Synthetic access to new pyridone derivatives through the alkylation reactions of hydroxypyridines with epoxides

Article abstract of DOI:10.1080/00397910701569254

General methods for the preparation of a variety of pyridone and oxypyridine derivatives are described. 2-,3-,4-Hydroxy pyridine and 2-pyridinemethanol were alkylated with ethylene-, propylene-, and stryrene-oxide and epichlorohydrin in the presence of di

Full text of DOI:10.1080/00397910701569254

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Synthetic Access to New Pyridone Derivatives
through the Alkylation Reactions of
Hydroxypyridines with Epoxides
Ahmet Kocak a , Sultan Kurbanli a & Sait Malkondu a
a Faculty of Science and Arts, Department of Chemistry , University of
Selcuk , Campus, Konya, Turkey
Published online: 19 Oct 2007.
To cite this article: Ahmet Kocak , Sultan Kurbanli & Sait Malkondu (2007) Synthetic Access to New Pyridone
Derivatives through the Alkylation Reactions of Hydroxypyridines with Epoxides, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:21, 3697-3708, DOI:
10.1080/00397910701569254
To link to this article: http://dx.doi.org/10.1080/00397910701569254
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Synthetic Communicationsw, 37: 3697–3708, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701569254
Synthetic Access to New Pyridone
Derivatives through the Alkylation
Reactions of Hydroxypyridines
with Epoxides
Ahmet Kocak, Sultan Kurbanli, and Sait Malkondu
Faculty of Science and Arts, Department of Chemistry, University of
Selcuk, Konya, Turkey
Abstract: General methods for the preparation of a variety of pyridone and oxypyridine
derivatives are described. 2-,3-,4-Hydroxy pyridine and 2-pyridinemethanol were
alkylated with ethylene-, propylene-, and stryrene-oxide and epichlorohydrin in the
presence of different Lewis acids as a catalyst. The best yield of 3a was achieved in
.
the presence of CdI2/BF3 OEt2. The corresponding pyridone derivatives (3a–d,
7a–d) were obtained from the reaction of 2- and 4-hydroxypyridine with oxiranes in
good yields, whereas oxypyridine derivatives (5a–d, 9a,b) were obtained from
reactions of 3-hydroxypyridine and 2-pyridinemethanol with oxiranes. Chlorohydrines
(3d, 5d, 7d) were easily converted to corresponding epoxy derivatives (10, 11, 12) in
basic medium; then amino alcohols (13–17) were obtained from the reaction of these
epoxy derivatives with amines.
Keywords: alkylation, amino alcohol, Lewis acid, oxiranes, pyridone
2- and 4-Hydroxypyridines exist in equilibrium with 2- and 4-pyridones. The
keto-enol tautomerization between 2-pyridone and 2-hydroxypyridine has
been extensively studied experimentally in various phases,[1,2] in matrixes,[3,4]
and theoretically[5–7] as one of the simplest systems of the intramolecular
Received in Poland January 11, 2007
Address correspondence to Sultan Kurbanli, Faculty of Science and Arts,
Department of Chemistry, University of Selcuk, Campus 42075, Konya, Turkey.
E-mail: skurbanli@gmail.com
3697

3698
A. Kocak, S. Kurbanli, and S. Malkondu
proton-transfer reaction. The long-accepted idea that 2-pyridone is more stable
than 2-hydroxypyridone has recently been shown to result from differences in
solvation between the two isomers. In fact, 2-hydroxypyridine has a slightly
lower free energy in the vapor phase, and there is no significant
difference in the fundamental stabilities of the tautomers.[8] Tautomerization
paths of 2- and 4-hydroxypyridine (HP) to 2- and 4-pyridone (PY) with water
molecules were investigated by the use of density functional theory calcu-
lations. Potential energies were compared for a number of water molecules.
The 2-HP molecule was found to be isomerized most readily and concertedly
to the 2-PY by means of proton relays with two water molecules.[9]
2- and 4-Hydroxypyridines have especially interesting chemistry because
the presence of two different nucleophilic centers. In simple alkylation
chemistry, either the phenolic oxygen or the pyridine nitrogen may be
reacted depending on the specific alkylating agent and conditions. For
example, phase-transfer alkylation with simple alkyl halides produces a
mixture of O- and N-alkylation,[10] whereas N-alkylation occurs exclusively
when a,a0-dibromo-o-xylene reacts with 2- and 4-hydroxypyridines.
Generally, reactions were performed using excess of 4-hydroxypyridine and
potassium carbonate in N-methylpyrrolidinone or water as solvent. Aromatic
pyridone derivatives have been synthesized from the alkylation of aromatic
compounds having various nucleophilic and electrophilic substituents.[11]
Numerouspyridine derivatives are usefulasmedicament,[12–16] and thus, the
synthesis of new pyridine derivatives as physiologically active agent has
remained an important research topic. The alkylation reactions of pyridines and
pyridones with alkyl halides have been extensively investigated under various
conditions.[17–23] However, there have been only a few reports on the preparation
of pyridones from the reaction of hydroxy pyridines with oxiranes in the presence
of Lewis acid. Knunyantz[24] reported the synthesis of 1-(b-hydroxyethyl)-2-
pyridone (3a) by the reaction of 2-aminopyridine with ethylene oxide in 5%
yield. In another method, 2-sulfanilamidopyridine and 2-sulfanilamidothiazole
in absolute ether suspension both react rapidly with diazomethane at room temp-
erature to give two methylated isomers. 1-(b-Hydroxyethyl)-2-sulfanilimido-1,2-
dihydropyridineobtainedfrom thereactionof sodium sulfonamideswithethylene
chlorohydrin was hydrolyzed to sulfanilamide and 1-(b-hydroxyethyl)-2-
pyridone (3a) in basic media.[25] In addition to previously mentioned procedures,
3a was synthesized fromthe condensation of 2-pyridone with 2-bromoethanolein
55% yield.[26] The compounds, 1-(2-hydroxyprop-1yl)-2-pyridone (3b) and 1-(2-
pheyl-2-hydroxyeth-1yl)-2-pyridone (3c), were prepared by sodium borohydride
reduction of 1-acetonyl-2-pyridone and 1-phenacyl-2-pyridone, respectively.[27]
A series of pyridone derivatives and 1-(2-hydroxy-2-phenylethyl)-pyridone-2
(3c) were synthesized by hydrolysis of 1-(tetrahydropyridin)-2-hydroxypheyl
with water in the presence of Hg(II)–EDTA in 3% yield.[28] Another method
describes 1-(b-hydroxyphenethyl)-2-pyridone (3c) prepared from the reaction
of 1-(b-hydroxyphenethyl)-2-imino-1,2-dihydropyridine in basic media in 67%
yield.[29]

New Pyridone Derivatives
3699
In the present article, the preparation of a series of pyridone and
oxypyridine derivatives in the presence of Lewis acid has been described.
.
High yields were achieved using a mixed catalyst, CdI2/BF3 OEt2 (1:1).
Pyridones were obtained from the reaction of 2- and 4-hydroxypyridines
with ethylene-, propylene-, and styrene-oxide and epichlorohydrine in good
yields. In contrast, the reaction of 3-hydroxypyridine with oxiranes gave
O-alkylation products. The reaction of 3-hydroxypyridine with oxiranes
proceeds in the opposite way, and 3-hydroxypyridine shows itself in the
character of phenol. Namely, it was concluded that 3-hydroxypyridine, like 2-
and 4-hydroxypyridines, could not tautomerize to a pyridone derivative. In
general, the literature on pyridones is not extensive. Therefore, this study
may be accepted as a new synthetic procedure to access to pyridone derivatives.
An important effect of catalyst and solvent among effective factors in the
synthesis of pyridones should be considered. Reactions in dimethylformamide
(DMF), dimethylsulfoxide (DMSO), methanol, or ethanol were homogenous
and proceeded at reasonable rates, but reactions with suspensions in nonpolar
solvents such as benzene, hexane, and THF did not occur. For instance, if alky-
lation reactions of 2-,4-hydroxypyridines with epoxides are carried out in basic
medium (40% NaOH, aqueous), a mixture of 50–55% pyridones 3a–d, 7a–d,
and 45–50% O-alkylation adducts 5a–d are formed. However, to stereospecifi-
cally direct reaction to the production of pyridone derivatives, the use of Lewis
acid as a catalyst and dichloromethane or a mixture of DMSO/DMF mixture as a
solvent is required. It was determined that such factors did not influence the
reaction of 3-hydroxypyridines with oxiranes. Whether the reaction was
performed in basic media or in the presence of Lewis acids, only O-alkylation
products 5a–d were obtained without isomerization to pyridone (Scheme 1
and Table 1).
Pure compounds 3a–d were obtained in good yields at rt for 5–6 h in the
.
presence of mixed Lewis acid, CdI2/BF3 OEt2 (50% mol/50% mol)
(Table 2). Besides, the same results were obtained upon using SnCl4/
Bu3SnI (1:1) as catalyst. The chlorohydrins 3d, 5d, and 7d were easily
converted into corresponding epoxide compounds 10–12 in the presence of
NaOH and anhydrous ether in good yields (Scheme 2). The previously
mentioned epoxy compounds 10–12 were also synthesized from the
reaction of 2-,3- and 4-hydroxypyridines with 3-chloro-1,2-epoxypropane.
Compounds 10–12 were converted into corresponding new amino alcohols
13–17 by reacting with isopropylamine, isobutylamine, tert-butylamine, mor-
pholine, and piperidine (Scheme 3). The structures of synthesized compounds
1
were confirmed by IR, H NMR, and elemental analysis.
EXPERIMENTAL
All starting materials were purchased from Aldrich and Fluka and used
1
without further purification. H NMR spectra were recorded using a Bruker

3700
A. Kocak, S. Kurbanli, and S. Malkondu
Scheme 1.
Table 1. Reactions of hydroxypyridines with oxiranes in the presence of CdI2/
.
BF3 OEt2 (50% mol/50% mol)
Pyridinol
Epoxide
Product
Yielda,b (%)
Temp. (8C)
Time (h)
1
1
1
1
4
4
4
4
6
6
6
6
8
8
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2d
3a
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
7d
9a
9b
48
52
49
54
58
49
38
56
45
39
48
57
46
54
20
25
20
30
22
18
20
18
20
25
24
22
25
20
4
5
6
5
5
4
6
5
5
4
6
5
6
7
aYields of isolated products and all products were characterized by mp and spectro-
scopic methods.
bLarge amounts of unreacted starting materials were recovered from the reaction
mixture by distillation.

New Pyridone Derivatives
3701
Table 2. Lewis acid catalysis in the reaction of 1 with ethylene oxide 2a in CH2Cl2 or
DMSO at room temperature
Lewis acid
Mol (%)
Time (h)
Yield of 3a (%)
CdI2
CdI2
50
100
36
8
42
54
42
58
84
.
BF3 OEt2
50
100
36
8
.
BF3 OEt2
.
CdI2/BF3 OEt2
50/50
8
Spectrospin Advance DPX 400 spectrometer in CDCl3. Chemical shifts are
given in parts per million (ppm) downfield from tetramethylsilane.
Elemental analyses were obtained using a Carlo Erba 1106 automatic
elemental analysis instrument. Melting points were determined on an electro-
thermal digital melting point apparatus. All chromatography solvents were
analytical grade and freshly distilled prior to use. Thin-layer chromatography
(TLC) was carried out on Merck 5735 Kieselgel 60 F254 fluorescent plates.
Alkylation of Hydroxypyridines: General Procedure
.
2-,3, or 4-Hydroxypyridine (0.90–1.00 mmol) and BF3 O(C2H5)2 (2.1 mmol)
were dissolved in 15 mL of CH2Cl2. A solution of oxirane (0.95 mmol) in
10 mL of CH2Cl2 was added dropwise to the mixture with stirring for 30 min
at 0–58C. After completion of the addition, mixture was stirred at rt for
4–7 h more. The progressing reaction was monitored by TLC. After completion
of reaction, CH2Cl2 was evaporated, and the oily residue was recrystallized with
EtOAc–hexane (5:1).
Alkylation of 2- and 4-Hydroxypyridine
Sodium (or potassium) hydroxide (2.16 g or 3 g, 0.54 mol) in 40 mL of
absolute ethanol was added slowly to the solution of 1 or 6 (0.05 mol) in
100 mL of absolute ethanol. Then, alkylating agent 2a–d (0.064 mol) was
Scheme 2. Conversion chlorohydrins 3d, 5d, and 7d into epoxides 10–12.

3702
A. Kocak, S. Kurbanli, and S. Malkondu
Scheme 3. Synthesis of pyridine and pyridone amino alcohols: R ¼ 3-Py, R0 ¼ i-Pr
(13); R ¼ 3-Py, R0 ¼ i-Bu (14); R ¼ 2-Pyridonyl, R0 ¼ t-Bu (15); R ¼ 2-Pyridonyl,
R0 ¼ morpholyl (16); R ¼ 4-Pyridonyl, R0 ¼ piperidyl (17).
added to mixture. After the reaction mixture was stirred at rt for 5–6 h, the
solvent was removed under reduced pressure, and the residue was extracted
with ether (3 ꢀ 50 mL). After removing ether under reduced pressure, the
residue was extracted with chloroform (3 ꢀ 40 mL). The chloroform layer
was washed with 50 mL of ammonium hydroxide (25%) to remove
unreacted 1 or 6 and then washed with 100 mL of water. The mixture was
dried over MgSO4 and filtered, and the solvent evaporated. The residue recrys-
tallized from a mixture of EtOAc–hexane (5:1). The products 3a–d and 7a–d
were obtained in 39–57% yields.
Data
1-(2-Hydroxyethyl)pyridin-2-one (3a). Mp 95–968C (lit. 95–978C).[24–26]
1H NMR (CDCl3) d 3.30 (1H, t, N-CH2), 3.52 (2H, t, CH2-O), 4.36 (1H, s,
OH), 6.24 (1H, t, H3), 6.58 (1H, d, H4), 7.22 (1H, t, H5), 7.32 (1H, d, H2).
Anal. calcd. for C7H9NO2: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.25; H,
6.47; N, 10.13.
1-(2-Hydroxypropyl)pyridin-2-one (3b). Mp 96–978C (lit. 95–96.58C).[27]
1H NMR (CDCl3) d 1.06 (3H, d, CH3), 3.42 (2H, t, N-CH2), 3.76 (1H, s, OH),
3.98 (1H, t, CH-O), 6.02 (1H, d, H4), 6.72 (1H, d, H2), 7.30 (1H, t, H3), 7.41
(1H, t, H5). Anal. calcd. for C8H11NO2: C, 62.73; H, 7.24; N, 9.14. Found: C,
62.65; H, 7.08; N, 9.03.
1-(2-Hydroxy-2-phenylethyl)pyridin-2-one (3c). Mp 125–1268C (lit. 124–
1288C).[27–29] 1H NMR (CDCl3) d 3.00 (1H, s, OH), 3.98 (2H, m, N-CH2),
4.88 (1H, t, CH-O), 5.96 (1H, t, H3), 6.58 (1H, d, H5), 7.10–7.18 (5H, m,
Ar), 7.28 (1H, m, H4), 7.32 (1H, d, H2). Anal. calcd. for C13H13NO2: C,
72.54; H, 6.09; N, 6.51. Found: C, 72.61; H, 6.23; N, 6.72.
1-(3-Chloro-2-hydroxypropyl)pyridin-2-one (3d). Mp 136–1388C. 1H
NMR (CDCl3) d 3.42 (2H, t, CH2Cl), 3.50 (1H, m, OH), 3.52 (1H, m, CH-
O), 3.90 (2H, m, N-CH2), 6.02 (1H, t, H3), 6.58 (1H, d, H5), 7.26 (1H, d,
H2), 7.32 (1H, t, H4). Anal. calcd. for C8H10ClNO2: C, 51.21; H, 5.37; Cl,
18.90; N, 7.47. Found: C, 51.14; H, 5.44; Cl, 18.82; N, 7.52.

New Pyridone Derivatives
3703
1-(2-Hydroxyethyl)pyridin-4-one (7a). Mp 110–110.58C. 1H NMR (CDCl3)
d 3.58 (2H, t, N-CH2), 3.64 (2H, t, CH2-O), 3.92 (1H, s, OH), 5.12 (2H, d, H3,
H5), 7.12 (2H, s, H2, H4). Anal. calcd. for C7H9NO2: C, 60.42; H, 6.52; N,
10.07. Found: C, 60.24; H, 6.37; N, 9.98.
1-(2-Hydroxypropyl)pyridin-4-one (7b). Mp 104–1068C. 1H NMR (CDCl3)
d 1.10 (3H, d, CH3), 3.50–3.72 (2H, m, N-CH2), 3.84 (1H, m, CHO), 5.16
(2H, s, H3, H5), 7.04 (2H, s, H2, H4). Anal. calcd. for C8H11NO2: C, 62.73;
H, 7.24; N, 9.14. Found: C, 62.64; H, 7.35; N, 9.02.
1-(2-Hydroxy-2-phenylethyl)pyridin-4-one (7c). Mp 146–1478C. 1H NMR
(CDCl3) d 3.22 (1H, s, OH), 3.86–4.04 (2H, m, CH2N), 4.68 (1H, t, CH-O),
5.16 (2H, s, H3, H5), 7.06 (2H, s, H2, H4), 7.10–7.22 (5H, m, Ar). Anal. calcd.
for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.34; H, 6.28; N, 6.42.
1-(3-Chloro-2-hydroxypropyl)pyridin-4-one (7d). Mp 151–1528C. 1H
NMR (CDCl3) d 3.32 (1H, m, CH-O), 3.38–3.58 (2H, m, CH2Cl), 3.98
(2H, m, CH2N), 5.16 (2H, s, H3, H5), 7.03 (2H, s, H2, H4). Anal. calcd. for
C8H10ClNO2: C, 51.21; H, 5.37; Cl, 18.90; N, 7.47. Found: C, 51.35; H,
5.41; Cl, 18.97; N, 7.59.
Alkylation of 3-Hydroxypyridine
Freshly cut sodium (2.3 g, 0.1 g-atom) dissolved in 100 mL of ethanol was
added to a solution of 3-hydroxypyridine (4.4 g, 0.1 mol) suspended in
100 mL of absolute ethanol. After stirring at rt overnight, the solvent was
removed under reduced pressure, and 30 mL of anhydrous ether was added.
Then, 2a–d (4.4 g, 0.1 mol) was added to the suspension, and it was stirred
at rt for 5 h (completion of the reaction was monitored by TLC). After the
mixture was neutralized to pH ¼ 6.8–7.0 with acetic acid (2 N), it was
extracted with 50 mL of chloroform, dried over MgSO4, and filtered. The
solvent was evaporated under reduced pressure. The products 5a–d were
obtained in 38–58% yields after recrystallization from ethyl acetate.
Data
2-(Pyridin-3-yloxy)ethanol (5a). Mp 98–998C. 1H NMR (CDCl3) d 3.95 (2H,
d, CH2-O), 4.10(2H, d, O-CH2), 5.10(1H, br, OH), 7.15 (1H, m, H4), 7.21 (1H, d,
H3), 8.15 (1H, d, H2), 8.36 (1H, t, H5), 8.50 (1H, d, H6). Anal. calcd. for
C7H9NO2: C, 60.42; H, 6.52; N, 10.06. Found: C, 60.37; H, 6.61; N, 9.93.
1-(Pyridin-3-yloxy)propan-2-ol (5b). Mp 102–1038C. 1H NMR (CDCl3)
d 1.10 (3H, d, CH3), 3.25 (1H, br, OH), 3.58–4.02 (3H, m, O-CH2, CH),
6.97 (1H, d, H3), 7.25 (1H, d, H4), 8.10 (1H, s, H2), 8.34 (1H, d, H5). Anal.

3704
A. Kocak, S. Kurbanli, and S. Malkondu
calcd. for C8H11NO2: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.65; H, 7.08;
N, 9.03.
1-Phenyl-2-(pyridin-3-yloxy)ethanol (5c). Mp 134–1358C. 1H NMR
(CDCl3) d 3.60 (1H, s, OH), 4.20 (2H, d, O-CH2), 4.70 (1H, m, CH-O),
7.02 (1H, d, H3), 7.24 (1H, d, H4), 7.27–7.30 (5H, m, Ar), 8.16 (1H, d, H2),
8.33 (1H, d, H5). Anal. calcd. for C13H13NO2: C, 72.54; H, 6.09; N, 6.51.
Found: C, 72.69; H, 5.95; N, 6.66.
1
1-Chloro-3-(pyridin-3-yloxy)propan-2-ol (5d). Mp 128–1298C. H NMR
(CDCl3) d 3.20 (1H, s, OH), 3.40–3.70 (3H, m, O-CH2, CH), 4.02 (2H, d,
CH2), 7.02 (1H, d, H3), 7.33 (1H, d, H4), 8.15 (1H, s, H2), 8.33 (1H, d, H2).
Anal. calcd. for C8H10ClNO2: C, 51.21; H, 5.37; Cl, 18.90; N, 7.47. Found:
C, 51.35; H, 5.45; Cl, 18.62; N, 7.31.
Alkylation of 2-Pyridinemethanol
The procedure used for the preparation of 5a–d was used here with exception
.
that the reaction was performed in the presence of Lewis acid (BF3 O(C2H5)2,
0.08 mol). The products 9a–b were isolated in 46 and 54% yields, respectively.
Data
1
2-(Pyridin-2-ylmethoxy)ethanol (9a). Mp 106–1088C. H NMR (CDCl3) d
3.55 (2H, d, O-CH2), 3.69 (2H, d, CH2-O), 4.37 (2H, d, CH2-O), 5.22 (1H, br,
OH), 7.02 (1H, m, H4), 7.26 (1H, d, H2), 7.56 (1H, d, H3), 8.32 (1H, t, H5).
Anal. calcd. for C8H11NO2: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.82; H,
7.13; N, 9.21.
1-Chloro-3-(pyridin-2-ylmethoxy)propan-2-ol (9b). Mp 138–1398C. 1H
NMR (CDCl3) d 3.38 (2H, d, O-CH2), 3.44 (1H, s, OH), 3.81 (2H, m,
CH2Cl), 3.89 (1H, m, CH-O), 4.40 (2H, t, CH2-O), 7.01 (1H, s, H4), 7.37
(1H, d, H2), 7.54 (1H, t, H3), 8.25 (1H, t, H5). Anal. calcd: C, 53.61; H,
6.00; Cl, 17.58; N, 6.95. Found: C, 53.78; H, 6.12; Cl, 17.45; N, 7.08.
Synthesis of Epoxides
Chlorohydrines 3d, 5d, and 7d (0.25 mol) and NaOH pellets (0.30 mol) in
ether (65 mL) were refluxed for 5 h. The organic phase was separated from
the precipitated salt, washed with distilled water until the solution become
neutral, and dried over Na2SO4. After evaporation of the solvent in vacuum,
the residue was recrystallized from ethyl acetate to afford 10, 11, and 12.

New Pyridone Derivatives
Data
3705
1
1-(Oxiran-2-ylmethyl)pyridin-2-one (10). Yield 69%, mp 116–1178C. H
NMR (CDCl3) d 2.46 (2H, d, CH2-O), 2.86 (1H, t, CH-O), 3.50–3.68 (2H,
m, N-CH2), 6.03 (1H, d, H2), 6.62 (1H, s, H4), 7.30 (1H, t, H3), 7.30 (1H, s,
H1). Anal. calcd. for C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.41; H, 6.15; N, 9.48.
3-(Oxiran-2-ylmethoxy)pyridine (11). Yield 72%, mp 112–112.58C. 1H
NMR (CDCl3) d 2.56 (2H, d, CH2-O), 2.98 (1H, d, CH-O), 3.76–3.92 (2H,
m, O-CH2), 6.96 (1H, d, H2), 7.22 (1H, d, H3), 8.10 (1H, s, H1), 8.32 (1H,
s, H4). Anal. calcd. for C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.48; H, 6.21; N, 9.21.
1
1-(Oxiran-2-ylmethyl)pyridin-4-one (12). Yield 76%, mp 131–1328C. H
NMR (CDCl3) d 2.36 (2H, t, CH2O), 2.94 (1H, d, CHO), 3.60–3.80 (2H,
m, CH2N), 5.20 (2H, s, H2, H4), 7.06 (2H, s, H1, H3). Anal. calcd. for
C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.45; H, 6.12; N, 9.45.
Synthesis of Amino Alcohols
Compounds 10–12 (0.22 mol), the amine (0.32 mol), and 5–6 drops of
distilled water were heated to 65–708C with stirring for 6–7 h (or 33–34 h
at rt). After evaporation of excess amine, the amino alcohols were fractionally
distilled under reduced pressure. After recrystallization with EtOAc–hexane
(5:1), the products 13–17 were obtained in good yields.
Data
1-(Isopropylamino)-2-(pyridin-3-yloxy)ethanol (13). Yield 65%, mp 148–
1
148.58C. H NMR (CDCl3) d 1.28 (6H, d, 2CH3), 2.98 (2H, m, OH, NH),
3.32 (1H, t, CH-CH3), 3.96 (1H, m, CH-O), 4.00 (2H, t, O-CH2), 6.86 (1H,
t, H3), 7.18 (1H, t, H4), 8.02 (1H, d, H2), 8.32 (1H, d, H5). Anal. calcd. for
C10H16N2O2: C, 62.83; H, 8.63; N, 13.32. Found: C, 62.76; H, 8.51; N, 13.47.
1-(Isobutylamino)-2-(pyridin-3-yloxy)ethanol (14). Yield 68%, mp 138–
1
1408C. H NMR (CDCl3) d 1.12 (6H, t, 2CH3), 1.21 (3H, d, CH3), 2.40–
2.60 (2H, m, CH2-NH), 3.08 (2H, s, br, OH, NH), 3.18 (1H, m, CH-CH3),
3.76–3.96 (2H, m, O-CH2), 4.12–4.16 (1H, m, CH-O), 6.86 (1H, t, H3),
7.18 (1H, t, H4), 8.00 (1H, s, H2), 8.32 (1H, d, H4). Anal. calcd. for
C11H18N2O2: C, 64.26; H, 8.99; N, 12.49. Found: C, 64.35; H, 8.87; N, 12.63.
1-(2-(Tert-butylamino)-2-hydroxyethyl)pyridin-2-one (15). Yield 54%, mp
162–1638C. 1H NMR (CDCl3) d 1.06 (9H, s, 3CH3), 2.30 (2H, m, CH2-NH),

3706
A. Kocak, S. Kurbanli, and S. Malkondu
3.96–4.01 (2H, m, N-CH2), 4.38 (2H, s, OH, NH), 6.04 (1H, t, H3), 6.60 (1H,
d, H5), 7.32 (1H, d, H5), 7.34 (1H, t, H2). Anal. calcd. for C11H18N2O2: C,
64.26; H, 8.99; N, 12.49. Found: C, 64.23; H, 9.08; N, 12.57.
1-(2-Hydroxy-2-morpholinoethyl)pyridin-2-one (16). Yield 72%, mp 176–
1
1788C. H NMR (CDCl3) d 1.96–2.16 (2H, m, CH2-N), 2.28–3.46 (8H, m,
4H2 ring morpholine), 3.50 (2H, m, N-CH2), 4.28 (1H, t, CH-O), 5.42 (1H,
s, OH), 6.02 (1H, d, H3), 7.32 (1H, t, H4), 7.36 (1H, s, H2). Anal. calcd. for
C11H16N2O3: C, 60.49; H, 7.61; N, 11.76. Found: C, 60.61; H, 7.52; N, 11.63.
1-(2-Hydroxy-2-(piperidin-1-yl)ethyl)pyridin-4-one (17). Yield 76%, mp
1
188–1908C. H NMR (CDCl3) d 1.18–1.36 (10H, m, 5H2, ring piperidine),
1.98–2.10 (2H, m, CH2-N), 3.58 (2H, m, N-CH2), 3.96 (1H, t, CH-O), 5.32
(2H, s, H3, H5), 5.64 (1H, s, OH), 7.06 (2H, s, H2, H4). Anal. calcd. for
C12H18N2O2: C, 66.07; H, 8.55; N, 11.85. Found: C, 65.93; H, 8.62; N, 11.93.
ACKNOWLEDGMENT
Financial support for this research from the Selcuk University Scientific
Research Project (Number 2004/019) is gratefully acknowledged.
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