Synthesis of New Substituted Kynurenic Acids

Full text of DOI:10.1080/00304948.2017.1260397

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of New Substituted Kynurenic Acids
Ajoy K. Banerjee & William J. Vera
To cite this article: Ajoy K. Banerjee & William J. Vera (2017) Synthesis of New Substituted
Kynurenic Acids, Organic Preparations and Procedures International, 49:1, 53-58, DOI:
10.1080/00304948.2017.1260397
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Organic Preparations and Procedures International, 49:53–58, 2017
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1260397
Synthesis of New Substituted Kynurenic Acids
Ajoy K. Banerjee and William J. Vera
Chemistry Center, Venezuelan Institute of Scientific Research (IVIC),
Caracas, Venezuela
Kynurenic acid (4-hydroxyquinoline-2-carboxylic acid) and its derivatives play a crucial
role in maintaining normal brain function.1 Several kynurenic acid derivatives containing
halo, amino, hydroxy and carboxy group in ring B have been prepared and their pharma-
logical activities studies2–9 and thus are attractive targets for organic synthesis. These
findings encouraged us to synthesize three - to the best of ourknowledge - previously
unreported kynurenic acid derivatives 1–3 (Figure 1) with propionyl, cyclo-hexanone
and methoxy groups respectively on ring B with the hope that they too might also exhibit
useful biological activities. The present article describes the prepa-ration of kynurenic
acid derivatives 1, 2 and 3.
Figure 1
The preparation of 1 was approached by condensation of the previously reported10 aniline
4, prepared from 3-methoxypropiophenone in four steps (Wolff-Kishner reduction, nitration,
oxidation at the benzylic position and reduction of the nitro group), condensed with
dimethylacetylene dicarboxylate 5 (DMAD) in methanol at room temperature to afford prod-
uct 6 in 90% yield; its spectral data indicated the trans-configuration about the double bond.
Cyclization of 6 with polyphosphoric acid (PPA) yielded the kynurenic acid 1
(Scheme 1) in 60% (an overall yield 6% from 3-methoxypropiophenone). Although this
type of cyclization had been performed3,6,7 by heating in diphenyl ether (bp. 250ꢀC) or in
Dowtherm (bp. 235ꢀC), the major disadvantages of these methods are the in-conveniently
high temperature and potential problem in isolation; if the kynurenic acid derivative does
not precipitate completely, then it becomes extremely difficult to isolate it from the
reaction mixture by the usual work-up and the resulting product will remain contaminated
with the solvents which are very difficult to remove.
Received August 2, 2016; in final form September 27, 2016.
Address correspondence to Ajoy K. Banerjee, Centro de Quimica, IVIC, Apartado- 21827,
Caracas-1020A, Venezuela. E-mail: aabanerje@gmail.com
53

54
Banerjee and Vera
Scheme 1
Treatment of the known11 7-amino-1-tetralone 7 (prepared from the commer-cially
available 1-tetralone in two steps (43% yield) was similarly condensed with DMAD in
methanol to afford the trans adduct 8 in 90% yield (Scheme 2). Conversion of 8 to kynur-
enic acid 2 in 60% yield
Scheme 2
(overall yield 23%) was realized by cyclization using polyphosphoric acid. The
struc-ture 2 was assigned to the resulting kynurenic acid on the basis of its 1H
NMR and IR spectroscopic data. In assition to the signal at d 13.46 for the pheno-
lic hydrogen in 1H NMR spectrum, the presence of two doublets at d 8.31 and
7.51 for hydrogens at C-7 and C-8 and a singlet at d 7.65 (hydrogen at C-3) pro-
vide strong support for the structure 2 and thus indicating that cyclization had not
occurred in the alternate direction to give compound 9. If the compound 9 had
been formed, then three singlets ascribable to three aromatic protons would have
1
appeared in the H-NMR spectrum. Furthermore the IR spectrum also lent strong
evidence in favor of the structure 2. The absorption at 1727 cm¡1 was sassigned to
the ester carbonyl group and the keto carbo-nyl group at 1642 cm¡1 was shifted to
lower frequency (cyclohexanone absorbs at 1715 cm¡1) presumably because of the
intramolecular bonding. These spectroscopic data clearly indicate the absence of
the compound 9.
Theoretical calculations performed in order to rationalize the formation of 2 in pref-
erence to 9 indicate that the intermediate leading to formation of 9 is not stable and cannot
be formed but the intermediate to 2 maintains the cyclic conformation with an energetic
cost of only 50 kcal/mol.12

Synthesis of New Substituted Kynurenic Acids
55
Lastly for the synthesis of the kynurenic acid derivative 3 (Scheme 3), catalytic
hydrogenation of the known13 nitrobenzaldehyde 10 [surprisingly obtained in 75% yield
by nitration of commercially available 2,3,4-trimethoxybenzaldehyde (Scheme 3)] led to
the reduction of both the nitro and the aladehyde groups. Since the amino compound 11
has a strong tendency to decomposition,14 the crude hydrogenation product was con-
densed was condensed with DMDA without purification to give 12 in 67% yield. Conver-
sion of 12 to 3 proceeded in 75% yield and the overall yield to the kynurenic acid
derivative 3 was 34% from 2,3,4-trimethoxybenzaldehyde.
Scheme 3
In conclusion, three new substituted kynurenic acids have been synthesized in good
yields. No difficulty was experienced in the isolation of the hydroxyquinolines with the
use of polyphosphoric acid as the cyclization agent. The biological activities of these
kynurenic acid derivatives will be reported elsewhere at a later date.
Experimental Section
Unless otherwise stated all melting points are uncorrected and were determined on an
Electrothermal melting point apparatus. Infrared (IR) spectra were recorded on a Nicolet-
Fourier Transform (FT) instrument and NMR (1H and 13C) spectra were determined on a
Bruker AM-300 spectrometer in CDCl3. Chemical shifts (d) are expressed in ppm. Mass
spectra were recorded on Thermo Scientific TSQ Quantum Ultra AM Triple Quadrupole
mass spectrometer. Column chromatography was carried out on silica gel 60 (Merck).
Thin layer chromatography (TLC) plates were coated with silica gel and the spots were
visualized using ultraviolet light. All organic solvents were dried over anhydrous MgSO4
and evaporated in vacuo. Microwave irradiations were carried out using a monomode
CEM Discovery Labmate microwave oven (2.45 GHZ, 300 W). Elemental analyses were
performed on a Carlo-Erba 1108 Elemental Analyser.
trans-Dimethyl 2-[(20-Methoxy-40-propionylphenyl)amino]-2-butendioate (6)
To a solution of the amine 4 (70 mg, 0.39 mmol) in methanol (2ml) was added DMAD 5
(0,05 ml, 0.40 mmol). The resulting solution was stirred for 24 h at room temperature
and concentrated in vacuo. The residue was dissolved in chloroform and the solution was
washed, dried and evaporated. The resulting oil on purification using preparative chroma-
tography plate (hexane-ether 9:1) afforded the adduct 6 (113 mg, 90%), a pale yellow
solid, mp. 73–75ꢀC (hexane); IR (cm¡1): 1675, 1740 (CO); MS (m/z): 289 (MC
-
1
MeOH), 260 (MC - MeOH- Et), 200 (260 – HCOOMe); H NMR: d 9.76 (bs, 1H, NH);
7.48 (d, 1H, J D 1.77 Hz) (H at C-5), 7.46–7.43 (dd, 1H, J D 8.16 Hz, J D 1.77 Hz) (H at

56
Banerjee and Vera
C- 3), 6.65 (d, 1H, J D 8.16 Hz) (H at C-2), 5.50 (s, 1H) (H at C-8), 3.91 (s, 3H, OMe),
3.73 (s, 3H,OMe), 3.71 (s, 3H, OMe), 2.91 (q, 2H, J D 7.3 Hz) (H at C-14), 1.16 (t, 3H, J
D 7.3 Hz) (H at C-15); 13C NMR: d 199.34 (C-13), 169.21 (C-9), 164.38 (C-11), 149.43
(C-6), 145.81 (C-7), 133.85 (C-1), 132.12 (C-4), 121.61 (C3), 117.34 (C-5), 109.63 (C-
2), 96.18 (C-8), 55.71 (C-16), 52.76 (C-12), 51.32 (C-10), 31.28 (C-14), 8.34 (C-15).
Anal. Calcd for C16H19NO6: C, 59.81; H, 5.91. Found: C, 60.07; H, 6.06
4-Hydroxy-8-methoxy-6-propionylquinoline-2-carboxylic Acid Methyl Ester (1)
To polyphosphoric acid (724 mg, 2.1 mmol) previously heated to and kept at 100ꢀC
was added adduct 6 (172 mg, 0.54 mmol) and the mixture was stirred for 2 h at
100ꢀC. It was then cooled, quenched with water and extracted with chloroform. The
organic extracts were washed, dried and evaporated. Preparative chromatography of
the resulting residue (hexane-chloroform 9:1) afforded adduct 1 (92 mg, 60%), a
pale yellow solid, mp. 183–185ꢀC (hexane); IR (cm¡1): 3386 (OH), 1732 (CO),
1
1678 (CO); MS (m/z): 289 (MC), 260 (MC - Et), 207 (MC – C5H6O),; H NMR:
d 9.46 (s, 1H, OH), 8.47 (s, 1H) (H at C-3), 7.72 (d, 1H, J D 1.6 Hz) (H at C-5),
7.01 (s, 1H, J D 1.6Hz) (H at C-7), 4.07 (s, 3H, OMe), 4.04 (s, 3H, COOMe), 3.11
(q, 2H, J D 7.2Hz), 1.23 (s, 3H, Me); 13C NMR: d 199 (C-11), 179 (C-15), 162
(C-4), 148 (C-8), 135 (C-6), 133 (C-2), 132 (C-9), 126 (C-10), 119 (C-5), 113 (C-7),
109 (C-3), 56 (C-14), 53 (C-16), 31 (C-12), 8 (C-13).
Anal. Calcd for. C15H15NO5: C, 62.28; H, 5.19. Found: C, 62.54; H, 5.32
Dimethyl (2Z)-2-[(8-Oxo-5,6,7,8-tetrahydronaphthalene-2-yl)amino]but-2-
enedioate (8)
To a solution of aminotetralone 7 (614 mg, 3.82 mmol) in methanol (10 ml) was
added DMAD 5 (0.5 ml, 4.01 mmol) and the mixture was stirred at room tempera-
ture for 20 h and then heated under reflux in a microwave oven at 65W for 20 min.
to complete the reaction. The solution was cooled and evaporated to afford an oil
which was chromatographed (hexane-ethyl acetate 8:2) to give adduct 8 (1.04 g,
90%) as yellow liquid; IR (cm¡1): 3364 (NH), 1725 (CO), 1679 (CO); MS (m/z):
1
304 (MHC); H NMR: d 9.62 (s, 1H, NH), 7.47 (d, 1H, J D 2.5 Hz) (H at C-8) 7.13
(d, 1H, J D 8.2 Hz) (H at C-5), 6.98–6.95 (dd, 1H, J D 8.2 Hz, J D 2.5 Hz) (H at
C-6), 5.38 (s, 1H,) (H at C-12), 3.70 (s, 3H) (H at C-16), 3.69 (s, 3H) (H at C-14)),
2.86 (t, 2H, J D 6.1 Hz) (H at C-2), 2.57 (t, 2H, J D 6.1 Hz) (H at C-4), 2.15–2.02
(m, 2H) (H at C-3); 13C NMR: d 197 (C-1), 169 (C-13), 164 (C-15), 147 (C-7), 140
(C-11), 138 (C-9), 132 (C-10), 129 (C-5), 125 (C-6), 118 (C-8), 94 (C-12), 52
(C-16), 51 (C-14), 38 (C-2), 28 (C-4), 23 (C-3).
Anal. Calcd for C16H17NO5: C, 63.36; H, 5.61. Found: C, 63.61; H, 5.78.
Methyl 1-Hydroxy-9-oxo-7,8,9,10-tetrahydrobenzo[f]quinolone-3-carboxylate (2)
To polyphosphoric acid (9.49 g, 28.08 mmol) heated to and kept at 80ꢀC was added
adduct 8 (2.13 g, 7.02 mmol) and the mixture was stirred at the same temperature for
1 h. It was then cooled, added to ice-cold water and extracted with chloroform. The
organic extracts were washed with sodium bicarbonate solution (5%), water, dried and
evaporated. The resulting oily material was chromatographed (hexane-CHCl3 6:4) to
yield compound 2 (1.14 g, 60%) as yellow solid, mp.161–163ꢀC (ether); IR (cm¡1): 1727

Synthesis of New Substituted Kynurenic Acids
57
(CO), 1642 (CO); MS (m/z): 272 (MHC); 1H NMR: d 13.46 (s, 1H, OH), 8.31 (d, 1H, J D
8.7 Hz) (H at C-7), 7.65 (s, 1H) (H at C-3), 7.51 (d, 1H, J D 8.7 Hz) (H at C-8), 3.99 (s,
3H, OMe), 3.17 (t, 2H, J D 6.1 Hz) (H at C-14), 2.87 (t, 2H, J D 6.8 Hz) (H at C-12),
2.18–2.13 (m, 2H) (H at C-13),13C NMR: d 205 (C-11), 165 (C-15), 163 (C-4), 152 (C-
2), 150 (C-10), 149 (C-6), 139 (C-7), 131 (C-8), 128 (C-9), 121 (C-5), 111 (C-3), 53 (C-
16), 40 (C-12), 32 (C-14), 21 (C-13).
Anal. Calcd. for C15 H13NO4: C, 66.42; H, 4.79. Found: C, 66.65; H, 4.93.
Dimethyl 2[(20-Methyl-30, 40, 50,-trimethoxyphenyl)amino]-2-butendioate (12)
A solution of the nitrobenzaldehyde 10 (608 mg, 2.52 mmol) in ethyl acetate (25 mL)
was hydrogenated in presence of (164 mg) Pd-C (10%) at room temperature for 3 h at
atmospheric pressure. Removal of the catalyst and solvent afforded an crude oil (532 mg)
which was dissolved in methanol (10 mL) and treated with DMAD 5 (0.33 ml,
2.65 mmol). The reaction mixture was stirred at room temperature for 20 h and then
heated under reflux in a microwave oven at 65W for 20 min. The solution was cooled,
evaporated and the residue afforded adduct 12 as a yellow oil (574 mg, 67%) after prepar-
ative chromatography (hexane-ether 6:4). MS (m/z): 339 (MC), 324 (MC–Me), 307 (MC -
MeOH), 280 (MC - CO2Me); 1H NMR: d 9.38 (s, 1H, NH), 6.11 (s, 1H) (H at C-6), 5.27
(s, 1H) (H at C-8), 3.78 (s, 3H, OMe at C-5), 3.77 (s, 3H, OMe at C-3), 3.68 (s, 3H) (H at
C-12), 3.67 (s, 3H, OMe at C-4), 3.60 (s, 3H) (H- at C-10), 2.10 (s, 3H) (H at C-13); 13
C
NMR: d 170 (C-9), 164.8 (C-11), 152.2 (C-3), 151.1 (C-5), 149.1 (C-1), 139.7 (C-7),
134.4 (C-4), 117.1 (C-2), 102.1 (C-6), 91.9 (C-8), 60.8 (C-15), 60.5 (C-14), 55.8 (C-16),
52.6 (C-12), 50.9 (C-10), 10.1 (C-13).
Anal. Calcd for C16 H21NO7: C, 56.63; H, 6.19. Found: C, 56.88; H, 6.37.
2-Carboxymethyl-4-hydroxy-5,6,7-trimethoxy-8-methylquinoline (3)
To polyphosphoric acid (1.42 g, 4.2 mmol) heated to and kept at 100ꢀC was added adduct
12 (356 mg, 1.05 mmol) and the mixture was stirred for 2 h at that temperature. It was
then cooled, diluted with cold water and extracted with chloroform. The organic extracts
were washed with a solution of sodium bicarbonate (5%), dried and evaporated. The
resulting yellow oily material on preparative chromatography (hexane-ether 6:4) yielded
the product 3 (242 mg, 75%) as pale yellow solid, mp.105–107ꢀC (hexane); IR (cm¡1
)
3407(OH), 1726(CO); MS (m/z): 307 (MC), 292 (MC - Me), 261(MC - Me - OMe), 232
1
(MC - Me - HCOOMe); H NMR: d 10.1 (s, 1H, OH), 7.44 (s, 1H) (H at C-3), 3.98 (s,
6H) (H at C-11, C-16) 3.90 (s, 6H) (H at C-12, C-13); 2.66 (s, 3H) (H at C-14); 13C
NMR: d 162.5 (C-15), 153.9 (C-9), 147.9 (C-7), 145.5 (C-5), 144.9 (C-4), 143.5 (C-2),
127.1 (C-6), 112.5 (C-10), 105.6 (C-3), 62.4 (C-12), 61.2 (C-13), 60.9 (C-11), 52.8 (C-
16), 10.7 (C-14).
Anal: Calcd for C15H17NO6: C, 58.63; H, 5.53. Found: C, 58.82; H, 5.65
Acknowledgements
The authors would like to thank Dr. David Santiago Coll from computational chemistry
laboratory of Venezuelan Institute of Scientific Research (IVIC) for discussions and col-
laborations on theoretical calculations.

58
Banerjee and Vera
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