An efficient synthesis of 2,3,4-trisubstituted quinolines through alkynylation-cyclization at ambient temperature

Article abstract of DOI:10.1002/jhet.715

A series of 2,3,4-trisubstituted quinoline derivatives have been synthesized by reactions between 2-aminoaryl ketones and dialkyl acetylenedicarboxylate. The synthetic pathway allows for the direct construction of said quinoline derivatives in pyridine/et

Full text of DOI:10.1002/jhet.715

1414
An Efficient Synthesis of 2,3,4-Trisubstituted Quinolines Through
Alkynylation-Cyclization at Ambient Temperature
Vol 48
Dipti R. Patil, Sonali M. Salunkhe, Madhukar B. Deshmukh,
and Prashant V. Anbhule*
Department of Chemistry, Shivaji University, Kolhapur, Maharashtra 416 004, India
*E-mail: pvanbhule@gmail.com
Received May 28, 2010
DOI 10.1002/jhet.715
Published online 19 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 2,3,4-trisubstituted quinoline derivatives have been synthesized by reactions between 2-amino-
aryl ketones and dialkyl acetylenedicarboxylate. The synthetic pathway allows for the direct construction of
said quinoline derivatives in pyridine/ethanol at ambient temperature through a zwitterion intermediate.
J. Heterocyclic Chem., 48, 1414 (2011)
INTRODUCTION
stabilized product, and this interception can either be
two-component or multicomponent reaction. The 1:4
zwitterionic intermediate has been exploited in the syn-
thesis of aminofurans [19], iminolactones [19], and 2-
aminopyrroles [20].
Incorporation of the quinoline moiety is very important
in heterocyclic chemistry as it leads to biological activity
in such areas as antiplasmodial [1], intrinsic [2], cytotoxic
[3], functional [4], antibacterial [5], antiproliferative [6],
antimalarial [7], and anticancer activity [8]. In addition,
quinolines are important synthetic materials for the prepa-
ration of nano and mesostructures [9]. In view of their re-
markable significance, a number of methods have
been reported for the synthesis of quinoline derivatives
[10a–h]. Despite the available methods efforts have been
devoted to the development of new quinoline-based struc-
tures [11] and some new synthetic methodology for their
construction [12]. Among them, very few reports are
available on synthesis of 2,3,4-trisubstituted quinoline
derivatives by using 2-aminoaryl ketones and dimethyl
acetylenedicarboxylate (DMAD) and such type of com-
pound shows antiallergic properties [13a–e]. However,
most of the reported methods have significance draw-
backs such as difficulties in workup, drastic reaction con-
ditions and lack of mechanistic details.
Considering the literature background given above
and in view of our general interest in synthesis of heter-
ocyclic compounds [21], herein, we describe an efficient
synthesis of 2,3,4-trisubstituted quinoline derivatives via
the reaction of 2-aminoaryl ketone with dialkyl acetyle-
nedicarboxylate in pyridine/ethanol at room temperature
without using any catalyst through zwitterionic inter-
mediates (Scheme 1).
RESULTS AND DISCUSSION
Our primary investigation was initiated with the reac-
tion of 2-aminoacetophenone and DMAD in ethanol
(5 mL) stirred at ambient temperature without any cata-
lyst or additive gave the desired cyclization product
dimethyl 4-methylquinoline-2,3-dicarboxylate 3a. The
structure of the product was assigned on the basis of
spectroscopic analysis. This initial success enforced us to
check the capability of the protocol by variation in 2-ami-
noaryl ketones and dialkyl acetylenedicarboxylate. But
the limitation of the said process occurred when DMAD
has been replaced by diethyl acetylenedicarboxylate
(DEAD). The reaction didn’t proceed even for a long
time (24 h). To overcome the limitation of above reac-
tion, we have carried out the same reaction in presence
The reaction of nucleophiles with activated acetylenes
has attracted the attention of organic chemists for a long
time, especially from vantage point of heterocyclic syn-
thesis. In these reaction processes, zwitterionic species
are known to arise from the addition of nucleophiles
such as triphenylphosphine [14], pyridine [15], dime-
thylsulphoxide [16], isocyanides [17], and ethanol [18]
to activated acetylenes. The formed zwitterionic inter-
mediates can be trapped by suitable substrates to give
C
V
2011 HeteroCorporation

November 2011
An Efficient Synthesis of 2,3,4-Trisubstituted Quinolines through
Alkynylation-Cyclization at Ambient Temperature
1415
Scheme 1. Synthesis of 2,3,4-trisubstituted quinoline derivatives.
After 15 min stirring 2-amino-5-chlorobenzophenone (0.462 g,
2 mmol) was added, and the mixture was stirred at room tem-
perature. The precipitate obtained was then filtered, washed
with water and petroleum ether, and dried in vacuum. The
crude product was recrystalized from methanol. In some cases
(entry f, i, j) products were obtained by keeping the reaction
mixture for several hours after completion of reaction.
Spectral data. Dimethyl 4-methylquinoline-2,3-dicarbox-
ylate: (a). Creamish powder, mp 99–101ꢁC; IR (KBr): 2958,
1
1733, 1679, 1231, 812, 785, 767 cmꢀ1; H NMR (CDCl3 300
of pyridine (20 mol %). Surprisingly, in pyridine the
reaction proceeds smoothly at room temperature to afford
expected product. Pyridine is found to be effective pro-
moting medium to complete the reaction with variations
in both the substrates in shorter time with excellent
yields. The results are summarized in Table 1.
MHz): d ¼ 2.65 (s, 3H, ACH3), 3.75(s, 3H, AOCH3), 3.79 (s,
3H, AOCH3), 6.638–6.666 (dd, 1H, Ar-H), 6.994–7.045 (t,
1H, Ar-H), 7.336–7.392 (t, 1H, Ar-H), 7.821–7.852 (dd, 1H,
Ar-H); 13C NMR (CDCl3 300 MHz): d ¼ 28.22, 51.55, 52.88,
100.24, 118.54, 121.20, 123.84, 131.55, 133.25, 141.89,
144.19, 165.46, 167.84; ms: m/z ¼ 259 [Mþ]. Anal. Calcd. For
C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.84; H,
5.00; N, 5.37.
Based on the experimental observations, the possible
mechanism for this transformation is depicted in
Scheme 2. The initial event involves the nucleophilic
attack of ethanol or pyridine on dialkyl acetylenedicar-
boxylate form 1:4 zwitterion (I) followed by subsequent
[2 þ 2] cycloaddition of zwitterion to the carbonyl
group of 2-aminoaryl ketone to give an unstable oxetene
[22], which undergoes ring opening followed by cyclo-
dehydration resulting in the formation of 2,3,4-trisubsti-
tuted quinolines.
Dimethyl 4-phenyl-6-chloroquinoline-2,3-dicarboxylate: (b). Pale
yellow powder, mp152–158ꢁC; (lit.162.5–163ꢁC [13a]); IR
(KBr): 2954, 1727, 1441, 1220, 1054, 866, 833, 755, 702
1
cmꢀ1; H NMR (CDCl3 300 MHz): d ¼ 3.64 (s, 3H,AOCH3),
4.07(s, 3H AOCH3), 7.26–7.78(m, 7H, Ar-H), 8.26–8.29 (d,
1H, Ar-H); 13C NMR (CDCl3 300 MHz): d ¼ 52.56, 53.56,
99.99, 125.40, 128.43, 128.51, 129.17, 129.24, 132.18, 133.78,
135.66, 145.45, 164.09, 167.04; ms: m/z ¼ 355 [Mþ]. Anal.
Calcd. For C19H14NO4Cl: C, 64.14; H, 3.97; N, 3.94. Found:C,
64.11; H, 3.96; N, 3.89.
Dimethyl 4-phenylquinoline-2,3-dicarboxylate: (c). Pale
yellow powder; mp 128–129ꢁC (lit.129–130ꢁC [13a]); IR
(KBr): 3048, 2949, 1736, 1686, 1238, 819, 776, 751, 705
CONCLUSIONS
1
cmꢀ1; H NMR (CDCl3 300 MHz): d ¼ 3.76 (s, 3H,AOCH3),
A convenient and an efficient one-pot method for the
synthesis of quinoline derivatives from readily accessi-
ble precursors have been developed. Finally, we con-
cluded that pyridine is the most suitable promoting me-
dium for the synthesis of 2,3,4-trisubstituted quinoline
derivatives as compared with ethanol. The simplicity of
the present procedure makes it an interesting alternate to
other approaches. The biomedical applications of these
compounds are under study.
3.80 (s, 3H AOCH3), 6.782–6.809 (dd, 1H, Ar-H) 7.028–7.053
(t, 1H, Ar-H), 7.26(s, 1H, Ar-H) 7.39–7.58 (m, 5H, Ar-H),
7.835–7.864 (dd, 1H, Ar-H); 13C NMR (CDCl3 400 MHz): d
¼ 51.56, 52.85, 98.56, 119.89, 121.45, 126.30, 138.08, 141.76,
145.10, 165.09, 168.46; ms: m/z ¼ 321 [Mþ]. Anal. Calcd. For
C19H15NO4: C, 71.02; H, 4.71; N, 4.36. Found: C, 71.00; H,
4.67; N, 4.34.
Dimethyl 4-(2- chlorophenyl)-6-chloroquinoline-2,3-dicar-
boxylate: (d). Pale yellow powder; mp >300ꢁC; IR (KBr):
1
2950, 1731, 1685, 1052 826, 774, 736 cmꢀ1; H NMR (CDCl3
300 MHz): d ¼ 3.78 (s, 3H AOCH3), 3.81 (s, 3H, AOCH3),
7.257–7.267 (d, 1H, Ar-H), 7.32–7.47 (m, 6H, Ar-H); 13C
NMR (CDCl3 300 MHz): d ¼ 51.69, 53.02, 101.20, 120.45
125.53, 126.40, 126.85, 129.64, 130.24, 131.58, 131.73,
132.58, 133.43, 138.07, 141.16, 143.86, 164.85, 167.88; ms:
m/z ¼ 389 [Mþ]. Anal. Calcd. For C19H13NO4Cl2: C, 58.48;
H, 3.36; N, 3.59 Found: C, 58.49; H, 3.32; N, 3.56.
Diethyl 4-phenylquinoline-2,3-dicarboxylate: (e). White
crystals; mp 97–102ꢁC; IR (KBr): 2992, 1745, 1723, 1377,
1202, 1021, 860,768, 756, 704 cmꢀ1 1H NMR (CDCl3 400
;
MHz): d ¼ 0.97–1.00 (t, J ¼ 12Hz, 3H, ACH2ACH3) 1.44–1.48
(t, 3H, J ¼16Hz, ACH2ACH3), 4.06–4.10 (q, 2H, J ¼ 16Hz,
ACH2ACH3), 4.51–4.54 (q, 2H, J ¼ 12Hz, ACH2ACH3), 7.26
(s, 2H, Ar-H), 7.36–7.37 (m, 3H, Ar-H), 7.37–7.62 (m, 3H, Ar-
H), 8.32–8.34 (d, 1H, Ar-H); 13C NMR (CDCl3 400 MHz): d ¼
13.69,14.29, 61.64, 62.72, 126.68, 127.14, 127.60, 128.31,
128.74, 128.82, 128.97, 129.33, 129.49, 130.74, 130.91, 130.99
134.82, 145.89, 147.16, 148.05, 165.36, 167.24; ms: m/z ¼ 349
[Mþ]. Anal. Calcd. For C21H19NO4: C, 72.20; H, 5.44; N, 4.01.
Found: C, 72.22; H, 5.42; N, 4.03.
EXPERIMENTAL
All chemicals and solvents were reagent grade and used as
purchased without any further purification. Analytical thin-
layer chromatography was performed on percolated silica gel
60-F 254 plates. The data found were in consistent with the
proposed structure. IR spectra on KBr disks were recorded on
a Shimadzu IR-470 FT-IR spectrophotometer in cmꢀ1. The
routine nuclear magnetic resonance spectra were taken in
CDCl3 using a Bruker Spectrospin Avance II-300-MHz spec-
trophotometer and Jeol-400-MHz spectrophotometer with tetra-
methyl silane (TMS) as an internal standard. Gas chromatogra-
phy mass spectrometry (GCMS) spectra analyses were done on
Shimadzu QP 2010 GCMS. Melting points were determined in
an open capillary tube and were found to be uncorrected.
General procedure for the synthesis of 2,3,4-trisubsti-
tuted quinoline derivatives. To DEAD (0.278 mL, 2 mmol),
pyridine (20 mol %) was added at 0–10ꢁC temperature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1416
D. R. Patil, S. M. Salunkhe, M. B. Deshmukh, and P. V. Anbhule
Vol 48
Table 1
Synthesis of 2,3,4-trisubstituted quinolines at room temperature.
Entry
R
R1
R0
Medium
EtOH
Product
Time/h
20
Yielda
79
a
AH
ACH3
ACH3
b
c
ACl
AH
-Ph
-Ph
ACH3
ACH3
EtOH
EtOH
21
23
77
75
d
e
f
ACl
AH
2-ClC6H4
ACH3
ACH2CH3
ACH3
EtOH
24
15
14
12
12
14
15
78
88
87
88
89
86
85
-Ph
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
AH
-Ph
g
h
i
ACl
ACl
ACl
ACl
-Ph
ACH2CH3
-Ph
ACH3
2-ClC6H4
2-ClC6H4
ACH2CH3
j
ACH3
a Yields refers to pure isolated product.
(s, 3H, AOCH3), 7.26 (s, 2H, Ar-H), 7.37–7.38(m, 3H, Ar-H),
7.50–7.63 (m, 3H Ar-H), 8.32–8.35(d, 1H, Ar-H); 13C NMR
(CDCl3 400 MHz): d ¼ 52.50, 53.52, 100.01, 126.67, 127.24,
127.65, 128.31, 128.86, 129.29, 129.34, 130.65, 131.07,
Dimethyl 4-phenylquinoline-2,3-dicarboxylate: (f). Pale
yellow crystals; mp 128ꢁC (lit. 129–130ꢁC [13a]); IR (KBr):
2952, 1725, 1443, 1205, 1051, 865,794, 966, 769, 605 cmꢀ1
;
1H NMR (CDCl3 400 MHz): d ¼ 3.64 (s, 3H, AOCH3), 4.08
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
An Efficient Synthesis of 2,3,4-Trisubstituted Quinolines through
Alkynylation-Cyclization at Ambient Temperature
1417
Scheme 2. The possible mechanism for the synthesis of compounds
3a–j.
Diethyl 4-(2-chlorophenyl)-6-chloroquinoline-2,3-dicarbox-
ylate: (i). Creamish powder; mp 98–107ꢁC; IR (KBr): 3059,
2981, 1722, 1239, 1146, 829, 812, 759, 741 cmꢀ1 1H NMR
;
(CDCl3 300 MHz): d ¼ 0.98–1.01 (t, 3H, J ¼ 12 Hz,
ACH2ACH3), 1.44–1.48 (t, 3H, J ¼ 16 Hz, ACH2ACH3),
4.09–4.12 (q, 2H, J ¼ 12 Hz, ACH2ACH3), 4.52–4.56 (q, 2H,
J ¼ 16 Hz, ACH2ACH3), 7.24–7.28 (m, 1H, Ar-H), 7.32–7.36
(d, 1H, Ar-H), 7.37–7.42 (m, 1H, Ar-H), 7.44–7.50 (m, 1H,
Ar-H), 7.53–7.57 (d, 1H, Ar-H), 7.73–7.77 (dd, 1H, Ar-H),
8.24–8.28 (d,1H, Ar-H); 13C NMR (CDCl3 400 MHz): d ¼
13.66, 14.26, 61.83, 62.88, 125.00, 126.88, 127.80, 127.87,
129.82, 130.77, 131.15 132.38, 133.20, 133.68, 135.79,144.85,
145.47, 146.67,165.04, 166.27; ms: m/z- 417[Mþ]. Anal.
Calcd. For C21H17NO4Cl2: C, 60.43; H, 4.07; N, 3.35. Found:
C, 60.40; H, 4.03; N, 3.32.
Dimethyl 4-(2-chlorophenyl)-6-chloroquinoline-2,3-dicar-
boxylate: (j). Pale yellow powder; mp > 300ꢁC; IR (KBr):
3067, 2952,1728, 1607, 1442, 1222, 1149, 1064, 849, 813,
1
760, 744 cmꢀ1; H NMR (CDCl3 300 MHz): d ¼ 3.77 (s, 3H,
AOCH3), 4.10 (s, 3H, AOCH3), 7.27–7.31 (d, 1H, Ar-H),
7.36–7.38 (d, 1H, Ar-H), 7.40–7.46 (m, 1H, Ar-H), 7.47–7.52
(m, 1H, Ar-H), 7.56–7.60 (d, 1H, Ar-H), 7.76–7.80 (dd, 1H,
Ar-H), 8.26–8.31 (d, 1H, Ar-H); 13C NMR (CDCl3 400 MHz):
d ¼ 52.79, 53.73, 125.06, 126.93, 127.98, 129.92, 130.88,
131.02, 132.36, 132.55, 132.88, 133.58, 136.07, 145.43,
165.34 166.80; ms: m/z ¼ 389 [Mþ]. Anal. Calcd. For
C19H13NO4Cl2: C, 58.48; H, 3.96; N, 3.59. Found: C, 58.22;
H, 3.76; N, 3.55.
Acknowledgments. We gratefully acknowledge financial sup-
port from UGC, New Delhi and Department of Science and Tech-
nology, Government of India through FIST programme. One of
the authors (DRP) is thankful to UGC for the award of UGC
Research Fellowship in sciences for meritorious students.
134.49, 144.83, 147.08, 148.09, 165.56, 167.67; ms: m/z ¼
321 [Mþ]. Anal. Calcd. For C19H15NO4: C, 71.02; H, 4.71; N,
4.36. Found: C, 71.00; H, 4.67; N, 4.32.
Diethyl 4-phenyl-6-chloroquinoline-2,3-dicarboxylate: (g). Creamish
powder; mp 255–263ꢁC; IR (KBr): 2980, 1733, 1718, 1292,
1145, 1051, 831, 808, 753, 700 cmꢀ1 1H NMR (CDCl3 400
;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet