Synthesis of highly substituted cyclopentadienes containing quinoline nucleus

Article abstract of DOI:10.1007/s13738-015-0630-z

Synthesis of novel highly substituted cyclopentadienes containing quinoline nucleus is described. The initially prepared Kn?evenagel adducts of 2-chloroquinoline-3-carbaldehydes and malononitrile or ethyl cyanoacetate underwent reaction with acetylenecarboxylates and isocyanide in dichloromethane at room temperature within 12 h, affording a variety of the desired products in moderate to good yields. Mild reaction condition, use of simple experimental procedure and prompt isolation of the products are some advantages of this protocol.

Full text of DOI:10.1007/s13738-015-0630-z

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0630-z
ORIGINAL PAPER
Synthesis of highly substituted cyclopentadienes containing
quinoline nucleus
1
1
1
Mehdi Ghandi · Nahid Zarezadeh · Shahnaz Rahimi
Received: 28 January 2015 / Accepted: 6 March 2015
©
Iranian Chemical Society 2015
Abstract Synthesis of novel highly substituted cyclopen-
tadienes containing quinoline nucleus is described. The ini-
tially prepared Knöevenagel adducts of 2-chloroquinoline-
in the one-pot transformation are some of the advantages of
these reactions.
As an important subclass of MCRs, the isocyanide-
based multicomponent reactions (IMCRs) are processes in
which an isocyanide is used as one of the starting materials
to obtain new compounds [14–20]. The pioneering work of
Ugi describes the most popular IMCR in which a carbox-
ylic acid, a primary amine, an aldehyde, and an isocyanide
react in a one-pot manner to afford an N-substituted acyl
aminoamide containing four independently varying groups
3
-carbaldehydes and malononitrile or ethyl cyanoacetate
underwent reaction with acetylenecarboxylates and isocya-
nide in dichloromethane at room temperature within 12 h,
affording a variety of the desired products in moderate to
good yields. Mild reaction condition, use of simple experi-
mental procedure and prompt isolation of the products are
some advantages of this protocol.
[21–25].
Keywords Knöevenagel condensation ·
Cyclopentadienes containing quinoline nucleus ·
Isocyanide · Acetylenecarboxylate
The reaction of isocyanides and acetylene compounds,
first described by Winterfeld in 1969, is perhaps the found-
ing basis for a large class of new, accessible scaffolds [26].
This reaction initially affords a zwitterionic adduct, which
might undergo cycloaddition to activated alkenes, leading
to a variety of novel highly substituted cyclopentadienoid
systems [27–36].
Introduction
The so-called multicomponent reactions (MCRs) are one-
pot processes in which at least three or more different sim-
ple substrates react for the preparation of target materials
On the other hand, quinoline-containing compounds
have been extensively used in medicinal chemistry because
of various biological activities such as anti-inflammatory
[37], antimalarial [38–40], anticancer [41, 42], analgesic
[43, 44], and antifungal [45].
The zwitterion derived from isocyanide and dimethyl
acetylenedicarboxylate (DMAD) has been shown to be
efficiently trapped by dipolarophiles such as aryl aldehydes
and N-tosylimines leading to a facile synthesis of furan
and pyrrole derivatives, respectively [35, 36]. The reported
cycloaddition trapping of these species by activated alkenes
to highly substituted cyclopentadienoid systems [46, 47],
along with the documented properties of quinoline-contain-
ing heterocycles prompted us to examine the one-pot three
component reaction of 2-((2-chloroquinolin-3-yl)methyl-
ene)malononitrile or ethyl 3-(2-chloroquinolin-3-yl)-2-cy-
anoacrylate with acetylenecarboxylates and isocynanides.
[1–7]. These reactions, which have gained much attention
during the past years, are frequently occurring not through
a single-step procedure but rather by several sequential
steps [8–13]. Simplicity, greater efficiency, and atom econ-
omy with generation of molecular complexity and diversity
*
Mehdi Ghandi
ghandi@khayam.ut.ac.ir
1
School of Chemistry, College of Science, University
of Tehran, P.O. Box 14155-6455, Tehran, Iran
1
3

J IRAN CHEM SOC
Experiment
420 (8), 396 (16), 382 (20), 350 (16), 316 (16), 290 (8),
8
3 (35), 55 (100), 41 (50). Anal. Calcd for C H ClN O
28 28 3 6
General information
(538.17): C 62.51, H 5.25, N 7.81 %. Found: C 62.21, H
.43, N 7.76 %.
5
All commercially available chemicals and reagents were
purchased from Merck Chemical Company and used
without further purification. Melting points were deter-
mined with an Electrothermal model 9100 apparatus and
are uncorrected. IR spectra were recorded on a Bomem
4‑Ethyl 1,2‑dimethyl 3‑(2‑chloroquinolin‑3‑yl)‑4‑cyano‑5‑
((2,4,4‑trimethylpentan‑2‑yl)amino)cyclopenta‑2,
5‑diene‑1,2,4‑tricarboxylate (7b)
−
1
1
13
B100 series spectrophotometer, in cm . H and C NMR
spectra were recorded on a Bruker DRX-300-ADVANCE
White solid, mp: 121–123 °C, yield: 0.39 g (68 %). IR
−
1
1
(KBr) (νmax, cm ): 2955, 2235, 1725, 1668, 1627; H-
NMR (300 MHz, CDCl ): δ = 0.93 (s, 9H, CMe ), 1.36
1
13
spectrometer at 300 ( H) and 75 MHz ( C) using CDCl
3
3
H
3
and D2O as solvents and with the residual solvent signal
(s, 3H, CMe ), 1.38 (s, 3H, OCH Me), 142 (s, 3H, CMe ),
2 2 2
as internal reference (CDCl , 7.24 and 77.0 ppm), respec-
1.70 (ABq, J = 14.2 Hz, 2H, CCH C), 3.62 (s, 3H, OMe),
3
2
tively. Mass spectra of the products were obtained with an
HP (Agilent Technologies) 5937 Mass Selective Detector.
Elemental analyses were carried out by a CHN-Rapid Her-
aeus elemental analyzer (Wellesley, MA).
3.92 (s, 3H, OMe), 4.39 (q, J = 7.1 Hz, 2H, OCH Me),
2
5.44 (s, 1H, NH), 7.56 (t, J = 7.4 Hz, 1H, Ar), 7.75 (t,
J = 7.4 Hz, 1H, Ar), 7.82 (d, J = 8.1 Hz, 1H, Ar), 7.89 (s,
1
3
1H, Ar), 8.01 (d, J = 8.4 Hz, 1H, Ar); C NMR (75 MHz,
CDCl ): δ = 13.9, 28.4, 30.0, 31.3 (3C), 31.8, 52.8, 53.0,
3
c
General procedure for the preparation of 7a–j
54.2, 57.8, 63.2, 64.2, 115.0, 126.8, 127.8, 127.9, 128.4,
1
28.8, 131.5, 137.4, 140.8, 146.7, 147.4, 148.5, 150.2,
+
To a solution of aldehyde 4 (1 mmol) in EtOH (5 mL)
was added malononitrile or ethyl cyanoacetate (1 mmol)
and triethylamine (0.101 g, 1 mmol) and the mixture was
stirred for 15 min at room temperature. The solid was
separated by simple filtration and subsequently added to
a solution of acetylenecarboxylate (1.00 mmol) and iso-
cyanide (1.00 mmol) in CH Cl (5 mL). After stirring for
150.5, 162.0, 163.7, 165.7; EI-MS: m/z (%): 568 (9, M
3
5
+
37
[ Cl]), 570 (4, M [ Cl]), 496 (14), 455 (30), 420 (13),
396 (20), 382 (15), 249 (61), 212 (13), 144 (91), 107 (48),
91 (100), 57 (94), 41 (33). Anal. calcd for C H ClN O
3
0
34
3
6
(568.06): C 63.43, H 6.03, N 7.40 %. Found: C 63.59, H
5.83, N 7.31 %.
2
2
1
2 h at RT and completion as indicated by TLC, the solvent
Triethyl 3‑(2‑chloroquinolin‑3‑yl)‑4‑cyano‑5‑((2,4,
4‑trimethylpentan‑2‑yl) amino)cyclopenta‑2,
5‑diene‑1,2,4‑tricarboxylate (7c)
was removed under reduced pressure and the residue was
recrystallized, respectively, from methanol and hexane–eth-
ylacetate 3:1 to afford products 7a–j.
White solid, mp: 124–126 °C, yield: 0.42 g (71 %). IR
−
1
1
4
5
4
‑Ethyl 1,2‑dimethyl 3‑(2‑chloroquinolin‑3‑yl)‑4‑cyano‑
‑(cyclohexylamino)cyclopenta‑2,5‑diene‑1,2,
‑tricarboxylate (7a)
(KBr) (νmax, cm ): 2957, 2247, 1742, 1716, 1630; H-
NMR (300 MHz, CDCl ): δ = 0.94 (s, 9H, CMe ), 1.04
3
H
3
(t, J = 7.1 Hz, 3H, OCH Me), 1.37 (s, 6H, CMe ), 1.38–
2
2
1
.40 (m, 3H, OCH Me), 1.43 (broad s, 3H, OCH Me),
2 2
White solid, mp: 159–161 °C, yield: 0.33 g (62 %). IR
1.72 (ABq, J = 14.2 Hz, 2H, CCH C), 3.99–4.14 (m, 2H,
2
−1
1
(
(
KBr) (νmax, cm ): 2933, 2207, 1744, 1664; H-NMR
300 MHz, CDCl ): δ = 1.26–1.32 (m, 4H, 2CH of
OCH Me), 4.31–4.49 (m, 4H, 2OCH Me), 5.47 (s, 1H,
2
2
NH), 7.57 (t, J = 7.5 Hz, 1H, Ar), 7.76 (t, J = 7.5 Hz, 1H,
3
H
2
cyclohexyl), 1.37 (t, J = 8.0 Hz, 3H, OCH Me), 1.42–
Ar), 7.83 (d, J = 8.0 Hz, 1H, Ar), 7.92 (s, 1H, Ar), 8.03
2
1
3
1
3
4
.75 (m, 6H, 3CH of cyclohexyl), 3.66 (s, 3H, OMe),
(d, J = 8.4 Hz, 1H, Ar); C NMR (75 MHz, CDCl ):
2
3
.87–3.91 (m, 1H, CH of cyclohexyl), 3.96 (s, 3H, OMe),
δ = 13.7, 13.9, 14.1, 28.4, 30.0, 31.3 (3C), 31.9, 54.5,
c
.39–4.42 (m, 2H, OCH Me), 5.48 (d, J = 4.9 Hz, 1H,
56.2, 57.8, 62.0, 63.2, 64.2, 115.1, 126.8, 127.7, 127.9,
128.4, 128.9, 131.4, 137.6, 140.9, 142.5, 146.3, 147.4,
150.2, 150.5, 161.5, 163.4, 165.9; EI-MS: m/z (%): 597
2
NH), 7.57 (t, J = 7.2 Hz, 1H, Ar), 7.73–7.87 (m, 3H, Ar),
1
3
8
.02 (d, J = 8.3 Hz, 1H, Ar); C NMR (75 MHz, CDCl ):
3
+
35
+
37
δ = 13.9, 23.7, 23.8, 25.3, 32.2, 32.7, 53.1, 53.4, 54.3,
(19, M [ Cl]), 599 (8, M [ Cl]), 524 (36), 483 (63), 448
(32), 410 (83), 364 (19), 336 (14), 302 (14), 228 (8), 97 (8),
57 (100), 41 (39). Anal. calcd for C H ClN O (597.24):
c
6
1
1
3.1, 64.6, 113.2, 126.8, 127.8, 127.9, 128.4, 128.6, 131.5,
37.3, 142.7, 146.0, 146.1, 147.4, 150.1, 155.7, 161.9,
3
2
38
3
6
+
35
63.0, 165.0; EI-MS: m/z (%): 538 (61, M [ Cl]), 540
C 64.47, H 6.43, N 7.05 %. Found: C 64.28, H 6.64, N
7.12 %.
+
37
(27, M [ Cl]), 505 (82), 478 (15), 464 (18), 432 (31),
1
3

J IRAN CHEM SOC
1
4
3
5
‑Ethyl 1,2‑dimethyl 3‑(2‑chloro‑6‑methylquinolin‑
‑yl)‑4‑cyano‑5‑(cyclohexylamino)cyclopenta‑2,
‑diene‑1,2,4‑tricarboxylate (7d)
H-NMR (300 MHz, CDCl ): δ = 0.94 (s, 9H, CMe ),
3
H
3
1.38 (s, 3H, CMe ), 1.40 (t, J = 7.8 Hz, 3H, OCH Me),
2
2
1.43 (s, 3H, CMe ), 1.71 (ABq, J = 14.2 Hz, 2H, CCH C),
2
2
2
.52 (s, 3H, Me), 3.64 (s, 3H, OMe), 3.94 (s, 3H, OMe),
White solid, mp: 143–145 °C, yield: 0.41 g (74 %). IR
4.40 (q, J = 7.1 Hz, 2H, OCH Me), 5.44 (s, 1H, NH),
2
−1
1
(KBr) (νmax, cm ): 2934, 2225, 1741, 1720, 1634; H-
7.58 (broad s, 1H, Ar), 7.61 (s, 1H, Ar), 7.81 (s, 1H, Ar),
1
3
NMR (300 MHz, CDCl ): δ = 1.26–1.35 (m, 4H, 2CH
7.92 (d, J = 8.5 Hz, 1H, Ar); C NMR (75 MHz, CDCl3):
3
H
2
of cyclohexyl), 1.40 (t, J = 7.1 Hz, 3H, OCH Me), 1.50–
δ = 13.9, 21.6, 28.4, 29.9, 31.3 (3C), 31.9, 52.7, 53.0,
2
c
1
.78 (m, 6H, 3CH of cyclohexyl), 2.50 (s, 3H, Me), 3.66
54.3, 57.9, 63.2, 64.2, 115.0, 126.8, 126.9, 128.1, 128.6,
133.7, 136.8, 137.9, 142.1, 146.1, 146.4, 149.3, 150.5,
2
(s, 3H, OMe), 3.86–3.94 (m, 1H, CH of cyclohexyl), 3.97
+
(
(
1
s, 3H, OMe), 4.41 (q, J = 6.7 Hz, 2H, OCH Me), 5.47
155.0, 162.1, 163.8, 165.8; EI-MS: m/z (%): 581 (54, M
2
3
5
+
37
d, J = 4.3 Hz, 1H, NH), 7.57 (broad s, 1H, Ar), 7.60 (s,
[ Cl]), 583 (27, M [ Cl]), 511 (42), 471 (62), 434 (48),
410 (43), 396 (38), 378 (14), 365 (14), 330 (18), 301 (8),
215 (5), 57 (100), 41 (24). Anal. calcd for C H ClN O
1
3
H, Ar), 7.79 (s, 1H, Ar), 7.92 (d, J = 8.4 Hz, 1H, Ar);
C
NMR (75 MHz, CDCl ): δ = 13.9, 21.5, 23.7, 23.8, 25.3,
3
c
31 36
3
6
3
1
1
2.2, 32.7, 53.0, 53.4, 54.4, 63.0, 64.5, 113.2, 126.8, 126.9,
28.0, 128.5, 133.7, 136.6, 137.9, 142.8, 146.0, 146.1,
46.9, 149.2, 155.7, 161.9, 163.0, 165.0; EI-MS: m/z
(581.23): C 63.96, H 6.23, N 7.22 %. Found: C 63.89, H
6.28, N 7.09 %.
+
35
+
37
(
%): 551 (80, M [ Cl]), 553 (41, M [ Cl]), 519 (55),
Triethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑4‑cyano‑
5‑((2,4,4‑trimethylpentan‑2‑yl)amino)cyclopenta‑2,
5‑diene‑1,2,4‑tricarboxylate (7 g)
4
3
2
92 (36), 478 (69), 447 (50), 434 (12), 410 (27), 396 (58),
80 (20), 364 (66), 350 (14), 330 (37), 314 (16), 270 (20),
37 (15), 215 (11), 111 (35), 83 (31), 55 (100), 41 (68).
Anal. calcd for C H ClN O (551.18): C 63.10, H 5.48, N
White solid, mp: 136–138 °C, yield: 0.44 g (73 %). IR
2
9
30
3
6
−1
1
7
.61 %. Found: C 62.91, H 5.18, N 7.86 %.
(KBr) (νmax, cm ): 2945, 2341, 1742, 1719, 1664; H-
NMR (300 MHz, CDCl ): δ = 0.95 (s, 9H, CMe ), 1.04
3
H
3
Triethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑4‑cyano‑
(t, J = 7.1 Hz, 3H, OCH Me), 1.38–1.43 (m, 12H, CMe ,
2
2
5
4
‑(cyclohexylamino)cyclopenta‑2,5‑diene‑1,2,
‑tricarboxylate (7e)
2OCH Me), 1.72 (ABq, J = 14.2 Hz, 2H, CCH C), 2.51
2
2
(s, 3H, Me), 4.01–4.12 (m, 2H, OCH Me), 4.31–4.49 (m,
2
4
H, 2OCH Me), 5.45 (s, 1H, NH), 7.57 (broad s, 1H, Ar),
2
White solid, mp: 142–143 °C, yield: 0.40 g (69 %). IR
7.60 (s, 1H, Ar), 7.84 (s, 1H, Ar), 7.92 (d, J = 8.4 Hz,
−1
1
13
(KBr) (νmax, cm ): 2935, 2342, 1744, 1715, 1658; H-
1H, Ar); C NMR (75 MHz, CDCl ): δ = 13.7, 13.9,
3
c
NMR (300 MHz, CDCl ): δ = 1.06 (t, J = 7.1 Hz, 3H,
14.1, 21.5, 28.4, 29.9, 31.3 (3C), 31.9, 54.5, 56.3, 57.9,
62.0, 63.2, 64.1, 115.1, 126.8, 126.9, 128.0, 128.8, 133.7,
136.9, 137.8, 142.2, 146.0, 146.4, 149.3, 150.6, 155.1,
3
H
OCH Me), 1.26–1.31 (m, 4H, 2CH of cyclohexyl), 1.33–
2
2
1
.44 (m, 6H, 2OCH Me), 1.47–1.80 (m, 6H, 3CH of
2 2
+
35
cyclohexyl), 2.50 (s, 3H, Me), 3.80–3.86 (m, 1H, CH of
161.5, 163.4, 165.9; EI-MS: m/z (%): 610 (9, M [ Cl]),
+
37
cyclohexyl), 4.05–4.15 (m, 2H, OCH Me), 4.37–4.47 (m,
612 (4, M [ Cl]), 538 (24), 497 (46), 462 (35), 424 (71),
378 (13), 350 (9), 316 (11), 57 (100), 41 (35). Anal. calcd
for C H ClN O (610.14): C 64.96, H 6.61, N 6.89 %.
2
4
H, 2OCH Me), 5.47 (d, J = 4.8 Hz, 1H, NH), 7.56–7.60
2
(
m, 2H, Ar), 7.81 (s, 1H, Ar), 7.91 (d, J = 8.4 Hz, 1H, Ar);
3
3
40
3
6
1
3
C NMR (75 MHz, CDCl ): δ = 13.7, 13.9, 14.2, 21.5,
Found: C 64.83, H 6.87, N 6.71 %.
3
c
2
1
1
1
[
3.6, 23.7, 25.4, 32.2, 32.7, 53.5, 54.3, 62.2, 62.9, 64.5,
13.4, 126.7, 126.8, 128.0, 128.6, 133.6, 136.8, 137.9,
42.9, 145.7, 146.0, 146.2, 149.2, 155.9, 161.4, 162.6,
Dimethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑4,4‑dicyano‑
5‑((2,4,4‑trimethylpentan‑2‑yl)amino)cyclopenta‑2,
5‑diene‑1,2‑dicarboxylate (7 h)
+
35
+
65.2; EI-MS: m/z (%): 579 (42, M [ Cl]), 581 (19, M
3
7
Cl]), 544 (35), 506 (30), 461 (20), 424 (13), 378 (16),
3
50 (16), 270 (24), 83 (26), 55 (100), 41 (44). Anal. calcd
White solid, mp: 153–155 °C, yield: 0.34 g (63 %). IR
−1
1
for C H ClN O (579.21): C 64.19, H 5.91, N 7.24 %.
Found: C 64.05, H 5.74, N 7.29 %.
(KBr) (νmax, cm ): 2953, 2332, 1748, 1726; H-NMR
(300 MHz, CDCl ): δ = 0.96 (s, 9H, CMe ), 1.52 (s, 3H,
3
1
34
3
6
3
H
3
CMe ), 1.65 (s, 3H, CMe ), 1.77 (ABq, J = 14.2 Hz, 2H,
2
2
4
‑Ethyl 1,2‑dimethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑
CCH C), 2.51 (s, 3H, Me), 3.69 (s, 3H, OMe), 3.96 (s, 3H,
2
yl)‑4‑cyano‑5‑((2,4,4‑trimethylpentan‑2‑yl)amino)
OMe), 5.71 (s, 1H, NH), 7.60 (s, 1H, Ar), 7.63 (broad s,
cyclopenta‑2,5‑diene‑1,2,4‑tricarboxylate (7f)
1H, Ar), 7.72 (s, 1H, Ar), 7.94 (d, J = 8.4 Hz, 1H, Ar);
1
3
C NMR (75 MHz, CDCl ): δ = 21.6, 29.5, 30.2, 31.3
3
c
White solid, mp: 135–137 °C, yield: 0.46 g (79 %).
(3C), 31.8, 53.1, 53.4, 55.0, 57.9, 64.5, 111.6, 113.4, 126.6,
126.8, 127.2, 128.2, 134.2, 136.3, 138.3, 140.6, 144.7,
−
1
IR (KBr) (νmax, cm ): 2952, 2282, 1742, 1667, 1632;
1
3

J IRAN CHEM SOC
Scheme 1 Synthesis of
-chloroquinoline-3-carbalde-
hydes 3a–b
O
CH COCl
3
2
R1
R1
R1
K CO acetone
3,
DMF POCl3
,
2
O
NH2
30 °
N
H
2a-b
80 °C
N
Cl
C
1
a-b
3a-b
1
5
3
4
46.2, 149.2, 150.5, 155.1, 161.4, 162.9; EI-MS: m/z (%):
R2 CN
+
35
+
37
O
35 (24, M [ Cl]), 537 (8, M [ Cl]), 463 (6), 422 (57),
87 (55), 368 (25), 328 (13), 112 (12), 97 (19), 57 (100),
1 (55). Anal. calcd for C H ClN O (535.03): C 65.10,
R1
NC R2
R1
2
9
31
4
4
N
Cl
N
Cl
Et N, EtOH,
3
H 5.84, N 10.47 %. Found: C 65.04, H 5.96, N 10.31 %.
3
a-b
RT, 15 min
4a-d
Diethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑4,4‑dicyano‑
Scheme 2 Synthesis of Knöevenagel adducts 4a–d
5
5
‑((2,4,4‑trimethylpentan‑2‑yl)amino)cyclopenta‑2,
‑diene‑1,2‑dicarboxylate (7i)
C H ClN O (532.19): C 65.35, H 5.48, N 10.51 %.
2
9
29
4
4
White solid, mp: 150–152 °C, yield: 0.38 g (66 %). IR
Found: C 65.21, H 5.62, N 10.46 %.
−1)
1
(
(
(
KBr) (νmax, cm : 2957, 2219, 1721, 1638; H-NMR
300 MHz, CDCl ): δ = 0.96 (s, 9H, CMe ), 1.38–1.43
3
H
3
m, 12H, CMe , 2OCH Me), 1.72 (ABq, J = 14.2 Hz, 2H,
Results and discussion
2
2
CCH C), 2.52 (s, 3H, Me), 4.07–4.13 (m, 4H, 2OCH Me),
2
2
5
7
.47 (s, 1H, NH), 7.57 (broad s, 1H, Ar), 7.60 (s, 1H, Ar),
Initially, 2-chloroquinoline-3-carbaldehydes 3a–b were
prepared using the traditional Vilsmeier–Haack cyclization
of acetanilides 2a–c (Scheme 1) [48, 49].
In the next step, reaction of 3a–b with malononitrile or
ethylcyanoacetate in the presence of triethylamine in EtOH
within 15 min afforded the Knöevenagel adducts 4a–d
(Scheme 2).
1
3
.79 (s, 1H, Ar), 7.93 (d, J = 8.4 Hz, 1H, Ar); C NMR
(
(
75 MHz, CDCl ): δ = 13.7, 13.9, 21.5, 28.4, 30.0, 31.3
3
c
3C), 31.9, 54.3, 57.9, 62.0, 62.9, 64.2, 114.1, 115.2, 126.4,
1
1
26.7, 128.0, 128.4, 133.5, 136.6, 137.6, 142.6, 146.1,
46.2, 149.2, 150.3, 155.3, 161.6, 163.4; EI-MS: m/z
+ +
35
37
(%): 562 (53, M [ Cl]), 564 (23, M [ Cl]), 492 (13),
4
5
50 (60), 415 (57), 377 (52), 341 (12), 314 (9), 269 (7),
7 (100), 41 (19). Anal. calcd for C H ClN O (562.23):
Products 4a–d without characterization were then treated
with dimethyl acetylenecarboxylate and isocyanide in
CH Cl at RT. The highly substituted cyclopentadienes con-
3
1
35
4
4
C 66.12, H 6.27, N 9.95 %. Found: C 65.98, H 6.35, N
.83 %.
2
2
9
taining quinoline nucleus 7a–j were obtained in moderate
to good yields (Scheme 3; Table 1). The structure of 7a–j
was deduced by their analytical and spectral data. The mass
Diethyl 3‑(2‑chloro‑6‑methylquinolin‑3‑yl)‑4,4‑dicyano‑
+
5
2
‑(cyclohexylamino)cyclopenta‑2,5‑diene‑1,
‑dicarboxylate (7j)
spectra of 7a displayed the molecular ion peak at 538 for M
35
+
37
([ Cl]) and 540 for M ([ Cl]) consistent with the molecu-
lar structure. The H-NMR spectrum of 7a exhibited charac-
1
White solid, mp: 163–165 °C, yield: 0.32 g (61 %). IR
teristic singlets at δ 3.66 and 3.96 and two triplet and mul-
tiplet at δ 1.37 and 4.39–4.42 for OCH Me and OCH Me,
−1
1
(
KBr) (νmax, cm ): 2937, 2131, 1735, 1708; H-NMR
300 MHz, CDCl ): δ = 1.17–1.29 (m, 4H, 2CH of
2
2
(
respectively, along with a doublet at 5.48 due to NH. The
3
H
2
13
cyclohexyl), 1.30–1.38 (m, 6H, 2OCH Me), 1.50–1.96 (m,
ester carbonyl groups displayed C resonance signals at
2
6
H, 3CH of cyclohexyl), 2.51 (s, 3H, Me), 3.99 (broad
δ 161.9, 163.0 and 165.0 supporting the IR absorption at
2
−1
−1
13
s, 1H, CH of cyclohexyl), 4.02–4.39 (m, 4H, 2OCH Me),
1744 cm . The IR absorption at 2207 cm and the C res-
onance signal at δ 113.2 were attributed to the cyano group.
Although the precise mechanism is not known, a mecha-
nistic postulate as shown in Scheme 3 may be invoked to
rationalize the formation of 7a. It is conceivable that the
zwitterionic intermediate I, formed by the 1:1 interaction
between the acetylenedicarboxylate 5a and isocyanide 6a,
attacks 4a leading to a 1,5-dipolar intermediate II. The sub-
sequently generated III upon ring closure is finally trans-
formed into 7a via a [1, 5] H shift.
2
5
7
.65 (d, J = 5.1 Hz, 1H, NH), 7.56–7.60 (m, 2H, Ar),
1
3
.81 (s, 1H, Ar), 7.91 (d, J = 8.4 Hz, 1H, Ar); C NMR
(
75 MHz, CDCl ): δ = 13.5, 13.9, 21.0, 23.2, 24.3, 24.7,
3
c
3
1
1
5
4
1.6, 32.5, 53.0, 61.3, 61.9, 63.4, 110.5, 112.0, 125.9,
26.4, 127.2, 127.3, 134.2, 136.6, 138.0, 142.6, 145.3,
45.6, 148.3, 149.0, 152.5, 161.5, 162.4; EI-MS: m/z (%)
+
35
+
37
32 (12, M [ Cl]), 534 (5, M [ Cl]), 486 (9), 422 (9),
04 (10), 377 (100), 363 (16), 349 (13), 314 (16), 254
(20), 177 (16), 83 (57), 55 (88), 41 (35). Anal. calcd for
1
3

J IRAN CHEM SOC
Scheme 3 Synthesis of
cyclopentadienes containing
quinolones 7a–j
NC HN R4
R2 CN CO R3
R2
2
C
3
R1
CO R
2
R1
2
CH Cl2
+
N
R4
3
+
CO R
2
CO R3
R.T, 12 h
N
Cl
N
Cl
2
4
a-d
5a-b
6a-b
7a-j
Table 1 Structures of products 7a–j
Entry
Alkene
Isocyanide
DMAD/DEAD
DMAD
Product
Yield (%)
1
62
7
a
2
3
4
5
DMAD
DEAD
DMAD
DEAD
68
7
b
71
74
69
7
c
7
d
7
e
1
3

J IRAN CHEM SOC
Table 1 continued
Entry
Alkene
Isocyanide
DMAD/DEAD
DMAD
Product
Yield (%)
6
7
8
79
73
63
7
f
DEAD
7
g
DMAD
7
h
9
DEAD
66
61
7
i
1
0
DMAD
7
j
As is evident in Table 1, the isocyanide component of
the MCR was variable. Compared to cyclohexyl isocya-
nide, utilization of tetramethylbutyl isocyanide afforded
the desired products in higher yields (entries 1 and 4 versus
yields [31]. The alkene component of the MCR was also
variable. When malononitrile was used in the reaction
instead of ethylcyanoacetate, lower yields of the products
were obtained (entries 4 and 6 versus 10 and 8, Table 1).
2
and 6 or 5 versus 7, Table 1). Tetramethylbutyl isocya-
Whereas the pK of the former is smaller (11.25) than that
a
nide as an electron-rich nucleophile seems to be responsi-
ble for affording the corresponding products in higher
of the latter (11.70) [50], the formation of the products
with ethyl cyanoacetate in higher yields is anticipated if the
1
3

J IRAN CHEM SOC
Scheme 4 Mechanistic ration-
alization for the formation of
compound 7a
transformation of II to III becomes rate determining step
2. B. Ganem, Acc. Chem. Res. 42, 463 (2009)
3
4
.
.
S.L. Cui, X.F. Lin, Y.G. Wang, Org. Lett. 8, 4517–4520 (2006)
C. Simon, T. Constantieux, J. Rodriguez, Eur. J. Org. Chem.,
(RDS) (see Scheme 4). This proposal finds support, since
the products resulted from alkene component containing
electro-donating quinolines were generated in higher yields
4
957 (2004)
5. M. Murakami, Angew. Chem. Int. Ed. 42, 718 (2003)
6. A. Jacobi Von Vangelin, H. Neumann, D. Grdes, S. Klaus, D.
Strübing, M. Beller, Chem. Eur. J. 9, 4286 (2003)
(entries 1 and 2 versus 4 and 6, Table 1). Such behavior is
expected if II is generated in a rapid equilibrium step (see
Scheme 4).
7
8
9
.
.
.
G. Balme, E. Bossharth, N. Monterio, N. Eur. J. Org. Chem.
101 (2003)
K. Kriis, K. Ausmees, T. Pehk, M. Lopp, T.A. Kanger, Org. Lett.
2, 2230 (2010)
A. Dömling, Chem. Rev. 106, 17 (2006)
4
1
Conclusion
1
1
0. C. Hulme, V. Gore, Curr. Med. Chem. 10, 51 (2003)
1. V. Nair, C. Rajesh, A.U. Vinod, S. Bindu, A.R. Sreekanth, J.S.
Mathen, L. Balagopal, Acc. Chem. Res. 36, 899 (2003)
In conclusion, a number of highly substituted cyclopen-
tadienes containing quinoline nucleus were synthesized
in moderate to high yields. These new structures broaden
the scaffolds that are accessible through multicomponent
cyclization of Knöevenagel adducts of 2-chloroquinoline-
12. I. Ugi, B. Verner, A. Dömling, Molecules 8, 53 (2003)
1
1
3. G. Zhu, Eur. J. Org. Chem. 1133 (2003)
4. L.H. Zhou, G. Su, W. Zhang, B. Yan, J. Comb. Chem. 11, 1083
(2009)
15. K. Lu, T. Luo, Z. Xiang, Z. You, R. Fathi, J. Chen, Z. Yang, J.
3
-carbaldehydes and malononitrile or ethyl cyanoacetate
Comb. Chem. 7, 958 (2005)
1
1
6. H. Bienaymé, C. Hulme, G. Oddon, P. Schmidt, Chem. Eur. J. 6,
321 (2000)
7. R.V.A. Orru, M. de Greef, Synthesis 1471 (2003)
with acetylenecarboxylates and isocyanides. In contrast to
many other multicomponent reactions in which heterocycle
scaffolds are generally produced, these reactions delivered
quinoline-based cyclopentadiene carbocycles that some of
them may represent interesting pharmacophores.
3
18. A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 39, 3168 (2000)
19. D. Lee, J.K. Sello, S.L. Schreiber, Org. Lett. 2, 709 (2000)
0. R.W. Armstrong, A.P. Combs, P.A. Tempest, A.D. Brown, A.K.
Thomas, Acc. Chem. Res. 29, 123 (1996)
2
2
2
1. D.G. Hall, S. Manku, F. Wang, J. Comb. Chem. 3, 125 (2001)
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Acknowledgments The authors acknowledge the University of
Tehran and Radioisotope Research Group of NSTRI for financial sup-
port of this research.
2
2
2
3. P.J.T. Reeves, R. Balachandran, K.A. Giuliano, E. Hamel, B.W.
Day, J. Am. Chem. Soc. 122, 9391 (2000)
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