Synthesis of 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2h- pyrano[2,3-c]pyridin-2-ones and their esters

Article abstract of DOI:10.1080/00397910802219445

New 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano-[2, 3-c]pyridin-2-ones and their esters were synthesized. The structure of obtained compounds was determined through a complete 1H NMR analysis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802219445

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Synthesis of 5-
Hydroxymethyl-8-methyl-3-(3-
aryl-[1,2,4]oxadiazol-5-yl)-2H-
pyrano[2,3-c]pyridin-2-ones
and Their Esters
Irina O. Zhuravel a , Sergiy M. Kovalenko a , Oleg
V. Zaremba b , Oleksandr S. Detistov b , Svitlana S.
Kovalenko a & Valentin P. Chernykh a
a National University of Pharmacy, Kharkiv, Ukraine
b Institute of Combinatorial Organic Chemistry,
Kharkiv, Ukraine
Published online: 14 Oct 2008.
To cite this article: Irina O. Zhuravel , Sergiy M. Kovalenko , Oleg V. Zaremba ,
Oleksandr S. Detistov , Svitlana S. Kovalenko & Valentin P. Chernykh (2008) Synthesis
of 5-Hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-
c]pyridin-2-ones and Their Esters, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:21, 3778-3784, DOI:
10.1080/00397910802219445
To link to this article: http://dx.doi.org/10.1080/00397910802219445
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Synthetic Communications1, 38: 3778–3784, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219445
Synthesis of 5-Hydroxymethyl-8-methyl-3-(3-
aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]
pyridin-2-ones and Their Esters
Irina O. Zhuravel,1 Sergiy M. Kovalenko,1 Oleg V. Zaremba,2
Oleksandr S. Detistov,2 Svitlana S. Kovalenko,1
and Valentin P. Chernykh1
1National University of Pharmacy, Kharkiv, Ukraine
2Institute of Combinatorial Organic Chemistry, Kharkiv, Ukraine
Abstract: New 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-
pyrano-[2,3-c]pyridin-2-ones and their esters were synthesized. The structure of
1
obtained compounds was determined through a complete H NMR analysis.
Keywords: 5-Hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano-
[2,3-c]pyridin-2-ones, [1,2,4]oxadiazoles
Substances that contain a fragment of disubstituted [1,2,4]oxadiazoles
are commonly used in drug discovery research as an important bioisos-
tere for esters and amides to improve pharmacokinetic properties of drug
candidates.[1]
Oxadiazoles have been the subject of investigation in a number of
different therapeutic areas, usually as an alternative for ester or amide
functionalities. [1,2,4]Oxadiazoles have been proposed as muscarinic
receptor agonist,[2,3] benzodiazepine receptor agonist,[4] histamine H3
receptor antagonist,[5] and antiviral compound.[6] Usually the examples
described have been primarily limited by simple alkyl and aryl derivatives.
Nowadays, the group of compounds that include [1,2,4]oxadia-
zole and coumarine cycles in the same molecule has been successfully
synthesized. Thus, the synthetic procedure of 3-(coumarin-4-yl)-
[1,2,4]oxadiazoles[7–9] I, 5-(coumarin-4-yl)-[1,2,4]oxadiazoles[10] II, and
Received in the U.K. October 26, 2007
Address correspondence to Sergiy M. Kovalenko, National University of Phar-
macy, 53 Pushkinstka str., Kharkov 61002, Ukraine. E-mail:kosn@ic.kharkov.ua
3778

Synthesis of Oxadiazoles
3779
5-(coumarin-3-yl)-[1,2,4]oxadiazoles[11–13] III were described. For the
structures of I–III types, the antioxidant, anti-inflammatory, and
anticancer activities were revealed, and the inhibition activity for some
proteolytic enzymes was studied.
Azaanalogs of coumarines of type IV are novel and have not been
synthesized before. However, taking into account the idea of bio-
isosterism, these compounds should have considerable pharmacological
potential.
Earlier, the reaction of pyridoxal hydrochloride with methyleneactive
nitriles in an alkaline water media in the presence of the phase-transfer
catalyst (cetylmethylammonium bromide) was described by Brufola
et al.[14] Only the 2H-pyrano[2,3-c]pyridines with 2-pyridyl, 2-thienyl or
2-benzothiazolyl heterocyclic moieties in position 3 were successfully
obtained by the authors.
Continuing the investigations in the synthesis of 3-heterylcouma-
rines[15–18] and their 7-azaanalogs,[19,20] this research work is devoted to
preparation of 5-hydroxymethyl-8-methyl-3-(3-aryl-[1,2,4]oxadiazol-5-yl)-
2H-pyrano[2,3-c]pyridin-2-ones and their esters.
For synthesis of required compounds, the Knoevenagel conden-
sation of pyridoxal hydrochloride (1) with 3-aryl-[1,2,4]oxadiazol-5-yl-
acetonitriles (2a,b) was developed. The interaction of initial reactants
was conducted in homogeneous media in methanol at 45–50 ꢀC in pres-
ence of piperidine excess (Scheme 1).
3-Aryl-[1,2,4]oxadiazol-5-yl-acetonitriles (2a,b) were obtained by the
reaction of corresponding arylamidoximes with 3-(3,5-dimethyl-1H-
pyrazol-1-yl)-3-oxopropanonitrile in 1,4-dioxane.
Thin-layer chromatography (TLC) showed that along with formation
of 2-imino-2H-pyrano[2,3-c]pyridines (3a,b), their partial hydrolysis takes
place, and admixture 2-oxoanalogs (4a,b) were identified. For obtaining
pure substances (4), we conducted the hydrolysis of the products of
the reaction in an aqueous–alcoholic media without isolation of the
intermediates (3).
1
The H NMR spectra of obtained compounds (4a,b) contain singlet
signals at 8.40–8.42 ppm and 9.07–9.11 ppm, which are caused by the
protons H-6 and H-4 in the structure of 2H-pyrano[2,3-c]pyridine and

3780
I. O. Zhuravel et al.
Scheme 1.
signals of methyl (singlet at 2.60 ppm) and hydroxymethyl (doublet at
4.80 ppm and triplet at 5.67–5.69 ppm) substitutes. All the spectra of com-
pounds (4) also contain signals of aromatics cycle.
The treatment of compounds 4a,b with anhydride of carbonic
acids in boiling glacial acetic acid leads to the corresponding O-acylation
products (6a–f). Isolated yields of 6 were generally high and ranged from
79 to 92%.
1
In the H NMR spectra of O-acylderivatives (6a–f), the signal of
the proton of the hydroxyl group disappears, the multiplicity of H-signals
of methylene fragment changes; the H-signals of corresponding acylsub-
stituents can be observed.
Thus, as a result, a facile approach to 5-hydroxymethyl-8-methyl-
3-(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]pyridin-2-ones and their
esters as potential pharmaceutical agents has been developed.
EXPERIMENTAL
Melting points were measured with a Buchi B-520 melting-point appar-
atus and were not corrected. IR spectra were recorded on Specord
1
M80 spectrometers in KBr. H NMR spectra were recorded on Varian
Gemini-300 spectrometers in DMSO-d6 using TMS as an internal
standard. Chemical shifts were expressed in d (ppm) relative to TMS as
internal standard and coupling constants (J) in hertz. Mass spectral
analyses were obtained on a PE Sciex API 150EX mass spectrometer.
Elemental analysis were within þ0.4% of the theoretical value.

Synthesis of Oxadiazoles
3781
Thin-layer chromatography (TLC) was performed on aluminum sheets
precoated with silica gel (Merck, Kieselgel 60 F-254). The solvent system
for the TLC method is ethyl acetate–toluene (1:1 or 1:2).
Arylamidoximes (N-hydroxyamidine of arylcarboxylic acids) were
prepared using a previously described approach.[21]
General Procedure for Synthesis of 3-Aryl-[1,2,4]oxadiazol-5-yl-
acetonitriles (2a,b)
The mixture of corresponding of arylamidoxime (20 mmol) and 3-(3,5-
dimethyl-1H-pyrazol-1-yl)-3-oxopropanonitrile (20 mmol, 3.26 g) in 1,4-
dioxane (20 mL) was heated at reflux and stirred for 5 h. The reaction
mixture was cooled and poured out in ice-cold water (100 mL). The pro-
duct of the reaction formed in unctuous consistency and precipitated in a
few hours. For purification, flash chromatography was used.
3-Phenyl-[1,2,4]oxadiazol-5-yl-acetonitrile (2a): Yield 79%, mp: 77 ꢀC.
3-(4-Methoxyphenyl)-[1,2,4]oxadiazol-5-yl-acetonitrile (2b): Yield 85%,
mp: 69 ꢀC.
General Procedure for Synthesis of 5-Hydroxymethyl-8-methyl-3-
(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]pyridin-2-ones (4a,b)
The pyridoxal hydrochloride (1) (5 mmol, 1.0 g) of was dissolved at
45–50 ꢀC in methanol (50 mL). Piperidine (0.4 g) was added to obtained
solution, and 3-aryl-[1,2,4]oxadiazol-5-yl-acetonitriles (2) (5.5 mol) were
added after 5 min. The resulting mixture was standing for 15 min and
then cooled. The formed precipitate was filtered out and dissolved in
50 mL of methanol with 10 mL of diluted HCl (1:10). The resulting
mixture was refluxed at 3 h and then cooled. The formed precipitate
was filtered out, washed with water (3 ꢁ 50 mL), and recrystallized from
methanol.
5-Hydroxymethyl-8-methyl-3-(3-phenyl-[1,2,4]oxꢀadiazol-5-yl)-2H-pyrano
[2,3-c]pyridin-2-one (4a): Yield 72%, mp: 235–236 C; IR, n, cmꢂ1: 3460,
1
3308 (OH), 1752 (CO), 1624 (CN), 1600, 1444, 1352; H NMR, d, ppm:
2.60 (s, 3H, CH3), 4.80 (d, J ¼ 6.8 Hz, 2H, ꢂCH2ꢂ), 5.69 (t, J ¼ 4.9 Hz,
1H, OH), 7.59 (m, 3H), 8.07 (d, J ¼ 5.0 Hz, 2H, H-20,60), 8.42 (s, 1H, H-
6), 9.11 (s, 1H, H-4). Anal. Calcd. for C18H13N3O4: C, 64.48; H, 3.91; N,
12.53. Found: C, 64.49; H, 3.90; N, 12.53.
5-Hydroxymethyl-8-methyl-3-[3-(4-methoxyphenyl)-[1,2,4]oxadiazol-5-
yl]-2H-pyrano-[2,3-c]pyridin-2-one (4b): Yield 81%, mp.: 265–267 ꢀC; IR,
n, cmꢂ1: 3332, 3012 (OH), 2396, 2088, 1768 (CO), 1612, 1476, 1428,

3782
I. O. Zhuravel et al.
1
1264; H NMR, d, ppm: 2.60 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 4.80
(d, J ¼ 5.9 Hz, 2H, ꢂCH2ꢂ), 5.67 (t, J ¼ 4.7 Hz, 1H, OH), 7.11 (d,
J ¼ 10.7 Hz, 2H, H-20,60), 8.00 (d, J ¼ 10.7 Hz, 2H, H-30,50), 8.40 (s,
1H, H-6), 9.07 (s, 1H, H-4). Anal. Calcd. for C19H15N3O5: C, 62.46;
H, 4.14; N, 11.50. Found: C, 64.48; H, 4.14; N, 11.50.
General Procedure for Acylation of 5-hydroxymethyl-8-methyl-3-
(3-aryl-[1,2,4]oxadiazol-5-yl)-2H-pyrano[2,3-c]pyridin-2-ones
Compound 4a,b (2 mmol) was dissolved at 40 ꢀC in a mixture of glacial
acetic acid (10 mL) and corresponding anhydride (5a–c) (10 mL). The
reaction mixture was heated at reflux for 30 min and then cooled to rt.
Ice-cold water (50 mL) was added, and the formed precipitate was filtered
out and recrystallized from a mixture of ethanol and dimethylformamide
to afford the corresponding ether (6a–f) as a crystalline solid.
Acetic acid 8-methyl-2-oxo-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-2H-pyr-
ano[2,3-c]pyridin-5-ylmethyl ester (6a): Yield 86%, mp: 200–201 ꢀC; IR,
n, cmꢂ1: 1756 (CO), 1744 (CO), 1628 (CN), 1596, 1448, 1244; 1H
NMR, d, ppm: 2.02 (s, 3H, COCH3), 2.60 (s, 3H, CH3), 5.48 (s, 2H,
ꢂCH2ꢂ), 7.60 (s, 3H), 8.09 (d, J ¼ 4.8 Hz, 2H, H-20,60), 8.52 (s, 1H,
H-6), 9.05 (s, 1H, H-4). Anal. Calcd. for C20H15N3O5: C,
63.66; H, 4.01, N; 11.14. Found: C, 63.66; H, 4.00; N, 11.13.
Propyonic acid 8-methyl-2-oxo-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-2H-
pyrano[2,3-c]pyridin-5-ylmethyl ester (6b): Yield 91%, mp: 162–163 ꢀC;
1H NMR, d, ppm: 1.00 (t, J ¼ 9.4 Hz, 3H, CH2CH3), 2.32 (q, J ¼ 8.5 Hz,
2H, CH2CH3), 2.60 (s, 3H, CH3), 5.48 (s, 2H, ꢂCH2ꢂ), 7.60 (m, 3H),
8.08 (dd, J ¼ 6.4 Hz, J ¼ 3.5 Hz, 2H, H-20,60), 8.50 (s, 1H, H-6), 9.05
(s, 1H, H-4). Anal. Calcd. for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74.
Found: C, 64.45; H, 4.40; N, 10.75.
Butyric acid 8-methyl-2-oxo-3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-2H-
pyrano[2,3-c]pyridin-5-ylmethyl ester (6c): Yield 79%, mp: 145–146 ꢀC;
1H NMR, d, ppm: 0.83 (t, J ¼ 9.6 Hz, 3H, CH2CH2CH3), 1.55 (qv,
J ¼ 8.7 Hz, 2H, CH2CH2CH3), 2.30 (t, J ¼ 8.3 Hz, 2H, CH2CH2CH3),
2.60 (s, 3H, CH3), 5.49 (s, 2H, -CH2-), 7.61 (m, 3H), 8.08 (m, 2H, H-
20,60), 8.52 (s, 1H, H-6), 9.05 (s, 1H, H-4). Anal. Calcd. for
C22H19N3O5: C, 65.18; H, 4.72, N; 10.36, Found: C, 65.21; H, 4.71; N,
10.34.
Acetic acid 8-methyl-2-oxo-3-{3-(4-methoxyphenyl)-[1,2,4]oxadiazol-
5-yl}-2H-pyrano[2,3-c]pyridin-5-ylmethyl ester (6d): Yield 92%, mp: 180–
181 ꢀC; 1H NMR, d, ppm: 2.02 (s, 3H, COCH3), 2.60 (s, 3H, CH3),
3.80 (s, 3H, OCH3), 5.46 (s, 2H, ꢂCH2ꢂ), 7.12 (d, J ¼ 9.4 Hz, 2H, H-
20,60), 8.02 (d, J ¼ 9.9 Hz, 2H, H-30,50), 8.50 (s, 1H, H-6), 9.03 (s, 1H,

Synthesis of Oxadiazoles
3783
H-4). Anal. Calcd. for C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found:
C, 61.91; H, 4.21; N, 10.30.
Propyonic acid 8-methyl-2-oxo-3-{3-(4-methoxyphenyl)-[1,2,4]oxadia-
zol-5-yl}-2H-pyrano[2,3-c]pyridin-5-ylmethyl ester (6e): Yield 88%, mp:
ꢀ
1
154–156 C; H NMR, d, ppm: 1.00 (t, J ¼ 8 Hz, 3H, CH2CH3), 2.33
(q, J ¼ 9 Hz, 2H, CH2CH3), 2.60 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.49
(s, 2H, ꢂCH2ꢂ), 7.13 (d, J ¼ 9.1 Hz, 2H, H-20,60), 8.00 (d, J ¼ 9.8 Hz,
2H, H-30,50), 8.50 (s, 1H, H-6), 9.02 (s, 1H, H-4). Anal. Calcd. for
C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.70; H, 4.51; N, 10.00.
Butyric acid 8-methyl-2-oxo-3-{3-(4-methoxyphenyl)-[1,2,4]oxadiazol-
5-yl}-2H-pyrano[2,3-c]pyridin-5-ylmethyl ester (6f): Yield 87%, mp:
ꢀ
1
160 C; H NMR, d, ppm: 0.91 (t, J ¼ 7.8 Hz, 3H, CH2CH2CH3), 1.52
(qv, J ¼ 8.7 Hz, 2H, CH2CH2CH3), 2.31 (t, J ¼ 8.7 Hz, 2H, CH2CH2CH3),
2.60 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.49 (s, 2H, ꢂCH2ꢂ), 7.10
(d, J ¼ 10.2 Hz, 2H, H-20,60), 7.97 (d, J ¼ 8.7 Hz, 2H, H-30,50), 8.50
(s, 1H, H-6), 9.00 (s, 1H, H-4). Anal. Calcd. for C23H21N3O6:
C, 63.44; H, 4.86; N, 9.65. Found: C, 63.45; H, 4.87; N, 9.66.
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