.0 Hz, 2H), 7.97 (m, 3H), 8.11 (m, 2H),
8.23 (d, J = 8.4 Hz, 1H), 9.45 (s, 1H). 13C NMR
(101 MHz, DMSO‐d6, δ, ppm): 21.7, 102.5, 115.3, 127.2,

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TANBAKOUCHIAN ET AL.
129.4, 129.5, 130.0, 130.7, 131.6, 134.7, 135.4, 146.3, 146.4,
148.8, 155.9. Anal. calcd for C17H12N2O2S (%): C, 66.22;
H, 3.92; N, 9.08, S, 10.40. Found (%): C, 66.48; H, 3.72;
N, 9.19; S, 10.28.
4.3.5 | 6‐Methyl‐2‐tosylquinoline‐3‐
carbonitrile (6e)
Yield: 0.183 g (57%); white solid; m.p. 200–202°C. FT‐IR
(KBr, νmax, cm−1): 2922, 2229, 1619, 1544, 1458, 1323.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.53 (s, 3H),
2.80 (s, 3H), 7.54 (d, J = 8.0 Hz, 2H), 7.96 (dd, J = 6.8,
11.6 Hz, 3H), 8.1 (m, 1H), 8.23 (d, J = 8.4 Hz, 1H), 9.45
(s, 1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 16.4,
21.7, 104.4, 106.3, 117.5, 126.6, 126.8, 128.6, 131.2, 133.8,
134.6, 144.7, 147.8, 154.7. Anal. calcd for C18H14N2O2S
(%): C, 67.06; H, 4.38; N, 8.69, S, 9.95. Found (%): C,
67.08; H, 4.51; N, 8.55; S, 10.06.
4.3.2 | 8‐Methyl‐2‐tosylquinoline‐3‐
carbonitrile (6b)
Yield: 0.289 g (90%); white solid; m.p. 199–201°C. FT‐IR
(KBr, νmax, cm−1): 2922, 2229, 1619, 1544, 1458, 1323.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.44 (s, 3H),
2.45 (s, 3H), 7.55 (d, J = 8.0 Hz, 2H), 7.80 (t, J = 6.1 Hz,
1H), 7.91 (d, J = 4.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 8.0 Hz, 1H), 9.39 (s,1H). 13C NMR
(101 MHz, DMSO‐d6, δ, ppm): 16.8, 21.7, 101.6, 115.1,
127.1, 127.3, 129.9, 130.4, 131.3, 134.3, 135.1, 138.0,
144.9, 146.2, 148.6, 155.1. Anal. calcd for C18H14N2O2S
(%): C, 67.06; H, 4.38; N, 8.69, S, 9.95. Found (%): C,
67.11; H, 4.51; N, 8.58; S, 9.88.
4.3.6 | 2‐Tosylnicotinonitrile (6f)
Yield: 0.170 g (66%); white powder; m.p. 104–106°C. FT‐
IR (KBr, νmax, cm−1): 3045, 2854, 2228, 1961, 1584, 1493,
1
1245. H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.43 (s,
3H), 7.52 (d, J = 12.0 Hz, 2H), 7.92 (m, 3H), 8.67 (dd,
J = 4.0, 12.1 Hz, 1H), 8.91 (dd, J = 4.0, 8.2 Hz, 1H). 13C
NMR (101 MHz, DMSO‐d6): 21.7, 107.3, 114.6, 128.0,
129.5, 130.7, 134.6, 145.5, 146.4, 153.3, 159.2. Anal. calcd
for C13H10N2O2S (%): C, 60.45; H, 3.90; N, 10.85; S,
12.41. Found (%): C, 60.31; H, 3.81; N, 10.73; S, 12.29.
4.3.3 | 6‐Methoxy‐2‐tosylquinoline‐3‐
carbonitrile (6c)
Yield: 0.270 g (80%); white solid; m.p. 226–228°C. FT‐IR
(KBr, νmax, cm−1): 2924, 2233, 1648, 1384, 1150. 1H
NMR (400 MHz, DMSO‐d6, δ, ppm): 2.45 (s, 3H), 3.95
(s, 3H), 7.62–7.72 (m, 4H), 8.12 (d, J = 9.2 Hz, 2H), 8.19
(d, J = 9.2 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 9.01 (s,1H).
13C NMR (101 MHz, DMSO‐d6, δ, ppm): 21.7, 56.4,
104.5, 106.3, 117.5, 126.6, 126.8, 128.6, 131.2, 133.8,
134.6, 142.4, 144.7, 147.8, 154.7. Anal. calcd for
C18H14N2O3S (%): C, 63.89; H, 4.17; N, 8.28, S, 9.48.
Found (%): C, 63.68; H, 4.11; N, 8.39; S, 9.52.
4.3.7 | Ethyl 4‐cyanoimidazo[1,5‐a]quino-
line‐3‐carboxylate (8a)
Yield: 0.241 g (91%); yellow powder; m.p. 191°C. FT‐IR
(KBr, νmax, cm−1): 3446, 2958, 2854, 2229, 1868, 1717,
1456. 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.50
(t, J = 8.0 Hz, 3H), 4.56 (q, J = 8.0, 20.0 Hz, 2H), 7.64 (t,
J = 10.0, 1H), 7.86 (t, J = 12.0 Hz, 2H), 7.98 (s, 1H), 8.12
(d, J = 12.0 Hz, 1H), 8.79 (s, 1H). 13C NMR (101 MHz,
DMSO‐d6, δ, ppm): 14.7, 61.2, 29.4, 103.1, 115.2, 116.0,
122.0, 126.7, 127.4, 129.3, 130.0, 131.3, 133.2, 137.3,
162.1. Anal. calcd for C15H11N3O2 (%): C, 67.92; H, 4.18;
N, 15.84. Found (%): C, 67.80; H, 4.25; N, 15.71.
4.3.4 | 2‐Tosylbenzo[h]quinoline‐3‐
carbonitrile (6d)
Yield: 0.325 g (91%); white Solid; m.p. 180–182°C. FT‐IR
(KBr, νmax, cm−1): 2922, 2229, 1619, 1544, 1458, 1323.
1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.45 (s, 3H),
7.58 (d, J = 6.4 Hz, 2H), 7.85 (t, J = 12.0 Hz, 1H), 7.92
(t, J = 16.2 Hz, 1H), 8.04 (d, J = 13.2 Hz, 2H), 8.06
(d, J = 6.4 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H) 8.24
(d, J = 7.2 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 9.39 (s,
1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 21.7,
103.3, 115.1, 123.8, 124.8, 126.6, 128.8, 129.1, 129.6,
129.8, 130.6, 130.8, 131.4, 132.6, 134.7, 135.2, 145.6,
146.4, 146.6, 155.6. Anal. calcd for C21H14N2O2S (%): C,
70.37; H, 3.94; N, 7.82, S, 8.95. Found (%): C, 70.49; H,
3.71; N, 7.89; S, 9.03.
4.3.8 | Ethyl 4‐cyano‐9‐methylimidazo[1,5‐
a]quinoline‐3‐carboxylate (8b)
Yield: 0.234 g (84%); yellow powder; m.p. 207–209°C. FT‐
1
IR (KBr, νmax, cm−1): 3167, 2921, 2851, 2228, 1727. H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.48 (t, J = 8.0 Hz,
3H), 2.99 (s, 3H), 4.51 (q, J = 12.0, 20.0 Hz, 2H), 7.60
(m, 2H), 8.03 (d, J = 12.0 Hz, 1H), 8.64 (s, 1H), 9.01
(s, 1H). 13C NMR (101 MHz, DMSO‐d6, δ, ppm): 14.5,
24.6, 61.3, 109.1, 116.3, 122.4, 125.5, 126.0, 127.0, 127.2,
127.4, 130.7, 130.9, 133.8, 135.3, 162.6. Anal. calcd for

TANBAKOUCHIAN ET AL.
9 of 10
[7] G. De Nanteuil, A. Benoist, F. Lefoulon, J. Hickman, A. Pierre,
G. Tucker, D. Bridon, A. Ezrin, D. Holmes, X. Huang, Patent
WO2002070521, 2002.
C16H13N3O2 (%): C, 68.81; H, 4.69; N, 15.05. Found (%): C,
68.72; H, 4.81; N, 15.18.
[8] (a) P. Metzner, A. Thuillier, in Sulfur Reagents in Organic Syn-
thesis, (Eds: A. R. Katritzky, O. Meth‐Cohn, C. W. Rees),
Academic Press, London 1994. (b)P. Bichler, J. Love, in Topics
of Organometallic Chemistry, (Ed: A. Vigalok) Vol. 31,
Springer, Heidelberg 2010 39. (c)D. J. Ager, Chem. Soc. Rev.
1982, 11, 493. (d)M. D. McReynolds, J. M. Dougherty, P. R.
Hanson, Chem. Rev. 2004, 104, 2239. (e)N. V. Zyk, E. K.
Beloglazkina, M. A. Belova, N. S. Dubinina, Russ. Chem. Rev.
2003, 72, 769. (f)A. Y. Sizov, A. N. Kovregin, A. F. Ermolov,
Russ. Chem. Rev. 2003, 72, 357.
4.3.9 | Ethyl 4‐cyanobenzo[h]imidazo[1,5‐
a]quinoline‐3‐carboxylate (8c)
Yield: 0.247 g (79%); orange powder; m.p. 177–179°C. FT‐
1
IR (KBr, νmax, cm−1): 3417, 2921, 2851, 2230, 1619. H
NMR (400 MHz, DMSO‐d6, δ, ppm): 1.44 (t, J = 10.0 Hz,
3H), 4.53 (q, J = 12.0, 20.0 Hz, 2H), 7.69–7.83 (m, 3H),
7.93 (d, J = 12.0 Hz, 1H), 8.03 (m, 2H), 8.81 (d,
J = 12.0 Hz, 1H), 9.41 (s, 1H). 13C NMR (101 MHz,
DMSO‐d6, δ, ppm): 14.4, 61.2, 103.1, 121.2, 122.9, 123.1,
125.1, 128.5, 129.2, 129.8, 131.3, 132.6, 135.9, 137.3, 162.1.
Anal. calcd for C19H13N3O2 (%): C, 72.37; H, 4.16; N,
13.33. Found (%): C, 72.48; H, 4.21; N, 13.47.
[9] (a) S. ‐K. Kang, H. ‐W. Seo, Y. ‐H. Ha, Synthesis 2001, 2001,
1321. (b)K. Thommes, B. Içli, R. Scopelliti, K. Severin, Chem.
Eur. J. 2007, 13, 6899. (c)H. ‐H. Li, D. ‐J. Dong, Y. ‐H. Jin, S. ‐
K. Tian, J. Org. Chem. 2009, 74, 9501. (d)H. Jiang, Y. Cheng,
Y. Zhang, S. Yu, Eur. J. Org. Chem. 2013, 2013, 5485.
[10] (a) T. Taniguchi, A. Idota, H. Ishibashi, Org. Biomol. Chem.
2011, 9, 3151. (b)X. Li, X. Xu, C. Zhou, Chem. Commun. 2012,
48, 12240. (c)X. Li, X. Xu, Y. Tang, Org. Biomol. Chem. 2013,
11, 1739. (d)X. Li, X. Xu, P. Hu, X. Xiao, C. Zhou, J. Org. Chem.
2013, 78, 7343.
ACKNOWLEDGEMENTS
We are grateful to Bu‐Ali Sina University, Alzahra
University and the Iran National Science Foundation
(INSF) for financial support.
[11] (a) Q. Lu, J. Zhang, G. Zhao, Y. Qi, H. Wang, A. W. Lei, J. Am.
Chem. Soc. 2013, 135, 11481. (b)W. Wei, J. Li, D. Yang, J. Wen,
Y. Jiao, J. You, H. Wang, Org. Biomol. Chem. 2014, 12, 1861. (c)
T. Shen, Y. Yuan, S. Song, N. Jiao, Chem. Commun. 2014, 50,
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ORCID
Mohammad Ali Zolfigol https://orcid.org/0000-0002-4970-
8646
Morteza Shiri https://orcid.org/0000-0003-2908-3471
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How to cite this article: Tanbakouchian Z,
Zolfigol MA, Notash B, Ranjbar M, Shiri M.
Synthesis of four series of quinoline‐based
heterocycles by reacting 2‐chloroquinoline‐3‐
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