Alkylation of 2-pyridinones: Synthesis of novel acyclonucleosides

Article abstract of DOI:10.1002/jhet.5570410302

This paper presents the synthesis of some novel acyclonucleosides containing 2-pyridinones and 2-hydroxyethoxymethyl, 2,3-dihydroxy-propyl side chain. The tosylate of these nucleosides analogues could be modified to azido derivatives. Also, acyclonucleosides with 1-ethoxymethyl, 1-benzyloxymethyl, 1-methylthiomethyl and 2-hydroxyethyl side chains have been investigated. The O-alkylated pyridine derivatives were obtained during most reactions.

Full text of DOI:10.1002/jhet.5570410302

May-Jun 2004
311
Alkylation of 2-Pyridinones: Synthesis of Novel Acyclonucleosides
Farag A. El-Essawy and Ahmed F. Khattab*
Department of Chemistry, Faculty of Science, Monoufiya University
Shebien El-Koam, A. R. Egypt
Received March 10, 2003
This paper presents the synthesis of some novel acyclonucleosides containing 2-pyridinones and
2-hydroxyethoxymethyl, 2,3-dihydroxy-propyl side chain. The tosylate of these nucleosides analogues
could be modified to azido derivatives. Also, acyclonucleosides with 1-ethoxymethyl, 1-benzyloxymethyl,
1-methylthiomethyl and 2-hydroxyethyl side chains have been investigated. The O-alkylated pyridine deriv-
atives were obtained during most reactions.
J. Heterocyclic Chem., 41, 311 (2004).
Reverse transcriptase (RT), being the pivot in the human
toxyethoxy methyl bromide [13] to give two alkylated deriv-
atives 2a and 2b which were separated by column chro-
matography with ethyl acetate in chloroform (0-10%) to give
2a and 2b in 49% and 34% yield, respectively. The 1H nmr
spectra of 2a,b showed that the acetoxyethoxymethyl moiety
of the O-alkylated product 2b is shifted downfield compared
with that of N-alkylated product 2 a. The methylene singlet
signal appeared at δ 5.70 ppm for O-alkylated product 2b
compared to δ 5.57 ppm for the N-alkylated product 2a. In
addition, the infrared spectrum confirmed the absence of the
carbonyl functional group in the O-alkylated product 2 b,
immunodeficiency virus (HIV) replication [1], is still one of
the most attractive targets for the development of new antivi-
ral agents [2]. Among these compounds, 2-pyridinones (A)
have been described as HIV-1 specific reverse transcriptase
inhibitors [3]. The synthesis of acyclonucleosides such as 9-
(2-hydroxyethoxymethyl)guanine (acyclovir) [4], 1-[(2-
hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEBT) [5],
6-benzyl-1-ethoxymethy-5-isopropyluracil (MKC-442) [6]
and (S)-9-(2,3-dihydroxypropyl)adenine, ((S)-DHPA) [7] has
been also intensively investigated during the past years for
antiviral and anticancer therapy (Figure 1).
which is present in the N-alkylated product 2a. Also, the 13
C
nmr spectrum showed the chemical shift at C-1 of a cyclic
part of 2a at δ 73.04 ppm while that of compound 2b at δ
90.86 ppm. This indicated that the alkylation of 1 occurred
on the nitrogen atom to give 2a and on the oxygen atom to
give 2 b, respectively. The mass spectra of 2a and 2b showed
the same molecular ion peak at m/z 264. Treatment of these
compounds with ammonia in methanol at room temperature
for 24 h resulted in complete deprotection of the hydroxy
group and the corresponding compounds 3 and 4 were
obtained, respectively, in good yield. Tosylation of 3 was
easily performed in anhydrous pyridine with p-toluenesul-
fonyl chloride, and the product identified, besides nmr, mass
spectra and elemental analysis, by a characteristic peak at
1199 cm-1 in the infrared spectrum. However, tosylation of
the acetal 4, under the same condition, afforded the starting
material 1 and not tosyl derivative 6. The intermediate tosy-
late 5 could then be converted to 2-azido derivative 7 with
sodium azide. Ir, nmr and elemental analysis established the
structure of 7. The infrared spectrum showed the absorption
band of the N3 group at 2095 cm-1. Following the reported
method [14], we reduced the azido group of compound 7
using triphenylphosphine in pyridine and obtained the 2-
amino analogue 8 in 45% yield (Scheme 1).
Owing to the important pharmacological effects of both
classes of compounds and as a continuation of our interest in
the synthesis of nucleosides [8], we decided to synthesize
new acyclo-N-nucleosides having 2-pyridinones as nitrogen
base. A literature search revealed that such type compounds
are completely unknown, exception made for the recently
synthesized 1-hydroxyalkylpyrid-4-ones [9] starting from
the maltol or ethylmaltol. Furthermore, synthesis of N-glyco-
sylated pyridines by the condensation of acetobromosuger
with 3-cyanopyridones in the presence of potassium hydrox-
ide or their chloromercuric salt in anhydrous xylene has been
described [10]. The pyridinone derivative 1 was synthesized
by treatment of acetylacetone with cyanoacetamide in pres-
ence of base [11]. Following the reported method [12], com-
pound 1 was alkylated, after its treatment with 60% sodium
hydride in anhydrous N,N-dimethylformamide, with 2-ace-
(R)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesul-
fonate (9) was prepared by treating (S)-2,2-dimethyl-1,3-
dioxolane-4-methanol with 1 equivalent p-toluenesulfonyl
chloride in anhydrous pyridine [15]. For the synthesis of
dioxalane derivative 1 0, compound 1 was likewise treated
with 1 equiv. sodium hydride in anhydrous N,N-dimethyl-
formamide followed by 1 equiv. of 9. Treatment of 10, after
its chromatographic purification, with 80% acetic acid at
room temperature afforded the corresponding dihydroxy

312
F. A. El-Essawy and A. F. Khattab
Vol. 41
and 15b, 16b, respectively (Scheme 3). These product mix-
tures were separated by column chromatography with ethyl
acetate in chloroform (0-10%); nmr, mass spectra and
elemental analysis established their structures.
Finally, we investigated the preparation of the 1-(hydroxy-
ethyl)pyridine derivative 1 8 a. The compound 1 was alkyl-
ated with 2-bromoethyl acetate by the method of Sasaki et al
[12]. Alkylation at nitrogen and oxygen atoms took place to
compound 11, which was purified by column chromatogra-
phy with methanol in chloroform (0-10%) to give the prod-
uct 11 in 88% yield. Tosylation of 11 with 2 equiv. of tosyl
chloride in anhydrous pyridine, the ditosylate derivative 12
was obtained in 37% yield. Azidation of 12 was performed
in anhydrous N , N-dimethylformamide at 80 ˚C with sodium
azide. The product 13 was identified by nmr, mass spec-
troscopy, elemental analysis and by characteristic peaks at
2092 and 2127 cm-1 in the infrared spectrum (Scheme 2).
We have also investigated the preparation of 1-(ethoxy-
methyl) pyridinone derivative 14, which was obtained as a
sole product, by alkylation of compound 1, after its treat-
ment with 60% sodium hydride in anhydrous N,N-dimethyl-
formamide, with chloromethyl ethyl ether at room tempera-
ture followed by chromatographic purification. The struc-
ture of 1 4 was assigned on the basis of data of similar com-
pounds [16]. Its 1H nmr showed a singlet at δ 5.53 ppm cor-
responding to N-CH2-O group and 13C nmr showed a
chemical shift of C-1 of the a cyclic part at δ 72.57 ppm.
Similarly, treatment of 1 with sodium hydride in anhydrous
N , N-dimethylformamide, followed by reaction with, either
chloromethyl methyl sulfide, or benzyl chloromethyl ether
gave a mixture of N- and O-alkylated products, 1 5 a, 16a
afford two alkylated derivatives 17a and 17b, which could
be separated by column chromatography with ethyl acetate
in chloroform (0-10%). In the H1 nmr spectra of 17a,b, the
triplet signals of the methylene protons appear at about δ
4.42-
4.28-4.37 ppm for N-alkylated product 17a and at δ

May-Jun 2004
Alkylation of 2-Pyridinones: Synthesis of Novel Acyclonucleosides
313
4.62 ppm of O-alkylated product 17b. In addition, 13C nmr
spectra showed the chemical shift of C-1 of the a cyclic part
of 17a at δ 43.94 ppm, while that of compound 17b at δ
62.29 ppm. This indicated that the alkylation occurred on the
nitrogen atom to give 17a and on the oxygen atom to give
17b in 54 and 29% yield, respectively. The subsequent
ammonolysis of 17a,b, with 1:1 mixture of methanol and
concentrated ammonia at room temperature, afforded the
corresponding hydroxy compounds 18a,b in good yields
(Scheme 4).
ethyl ether or chloromethyl methylsulfide or benzyl chloromethyl
ether and/or bromo ethylacetate (14.1 mmol) was added dropwise
at 0 ˚C. After completion of the addition, the reaction mixture was
stirred for an additional 12 h at room temperature. The solvent
was removed by evaporation in vacuo and the resulting residue
was co-evaporated with anhydrous toluene (3x10 ml). The com-
pounds were purified by silica gel column chromatography with
ethyl acetate in chloroform: (0-10%). Fractions with O-alkylated
derivatives 2 b, 15b, 16b and 17b were eluted faster than their N-
alkylated counterparts 2 a, 1 5 a, 16a and 1 7 a. While, N-alkylated
product 14 was obtained as a sole product.
1-(2-Acetoxyethoxymethyl)-4,6-dimethyl-2-oxo-1,2-dihydropy-
ridine-3-carbonitrile (2a).
This compound was obtained as colorless prisms, yield 1.7 g
(49%); mp 74-76 ˚C (diisopropyl ether); ir (potassium bromide):
-1
1
CN 2219, CO 1745. CO 1650 cm ; H nmr (deuteriochloro-
form): δ 2.05 (s, 3H, CH ), 2.40 (s, 3H, CH ), 2.47 (s, 3H, CH ),
3.83 (t, J = 4.6 Hz, 2H, CH ), 4.18 (t, J = 4.6 Hz, 2H, CH ), 5.57
3
3
3
2
2
13
(s, 2H, NCH O), 6.06 (s, 1H, C -H); C nmr (deuteriochloro-
2
form): δ 20.01, 20.89, 21.15 (3 x CH ), 63.10, 68.06 (2 x CH ),
5
3
73.04 (NCH O), 102.01 (C-3), 109.91 (CN), 115.18 (C-4),
2
2
151.28 (C-5), 159.80 (C-6), 161.63 (C-2), 170.83 (CO); EI ms:
+
m/z 264 (30%, M ), 149 (15), 148 (17), 43 (100).
Anal. Calcd. for C
H N O (264.28): C, 59.08; H, 6.10; N,
13 16 2 4
10.60. Found: C, 59.29; H, 6.16; N, 10.51.
2-[(2-Acetoxyethoxymethoxy)]-4,6-dimethylpyridine-3-carboni-
trile (2b).
This compound was obtained as colorless prisms, yield 1.2 g
(34%); mp 49-51 ˚C (petroleum ether); ir (potassium bromide):
-1 1
CN 2222, CO 1741 cm ; H nmr (deuteriochloroform): δ 2.06 (s,
3H, CH ), 2.45 (s, 3H, CH ), 2.50 (s, 3H, CH ), 3.99 (t, J = 4.7
3
3
3
Hz, 2H, CH ), 4,26 (t, J = 4.7 Hz, 2H, CH ), 5.70 (s, 2H,
2
OCH O), 6.76 (s, 1H, C -H); C nmr (deuteriochloroform): δ
2
13
2
20.00, 20.78, 24.46 (3 x CH ), 63.18, 67.06 (2 x CH ), 90.86
5
3
2
(OCH O), 94.46 (C-3), 114.55 (CN), 118.44 (C-4), 154.53 (C-5),
EXPERIMENTAL
2
160.69 (C-6), 162.61 (C-2), 170.24 (CO); EI ms: m/z 264 (4%,
+
M ), 148 (5), 87 (20), 43 (100).
Melting points were determined on a Boetius melting point
apparatus, and are uncorrected. Optical rotations were measured
on Optical activity LTD, USA Patent NO. 4118125 at the Arab
Drug Company, Cairo, Egypt. NMR were recorded at 300 MHz
Anal. Calcd. for C
H N O (264.28): C, 59.08; H, 6.10; N,
13 16 2 4
10.60. Found: C, 58.73; H, 6.19; N, 10.47.
4,6-Dimethyl-1-ethoxymethyl-2-oxo-1,2-dihydropyridine-3-car-
bonitrile (14).
1
13
for H nmr, 75.5 MHz for C nmr on a Varian Gemini 2000 300
spectrometer; δ-values are in ppm relative to tetramethylsilane as
internal standard. Mass spectra (EI, 70 eV) were obtained on a
Varian Mat CH-6 spectrometer, and FAB spectra on a Kratos MS
50 RF spectrometer. The ir-spectra were recorded on a Nicolet
250 FT-IR spectrophotometer as potassium bromide pellets.
Analytical silica gel (tlc) was performed on Merck precoated 60
F254 plates. The silica gel (0.040-0.063 mm) used for column
chromatography was purchased from Merck. Elemental analyses
were performed at the Chemistry Institute, Copenhagen
University, Denmark and at the Micro Analytical Center, Faculty
of Science, Cairo University.
This compound was obtained as colorless prisms, yield 1.7 g
1
(59%); mp 94 – 96 ˚C (diisopropyl ether); H nmr (deuteriochloro-
form): δ 1.18 (t, J = 6.5 Hz, 3H, CH ) 2.39 (s, 3H, CH ), 2.51 (s,
3
3H, CH ), 3.64 (q, J = 7.0 Hz, 2H, CH ), 5.53 (s, 2H, CH ), 6.05 (s,
3
3
1H, C -H); C nmr (deuteriochloroform): δ 14.94, 19.84, 20.92 (3
2
2
13
5
x CH ), 65.43 (CH ) 72.57 (NCH O), 101.65 (C-3), 109.64 (CN),
3
115.17 (C-4), 151.29 (C-5), 159.37 (C-6), 161.41 (C-2), EI ms: m/z
2
2
+
206 (30%, M ), 177 (20), 162 (90), 149 (100).
Anal. Calcd. for C H N O (206.24): C, 64.06; H, 6.84; N,
11 14
13.58. Found: C, 64.00; H, 6.97; N, 13.42.
2 2
4,6-Dimethyl-1-(methylthiomethyl)-2-oxo-1,2-dihydropyridine-
3-carbonitrile (15a).
General Procedure for the Preparation of Compounds 2a,b, 14,
15a,b 16a,b and 17a,b.
This compound was obtained as yellow crystals, yield 0.9 g
1
(32%); mp 92-94 ˚C (diisopropyl ether); H nmr (deuteriochloro-
A mixture of 1 (2.0 g, 14 mmol) and 60% oil-immersed sodium
hydride (560 mg, 14 mmol) in anhydrous N, N-dimethylfor -
mamide (20 ml) was stirred at room temperature for 2 h. Then, the
appropriate 2-(acetoxyethoxy)methyl bromide or chloromethyl
form): δ 2.30 (s, 3H, CH ), 2.39 (s, 3H, CH ), 2.50 (s, 3H, CH ),
13
3
5.17 (s, 2H, CH ), 6.08 (s, 1H, C -H); C nmr (deuteriochloro-
3
3
2
5

314
F. A. El-Essawy and A. F. Khattab
Vol. 41
This compound was obtained as colorless prisms, yield 1.0 g
1
(29%); mp 74-76 ˚C (petroleum ether); H nmr (deuteriochloro-
form): δ 15.93, 20.70, 20.86 (3 x CH ), 46.69 (CH ), 101.24 (C-3),
3
109.97 (CN), 115.22 (C-4), 150.42 (C-5), 158.45 (C-6), 161.12
2
+
(C-2), EI ms: m/z 208 (50%, M ), 162 (55), 149 (40), 61 (100).
Anal. Calcd. for C H N O (208.24): C, 57.67; H, 5.81; N,
10 12 2 S
13.45. Found: C, 57.45; H, 5.83; N, 13.30.
form): δ 2.09 (s, 3H, CH ), 2.43 (s, 3H, CH ), 2.45 (s, 3H, CH ),
3 3 3
4.42 (t, J = 4.8 Hz, 2H, CH ), 4.62 (t, J = 4.8 Hz, 2H, CH ), 6.72 (s,
2
2
13
1H, C -H); C nmr (deuteriochloroform): δ 19.98, 20.78, 24.42 (3
5
x CH ), 62.29, 64.43 (2 x CH ), 94.05 (C-3), 114.67 (CN), 117.79
3
2
(C-4), 154.49 (C-5), 162.44 (C-6), 163.32 (C-2), 170.93 (CO); EI
4, 6-Dimethyl-2-(methylthiomethoxy)pyridine-3-carbonitrile
(15b).
+
ms: m/z 234 (2%, M ), 148 (10), 87 (50), 43 (100).
Anal. Calcd. for C
H N O (234.25): C, 61.53; H, 6.02; N,
This compound was obtained as yellow crystals, yield 1.3 g
1
(46%); mp 61-62 ˚C (petroleum ether); H nmr (deuteriochloro-
12 14 2 3
12.01. Found: C, 61.58; H, 6.14; N, 11.95.
form): δ 2.32 (s, 3H, CH ), 2.46 (s, 6H, 2 x CH ), 5.56 (s, 2H,
3
3
CH ), 6.74 (s, 1H, C -H); C nmr (deuteriochloroform): δ 15.16,
[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzene-
sulfonate (9) [15].
13
2
19.97, 24.43 (3 x CH ), 70.68 (CH ), 94.84 (C-3), 114.62 (CN),
5
3
2
118.10 (C-4), 154.49 (C-5), 160.45 (C-6), 162.70 (C-2); EI ms:
p-Toluenesulfonyl chloride (8.57 g, 50 mmol) was added to an
ice-cooled solution of (S)-2, 2-dimethyl-1, 3-dioxolane-4-
methanol (6.6 g, 50 mmol) in anhydrous pyridine (100 ml) and
left to stand for 24 h at 4 ˚C, then 4 h at room temperature. The
pyridine was removed by evaporation in vacuo, co-evaporated
with toluene (3x10 ml) and the residue purified by silica gel col-
umn chromatography with diethyl ether:petroleum ether (5:95,
+
m/z 208 (10%, M ), 162 (50), 149 (30), 61 (100).
Anal. Calcd. for C H N OS (208.24): C, 57.67; H, 5.81; N,
10 12 2
13.45. Found: C, 57.96; H, 5.64; N, 13.63.
1-Benzyloxymethyl-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-
carbonitrile (16a).
20
v/v) to give 9 (12.3 g. 97%) as a colorless viscous oil; [α]
1
This compound was obtained as colorless crystals, yield 1.9 g
D
+110º (c 0.113, MeOH); H nmr (deuteriochloroform): δ 1.16 (s,
3H, CH ), 1.19 (s, 3H, CH ), 2.30 (s, 3H, CH ), 3.62 (q, J = 4.9
1
(53%); mp 127-129 ˚C (diisopropyl ether); H nmr (deuteriochlo-
roform): δ 2.36 (s, 3H, CH ), 2.49 (s, 3H, CH ), 4.66 (s, 2H,
3
Hz, 1H, Ha of CH ), 3.82-3.90 (m, 3H, Hb of CH and CH ),
3
3
3
3
CH ), 5.60 (s, 2H, CH ), 6.00 (s, 1H, C -H), 7.30-7.33 (m, 5H,
2
4.12 (t, J = 5.7 Hz, 1H, CH), 7.20 (d, J = 8.2 Hz, 2H, Ar-H), 7.64
2
2
2
2
5
13
phenyl); C nmr (deuteriochloroform): δ 19.93, 20.94, (2 x
CH ), 72.08, 72.58 (2 x CH ), 102.02 (C-3), 109.70 (CN), 115.15
(C-4), 127.62, 127.69, 127.87, 128.34, 137.00 (Phenyl), 151.14
13
(d, J = 8.2, 2H, Ar-H); C nmr (deuteriochloroform): δ 21.59,
25.09, 26.58 (3 x CH ), 66.12, 69.44 (2 x CH ), 72.85 (CH),
3
2
3
109.99 (CMe ), 127.93, 129.86, 132.59, 145.02 (Ar).
2
+
(C-5), 159.48 (C-6), 161.45 (C-2); ms: m/z 268 (1%, M ), 238
(5), 162 (30), 91 (100).
2
1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-4,6-dimethyl-
2-oxo-1,2-dihydropyridine-3-carbonitrile (10).
Anal. Calcd. for C
H N O (268.31): C, 71.62; H, 6.01; N,
16 16 2 2
10.44. Found: C, 71.55; H, 5.80; N, 10.21.
To a stirred solution of 1 (2.0 g, 14 mmol) in anhydrous N,N-
dimethylformamide (20 ml) was added sodium hydride (560 mg
of 60% dispersion in mineral oil, 14 mmol), and after complete
evolving of hydrogen (2 h), then compound 9 (3.56 g, 14 mmol)
was added, the reaction mixture stirred for additional 12 h at 90
˚C, cooled to room temperature and filtered through Celite. The
filtrate was evaporated till dryness at reduced pressure, co-evapo-
rated with toluene (3x10 ml) and the residue was purified by sil-
ica gel column chromatography with ethyl acetate:chloroform
(10:90, v/v) to give 10 (1.5 g, 43%) as a white solid mp 142-
2-Benzyloxymethyloxy-4, 6-dimethylpyridine-3-carbonitrile
(16b).
This compound was obtained as colorless crystals, yield 1.0 g
1
(28%); mp 39-42 ˚C (petroleum ether); H nmr (deuteriochloro-
form): δ 2.45 (s, 6H,2 x CH ), 4.85 (s, 2H, CH ), 5.68 (s, 2H,
13
3
CH ), 6.66 (s, 1H, C -H), 7.25-7.41 (m, 5H, Phenyl); C nmr
2
2
(deuteriochloroform): δ 19.81, 23.97, (2 x CH ), 71.24, 89.77 (2
5
3
x CH ), 99.13 (C-3), 109.16 (CN), 118.34 (C-4), 127.66, 127.77,
2
127.88, 128.06, 137.78 (Phenyl), 154.55 (C-5), 160.82 (C-6),
20
1
144˚C; [α]
form): δ 1.30 (s, 3H, CH ), 1.40 (s, 3H, CH ), 2.39 (s, 3H, CH ),
-121º (c 1.10, MeOH); H nmr (deuteriochloro-
+
162.13 (C-2); HRms (MALADI): m/z 291 (M+Na ): Anal.
D
3
3
2.54 (s, 3H, CH ), 3.67-3.72 (m, 1H, CH ), 3.89-3.96 (m, 1H,
3
Calcd. For C H N O Na: 291.1104. Found: 291.1102.
2
16 16
Anal. Calcd. for C
2
3
CH ), 4.16-4.21 (m, 1H, CH) 4.37-4.52 (m, 2H, CH ), 6.07 (s,
1H, H-5); C nmr (deuteriochloroform): δ 20.81, 21.59, 24.91,
26.35 (4 x CH ), 47.86 (CH ), 67.11 (CH ), 73.66 (CH), 109.69
(CN), 109.73 (C(CH )2), 101.15 (C-3), 115.28 (C-4), 151.71 (C-
5), 158.34 (C-6), 161.07 (C-2); EI ms: m/z 262 (5%, M ), 247
(20), 148 (20), 43 (100).
2
H
N O (268.31): C, 71.62; H, 6.01; N,
16 16 2 2
10.44. Found: C, 71.34; H, 6.10; N, 10.00.
2
2
13
1-(2-Acetoxyethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-
carbonitrile (17a).
3
2
2
3
+
This compound was obtained as colorless prisms, yield 1.9 g
1
(54%); mp 119-121 ˚C (diisopropyl ether); H nmr (deuteriochlo-
roform): δ 2.05 (s, 3H, CH ), 2.39 (s, 3H, CH ), 2.48 (s, 3H,
Anal. Calcd. for C H N O (262.31): C, 64.11; H, 6.92; N,
14 18 2 3
10.68. Found: C, 63.88; H, 7.04; N, 10.45.
3
3
CH ), 4.28 (t, J = 5.3 Hz, 2H, CH ), 4.37 (t, J = 5.3 Hz, 2H, CH ),
3
6.08 (s, 1H, C -H); C nmr (deuteriochloroform): δ 20.67,
2
2
13
General Procedure for the Deprotection of Compounds 2a,b and
17a,b.
5
20.80, 21.07 (3 x CH ), 43.94, 61.18 (2 x CH ), 101.51 (C-3),
3
2
109.60 (CN), 115.18 (C-4), 150.83 (C-5), 158.45 (C-6), 160.77
A mixture of 2a or 2b or 17a and/or 17b (4 mmol), methanol (30
ml), and concentrated aqueous ammonia (25%, 30 ml) was stirred
at room temperature for 24 h. The solvent was evaporated invacuo
and the residue was triturated with a small volume of ethanol. A
white precipitate was collected by filtration, dried and recrystal-
lized from methanol to give 3, 4, 18a and 18b, respectively.
+
(C-2), 170.33 (CO); EI ms: m/z 234 (10%, M ), 173 (20), 149
(70), 43 (100).
Anal. Calcd. for C
H N O (234.25): C, 61.53; H, 6.02; N,
12 14 2 3
12.01. Found: C, 61.63; H, 6.13; N, 11.96.
2-(2-Acetoxyethoxy)-4,6-dimethylpyridine-3-carbonitrile (17b).

May-Jun 2004
Alkylation of 2-Pyridinones: Synthesis of Novel Acyclonucleosides
315
4,6-Dimethyl-1-(2-hydroxyethoxymethyl)-2-oxo-1,2-dihydropy-
ridine-3-carbonitrile (3).
2.48 (s, 3H, CH ), 3.75-3.84 (m, 3H, CH, CH ), 4.15-4.19 (m,
3
2
2H, CH ), 4.81 (br s, 1H, OH), 5.09 (br s, 1H, OH), 6.28 (s, 1H,
2
13
H-5); C nmr (dimethyl sulfoxide-d ): δ 19.75, 20.71 (2 x CH ),
6
3
47.66 (CH ), 63.58 (CH ), 67.99 (CH), 98.36 (C-3), 108.60
This compound was obtained as colorless prisms, yield 0.9 g
1
(89%); mp 91-93 ˚C; H nmr (dimethyl sulfoxide-d ): δ 2.32 (s,
2
(CN), 115.71 (C-4), 153.48 (C-5), 157.49 (C-6), 160.09 (C-2).
2
6
3H, CH ), 2.48 (s, 3H, CH ), 3.46-3.52 (m, 4H, 2 x CH ), 4.64
3
3
(br s, 1H, OH), 5.49 (s, 2H, NCH O), 6.32 (s, 1H, C -H);
2
Anal. Calcd. for C H N O •0.5H O (231.25): C, 57.13; H,
13
11 14
6.10; N, 12.11. Found: C, 56.75; H, 6.39; N, 11.72.
2
3
2
C
nmr (dimethyl sulfoxide-d ): δ 18.85, 20.03 (2 x CH ), 59.41,
2
5
6
3
70.42(2 x CH ), 72.09(NCH O) 99.18 (C-3), 108.99 (CN),
4,6-Dimethyl-1-(2-O- p- Tolylsulfonylethoxymethyl)-2-oxo-1,2-
dihydropyridine-3-carbonitrile (5).
2
115.29 (C-4), 152.17 (C-5), 159.43 (C-6), 160.32 (C-2); EI ms:
2
+
m/z 222 (3%, M ), 161 (40), 148 (100).
Anal. Calcd. for C H N O (222.24): C, 59.45; H, 6.35; N,
p-Toluenesulfonyl chloride (760 mg, 4 mmol) was added to an
ice-cooled stirred solution of 3 (890 mg, 4 mmol) in anhydrous
pyridine (15 ml) and left to stand overnight at 4 ˚C. Pyridine was
removed by evaporation under reduced pressure and the resulting
gum was triturated with ice water. The product solidified as a
white precipitate and was collected by filtration, washed with
water, dried and recrystallized from diethyl ether to afford 5 (0.9
g, 60%) as a colorless crystals mp 76-78 ˚C; ir (potassium bro-
11 14
12.60. Found: C, 59.21; H, 6.37; N, 12.61.
2 3
4,6-Dimethyl-2-(2-hydroxyethoxymethoxy)pyridine-3-carboni -
trile (4).
This compound was obtained as colorless prisms, yield 0.5 g
1
(63%); mp 36-38 ˚C; H nmr (deuteriochloroform): δ 2.46 (s, 3H,
CH ), 2.47 (s, 3H, CH ), 3.80 (t, J = 4.4 Hz, 2H, CH ), 3.91 (t, J
3
= 4.4 Hz, 2H, CH ), 4.78 (br s, 1H, OH), 5.71 (s, 2H, OCH O),
3
2
-1 1
mide): CN 2221, CO 1653, O-SO 1199 cm ; H nmr (deuterio-
2
chloroform): δ 2.39 (s, 3H, CH ), 2.45 (s, 3H, CH ), 2.46 (s, 3H,
2
2
6.78 (s, 1H, C -H); C nmr (deuteriochloroform): δ 19.95, 24.39
13
3
CH ), 3.82 (t, J = 1.3 Hz, 2H, CH ), 4.09 (t, J = 1.3 Hz, 2H, CH ),
3
5
(2 x CH ), 60.50, 71.45 (2 x CH ), 91.24 (OCH O), 94.32 (C-3),
3
5.49 (s, 2H, NCH O), 6.04 (s, 1H, C -H), 7.34 (d, J = 8.7 Hz, 2H,
2
2
3
2
2
114.57 (CN), 118.45 (C-4), 154.58 (C-5), 160.70 (C-6), 162.63
2
5
13
Ar-H), 7.76 (d, J = 8.7 Hz, 2H, Ar-H); C nmr (deuteriochloro-
form): δ 19.88, 21.05, 21.60 (3 x CH ), 67.57, 68.70 (2 x CH ),
72.78 (NCH O) 102.21 (C-3), 109.95 (CN), 115.06 (C-4),
+
(C-2); EI ms: m/z 222 (5%, M ), 148 (100), 119 (70).
Anal. Calcd. for C H N O (222.24): C, 59.45; H, 6.35; N,
3
2
11 14
2 3
12.60. Found: C, 59.62; H, 6.37; N, 12.63.
2
127.81, 129.86, 132.67, 144.99 (Ar), 151.10 (C-5), 159.84 (C-6),
+
161.58 (C-2); EI ms: m/z 376 (10%, M ), 229 (30), 155 (75), 91
(100).
4,6-Dimethyl-1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridine-3-
carbonitrile (18a).
Anal. Calcd. for C
H N O S (376.42): C, 57.43; H, 5.36; N,
This compound was obtained as colorless prisms, yield 0.7 g
1
(95%); mp 139-141 ˚C; H nmr (dimethyl sulfoxide-d ): δ 2.30
18 20 2 5
7.44 Found: C, 57.08; H, 5.45; N, 7.59.
3-Cyano-4,6-dimethyl-2(1H)pyridone (1).
6
(s, 3H, CH ), 2.48 (s, 3H, CH ), 3.62 (q, J = 5.6 Hz, 2H, CH ),
3
4.03 (t, J = 5.6 Hz, 2H, CH ), 4.96 (t, J = 5.5 Hz, 1H, OH), 6.29
3
2
This compound was prepared from 4 (890 mg, 4 mmol) and p-
toluenesulfonyl chloride (760 mg, 4 mmol) by the method
described for the preparation of 5 to afford a product, which was
spectroscopically equivalent with the starting material 1, and the
2
(s, 1H, C -H); C nmr (dimethyl sulfoxide-d ): δ 19.76, 20.50 (2
13
5
x CH ), 46.61, 57.53 (2 x CH ), 98.47 (C-3), 108.57 (CN),
6
3
115.64 (C-4), 153.04 (C-5), 157.62 (C-6), 159.88 (C-2); EI ms:
+
m/z 192 (15%, M ), 149 (100), 133 (40), 119 (50).
2
1
melting point of the two mixed materials was undepressed; H nmr
(dimethyl sulfoxide-d ): δ 2.23 (s, 3H, CH ), 2.30 (s, 3H, CH ),
13
Anal. Calcd. for C
H N O (192.22): C, 62.49; H, 6.29; N,
6
6.16 (s, 1H, C -H), 12.30 (br s, 1H, NH); C nmr (dimethyl sul-
3
3
10 12 2 2
14.57. Found: C, 62.54; H, 6.35; N, 14.56.
5
foxide-d ): δ 18.37, 20.10 (2 x CH ), 98.58 (C-3), 106.91(CN),
6
115.54 (C-4), 150.69 (C-5), 159.89 (C-6), 160.44 (C-2).
3
4,6-Dimethyl-2-(2-hydroxyethoxy)pyridine-3-carbonitrile (18b).
This compound was obtained as colorless prisms, yield 0.5 g
1
(65%); mp 43-45 ˚C; H nmr (dimethyl sulfoxide-d ): δ 2.40 (s,
(1R)-2-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2 H)-yl)-1-{[(4-
methylbenzenesulfonyl)oxy]methyl}ethyl 4-methylbenzene-
sulfonate (12).
6
3H, CH ), 2.41 (s, 3H, CH ), 3.72 (t, J = 5.1 Hz, 2H, CH ), 4.39
3
(t, J = 5.1 Hz, 2H, CH ), 4.88 (br s, 1H, OH), 6.95 (s, 1H, C -H);
3
2
2
C nmr (dimethyl sulfoxide-d ): δ 19.05, 23.68 (2 x CH ),
5
13
This compound was prepared from 11 (800 mg, 3.2 mmol) and
p-toluenesulfonyl chloride (1.2 g, 6.4 mmol) by the method
described for the preparation of 5. The crude product was recrys-
tallized from diethyl ether to give 12 (700 mg, 37%) as a color-
6
58.54, 67.74 (2 x CH ), 92.43 (C-3), 114.33 (CN), 117.22 (C-4),
3
2
154.23 (C-5), 159.95 (C-6), 162.81 (C-2); EI ms: m/z 192 (5%,
+
M ), 149 (40), 119 (60), 31 (100).
20
1
less crystals, mp 147-149 ˚C; [α]
+135º (c 0.052, MeOH); H
nmr (deuteriochloroform): δ 2.35 (s, 3H, CH ), 2.39 (s, 3H,
Anal. Calcd. for C
H N O (192.22): C, 62.49; H, 6.29; N,
D
10 12 2 2
14.57. Found: C, 62.17; H, 6.02; N, 14.88.
3
CH ), 2.51 (s, 3H, CH ), 2.53 (s, 3H, CH ), 4.03-4.36 (m, 4H, 2
3
3
3
CH ), 4.95-4.99 (dd, J = 2.7, J = 9.6, 1H, CH), 5.94 (s, 1H, H-
1-[(2 S)-2,3-dihydroxypropyl]-4,6-dimethyl-2-oxo-1,2-dihydro-
pyridine-3-carbonitrile (11).
2
5), 7.22 (d, J = 8.1 Hz, 2H, Ar-H), 7.39 (d, J = 8.0, 2H, Ar-H),
1
2
13
7.49 (d, J = 8.1, 2H, Ar-H), 7.80 (d, J = 8.0 Hz, 2H, Ar-H);
nmr (deuteriochloroform): δ 20.80, 21.25, 21.71, 21.85 (4 x
C
Compound 10 (400 mg) was stirred in 80% aqueous acetic
acid (10 ml) for 24 h at room temperature. The solvent was
removed by evaporation in vacuo and the resulting residue co-
evaporated with water (10 ml), and finally ethanol (3x5ml). The
residue was purified by silica gel column chromatography with
CH ), 45.75 (CH ), 68.77 (CH ), 74.46 (CH), 101.48 (C-3),
2
3
2
109.68 (CN), 114.65 (C-4), 127.69, 128.05, 129.93, 130.15,
131.11, 131.49, 145.58, 145.72 (Ar-C), 151.00 (C-5), 158.50 (C-
6), 160.39 (C-2).
Anal. Calcd. for C H N O S (530.61): C, 56.59; H, 4.94;
25 26 2 7 2
N, 5.28 Found: C, 56.36; H, 4.78; N, 5.11.
methanol:chloroform (10:90, v/v) to give 11 (300 mg, 88%) as a
20
white prisms, mp 201-203 ˚C (methanol); [α]
1
-275º (c 0.100,
MeOH); H nmr (dimethyl sulfoxide-d ): δ 2.30 (s, 3H, CH ),
D
6
3

316
F. A. El-Essawy and A. F. Khattab
Vol. 41
1-(2-Azidoethoxymethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (7).
"Development of New Drugs against Hepatitis" at Monoufiya
University, and Prof. E. B. Pedersen, Chemistry Institute, Odence
University, Denmark for recording spectra and Microanalysis.
A mixture of 5, (750 mg, 2 mmol) and sodium azide (130 mg,
2 mmol) in anhydrous N,N-dimethylformamide (10 ml) was
heated for 2 h at 80 ˚C. The solvent was removed by evaporation
under reduced pressure and the remaining syrup triturated with
ice water. A white precipitate was collected by filtration, washed
with ice-water. The product was recrystallized from diethyl ether
REFERENCES AND NOTES
*
To whom correspondence should be addressed.
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to give 7 as colorless crystals, 340 mg (75%); mp 87-89 ˚C; ir
-1 1
(potassium bromide): CN 2218, N 2095, CO 1651 cm ; H nmr
3
(deuteriochloroform): δ 2.40 (s, 3H, CH ), 2.52 (s, 3H, CH ),
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Baba, Z. Debyser, S. Shigeta and E. De Clercq, Drugs of the Future,
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3
3.37 (t, J = 4.6 Hz, 2H, CH ), 3.83 (t, J = 4.6 Hz, 2H, CH ), 5.58
3
2
(s, 2H, NCH O), 6.07 (s, 1H, C -H); C nmr (deuteriochloro-
2
13
[3a] W. S. Saari, J. S. Wai, T. E. Fisher, C. M. Thomas, J. M.
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22(1), 99 (2003).
2
form): δ 19.84, 21.02 (2 x CH ), 50.47, 69.01 (2 x CH ), 72.81
5
3
(NCH O), 101.84 (C-3), 109.87 (CN), 115.02 (C-4), 151.07
2
2
(C-5), 159.75 (C-6), 161.51 (C-2).
Anal. Calcd. for C H N O (247.25): C, 53.43; H, 5.30; N,
11 13
28.32 Found: C, 53.32; H, 5.31; N, 27.40.
5 2
1-(2-Aminoethoxymethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (8).
The azido compound 7 (250 mg, 1 mmol) and triphenylphos-
phine (263 mg, 1 mmol) were dissolved in 15 ml of pyridine and
stirred at room temperature for 1 h. Concentrated aqueous ammo-
nia (25%, 5 ml) was then added and the solution was stirred for 2
h. The solvent was removed by evaporation in vacuo and the
resulting residue was co-evaporated with anhydrous toluene (2x10
ml). The product was purified by silica gel column chromatogra-
phy in methanol:chloroform (0-30%) to give 8 (100 mg, 45%) as
a colorless crystals, mp 57-59 ˚C (methanol); ir (potassium bro-
-1
1
mide): NH 3400-3500, CN 2219, CO 1653 cm ; H nmr (deu-
2
teriumoxide): δ 2.40 (br s, 3H, CH ), 2.52 (br s, 3H, CH ), 2.80
3
(dd, J = 5.2 Hz, 2H, CH ), 3.66 (dd, J = 5.2 Hz, 2H, CH ), 4.76 (d,
3
2
J = 5.2 Hz, 2H, NH ), 5.55 (d, J = 5.5 Hz, 2H, CH ), 6.44 (d, J =
2
2
2
5.4 Hz, 1H, C -H); HRms (MALADI): m/z 244 (M+Na ): A n a l.
+
5
Calcd. for C H N O Na: 244.1057. Found: 244.1053.
11 15
3 2
1 - [ ( 2S)-2,3-diazidopropyl]-4,6-dimethyl-2-oxo-1,2-dihydropy-
ridin-3-carbonitrile (13).
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Pharmazie, 53, 377 (1998).
This compound was prepared from 12 (530 mg, 1 mmol) and
sodium azide (130 mg, 2 mmol) by the method described for the
preparation of 7. The product was recrystallized from diethyl ether
20
as colorless crystals, 0.12 g (60%); mp 83-86 ˚C; [α] -336º (c
0.052, MeOH); ir (potassium bromide): CN 2217, N 2127, N
D
3
3
-1
1
2092, CO 1646 cm ; H nmr (deuteriochloroform): δ 2.41 (s, 3H,
CH ), 2.50 (s, 3H, CH ), 3.46-3.52 (m, 1H, CH ), 3.69-3.83 (m,
3
3H, CH and CH ), 4.22-4.32 (m, 2H, CH ), 6.11 (s, 1H, C -H);
3
2
13
C
nmr (deuteriochloroform): δ 20.91, 21.54 (2 x CH ), 46.67 (CH ),
2
2
5
3
52.70 (CH ), 59.10 (CH), 101.55 (C-3), 110.06 (CN), 115.02 (C-4),
2
2
151.16 (C-5), 158.95 (C-6), 161.00 (C-2); HRms (MALDI): m/z
+
295 (M+Na ): Anal . Calcd. for C
H N ONa: 295.1026,
11 12 8
C H N ONa (MNa -N ): 239.0903, Found 295.1030, 239.0898.
+
11 12
Anal. Calcd. for C H N O (272.28): C, 48.52; H, 4.44; N,
4
4
11 12
41.16 Found: C, 48.16; H, 4.36; N, 40.86.
8
Acknowledgements.
DANIDA and Danish Ministry of Foreign Affairs are grate-
fully acknowledged for financial support through the project
[16] R. Benhida, A-M Aubertin, D. S. Grierson and C.
Monneret, Tetrahedron Lett., 37(7), 1031 (1996).