Synthesis of functionalized pyrano[3,2-c]pyridines and their transformations to 4-hydroxy-3[(1E)-N-hydroxyalkanimidoyl]pyridones

Article abstract of DOI:10.1080/00397910701547995

Reaction of 4-hydroxy-6-methyl-2(1H)-pyridones 1a and 4-hydroxy-1,6- dimethyl-2(1H)-pyridones 1b with diethyl malonates 2a-e leads to the formation of pyrano[3,2-c]pyridines 4a-j. Degradation of 4a-i affords the corresponding ketones 6a-i. Condensation of ketones 6a-i with hydroxyl amine or phenyl hydrazine hydrochloride is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701547995

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Synthesis of Functionalized
Pyrano[3,2‐c]pyridines and
Their Transformations to
4‐Hydroxy‐3[(1E)‐N‐hydroxyalkanimidoyl]pyridon
Farag A. El‐Essawy a , Ahmed F. Khattab a , Magdy A. Zahran a & Sherif H.
Gomaa a
a Faculty of Science, Chemistry Department , Monoufiya University , Shebin
El‐Koam, Egypt
Published online: 10 Sep 2007.
To cite this article: Farag A. El‐Essawy , Ahmed F. Khattab , Magdy A. Zahran & Sherif H.
Gomaa (2007) Synthesis of Functionalized Pyrano[3,2‐c]pyridines and Their Transformations to
4‐Hydroxy‐3[(1E)‐N‐hydroxyalkanimidoyl]pyridones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:18, 3225-3237, DOI: 10.1080/00397910701547995
To link to this article: http://dx.doi.org/10.1080/00397910701547995
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Synthetic Communicationsw, 37: 3225–3237, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701547995
Synthesis of Functionalized Pyrano[3,2-
c]pyridines and Their Transformations
to 4-Hydroxy-3[(1E)-N-
hydroxyalkanimidoyl]pyridones
Farag A. El-Essawy, Ahmed F. Khattab, Magdy A. Zahran,
and Sherif H. Gomaa
Faculty of Science, Chemistry Department, Monoufiya University,
Shebin El-Koam, Egypt
Abstract: Reaction of 4-hydroxy-6-methyl-2(1H)-pyridones 1a and 4-hydroxy-1,6-
dimethyl-2(1H)-pyridones 1b with diethyl malonates 2a–e leads to the formation of
pyrano[3,2-c]pyridines 4a–j. Degradation of 4a–i affords the corresponding ketones
6a–i. Condensation of ketones 6a–i with hydroxyl amine or phenyl hydrazine hydro-
chloride is described.
Keywords: ethyl malonates, 4-hydroxy-2-pyridones, pyrano[3,2-c]pyridines
Pyrano[3,2-c]pyridine derivatives are known to possess various important
biological properties such as antimicrobial, anti-angiogenic, antiviral, and
cytotoxic activities.[1–3] Although a great deal of work has been published
on polcyclic pyridine-containing compounds, much less is known about
pyrano[3,2-c]pyridine systems. However, in general there has little exploita-
tion in developing novel routes to synthesize pyrano[3,2-c]pyridines. Chakra-
sali et al. described synthesis based on the reaction of the acylketene
S,N-acetals with excess of malonyl chloride.[4] Mekheimer et al.[5] and
Stoyanov et al.[6] reported the cyclization of 4-hydroxy-2-pyridones with
Received in the U.K. October 3, 2006
Address correspondence to Ahmed F. Khattab, Faculty of Science, Chemistry
Department, Monoufiya University, Shebin El-Koam, Egypt. E-mail: khattab2000@
yahoo.com
3225

3226
F. A. El-Essawy et al.
either arylmethylene cyanoacetic esters or arylmethylene malononitriles to the
corresponding pyrano[3,2-c]pyridines. Toche et al.[7] obtained pyrano[3,2-
c]pyridines using the condensation reaction of 4-hydroxy-2-pyridones with
b-keto ester in the presence of ammonium acetate. Tchbanenko et al.[8]
described synthesis via Diels–Alder reaction of 3-methylenepyridin-4-one
with alkenes. Therefore, it seems to be possible to synthesize pyrano[3,2-
c]pyridines in high yields by a convenient method from simple laboratory
reagents. Pyrones have been obtained by the condensation of enols or
phenols with 2-unsubstituted or 2-monosubstituted diethyl malonates.[9] The
present study is a continuation of our previous efforts[10–14] to use
malonates in the development of a new, simple, efficient, and one-step
procedure for the synthesis of new heterocyclic compounds. We report here
a convenient synthesis of hitherto unknown polyfunctionally substituted
pyrano[3,2-c]pyridines and their reactions utilizing 4-hydroxy-2-pyridones
1a,b and malonates as the starting materials.
RESULTS AND DISCUSSION
The general method for the preparation of 4-hydroxy-7-methyl-3-(unsubstitu-
ted)substituted-2H-pyrano[3,2-c]pyridine-2,5(6H)-diones 4a–e is outlined in
Scheme 1 by condensation of 4-hydroxy-6-methyl-2(1H)-pyridone 1a with
diethyl malonates 2a–e in diphenyl ether at 200–2508C. Beside 4-hydroxy-
6-methyl-2(1H)-pyridone 1a, its N-methyl derivative 1b was also successfully
employed in the reaction to afford 4-hydroxy-6,7-dimethyl-3-(unsubstituted)-
substituted-2H-pyrano[3,2-c]pyridine-2,5(6H)-diones 4f–j. This propably
formed via the formation of ketene intermediate 3 as described earlier.[15]
The ketene mechanism is also supported by observations obtained during
the reaction where, at temperatures less than 2008C, the first mole of
alcohol is observed to be liberated when the open chain ester is formed.
Scheme 1.

Pyrano[3,2-c]pyridines
3227
Increasing the temperature up to 2508C leads to liberation of the second mole
of alcohol and forms the ketene intermediate 3. The yield ranges between
78 and 96%, which shows that no further activation of the malonates is
necessary. The only disadvantage of this reaction sequence is its high
reaction temperature, which prevents its use with sensitive substrates and
substituents.
The structures of 4a–j could be unambiguously deduced on the basis of
elemental analysis and their spectral properties. The lactone carbonyl group
1
showed strong IR absorption in the range 1701–1733 cm21. The H NMR
spectra of 4a–j are in full agreement with the suggested molecular structures
(Table 1).
Degradation of pyranopyridines 4a–i to the corresponding ketones 6a–i
was performed in 1,2-ethandiol/aqueous sodium hydroxide during 2 h,
instead of the 12 h necessary in aqueous sodium hydroxide solution,[16] to
yield the highly pure ketones 6a–i after acidification with conc. HCl
(Scheme 2).
The formation of 6a–i is assumed to proceed via the intermediate 5,
which is formed by carbonyllactone bond cleavage with pyrone ring
Table 1. 1H NMR spectral data of compounds 4a–j
Compd.
1H NMR (d in ppm)
4a
2.31 (s, 3H, 7-CH3), 5.34 (s, 1H, 3-H), 6.43 (s, 1H, 8-H), 12.75 (bs, 1H,
NH), 13.23 (bs, 1H, OH)
4b
4c
1.78 (s, 3H, 3-CH3), 2.29 (s, 3H, 7-CH3), 6.37 (s, 1H, 8-H), 12.60 (bs, 1H,
NH), 13.20 (bs, 1H, OH)
1.01 (t, 3H, J ¼ 7.4 Hz, CH3CH2), 2.33 (q, 2H, J1 ¼ 7.4 Hz,
J2 ¼ 10.8 Hz, CH2CH3), 2.52 (s, 3H, 7-CH3), 6.40 (s, 1H, 8-H), 12.69
(bs, 1H, NH), 13.25 (bs, 1H, OH)
4d
0.90 (t, 3H, J ¼ 7.2 Hz, CH3CH2-), 1.27–1.31 (m, 2H, -CH2-), 1.33–1.42
(m, 2H, -CH2-), 2.33 (t, 2H, J ¼ 6.3 Hz, -CH2CH2-), 2.50 (s, 3H,
7-CH3), 6.41 (s, 1H, 8-H), 12.68 (bs, 1H, NH), 13.26 (bs, 1H, OH)
2.36 (s, 3H, 7-CH3), 6,51 (s, 1H, 8-H), 7.28–7.47 (m, 5H, arom), 12.84
(bs, 1H, NH), 13.76 (bs, 1H, OH)
4e
4g
4h
1.81 (s, 3H, 3-CH3), 2.49 (s, 3H, 7-CH3), 3.51 (s, 3H, N-CH3), 6.57 (s, 1H,
8-H), 13.26 (s, 1H, OH)
1.01 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 2.36 (q, 2H, J1 ¼ 7.5 Hz, J2 ¼ 15 Hz,
CH2CH3), 2.50 (s, 3H, 7-CH3), 3.51 (s, 3H, N-CH3), 6.59 (s, 1H, 8-H),
13.33 (s, 1H, OH)
4i
4j
2.50 (s, 3H, 7-CH3), 3.54 (s, 3H, N-CH3), 6.68 (s, 1H, 8-H), 7.29–7.48
(m, 5H, arom),13.81 (s, 1H, OH)
0.88 (t, 3H, J ¼ 7.2 Hz, CH3CH2-), 1.27–1.31 (m, 2H, CH2-), 1.33-1.42
(m, 2H, CH2-), 2.34 (t, 2H, J ¼ 7.5 Hz, CH2CH2-), 2.50 (s, 3H,
7-CH3), 3.51 (s, 3H, N-CH3), 6.58 (s, 1H, 8-H), 13.33 (s, 1H, OH)

3228
F. A. El-Essawy et al.
Scheme 2.
opening under the influence of NaOH solution, followed by a proton shift and
intramolecular rearrangement with elimination of carbon dioxide to give the
final product 6a–i. Products 6a–i are characterized from their elemental
and spectral data. Condensation of ketones 6a–i with hydroxyl amine was
performed in a 1:1 ethanol/water mixture to afford the 4-hydroxy-3[(1E)-N-
hydroxyalkanimidoyl]pyridones 7a–i in 62–99% yield. Similarly,
4-hydroxy-3-[(1E)-N-phenylalkanehydrazonoyl]pyridons 8a–d are obtained
on the condensation of phenylhydrazine hydrochloride with ketones 6a, 6c,
6d, and/or 6f, respectively. The mass spectra of 7 and 8 confirmed the corre-
sponding molecular masses. IR and 1H NMR were not decisive for the elucida-
tion of the structure configuration of compounds 7. An absolute proof of the
structure was achieved by X-ray analysis of compound 7a. It shows that the
compound 7a, namely, 4-hydroxy-3-[(1E)-N-hydroxyethanimidoyl]-6-
methylpyridin-2(1H)-one, exists as E-configuration and not as Z-configuration
(Figure 1).
Crystallographic data for 7a: chemical formula: C9H12N2O3, molecular
weight: 196.206, temperature: 298 K, Mo Ka radiation: l ¼ 0.71073,
crystal color: colorless, crystal system: monoclinic, unit cell parameters:
˚
˚
˚
a ¼ 6.8949(4) A, b ¼ 13.2980 (7) A, c ¼ 11.5871 (8) A, a ¼ 90.008,
b ¼ 12; (18) ꢀ 1018, g ¼ 90.008; space group: P21/c, cell volume: 937.76
3
(10) A , cell formula units Z:4. Complete X-ray data for compound 7a was
˚
deposited at the Cambridge Crystallographic Data Centre under the

Pyrano[3,2-c]pyridines
3229
Figure 1.
reference number CCDC 292267; copies can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (Fax: þ44
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
All attempts to perform cyclization of either 7a or 8a to isoxazolopyridine
derivative 9 (X ¼ O) or pyrazolopyridine derivative 9 (X ¼ NPh) through
isomerization of E-configuration of 7 to Z-configuration and then intramolecu-
lar cyclization failed. Either no reaction took place or, under drastic con-
ditions, decomposition of starting material was observed.
EXPERIMENTAL
Melting points were determined on a Buchi melting-point apparatus and
are uncorrected. 1H NMR spectra were recorded on a Varian Germini-
2000 (300 MHz) instrument and registered in DMSO-d6, and chemical
shifts are expressed in parts per million (d) relative to internal Me4Si.
IR spectra were recorded on a Nicolet FT-IR spectrophotometer. Mass
spectra were measured on a Kratos 50 tc spectrometer. Microanalysis
was performed in the microanalysis laboratory at Cairo University.
X-ray calculations were performed using maXus (Bruker Nonius, Delft
and MaxScience) at the National Research Center, Dokki, Cairo,
Egypt. Common reagent-grade chemicals were either commercially
available and were used without further purification or were prepared
by standard literature procedure. All reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.2-mm silica gel 60 F-254
(Merck) plates using UV light (254 and 360 nm) for detection.
Preparation, analysis, and spectral data for compounds 4f and 6f have
been reported earlier.[11]

3230
F. A. El-Essawy et al.
General Procedure for Preparation of 4-Hydroxy-7-methyl-3-
(unsubstituted)substituted-2H -pyrano[3,2-c]pyridine-2,5(6H)-
diones (4a–e)
A mixture of 4-hydroxy-6-methyl-2(1H)-pyridone 1a (10 mmol) and the
appropriate ethyl malonate (10 mmol) in diphenyl ether (5 ml) was heated
at reflux in a distillation apparatus equipped with a 20-cm Vigreux column.
Over 2–3 h, the liberated ethanol was distilled until no more ethanol was
formed. Then the reaction mixture was allowed to cool to room temperature
and treated with diethylether; the obtained precipitate was filtered off,
washed with petroleum ether, dried and recrystallized from the appropriate
solvent. Experimental data: Table 2; spectroscopic data: Table 1.
General Procedure for the Preparation of 4-Hydroxy-6,7-dimethyl-
3-(unsubstituted)substituted-2H-pyrano[3,2-c]pyridine-2,5(6H)-
diones (4f–j)
A mixture of 4-hydroxy-1,6-dimethyl-2(1H)-pyridone 1b (10 mmol) and the
appropriate ethyl malonate (10 mmol) in diphenylether (5 ml) was heated at
reflux in a distillation apparatus equipped with a 20-cm Vigreux column for
2–3 h. Then the reaction mixture was worked up as described previously
for preparation of 4a–e to afford 4f–j. Experimental and infrared data:
1
Table 2; H NMR data: Table 1.
General Procedure for the preparation Of Compounds (6a–i)
A suspension of 4a–i (30 mmol) in 150 ml of ethylene glycol was treated with
a solution of 12 g (30 mmol) of sodium hydroxide in 15 ml of water. The
mixture was heated to a gentle boil for 2 h. Then it was poured into 200 ml
of ice/water, and the obtained solution was acidified with concentrated hydro-
chloric acid (pH ¼ 4) to precipitate the product. It was filtered off after
standing at 48C for about 12 h, washed with water, dried, and recrystallized
from ethanol to give the products as colorless crystals.
Data
3-Acetyl-4-hydroxy-6-methylpyridin-2(1H)-one (6a)
Mp 243–2458C, (yield 68%); IR: 3409 (NH), 3110 (OH), 1685 (CO), 1620
(CON); H NMR (DMSO): 2.17 (s, 3H, CH3), 2.57 (s, 3H, 6-CH3), 5.81
1
(s, 1H, 5-H), 11.45 (bs, 1H, NH), 14.24 (s, 1H, OH). Anal. calcd. for
C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.46; H, 5.41; N, 8.34.

Table 2. Experimental and infrared data of compounds 4a–j
Compd. Mp (8C) Solvent Yield (%) Mol. form. Mol.wt.
Analysis calcd./found
C
H
N%
IR (KBr)
4a
4b
4c
4d
4e
4g
4h
4i
265–267 AcOH
276–278 AcOH
266–268 AcOH
248–250 AcOH
316–318 AcOH
218–221 AcOH
220–223 AcOH
240–243 AcOH
189–191 AcOH
80
78
88
95
96
90
94
80
85
C9H7NO4 193.16
C10H9NO4 207.18
55.96/55.92 3.65/3.55 7.25/7.22 3069 (OH), 1733 (OCO), 1672 (CO)
57.97/57.86 4.38/4.22 6.76/6.66 3097 (OH), 1726 (OCO), 1667 (CO)
C11H11NO4 221.21 59.73/59.65 5.01/4.99 6.33/6.20 3076 (OH), 1714 (OCO), 1658 (CO)
C13H15NO4 249.26 62.64/62.43 6.07/6.04 5.62/5.43 3076 (OH), 1715 (OCO), 1661 (CO)
C15H11NO4 269.25 66.91/66.84 4.12/4.08 5.20/5.11
C11H11NO4 221.21 59.73/59.63 5.01/4.96 6.33/6.20 3095 (OH), 1702 (OCO), 1661 (CO)
C12H13NO4 235.24 61.27/61.18 5.57/5.45 5.95/5.91 3083 (OH), 1703 (OCO), 1575 (CO)
C16H13NO4 283.28 67.84/67.80 4.63/4.59 4.94/4.92 3089 (OH), 1701 (OCO), 1659 (CO)
C14H17NO4 263.29 63.87/63.83 6.51/6.49 5.32/5.26 3086 (OH), 1708 (OCO), 1663 (CO)
3059 (OH), 1716 (OCO), 1657(CO)
4j

3232
F. A. El-Essawy et al.
4-Hydroxy-6-methyl-3-propionylpyridin-2(1H)-one (6b)
Mp 231–2338C (yield 70%); IR: 3307 (NH), 3157 (OH), 1662 (CO), 1630
1
(CON). H NMR (DMSO): 1.03 (t, 3H, J ¼ 10.8 Hz, CH3CH2), 2.17 (s, 3H,
6-CH3), 3.06 (q, 2H, J1 ¼ 10.8, J2 ¼ 21.2 Hz, CH2CH3), 5.80 (s, 1H, 5-H),
11.51 (bs, 1H, NH), 14.89 (s, 1H, OH). Anal. calcd. for C9H11NO3: C,
54.66; H, 6.12; N, 7.73. Found: C, 54.56; H, 6.09; N, 7.64.
3-Butyryl-4-hydroxy-6-methylpyridin-2(1H)-one (6c)
Mp 180–1838C (yield 80%); IR: 3308 (NH), 3159 (OH), 1669 (CO), 1610
1
(CON). H NMR (DMSO): 0.09 (t, 3H, J ¼ 11.0 Hz, CH3CH2), 1.52–1.62
(m, 2H, CH3CH2CH2), 2.17 (s, 3H, 6-CH3), 3.03 (t, 2H, J ¼ 10.8 Hz,
CH3CH2CH2). 5.79 (s, 1H, 5-H), 11.50 (bs, 1H, NH), 15.74 (s, 1H, OH).
Anal. calcd. for C10H13NO3: C, 61.53; H, 6.71; N, 7.81. Found: C, 61.50;
H, 6.55; N, 7.74.
3-Hexanoyl-4-hydroxy-6-methylpyridin-2(1H)-one (6d)
Mp175–1778C (yield 80%); IR: 3304 (NH), 3157 (OH), 1667 (CO), 1611
1
(CON). H NMR (DMSO): 0.87 (t, 3H, J ¼ 10.5 Hz, CH3CH2), 1.08–1.28
(m, 4H, 2 CH2 of butyl), 1.43–1.56 (m, 2H, CH2), 2.18 (s, 3H, 6-CH3),
3.05 (t, 2H, J ¼ 10.5 Hz, CH2), 5.81 (s, 1H, 5-H), 11.50 (bs, 1H, NH),
15.76 (s, 1H, OH). Anal. calcd. for C12H17NO3: C, 64.55; H, 7.67; N, 6.27.
Found: C, 64.51; H, 7.63; N, 6.22.
4-Hydroxy-6-methyl-3-(phenylacetyl)pyridine-2(1H)-one (6e)
1
Mp 201–2048C (yield 69%); IR: 3057 (OH), 1662 (CO), 1615 (CON); H
NMR (DMSO): 2.19 (s, 3H, 6-CH3), 4.44 (s, 2H, CH2), 7.21–7.31 (m, 5H,
arom), 11.57 (bs, 1H, NH), 15.42 (s, 1H, OH). Anal. calcd. for C14H13NO3:
C, 69.12; H, 5.39; N, 5.76. Found: C, 69.10; H, 5.37; N, 5.66.
4-Hydroxy-1,6-dimethyl-3-proionylpyridin-2(1H)-one (6g)
1
Mp 148–1518C (yield 80%); IR: 3130 (OH), 1642 (CO), 1604 (CON); H
NMR (DMSO): 1.03 (t, 3H, J ¼ 9.9 Hz, CH3CH2), 2.37 (s, 3H, 6-CH3),
3.06 (q, 2H, J1 ¼ 10.4, J2 ¼ 20.9 Hz, CH2CH3), 3.75 (s, 1H, N-CH3), 6.00
(s, 1H, 5-H), 15.43 (s, 1H, OH). Anal. calcd. for C10H13NO3: C, 61.53; H,
6.71; N, 7.18. Found: C, 61.49; H, 6.64; N, 7.15.
3-Butyryl-4-hydroxy-1,6-dimethylpyridin-2(1H)-one (6h)
1
Mp 163–1658C (yield 99%); IR: 3231 (OH), 1643 (CO), 1619 (CON); H
NMR (DMSO): 0.90 (t, 3H, J ¼ 10.8 Hz, CH3CH2), 1.50–1.60 (m, 2H,

Pyrano[3,2-c]pyridines
3233
CH2CH2CH3), 2.35 (s, 3H, 6-CH3), 3.02 (t, 2H, J ¼ 10.8 Hz, CH2CH2CH3),
3.35 (s, 3H, N-CH3), 5.96 (s, 1H, 5-H), 15.47 (s, 1H, OH). Anal. calcd. for
C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.11; H, 7.19; N, 6.64.
4-Hydroxy-1,6-dimethyl-3-(phenylacetyl)pyridine-2(1H)-one (6i)
1
Mp 150–1538C (yield 82%); IR: 3059 (OH), 1652 (CO), 1667 (CON); H
NMR (DMSO): 2.38 (s, 3H, 6-CH3), 3.41 (s, 3H, N-CH3), 4.45 (s, 2H,
CH2), 7.19–7.32 (m, 5H, arom), 15.17 (s, 1H, OH). Anal. calcd. for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.98; H, 5.76; N, 5.37.
General Procedure for the Preparation of 4-Hydroxy-3-[(1E)-N-
hydroxyalkanimidoyl]-pyridones (7a–i)
A mixture of compound 4a–i (5 mmol), hydroxyl amine hydrochloride (0.7 g,
5 mmol), and sodium bicarbonate (0.84 g, 10 mmol) in 40 ml of ethanol/
water (3:1) was heated under reflux with stirring for 4 h. The solvent was
evaporated in vacuo, and the residue was triturated with cold water. The pre-
cipitated solid product was collected by filtration, washed with water, dried,
and recrystallized from an ethanol/water mixture (5:1) to afford the product
as colorless crystals.
Data
4-Hydroxy-3-[(1E)-N-hydroxyethanimidoyl]-6-methylpyridin-2(1H)-
one (7a)
Mp 153–1558C (yield 50%); IR: 3383 (NH), 3165 (OH), 1647 (CO); 1H NMR
(DMSO): 2.16 (s, 3H, 6-CH3), 2.29 (s, 3H, CH3), 5.72 (s, 1H, 5-H), 11.08 (bs,
1H, NH), 11.13 (bs, 1H, N-OH), 12.94 (bs, 1H, OH). MS (EI): m/z (%) 183
(Mþ, 1), 182 (Mþ, 26), 165 (100), 138 (33). Anal. calcd. for C8H10N2O3: C,
52.74; H, 5.53; N, 15.38. Found: C, 52.70; H, 5.48; N, 15.24.
4-Hydroxy-3-[(1E)-N-hydroxypropanimidoyl]-6-methylpyridin-2(1H)-
one (7b)
Mp 192–1948C (yield 65%); IR: 3312 (NH), 3159 (OH), 1634 (CO); 1H NMR
(DMSO): 1.03 (t, 3H, J ¼ 11.1 Hz, CH3CH2), 2.10 (s, 3H, 6-CH3), 2.89
(q, 2H, J1 ¼ 11.1, J2 ¼ 22.2, CH2CH3), 5.71 (s, 1H, 5-H), 11.04 (bs, 1H,
N-OH), 13.32 (bs, 1H, OH). MS (EI) m/z (%) 197 (Mþ þ 1, 18), 196 (Mþ,
12), 179 (100), 151 (19), 134 (12). Anal. calcd. for C9H12N2O3: C, 55.09;
H, 6.16; N, 14.28. Found: C, 55.06; H, 6.12; N, 14.24.

3234
F. A. El-Essawy et al.
4-Hydroxy-3-[(1E)-N-hydroxybutanimidoyl]-6-methylpyridin-2(1H)-
one (7c)
Mp 178–1808C (yield 44%); IR: 3310 (NH), 3159 (OH), 1636 (CO); 1H NMR
(DMSO): 0.88 (t, 3H, J ¼ 10.5 Hz, CH3CH2), 1.48–1.51 (m, 2H,
CH2CH2CH3), 2.11 (s, 3H, 6-CH3), 2.90 (t, 2H, J ¼ 11.0 Hz,
-CH2CH2CH3), 5.72 (s, 1H, 5-H), 11.06 (bs, 1H, NH), 11.08 (bs, 1H,
N-OH), 13.12 (bs, 1H, OH). MS (EI) m/z (%) 211 (Mþ þ 1, 5), 210 (Mþ,
16), 193 (100), 176 (53), 151 (49). Anal. calcd. for C10H14N2O3: C, 57.13;
H, 6.71; N, 13.33. Found: C, 57.10; H, 6.68; N, 13.29.
4-Hydroxy-3-[(1E)-N-hydroxyhexanimidoyl]-6-methylpyridin-2(1H)-
one (7d)
Mp 160–1638C (yield 53%); IR: 3408 (NH), 3161 (OH), 1631 (CO); 1H NMR
(DMSO): 0.84 (t, 3H, J ¼ 11.1 Hz, CH3CH2), 1.03–1.10 (m, 4H, 2 CH2 of
butyl), 1.31–1.40 (m, 2H, CH2 of butyl), 2.10 (s, 3H, 6-CH3), 2.91 (t, 2H,
J ¼ 10.5 Hz, CH2CH2), 5.72 (s, 1H, 5-H), 11.22 (bs, 1H, NH), 11.35 (bs,
1H, N-OH), 13.75 (bs, 1H, OH). MS (EI) m/z (%) 239 (Mþ þ 1, 3), 238
(Mþ, 12), 221 (100), 204 (26), 165 (37). Anal. calcd. for C12H18N2O3: C,
60.49; H, 7.61; N, 11.76. Found: C, 60.45; H, 7.58; N, 11.73.
4-Hydroxy-3-[(1E)-N-hydroxy-2-phenylethanimidoyl]-6-
methylpyridin-2(1H)-one (7e)
Mp 190–1938C (yield 92%); IR: 3384 (NH), 3160 (OH), 1655 (CO); 1H NMR
(DMSO): 2.08 (s, 3H, 6-CH3), 4.45 (s, 2H, CH2), 5.70 (s, 1H, 5-H), 7.12–7.21
(m, 5H, arom), 11.11 (bs, 1H, NH), 11.21 (bs, 1H, N-OH), 12.99 (bs, 1H, OH).
MS (EI) m/z (%) 259 (Mþ, 5), 258 (Mþ, 17), 241 (76), 91 (100). Anal. calcd.
for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.09; H, 5.40; N,
10.79.
4-Hydroxy-3-[(1E)-N-hydroxyethanimidoyl]-1,6-dimethylpyridin-
2(1H)-one (7f)
Mp 200–2038C (yield 62%); IR: 3165 (OH), 1652 (CO); 1H NMR (DMSO):
2.23 (s, 3H, 6-CH3), 2.39 (s, 3H, CH3), 3.36 (s, 3H, N-CH3) 5.88 (s, 1H, 5-H),
11.05 (bs, 1H, N-OH), 12.65 (bs, 1H, OH). MS (EI) m/z (%) 196 (Mþ, 32),
179 (100), 152 (38), 98 (25). Anal. calcd. for C9H12N2O3: C, 55.09; H,
6.16; N, 14.28. Found: C, 55.06; H, 6.14; N, 14.25.

Pyrano[3,2-c]pyridines
3235
4-Hydroxy-3-[(1E)-N-hydroxypropanimidoyl]-1,6-dimethylpyridin-
2(1H)-one (7g)
Mp 166–1708C (yield 60%); IR: 3141 (OH), 1639 (CO); 1H NMR (DMSO):
1.00 (t, 3H, J ¼ 7.8 Hz, CH3CH2), 2.26 (s, 3H, 6-CH3), 2.79 (q, 2H, J1 ¼ 5.7,
J2 ¼ 16.5 Hz, CH2CH3), 3.30 (s, 3H, N-CH3), 5.84 (s, 1H, 5-H), 10.94 (bs,
1H, N-OH), 12.53 (bs, 1H, OH). MS (EI) m/z (%) 211 (Mþ þ 1, 3), 210
(Mþ, 13), 193 (100), 176 (17), 166 (18), 165 (20). Anal. calcd. for
C10H14N2O3 (210.23): C, 57.13; H, 6.71; N, 13.33. Found: C, 57.11; H,
6.69; N, 13.30.
4-Hydroxy-3-[(1E)-N- hydroxybutanimidoyl]-1,6-dimethylpyridin-
2(1H)-one (7h)
Mp 185–1888C (yield 60%); IR: 3269 (OH), 1641 (CO); 1H NMR (DMSO):
0.84 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 1.36–1.51 (m, 2H, CH2), 2.28 (s, 3H,
6-CH3), 2.81 (t, 2H, J ¼ 9.6 Hz, CH2CH2), 3.36 (s, 3H, N-CH3), 5.86
(s, 1H, 5-H), 10.92 (bs, 1H, N-OH), 12.59 (bs, 1H, OH). MS (EI) m/z (%)
225 (Mþ þ 1, 14), 224 (Mþ, 9), 207 (100), 190 (40), 165 (21). Anal. calcd.
for C11H16N2O3: C, 58.91; H, 7.19; N, 12.49. Found: C, 58.88; H, 7.17; N,
12.46.
4-Hydroxy-3-[(1E)-N-hydroxy-2-phenylethanimidoyl]-1,6-
dimethylpyridin-2(1H)-one (7i)
Mp 172–1758C (yield 65%); IR: 3159 (OH), 3128 (OH), 1637 (CO); 1H NMR
(DMSO): 2.23 (s, 3H, 6-CH3), 3.41 (s, 3H, N-CH3), 4.34 (s, 2H, CH2), 5.85
(s, 1H, 5-H), 7.10–7.19 (m, 5H, arom), 11.21 (bs, 1H, N-OH), 12.64 (bs,
1H, OH). MS (EI) (%) 272 (Mþ, 13), 255 (73), 254 (100), 256 (17), 228
(24), 226 (14). Anal. calcd. for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29.
Found: C, 66.14; H, 5.89; N, 10.26.
General Procedure for the Preparation of 4-Hydroxy-3-[(1E)-N-
phenylalkanehydrazonoyl]-pyridones (8a–d)
A mixture of ketone 6a or 6c or 6d and/or 6f (5 mmol), phenyl hydrazine
hydrochloride (10 mmol), and sodium bicarbonate (10 mmol), in 40 ml of
ethanol/water (3:1) was heated under reflux with stirring for 4 h. The
reaction mixture was added to cold water with stirring; the colorless precipi-
tated solid product was collected by filtration, washed with water, dried, and
recrystallized from ethanol to afford the products as colorless crystals.

3236
F. A. El-Essawy et al.
Data
4-Hydroxy-6-methyl-3-[(1E)-N-phenylethanehydrazonoyl]pyridine-
2(1H)-one (8a).
1
Mp 212–2158C (yield 66%). IR: 3320, (NH), 3250 (OH), 1624 (CO); H
NMR (DMSO): 2.14 (s, 3H, 6-CH3), 2.58 (s, 3H, CH3), 5.74 (s, 1H, 5-H),
6.81–7.28 (m, 5H, arom), 9.15 (s, 1H, NH-Ph), 11.06 (bs, 1H, NH), 15.12
(bs, 1H, OH). MS (EI) m/z (%) 257 (Mþ, 100), 240 (49), 165 (38). Anal.
calcd. for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.29; H,
5.66; N, 16.25.
4-Hydroxy-6-methyl-3-[(1E)-N-phenylbutanehydrazonoyl]pyridine-
2(1H)-one (8b)
Mp 225–2308C (yield 65%); IR: 3368 (NH), 3277 (OH), 1626 (CO); 1H NMR
(DMSO): 0.95 (t, 3H, J ¼ 10.4 Hz, CH3CH2), 1.41–1.54 (m, 2H, CH2), 2.11
(s, 3H, 6-CH3), 3.16 (t, 2H, J ¼ 11.3 Hz, CH2CH2), 5.70 (s, 1H, 5-H), 6.65–
7.29 (m, 5H, arom), 9.18 (s, 1H, NH-Ph), 10.98 (bs, 1H, NH), 15.25 (bs, 1H,
OH). MS (EI) m/z (%) 286 (Mþ þ 1, 11), 285 (Mþ, 32), 193 (100). Anal.
calcd. for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.30; H,
6.62; N, 14.68.
4-Hydroxy-6-methyl-3-[(1E)-N-phenylhexanehydrazonoyl]pyridine-
2(1H)-one (8c)
Mp 200–2038C (yield 48%); IR: 3379 (NH), 3294 (OH), 1630 (CO); 1H NMR
(DMSO): 0.87 (t, 3H, J ¼ 5.1 Hz, CH3CH2), 1.28–1.50 (m, 6H, 3CH2 of
butyl), 2.10 (s, 3H, 6-CH3), 3.18 (t, 2H, J ¼ 11.3 Hz, CH2CH2), 5.69
(s, 1H, 5-H), 6.80–7.28 (m, 5H, Ph), 9.15 (s, 1H, NH-Ph), 10.95 (bs, 1H,
NH), 15.26 (bs, 1H, OH). MS (EI) m/z (%) 314 (Mþ þ 1, 22), 313 (Mþ,
48), 221 (100). Anal. calcd. for C18H23N3O2 (313.39): C, 68.98; H, 7.40; N,
13.41. Found: C, 68.88; H, 7.33; N, 13.32.
4-Hydroxy-1,6-methyl-3-[(1E)-N-phenylethanehydrazonoyl]pyridine-
2(1H)-one (8d)
Mp 225–2288C (yield 55%); IR: 3436 (NH), 329 (OH), 1665 (CO); 1H NMR
(DMSO): 2.32 (s, 3H, 6-CH3), 2.49 (s, 3H, N-CH3), 5.89 (s, 1H, 5-H), 6.78–
7.28 (m, 5H, arom), 9.19 (s, 1H, NH-Ph), 14.59 (bs, 1H, OH). MS (EI) m/z
(%) 272 (Mþ þ 1, 23), 271 (Mþ, 100), 255 (21), 179 (73). Anal. calcd. for
C15H17N3O2: C, 66.40; H, 6.32; H, 15.49. Found: C, 66.36; H, 6.28; N, 15.45.

Pyrano[3,2-c]pyridines
3237
ACKNOWLEDGMENT
The authors thank DANIDA for the financial support to carry out this work at
the Faculty of Science, Monoufiya University, through the project “Develop-
ment of New Drugs against Hepatitis.”
REFERENCES
1. El-Subbagh, H.; Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Al-Obaid, A. M.
J. Med. Chem. 2000, 43, 2915.
2. Zhuravel, I. O.; Kovalenko, S. M.; Ivachthenko, A. V.; Balakin, K. V.;
Kazmirchuk, V. V. Bioorg. Med. Chem. Lett. 2005, 15, 5483.
3. Lee, S.; Chae, S. M.; Yi, K. Y.; Kim, N.; Oh, C. H. Bull. Korean Chem. Soc. 2005,
26 (4), 619.
4. Chakrasali, R. T.; Ha, H.; Junjappa, H. Synthesis 1988, 87.
5. Mekheimer, R. A.; Mohamed, N. H.; Sadek, K. U. Bull. Chem. Soc. Jp. 1997, 70,
1625.
6. Stoyanov, E. V.; Ivanov, I. C.; Heber, D. Molecules 2000, 5, 19.
7. Toche, R. B.; Jachak, M. N.; Sabins, R. W.; Kappe, T. J. Hetercycl. Chem. 1999,
36, 467–471.
8. Tchabanenko, K.; Taylor, M. G. O.; Adlington, R. M.; Baldwin, J. E. Tetrahedron
Lett. 2006, 47, 39.
9. Roshger, P.; Fiala, W.; Stadlbauer, W. J. Heterocycl. Chem. 1992, 29, 225.
10. Khattab, A. F.; Tinch, D. V.; Stadlbauer, W. J. Prakt. Chem. 1996, 338, 151.
11. Khattab, A. F. Liebigs Ann. 1996, 393.
12. Khattab, A. F.; Kappe, T. Monatsh. Chem. 1996, 127, 917.
13. Khattab, A. F.; Abdel Megied, E.-S. A.; Pedersen, E. B. Nucleosides Nucleotides
2003, 22 (1), 99.
14. Khattab, A. F. Synth. Commun. 2006, 36 (8), 1097.
15. Ziegler, E.; Sterk, H. . Monatsh. Chem. 1968, 99, 1958.
16. Kappe, C. O.; Kappe, T. J. Heterocycl. Chem. 1989, 26, 1555.