TiO2 nanoparticles as an effective catalyst for the synthesis of hexahydro-2-quinolinecarboxylic acids derivatives

Article abstract of DOI:10.1016/j.cclet.2012.06.038

The one-pot three-component reaction of arylmethylidenepyruvic acids, 1,3-cyclohexandiones and ammonium acetate provides an economical and efficient synthetic route to 5-oxo-4-aryl-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid 4 under solvent-free cond

Full text of DOI:10.1016/j.cclet.2012.06.038

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1003–1006
www.elsevier.com/locate/cclet
TiO2 nanoparticles as an effective catalyst for the synthesis of
hexahydro-2-quinolinecarboxylic acids derivatives
Shahrzad Abdolmohammadi
Department of Chemistry, Faculty of Science, East Tehran Branch, Islamic Azad University, PO Box 33955-163, Tehran, Iran
Received 13 April 2012
Available online 18 July 2012
Abstract
The one-pot three-component reaction of arylmethylidenepyruvic acids, 1,3-cyclohexandiones and ammonium acetate provides
an economical and efficient synthetic route to 5-oxo-4-aryl-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid 4 under solvent-free
conditions using a catalytic amount of TiO2 nanoparticles (TiO2 NPs) as an effective heterogeneous catalyst.
# 2012 Shahrzad Abdolmohammad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: One-pot three-component reaction; Pyrido[2,3-d]pyrimidines; Solvent-free; TiO2 nanoparticles
Heterocycles, including quinolone ring system, represent biological and medicinal scaffolds. Thus they constitute
an important class of natural and non-natural products, and exhibit various important chemical and biological
activities such as antimalarial [1], antibacterial [2], antimicrobial [3], and anti-staphylococcal activities [4].
Meanwhile, an important class of antibiotics posses 4-quinolone framework in their structure [5]. Several of
synthesized 2,4-disubstituted polyhydroquinolines exhibited promising in vivo antihyperglycemic activity [6].
In recent years, inorganic solid oxides have attracted a great deal of interest in the laboratory and industry due to the
activation of adsorbed compounds and reaction rate enhancement, simplicity of operation, reusability of the catalyst
and their use of availability at low cost [7,8]. The most preferred surface of solids would be those which are easy to
handle, inexpensive, non-toxic, easily removed during work-up. TiO2 nanoparticles (TiO2 NPs) is an inexpensive, non-
toxic, moisture stable, reusable, commercially available white powder. It has been my interest to elaborate a novel
simple method for the synthesis of a new class of the quinolinecarboxylic acids derivatives 4a–f at 60 8C, using TiO2
NPs catalyst with an average size of 20 nm.
In order to investigate novel and efficient catalytic routes to heterocyclic compounds [9–11], I have been explored a
novel and efficient approach to hexahydro-2-quinolinecarboxylic acid 4, which was synthesized by a three-component
reaction of arylmethylidenepyruvic acids 1, 1,3-cyclohexandiones 2 and ammonium acetate 3, in the presence of TiO2
NPs as an efficient catalyst. Arylmethylidenepyruvic acids 1, as an attractive a,b-unsaturated carbonyl compound is
prepared easily according to the known procedure [12] by reaction of aromatic aldehydes and pyruvic acid in an
aqueous MeOH solution of KOH (Scheme 1 and Table 1).
E-mail addresses: abdolmohamadi_sh@yahoo.com, sabdolmohamadi@qdiau.ac.ir.
1001-8417/$ – see front matter # 2012 Shahrzad Abdolmohammad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.038

1004
S. Abdolmohammadi / Chinese Chemical Letters 23 (2012) 1003–1006
Scheme 1. Synthesis of hexahydro-2-quinolinecarboxylic acid derivatives in solvent-free conditions.
Table 1
Synthesis of hexahydro-2-quinolinecarboxylic acids 4a–f in solvent-free conditions using TiO2 NPs as catalyst.
Product
R1
R2
Mp (8C)
Yielda (%)
4a
4b
4c
4d
4e
4f
Cl
H
213–215
239–241
253–255
250–252
248–250
259–261
92
94
97
98
94
96
MeO
Me
Cl
H
H
Me
Me
Me
MeO
Me
a
1
Yields refer to pure isolated products characterized by IR, H NMR and 13C NMR spectroscopy, mass spectrometry and elemental analysis.
In order to optimize the reaction conditions, in the first set we used 4-methoxyphenylmethylidenepyruvic acid 1b,
1,3-cyclohexandione 2(R2 = H) and ammonium acetate 3 as a model. The results are summarized in Table 2. After
0.5 h in fact, 64, 94 and 94% progress were observed when 5, 10 and 15 mol% of TiO2 NPs were used at 60 8C
respectively. It is important to note that in the absence of TiO2 NPs, the reaction time was increased, meanwhile the
yield decreased (Table 2, entries 1–4).
According to Table 2, the replacement of TiO2 bulk with TiO2 NPs in the model reaction, increased the reaction
time by eight times with lower yield than TiO2 NPs (Table 2, entries 3 and 5).
To investigate the effect of reaction temperature, the model reaction was carried out at different temperatures under
similar experimental conditions. Evidently, increasing the temperature having no measurable effect on the yield and
reaction time (Table 2, entries 3 and 6).
The effect of solvents was also studied. It is notable that the best results were obtained in solvent-free conditions
(Table 2, entries 3 and 7–8).
A plausible mechanism for this reaction is illustrated in Scheme 2. According to both Lewis acid and Lewis base
character of TiO2, it is reasonable that the high formation of 4 over TiO2 NPs, is due to coordinate assisted internal
Table 2
Optimization of the TiO2 NPs catalyzed model reaction of 4-methoxyphenylmethylidenepyruvic acids, 1,3-cyclohexandione and ammonium acetate
for the synthesis of product 4b.
Entry
Catalyst (mol%)
Solvent
Temp (8C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
No catalyst
None
None
None
None
None
None
CH3CN
DMF
60
60
2
63
64
94
94
54
95
54
61
TiO2 NPs (5%)
TiO2 NPs (10%)
TiO2 NPs (15%)
TiO2 bulk (10%)
TiO2 NPs (10%)
TiO2 NPs (10%)
TiO2 NPs (10%)
0.5
0.5
0.5
1.5
0.5
1
60
60
60
90
80
100
1.5
a
Isolated yield.

S. Abdolmohammadi / Chinese Chemical Letters 23 (2012) 1003–1006
1005
Scheme 2. Suggested mechanism for the synthesis of hexahydro-2-quinolinecarboxylic acids in solvent-free conditions.
cyclization of intermediate 6, that can be formed via the initial Michael addition of intermediate 5 which is previously
obtained from the reaction between 1,3-cyclohexandiones 2 and ammonium acetate 3, to arylmethylidenepyruvic
acids 1. Intramolecular cyclization of 6 gives 4 after dehydration of intermediate 7. On the other hand the high surface
area-to-volume ratio of TiO2 NPs, is mainly responsible for its catalytic properties.
The structures of synthesized compounds 4(a–f) were confirmed by 1H NMR, 13C NMR and IR spectral data and
their molecular weight by mass spectrometry, and also by elemental analysis.
In conclusion, we have developed a novel and efficient solvent-free protocol for the synthesis of previously
unknown hexahydro-2-quinolinecarboxylic acids. The advantages of this environmentally benign and safe procedure
include simple reaction set-up, very mild reaction conditions, high yields and short reaction time.
General procedure for preparation of compounds 4a–f: A mixture of the arylmethylidenepyruvic acids (1,
1 mmol), 1,3-cyclohexandiones (2, 1 mmol), ammonium acetate 3 (0.144 mg, 2 mmol) and TiO2 NPs (7.9 mg,
10 mol%) was stirred at 60 8C for 0.5 h as required to complete the reaction (monitored by TLC). The solid mass was
then eluted with DMF (5 mL), and the mixture was centrifuged at 2000–3000 rpm, for 5 min to remove the catalyst.
The organic solution was then poured into cold water (20 mL), filtered and washed with aqueous ethanol to afford the
pure products 4 in high yields (92–98%).
5-Oxo-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4a): Yield: 289 mg (95%). White
powder. Mp: 213–215 8C. IR (KBr, cmꢀ1): 3326, 1690, 1654, 1567. 1H NMR (300 MHz, DMSO-d6): d 1.84 (m, 2 H,
H-7), 2.16 (m, 2 H, H-8), 2.43 (m, 1 H, H-6), 2.67 (m, 1 H, H-60), 4.59 (d, 1 H, J = 5.6 Hz, H-4), 5.90 (d, 1 H,
J = 4.8 Hz, H-3), 7.17 (d, 2 H, J = 8.3 Hz, H-Ar), 7.30 (d, 2 H, J = 8.3 Hz, H-Ar), 8.70 (s, 1 H, NH), 13.27 (brs, 1 H,
COOH). 13C NMR (75 MHz, DMSO-d6): d 20.8, 26.6, 36.4, 36.8, 105.6, 115.4, 127.1, 128.2, 129.1, 130.5, 145.8,
154.3, 163.6, 194.3. MS (EI 70 eV): m/z (%): 305 (M+2, 32), 303 (M+, 55), 285 (32), 257 (100), 192 (85), 174 (61), 146
(93). Anal. Calcd. for C16H14NO3Cl (303.74): C, 63.27; H, 4.65; N, 4.61. Found: C, 63.20; H, 4.62; N, 4.57.
5-Oxo-4-(4-methoxyphenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4b): Yield: 275 mg (92%). White
powder. Mp: 239–241 8C. IR (KBr, cmꢀ1): 3319, 1695, 1570, 1510. 1H NMR (300 MHz, DMSO-d6): d 1.81 (m, 2 H,
H-7), 2.17 (m, 2 H, H-8), 2.46 (m, 1 H, H-6), 2.63 (m, 1 H, H-60), 3.68 (s, 3 H, OCH3), 4.52 (d, 1 H, J = 5.6 Hz, H-4),
5.91 (dd, 1 H, J = 5.7, 1.5 Hz, H-3), 6.80 (d, 2 H, J = 8.6 Hz, H-Ar), 7.06 (d, 2 H, J = 8.6 Hz, H-Ar), 8.58 (s, 1 H, NH),
13.00 (brs, 1 H, COOH). 13C NMR (75 MHz, DMSO-d6): d 20.9, 26.6, 35.9, 36.8, 55.0, 106.2, 113.6, 116.0, 126.8,
128.2, 139.3, 153.8, 157.5, 163.9, 194.3. MS (EI 70 eV): m/z (%): 299 (M+, 19), 273 (100), 253 (79), 217 (87), 161
(60). Anal. Calcd. for C17H17NO4 (299.32): C, 68.21; H, 5.72; N, 4.68. Found: C, 68.18; H, 5.68; N, 4.71.

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S. Abdolmohammadi / Chinese Chemical Letters 23 (2012) 1003–1006
5-Oxo-4-(4-methylphenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4c): Yield: 263 mg (93%). White
powder. Mp: 253–255 8C. IR (KBr, cmꢀ1): 3322, 1693, 1654, 1568. 1H NMR (300 MHz, DMSO-d6): d 1.83 (m, 2 H,
H-7), 2.15 (m, 2 H, H-8), 2.21 (s, 3 H, CH3), 2.45 (m, 1 H, H-6), 2.66 (m, 1 H, H-60), 4.53 (d, 1 H, J = 5.6 Hz, H-4), 5.90
(d, 1 H, J = 4.9 Hz, H-3), 7.03 (s, 4 H, H-Ar), 8.60 (s, 1 H, NH), 13.00 (brs, 1 H, COOH). 13C NMR (75 MHz, DMSO-
d6): d 20.6, 20.9, 26.6, 36.4, 36.8, 106.0, 116.2, 126.7, 127.2, 128.8, 134.9, 144.0, 153.9, 163.7, 194.3. MS (EI 70 eV):
m/z (%): 283 (M+, 90), 265 (22), 237 (100), 192 (88), 174 (67), 146 (93). Anal. Calcd. for C17H17NO3 (283.33): C,
72.07; H, 6.05; N, 4.94. Found: C, 72.01; H, 6.02; N, 4.87.
7,7-Dimethyl-5-oxo-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4d): Yield: 325 mg
(98%). White powder. Mp: 250–252 8C. IR (KBr, cmꢀ1): 3375, 1701, 1663, 1564. 1H NMR (300 MHz, DMSO-d6): d
0.91 (s, 3 H, CH3), 0.98 (s, 3 H, CH3), 1.96 (d, 1 H, J = 16.1 Hz, H-6), 2.13 (d, 1 H, J = 16.1 Hz, H-60), 2.46 (m, 2 H, H-
8), 4.57 (d, 1 H, J = 5.5 Hz, H-4), 5.88 (d, 1 H, J = 5.5 Hz, H-3), 7.17 (d, 2 H, J = 8.3 Hz, H-Ar), 7.30 (d, 2 H,
J = 8.3 Hz, H-Ar), 8.64 (s, 1 H, NH), 13.28 (brs, 1 H, COOH). 13C NMR (75 MHz, DMSO-d6): d 27.0, 29.0, 31.9, 36.7,
50.3, 104.7, 115.4, 127.2, 128.2, 129.2, 130.5, 146.0, 152.4, 163.7, 193.9. MS (EI 70 eV): m/z (%): 333 (M+2, 22), 331
(M+, 60), 313 (13), 285 (100), 220 (95), 202 (47), 174 (94). Anal. Calcd. for C18H18NO3Cl (331.80): C, 65.16; H, 5.47;
N, 4.22. Found: C, 65.19; H, 5.51; N, 4.26.
7,7-Dimethyl-5-oxo-4-(4-methoxyphenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4e): Yield: 311 mg
(95%). White powder. Mp: 248–250 8C. IR (KBr, cmꢀ1): 3369, 1701, 1661, 1565. 1H NMR (300 MHz, DMSO-d6): d
0.92 (s, 3 H, CH3), 0.98 (s, 3 H, CH3), 1.96 (d, 1 H, J = 16.1 Hz, H-6), 2.12 (d, 1 H, J = 16.1 Hz, H-60), 2.45 (m, 2 H, H-
8), 3.68 (s, 3 H, OCH3), 4.49 (d, 1 H, J = 5.6 Hz, H-4), 5.88 (d, 1 H, J = 5.6 Hz, H-3), 6.80 (d, 2 H, J = 8.5 Hz, H-Ar),
7.06 (d, 2 H, J = 8.5 Hz, H-Ar), 8.53 (s, 1 H, NH), 13.00 (brs, 1 H, COOH). 13C NMR (75 MHz, DMSO-d6): d = 26.9,
29.1, 31.9, 36.2, 50.4, 55.0, 105.2, 113.6, 116.3, 126.6, 128.3, 139.5, 152.0, 157.6, 163.8, 193.9 ppm. MS (EI 70 eV):
m/z (%): 327 (M+, 71), 309 (6), 281 (100), 220 (54), 202 (24), 174 (67). Anal. Calcd. for C19H21NO4 (327.38): C,
69.71; H, 6.47; N, 4.28. Found: C, 69.68; H, 6.50; N, 4.22.
7,7-Dimethyl-5-oxo-4-(4-methylphenyl)-1,4,5,6,7,8-hexahydro-2-quinolinecarboxylic acid (4f): Yield: 292 mg
(94%). White powder. Mp: 259–261 8C. IR (KBr): 3369, 1702, 1661, 1564 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): d
0.92 (s, 3 H, CH3), 0.98 (s, 3 H, CH3), 1.95 (d, 1 H, J = 16.0 Hz, H-6), 2.11 (d, 1 H, J = 16.0 Hz, H-60), 2.21 (s, 3 H,
CH3), 2.45 (m, 2 H, H-8), 4.50 (d, 1 H, J = 5.2 Hz, H-4), 5.88 (d, 1 H, J = 4.8 Hz, H-3), 7.03 (s, 4 H, H-Ar), 8.51 (s, 1 H,
NH), 12.95 (brs, 1 H, COOH). 13C NMR (75 MHz, DMSO-d6): d 20.6, 26.9, 29.1, 31.9, 36.8, 50.3, 105.0, 116.2, 126.8,
127.3, 128.8, 135.0, 144.3, 152.1, 163.8, 193.8. MS (EI 70 eV): m/z (%): 311 (M+, 67), 293 (7), 265 (100), 220 (76),
202 (30), 174 (71). Anal. Calcd. for C19H21NO3 (311.38): C, 73.29; H, 6.80; N, 4.50. Found: C, 73.34; H, 6.82; N, 4.56.
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