Formation of trialkyl quinoline-2,3,4-tricarboxylates by reaction of isatin, dialkyl acetylenedicarboxylates, and sodium O-alkyl carbonodithioates

Article abstract of DOI:10.1016/j.tetlet.2010.02.107

An efficient one-pot synthesis of quinoline-2,3,4-tricarboxylates is described by reaction of isatin (indoline-2,3-dione) and electron-deficient acetylenic esters in the presence of sodium O-alkyl carbonodithioates, themselves prepared by addition of sodium hydride to a solution of an alcohol in CS₂.

Full text of DOI:10.1016/j.tetlet.2010.02.107

Tetrahedron Letters 51 (2010) 2193–2194
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formation of trialkyl quinoline-2,3,4-tricarboxylates by reaction of isatin,
dialkyl acetylenedicarboxylates, and sodium O-alkyl carbonodithioates
*
Issa Yavari , Samereh Seyfi, Zinatossadat Hossaini
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of quinoline-2,3,4-tricarboxylates is described by reaction of isatin (indo-
line-2,3-dione) and electron-deficient acetylenic esters in the presence of sodium O-alkyl carbonodithio-
ates, themselves prepared by addition of sodium hydride to a solution of an alcohol in CS2.
Ó 2010 Published by Elsevier Ltd.
Received 2 December 2009
Revised 6 February 2010
Accepted 19 February 2010
Available online 23 February 2010
Keywords:
Quinoline-tricarboxylate
Isatin
S-Nucleophile
Acetylenic ester
Carbon disulfide
OR'
Quinolines are an important group of heterocyclic compounds,
several derivatives of which have been found to possess useful bio-
logical activity such as antimalarial, antibacterial, anti-asthmatic,
antihypertensive, and anti-inflammatory.1–4 In addition, quino-
lines are valuable synthons for the preparation of nano- and
meso-structures with enhanced electronic and photonic func-
tions.5–7 Due to their importance as substructures in a broad range
of natural and designed products, significant effort continues to be
directed toward the development of new quinoline-based struc-
tures as well as new methods for their construction.8–11 A number
of procedures have been reported for the synthesis of quinolines
involving a variety of metal catalysts and Lewis acids.12–15 How-
ever, many of these methods suffer from harsh reaction conditions,
long reaction times, low yields, difficulties in work-up, and the use
of stoichiometric and/or relatively expensive reagents.
O
O
CO2R
S
CO2R
MeCN
r.t.
O +
+
Na
S
R'O
N
CO2R
N
CO2R
H
3
R'
R
R' Yield (%)
4
a
2
R
1
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
Et
Me
Et
Me
Et
a
87
85
90
Me
Et
b
b
nPr
iPr
c
nPr
iPr
d
e
82
86
92
83
83
92
89
87
tBu
tBu
Bn
f
Bn
g
Allyl
Me
Et
g
Allyl
h
i
j
Et
Et
Et
Bn
nPr
k
As part of our current studies on the development of new routes
in heterocyclic synthesis,16–18 we report an efficient synthetic
route to quinoline-2,3,4-tricarboxylates. Thus, the reaction of isatin
(indoline-2,3-dione, 1) with dialkyl acetylenedicarboxylates 2, in
the presence of sodium O-alkyl carbonodithioates 3 at room tem-
perature, produced trialkyl quinoline-2,3,4-tricarboxylates (4) in
good yields19 (Scheme 1). Nucleophiles 3 were derived from alco-
hols (R’OH) and carbon disulfide in the presence of sodium hydride
(10 mol %).
Scheme 1. Synthesis of compounds 4.
NMR spectrum of 4a exhibited three singlets for the methoxy pro-
tons at d = 3.89, 3.95 and 3.97, together with characteristic signals
for the aromatic moiety. In the 13C NMR spectrum, the signals cor-
responding to the ester carbonyl groups of 4a were observed at
d = 165.4, 165.5 and 165.6. The mass spectrum of 4a displayed
the molecular ion peak at m/z = 303. The 1H and 13C NMR spectra
of 4b–4k were similar to those of 4a except for the alkyl moieties,
which exhibited characteristic resonances in appropriate regions of
the spectrum.
The structures of compounds 4a–4k were assigned based on
their IR, 1H NMR and 13C NMR spectral data. For example, the 1H
Although the mechanistic details of the reaction are not known,
* Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
a plausible rationalization20 may be advanced to explain the
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.02.107

2194
I. Yavari et al. / Tetrahedron Letters 51 (2010) 2193–2194
CO2R
O
O
O
S
CO2R
R'
S
O
O
+
S
2
O
N
R'O
S
Na
NH
H
Na
5
3
1
S
S
O
O
R'
R'
S
O
O
CO2R
S
O
CO2R
S
O
HO
R'
_
S
O
R'OH
H2O
NH
N
N
H
Na
CO2R
CO2R
H
RO2C
CO2R
8
7
6
S
Na
S
R'
O
O
S
OR'
R'
O
CO2R'
CO2R
O
S
_
R'O Na
CO2R
CO2R
CO2R
R'O Na
_
CS2
N
CO2R
N
N
CO2R
4
9
10
Scheme 2. A proposed mechanism for the formation of compounds 4.
11. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider,
P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467.
12. Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002, 43,
6485.
13. Yadav, J. S.; Rao, P. P.; Sreenu, D.; Rao, R. S.; Kumar, V. N.; Nagaiah, K.; Prasad, A.
R. Tetrahedron Lett. 2005, 46, 7249.
14. Bose, D. S.; Kumar, R. K. Tetrahedron Lett. 2006, 47, 813.
15. Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.; Verron, J.;
Masciadri, R. Tetrahedron 2007, 63, 2811.
product formation (Scheme 2). Presumably, the reaction starts
with the formation of salt 5, followed by addition of the dialkyl
acetylenedicarboxylate 2 to generate intermediate 6. This interme-
diate undergoes a cyclization reaction to afford 7, which is proton-
ated by the alcohol (used to form 3 in situ) to generate 8.
Intermediate 8 is converted into thioanhydride 9 by elimination
of H2O. The alkoxide ion then attacks 9 to generate 10, which final-
ly undergoes a fragmentation reaction to produce product 4.
In conclusion, we have developed a convenient, one-pot method
for the synthesis of trialkyl quinoline-2,3,4-tricarboxylates using
isatin and acetylenic esters in the presence of sodium O-alkyl car-
bonodithioates. The present method may be considered as a prac-
tical route for the synthesis of quinoline ring systems.
16. Yavari, I.; Mirzaei, A.; Moradi, L.; Hosseini, S. Tetrahedron Lett. 2008, 49, 2355.
17. Yavari, I.; Moradi, L.; Mokhtarporyani-Sanandaj, A.; Mirzaei, A. Helv. Chim. Acta
2007, 90, 392.
18. Yavari, I.; Karimi, E. Tetrahedron Lett. 2008, 49, 6433.
19. Compounds 4: General procedure. To a stirred solution of the alcohol (2 mmol) in
CS2 (0.35 g, 5 mmol) containing NaH (10 mol %), was added, at rt, a solution of
0.30 g of isatin (1) (2 mmol) and the acetylenic ester (2) (2 mmol) in 2 mL of
MeCN. After completion of the reaction [2–4 h; TLC (EtOAc/hexane 2:1)], the
solvent was evaporated, and the residue was purified by column
chromatography [silica gel (230–240 mesh; Merck), hexane/EtOAc 4:1)].
Trimethyl quinoline-2,3,4-tricarboxylate (4a): Orange oil, yield: 0.53 g (87%). IR
Supplementary data
(KBr) (m
max/cmÀ1): 1721, 1719, 1717, 1549, 1431, 1308, 1265, 1230, 1195. 1H
NMR (500 MHz, CDCl3): d = 3.89 (3H, s, MeO), 3.95 (3H, s, MeO), 3.97 (3H, s,
MeO), 7.62 (1H, d, 3J = 7.8 Hz, CH), 7.77 (1H, t, 3J = 7.8 Hz, CH), 7.95 (1H, t,
3J = 7.8 Hz, CH), 8.16 (1H, d, 3J = 7.8 Hz, CH). 13C NMR (125 MHz, CDCl3):
d = 52.9 (MeO), 53.0 (MeO), 53.1 (MeO), 122.8 (C), 123.5 (C), 125.4 (CH), 129.8
(CH), 130.2 (CH), 131.9 (CH), 139.8 (C), 147.3 (C), 147.7 (C), 165.4 (C@O), 165.5
(C@O), 165.6 (C@O). MS (EI, 70 eV): m/z (%) = 303 (M+, 10), 288 (43), 273 (85),
244 (75), 187 (80), 129 (100), 59 (45). Anal. Calcd for C15H13NO6 (303.26): C,
59.41; H, 4.32; N, 4.62. Found: C, 59.75; H, 4.36; N, 4.65.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.107.
References and notes
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4-tert-Butyl, 2,3-dimethyl quinoline-2,3,4-tricarboxylate (4e): Yellow oil, yield:
0.59 g (86%). IR (KBr) (m
max/cmÀ1): 1732, 1725, 1720, 1545, 1425, 1380, 1362,
1210, 1159, 1100. 1H NMR (500 MHz, CDCl3): d = 1.35 (9 H, s, Me3C), 3.73 (3H, s,
MeO), 3.84 (3H, s, MeO), 7.35 (1H, d, 3J = 7.9 Hz, CH), 7.42 (1H, t, 3J = 7.9 Hz,
CH), 7.82 (1H, t, 3J = 7.9 Hz, CH), 8.16 (1H, d, 3J = 7.9 Hz, CH). 13C NMR
(125 MHz, CDCl3): d = 25.4 (Me3C), 52.3 (MeO), 53.0 (MeO), 86.4 (Me3C), 122.2
(C), 123.3 (C), 124.8 (CH), 129.5 (CH), 130.4 (CH), 132.0 (CH), 141.2 (C), 147.6
(C), 149.2 (C), 165.5 (C@O), 165.6 (C@O), 165.7 (C@O). MS (EI, 70 eV): m/z
(%) = 345 (M+, 7), 330 (32), 288 (54), 286 (65), 244 (71), 229 (39), 185 (73), 129
(80), 57 (100). Anal. Calcd for C18H19NO6 (345.35): C, 62.60; H, 5.55; N, 4.06.
Found: C, 62.52; H, 5.49; N, 4.08.
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