Microwave-assisted synthesis of 2(1H)-pyridones and their glucosides as cell proliferation inhibitors

Article abstract of DOI:10.1080/15257770.2010.551646

A new series of substituted 2(1H)-pyridones (4a-i) and their glucosides (5, 6a-e) were prepared as potential agents against leukemia (HL-60) cells. Glucosides (5,6a-e) were synthesized using three independent methods. Microwave protocol as an ecologically

Full text of DOI:10.1080/15257770.2010.551646

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Microwave-Assisted Synthesis of 2(1H)-
Pyridones and Their Glucosides as Cell
Proliferation Inhibitors
Shaikha S. Al-Neyadi a , Ahmed H. Hassan b & Ibrahim M. Abdou a
a Department of Chemistry, Faculty of Science , United Arab
Emirates University , Al-Ain , United Arab Emirates
b Department of Biochemistry, Faculty of Medicine & Health
Science , United Arab Emirates University , Al-Ain , United Arab
Emirates
Published online: 24 Feb 2011.
To cite this article: Shaikha S. Al-Neyadi , Ahmed H. Hassan & Ibrahim M. Abdou (2011) Microwave-
Assisted Synthesis of 2(1H)-Pyridones and Their Glucosides as Cell Proliferation Inhibitors,
Nucleosides, Nucleotides and Nucleic Acids, 30:2, 120-134, DOI: 10.1080/15257770.2010.551646
To link to this article: http://dx.doi.org/10.1080/15257770.2010.551646
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Nucleosides, Nucleotides and Nucleic Acids, 30:120–134, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2010.551646
MICROWAVE-ASSISTED SYNTHESIS OF 2(1H)-PYRIDONES AND
THEIR GLUCOSIDES AS CELL PROLIFERATION INHIBITORS
Shaikha S. Al-Neyadi,1 Ahmed H. Hassan,2 and Ibrahim M. Abdou1
1Department of Chemistry, Faculty of Science, United Arab Emirates University,
Al-Ain, United Arab Emirates
2Department of Biochemistry, Faculty of Medicine & Health Science, United Arab Emirates
University, Al-Ain, United Arab Emirates
A new series of substituted 2(1H)-pyridones (4a–i) and their glucosides (5,6a–e) were pre-
2
pared as potential agents against leukemia (HL-60) cells. Glucosides (5,6a–e) were synthesized
using three independent methods. Microwave protocol as an ecologically new method was used to
synthesize the target compounds. Structures of the new products were confirmed using one- and
two-dimensional NMR spectroscopy. In vitro exposure of pyridones substituted at position 4 with a
2-thienyl or 2-(trifluoromethyl)phenyl were found to exhibit high antiproliferation activities; in par-
ticular, 3-cyano-4-(thien-2ꢁ-yl)-6-(4ꢁꢁ-chlorophenyl)-2(1H)-pyridone (4c) and its glucoside analogue
(6c) had the highest activity.
Keywords Microwave synthesis; pyridone glucosides; spectroscopy; antiproliferation
activities
INTRODUCTION
Development of potent and effective anticancer drugs is one of the
more pressing goals of current medicinal chemistry.[1,2] Various nucleosides
have been reported to have important biological properties.[3] In particu-
lar, 4-amino-3-fluoro-1-(β-D-ribofuranosyl)-2(1H)-pyridone (1) inhibits the
growth of HL-60 lymphoid leukemia cells with IC50 = 1.07 × 10−5 M, while
2ꢁ-deoxy analogue of (1) is active against lymphoid leukemia L1210 cells.
Also, the acetyl derivative of (1) exhibits similar albeit less potent activities
than (1).[4] Selective inhibitors for the human immunodeficiency virus type1
reverse transcriptase (HIV-RT) are derivatives of pyridine.[5] For example, 3-
(4ꢁ,7ꢁ-dimethyl benzoxazol-2ꢁ-yl)-amino-5-ethyl-6-methyl pyridine-2(1H)-one
Received 25 August 2010; accepted 29 December 2010.
The authors thank the Deanship of the Graduate Studies, M.Sc. Program (Environmental Sciences)
and the Department of Chemistry, UAE University for Shaikha S. Al-Neyadi’s M.Sc. fellowship. This work
was published in ICHC-22, St. Johns’ NL, Canada, August 2009.
Address correspondence to Ibrahim M. Abdou, Department of Chemistry, Faculty of Science, UAE
University, Al-Ain 17551, UAE. E-mail: i.abdou@uaeu.ac.ae
120

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
121
(2) and its 4,7-dichloro analogue have been reported to inhibit the spread
of HIV-1 infection by 95% in MT4 cell culture and were selected for clini-
cal trials as antiviral agents. 4-Benzylpyridone (3) has been shown to posses
potent HIV-1 specific reverse transcriptase inhibitor properties.[5]
CH3
NH2
H3C
F
CH3
O
H
O
N
N
NH2
N
CH3
H3C
H3C
H3C
H3C
O
HO
O
N
O
N
H
H
OH
HO
(3)
(1)
(2)
FIGURE 1 Microwave synthesis of 2(1H)-pyridone derivatives.
In our previous study,[6,17] we reported the synthesis and biological ac-
tivities of pyrazolone and pyrimidine nucleosides.
The goal of this work is to develop an environmental and friendly proto-
col for the synthesis of some new pyridone nucleosides. We synthesize series
of pyridone and their nucleoside analogues using silica catalyzed microwave
(MW) protocol. MW synthesizer has an advantage method for its practical
cost and short reaction time. It is a new route with additional advantage
to enhance the reaction rates and to improve the yield. The new obtained
synthesized compounds will be used to study the cell proliferation effects
and to establish their structure-activity relationships.
RESULTS AND DISCUSSION
Chemistry
The synthesis of 2(1H)-pyridone derivatives (4a–i) was performed as out-
lined in Scheme 1 and isolated in a crystalline form in 58–86% yields by using
the methodology published previously.[7] Microwave synthetic protocol was
used to obtain the target compounds (4a–i) in 90–95% yield. Their struc-
tures were unambiguously confirmed by one- and two-dimensional NMR
spectroscopy and elemental analysis.[8] For example, the1H NMR spectrum
of compound (4d) shows a singlet at δ 6.98 corresponding to the pyridine
H-5. Protons at positions 3ꢁ, 4ꢁ, and 5ꢁ of the thiophene show absorption
pattern that is typical for the 2-thienyl group attached to an aromatic system.
Three different protocols for the synthesis of the targeted nucleo-
sides (5a–e)[9,13] were compared (Scheme 2). The silyl procedure (method
A)[11–14] was used to synthesize nucleosides (5a–e). For example, a silyl deriva-
tive of 3-cyano-4-(thiophen-2ꢁ-yl)-6-(p-chlorophenyl)-2(1H)-pyridone (4d)

122
S. S. Al-Neyadi et al.
SCHEME 1 Synthesis of 3-cyano-4,6-disubstituted pyridine-2(1H)-ones (4a–i).
was allowed to react with pentacetyl glucose in the presence of trimethylsi-
lyltriflate (TMSOTf) in 1,2-dichloroethane to produce (5d) in 81% yield
(Scheme 2). In method B,[9,10] the potassium salt of 2-pyridone (4a–i) was
subjected to a reaction with an α-acetobromoglucose to produce the tar-
get nucleoside (5a–e). In method C,[17] microwave was used to simplify the
formation of N -glucoside linkage in shorter time and in an accepted yield
(63%). In particular, the β-structure of the obtained nucleoside (5d) was de-
1
termined by using H NMR. More specifically, the large spin-spin coupling
constant (JH1 -H2 > 7 Hz) for a diaxial interaction between H-1ꢁꢁ and H-2ꢁꢁ
is fully consistent with the β-isomer.[15] Similar results were obtained for
the remaining glucosides. The conformation of the resultant nucleosides
was established using two-dimensional NMR analysis. The phase sensitive
NOESY spectrum of (6a) was collected at 25◦C. The inter-ring cross peaks
were observed between the anomeric proton H-1ꢁꢁ and ortho-phenyl protons
ꢁꢁ
ꢁꢁ

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
123
SCHEME 2 Synthetic pathways of pyridone glucosides (5,6a–e).
at the 6-position supporting the formation of N -glucosides as single isomer,
not O-glucosides.[16]
Antiproliferation Activity
Table 1 shows the in vitro antiproliferative activity of compounds (4a–i)
and their glucoside derivatives (5,6a–e) on human promyelotic leukemia
cells (HL-60) using the MTT cell proliferation assay. Introducing electron
withdrawal groups at the 4- and 6-positions of the pyridine ring have shown

124

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
125
significant increase in the antiproliferation activities. Glucoside (6c) with
2-thienyl group at the 4-position was found to have the highest ability to
inhibit HL-60 proliferation among all synthesized compounds. The viability
percentage of HL-60 cells treated with (6c) was reduced by 50% while that
treated with the pyridine analogue (4c) showed 40% antiproliferation activity
compared to the control. Glucoside (6e) substituted with trifluoromethyl
group enhanced the potency in inhibiting HL-60 cell by 40% or 30% at
concentration of 100 µM and 200 µM, respectively.
On the other hand, electron withdrawing substitutes in the 6-position
of the pyridine ring were found to enhance the antiproliferation activity.
Similar inhibitions in HL-60 cells were obtained by the acetylated compounds
(5c-e) at 100 µM and 200 µM (Table 1). Pyridone analogues substituted
with electron-donating groups (4b,f) showed no effect on HL-60 cell line
compared with the control.
As results, the antiproliferation activity of the analogues having electron-
withdrawing groups at positions 4- and 6- of the pyridine ring inhibited cell
viability relative to the control. Consequently, structures (6c-e) offer an inter-
esting model for the design of new glucosides endowed with antiproliferative
activity. These preliminary results will be part of future investigations.
EXPERIMENTAL
General
All air sensitive materials were handled under a nitrogen atmosphere.
Microwave synthesis was done using CEM discovery S-class (Matthews,
NC, USA). Melting points were determined on (Pyrex capillary) Gal-
lenkamp apparatus (Leicestershire, UK). Infrared spectra were recorded
with a Thermo Nicolet Nexus 470 FT-IR spectrometer (Barrington, IL,
USA) in the range 4000–400 cm−1 on samples in potassium bromide
disks. 1H NMR spectra (200 MHz) and 13C NMR spectra (75 MHz)
were obtained on Varian 200 MHz instrument (Crawley, West Sussex,
UK); chemical shifts were recorded in δ (ppm) units, relative to Me4Si
as an internal standard. Optical rotations were measured with a Perkin-
Elmer digital polarimeter at 589 nm (sodium D line) in a 1 dm cell
(Fremont, CA, USA). Thin layer chromatography (TLC) was carried out
on precoated Merck silica gel F254 plates and ultraviolet (UV) light was
used for visualization (Gibbstown, NJ, USA). Column chromatography was
performed on a Merck silica gel. Microanalytical data (C,H,N,S) were
performed on a Flash–EA-1112 series analyzer (CLU, UAE University).
The reagents were purchased from Aldrich and used without further
purification (Sigma-Aldrich, LABCO, Dubai, UAE).

126
S. S. Al-Neyadi et al.
General Procedure for the Synthesis of (4a–i)
Conventional Method[7]
A mixture of an aromatic aldehyde (10 mmol), ethyl cyanoacetate
(10 mmol), arylketone (10 mmol), and ammonium acetate (0.1 mol) in
ethanol (50 mL) was heated under reflux for approximately 6 hours. The
mixture was cooled, and the resultant precipitate was filtered, washed with
cold water (3 × 50 mL), and crystallized from appropriate solvent to give
the desired 2(1H)-pyridone derivatives (4a–i) in 67–86% yield.
Microwave Synthesis
Equimolar amounts of aromatic aldehyde (10 mmol), ethyl cyanoacetate
(10 mmol), arylketone (10 mmol), and ammonium acetate (0.1 mol) were ir-
radiated at 200 W for 5–7 minutes using microwave reactor CEM S-discovery.
The obtained product was purified by crystallization from EtOH-DMF to af-
ford 2(1H)-pyridone derivatives (4a–i) in 90–95% yields.
3-Cyano-4,6-diphenyl-2(1H)-pyridone (4a). Yellow crystals; m.p. 333◦C;
Rf = 0.53 (hexane/ethyl acetate, 6:4), IR (cm−1): 1600 (CO), 2220 (CN),
1
3440 (NH); H NMR (DMSO-d6): δ 6.82 (s, 1H, H-5), 7.54–7.89 (m, 10H,
aromatic), 12.81 (bs, 1H, NH, exchangeable in D2O); 13C NMR (DMSO-d6):
δ 106.3 (C-5), 116.5(CN), 116.0 (C-3), 127.8–136.0 (aromatic), 151.5 (C-6),
159.8 (C-2), 162.0 (C-4). Anal. Calcd. for C18H12N2O (272.30): C, 79.39; H,
4.44; N, 10.29. Found: C, 79.0; H, 4.46; N, 10.20.
3-Cyano-6-phenyl-4-(2 ꢁ-tolyl)-2(1H)-pyridone (4b). Pale yellow crystals; m.p.
284◦C; Rf = 0.38 (6:4 hexane/ethyl acetate), IR (KBr, cm−1) 1641 (CO), 2350
(CN), 3420 (NH); 1H NMR (DMSO-d6): δ 2.36 (s, 3H, o-CH3), 6.71 (s, 1H, H-
5), 7.31–7.89 (m, 12H, aromatic), 12.81 (bs, 1H, NH, exchangeable in D2O);
13C NMR (DMSO-d6): δ 107.5 (C-5), 116.6 (CN),116.0 (C-3), 126.7–137.1
(aromatic), 151.9 (C-6), 161.8 (C-2), 162.4 (C-4); Anal. Calcd. for C19H14N2O
(286.33): C, 79.70; H, 4.93; N, 9.78; found: C, 79.9; H, 5.06; N, 9.87%.
3-Cyano-6-phenyl-4-(thiophen-2 ꢁ-yl)-2(1H)-pyridone (4c). Yellow crystals;
m.p. 315◦C; Rf = 0.62 (6:4 hexane/ethyl acetate), IR (KBr, cm−1) 1643
(CO), 2220 (CN), 3425 (NH); 1H NMR (DMSO-d6): δ 6.90 (s, 1H, H-5), 7.31
(t, 1H, H-4ꢁ, J = 5.0 Hz), 7.55 (m, 3H), 7.58 (m,2H), 7.98 (d, 1H, H-5ꢁ, J =
5.0 Hz), 8.05 (d, 1H, H-3ꢁ, J = 2.6 Hz) 12.65 (bs, 1H, NH, exchangeable with
D2O); 13C NMR (DMSO-d6): δ 95.3 (C3), 104.5 (C-5), 117.0 (CN), 127.8,
128.7, 128.9, 131.2, 131.4, 131.9, 132.2, 136.8, 150.8 (C6), 151.2 (C-2), 162.2
(C-4); Anal. Calcd. for C16H10N2OS (278.33): C, 69.04; H, 3.62; N, 10.06; S,
11.52%, found: C, 68.70; H, 3.63; N, 10.0; S, 11.50%.
3-Cyano-6-(4 ꢁ-chlorophenyl)-4-(thiophen-2 ꢁ-yl)-2(1H)-pyridone (4d). Pale yel-
low crystals; m.p. 342–343◦C; Rf = 0.32 (6:4 hexane/ethyl acetate), IR (KBr,
cm−1) 1660 (CO), 2220 (CN), 3430 (NH); 1H NMR (DMSO-d6): δ 6.98 (s, 1H,
H-5), 7.32 (dd, 1H, H-4ꢁ, J = 3.8, 5.0 Hz), 7.62 (d, 2H, J = 8.6 Hz), 7.88–7.93
(d, 2H, J = 8.6 Hz), 7.98 (d, 1H, H-5ꢁ, J = 5.0 Hz), 8.01 (d, 1H, H-3ꢁ, J =

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
127
3.8 Hz) 12.74 (bs, 1H, NH, exchangeable with D2O);13C NMR (DMSO-d6): δ
104.8 (C-5), 116.9 (CN), 116.0 (C-3),128.7–128.9, 129.7, 131.2, 131.6, 132.0,
136.1, 136.7 (aromatic), 150.2 (C-6),150.7 (C-2), 162.3 (C-4). Anal. Calcd.
for C16H9N2OClS (312.77): C, 61.44; H, 2.90; N, 8.96; S, 10.25%.Found:C,
61.4; H, 2.9; N, 8.94; S, 10.3%.
3-Cyano-6-phenyl-4-(2 ꢁ-trifluoromethylphenyl)-2(1H)-pyridone (4e). Yellow
crystals; m.p. 306–307◦C; Rf = 0.34 (6:4 hexane/ethyl acetate), IR (KBr,
1
cm−1) 1637 (CO), 2349 (CN), 3446 (NH); H NMR (DMSO-d6): δ 6.84 (s,
1H, H-5), 7.50 (m, 3H), 7.89 (m, 6H), 12.81 (bs, 1H, NH, exchangeable with
D2O); 13C NMR (DMSO-d6): δ; 98.0 (CN), 106.3 (C-5), 116.2 (CN), 125.6,
125.7, 125.8, 126.7, 127.9, 129.0, 130.2, 130.8, 132.3, 150.2 (C-4), 158.4
(C-6), 161.8 (C-4), 161.9 (C-2). Anal. Calcd. for C19H11N2OF3 (340.30): C,
67.06; H, 3.26; N, 8.23%, found: C, 67.4; H, 3.30; N, 8.30%.
3-Cyano-6-phenyl-4-(3 ꢁ-tolyl)-2(1H)-pyridone (4f). Yellow crystals; m.p.
263◦C, Rf = 0.26 (6:4 hexane/ethyl acetate), IR (KBr, cm−1) 1650 (CO),
1
2229 (CN), 3442 (NH); H NMR (DMSO-d6): δ 2.38 (s, 3H, m-CH3), 6.78
(s, 1H, H-5), 7.34–7.55 (m, 7H), 7.86–7.88 (m, 2H), 12.81 (bs, 1H, NH,
exchangeable with D2O); 13C NMR (DMSO-d6): δ 98.4 (C-3), 106.3 (C-5),
116.6 (CN), 125.4, 127.8, 128.8, 131.1, 131.3, 132.3, 136.1, 138.3, 151.4 (C-6),
159.9 (C-2), 162.2 (C-4); Anal. Calcd. for C19H14N2O (286.33): C, 79.70; H,
4.93; N, 9.78%, found: C, 79.71; H, 5.04; N, 9.77%.
3-Cyano-6-(4 ꢁ-chlorophenyl)-4-(4 ꢁ-tolyl)-2(1H)-pyridone (4g). Yellow crystals;
m.p. 312–313◦C; Rf = 0.180(6:4 hexane/ethyl acetate); IR (KBr, cm−1) 2349
(CN), 1636 (CO), 3433 (NH), 1H NMR (DMSO-d6): δ 2.37 (s, 3H, CH3), 6.83
(s, 1H, H-5), 7.34 (d, 2H, J = 8.2 Hz), 7.57 (d, 2H, J = 8.2 Hz), 7.62 (d, 2H,
J = 8.6 Hz), 7.90 (d, 2H, J = 8.6 Hz), 12.38 (bs, 1H, NH, exchangeable with
D2O);13C NMR (DMSO-d6): δ 98.0 (C-5), 107.3 (C-3), 117.2 (CN), 128.9,
129.6, 130.0, 130.3, 132.0, 133.7, 136.6, 141.2 (C-6), 160.2 (C-2), 162.8 (C-4);
Anal. Calcd. for C19H13ClN2O (320.77): C, 71.14; H, 4.08; N, 8.73% found:
C, 71.2; H, 4.03; N, 8.67%.
3-Cyano-6-(4 ꢁ-methoxyphenyl)-4-(pyridin-4 ꢁ-yl)-2(1H)-pyridone (4h). Yellow
crystals; m.p. 306–307◦C; Rf = 0.34 (6:4 hexane/ethyl acetate), IR (KBr,
1
cm-1)1637 (CO), 2349 (CN), 3446 (NH); H NMR (DMSO-d6): δ 3.82 (s,
3H, p-OCH3), 6.84 (s, 1H, H-5), 7.07 (d, 2H, J = 9.0 Hz), 7.67 (d, 2H, J =
4.4 Hz),7.87 (d, 2H, J = 9.0 Hz) 8.76 (d, 2H, J = 4.4 Hz), 12.81 (bs, 1H,
NH, exchangeable with D2O); 13C NMR (DMSO-d6): δ 55.6 (p-OCH3), 104.8
(C-5), 114.4, 116.1 (CN), 122.6, 124.1, 129.6, 143.6, 150.2, 157.1, 161.8 (C-4),
161.9 (C-2); Anal. Calcd. for C18H13N3O2 (303.30): C, 71.28; H, 4.32; N,
13.85%, found: C, 71.25; H, 4.35; N, 13.82%.
3-Cyano-6-(4 ꢁ-chlorophenyl)-4-phenyl-2(1H)-pyridone (4i):. Yellow crystals;
m.p. 305–306◦C; Rf = 0.22 (6:4 hexane/ethyl acetate); IR (KBr, cm−1)
1
2216 (CN), 1635 (CO), 3446 (NH); H NMR (DMSO-d6): δ 6.87 (s, 1H,
H-5), 7.55 (m, 5H), 7.70 (d, 2H, J = 10.8 Hz), 7.91 (d, 2H, J = 10.8 Hz),

128
S. S. Al-Neyadi et al.
12.42 (bs, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6): δ 98.5
(CN), 107.4 (C-5), 117.1 (C-3), 128.9, 129.4, 129.6, 130.3, 131.1, 132.0, 136.6,
136.7, 151.2 (C-6), 160.3 (C-2), 162.8 (C-4); Anal. Calcd. for C18H11ClN2O
(306.75): C, 70.48; H, 3.61; N, 9.13%; found: C, 70.58; H, 3.62; N,
9.01%.
General Procedures for 3-Cyano-4,6-disubistituted-1-(2ꢀꢀ,3ꢀꢀ,
4ꢀꢀ,6ꢀꢀ-tetra-O-acetyl-β-D-glucopyranosyl)- 2-pyridone (5a–e)
Method A
A mixture of 2-pyridone (4a–e) (0.01 mol), 1,1,1,3,3,3 hexamethyl dis-
ilazane (HMDS, 60 mL), ammonium sulfate (0.125 g) and few drops of
chlorotrimethylsilane was heated under nitrogen for 2–6 hours. Excess
HMDS was removed by distillation, and the residue was dried under a re-
duced pressure. The resulting silyl intermediate was dissolved in anhydrous
MeCN (20 mL). A solution of a 1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose
(3.91 g,0.01 mol) and TMSOTf (2.17 ml, 0.015 mol) in MeCN (20 mL)
was added at 5◦C with stirring. The stirring was continued at room temper-
ature for 3–6 hours until the reaction was completed as observed by TLC
analysis (chloroform/acetone, 1:1). The mixture was diluted with CHCl3
(150 mL), and the organic solution was washed with a saturated NaHCO3
solution (50 mL), and then with water (2 × 50 mL). After drying (anhy-
drous Na2SO4), the solvent was removed under a reduced pressure and
a crude product thus obtained was purified by column chromatography
(CHCl3/ethyl acetate, 1:9) to give (5a–e) in 81–93% yield (Scheme 2).
Method B
To a solution of 4,6-disubstituted-2(1H)-pyridone (4a–e) (0.01 mol) in
aqueous KOH [(0.56 g, 0.01 mol) in water (6 mL)], a solution of 2,3,4,6-
tetra-O-acetyl-α-D-glucopyranosyl bromide (4.12 g, 0.011 mol) in acetone
(30 mL) was added. The mixture was stirred at room temperature until the
reaction was judged completed by TLC (4–6 hours). The reaction mixture
was diluted using 30 ml of CH2Cl2. The organic layer was separated, dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified using column chromatography (CHCl3/ ethyl ac-
etate, 1:9) to give after crystallization in ethanol the desired products (5a–e)
in 58–69% yield (Scheme 2).
Method C[17]
A mixture of 3-cyano-4,6-diphenyl-2-pyridone (4a) (2.72 g, 0.01 mol) was
suspended in anhydrous MeCN (20 mL). A solution of a 1,2,3,4,6-penta-O-
acetyl-α-D-glucopyranose (3.91 g, 0.01 mol) in MeCN (20 mL) was added
with stirring at room temperature. A catalytic amount of silica gel (1.0 g) was

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
129
added. The solvent was removed and the mixture irradiated at 90◦C (5–200
W) for 3–5 minutes in a 35 mL closed vial using CEM S-discovery microwave
reactor. The mixture was suspended in CHCl3 (150 mL), filtered and the
organic solution was washed with a saturated NaHCO3 solution (50 mL), and
then with water (2 × 50 mL). After drying (anhydrous Na2SO4), the solvent
was removed under a reduced pressure and the crude product obtained was
purified by column chromatography (CHCl3/ethyl acetate, 1:9) to give (5a)
in 63% yield (Scheme 2).
3-Cyano-4,6-diphenyl-1-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-glucopyranosyl)-2-pyridone
(5a). White crystals; yield 85% (method A), 66% (method B); (method
C) 63%; m.p. 193◦C, from ethanol; Rf = 0.48 (6:4 hexane/ethyl acetate),
IR (KBr, cm−1) 1640 (C-2), 1752 (acetyl carbonyl CO), 2354 (CN); [α]25
=
25.4◦ (c = 4.92 mg/mL, chloroform);1H NMR (CDCl3): δ 1.91–2.07 (4s,
12H, 4CH3CO), 4.03–4.25(m, 3H, H-5ꢁ, H-6ꢁa,H-6ꢁb), 5.21–5.27 (dd, 1H,
H-4ꢁ, J = 3.6 Hz, J = 7.8 Hz), 5.51–5.53 (t, 1H, H-3ꢁ, J = 3.6 Hz), 5.65–5.74
(t, 1H, H-2ꢁ, J = 3.6 Hz, J = 7.8 Hz), 6.27–6.31 (d, 1H, H-1ꢁ, J 1 -2 = 7.8 Hz),
7.49–8.00 (m, 10H, aromatic); 13C NMR (CDCl3): δ 20.3–20.5 (4CH3), 62.0
(C-6ꢁ), 68.3 (C-4ꢁ), 70.3 (C-2ꢁ), 72.6 (C-3ꢁ), 72.8(C-5ꢁ), 94.3 (C-1ꢁ), 94.3(C-5),
113.9 (C-3), 115.5 (CN), 127.2–136.8 (aromatic), 157.3 (C-6), 157.8 (C-2),
162.3 (C-4), 168.9–170.6 (four acetoxy carbonyl carbon). Anal. Calcd. for
C32H30N2O10 (602.59): C, 63.78; H, 5.02; N, 4.65%, found: C, 64.01; H,
5.14; N, 4.61%.
ꢁ
ꢁ
3-Cyano-6-phenyl-1-(2ꢁꢁ,3ꢁꢁ,4ꢁꢁ,6ꢁꢁ-tetra-O-acetyl-β-D-glucopyranosyl)-4-(2ꢁ-tolyl)-
2-pyridone (5b). White crystals; yield 87% (method A), 69% (method B);
m.p. 189–190◦C, from ethanol; Rf = 0.38 (6:4 hexane/ethyl acetate), IR
(KBr, cm−1) 1659 (C-2), 1765 (acetoxy carbonyl), 2352 (CN); [α]25
=
26.1◦ (c = 3.84 mg/ml, chloroform);1H NMR (CDCl3): δ 1.93–2.08 (4s,
12H, 4CH3), 2.28 (s, 3H, o-CH3), 4.00 (m, 1H, H-5ꢁ), 4.25–4.27 (m, 2H,
H-6ꢁꢁa,H-6ꢁꢁb), 5.23–5.47 (m, 3H, H-2ꢁꢁ, H-3ꢁꢁ, H-4ꢁꢁ), 6.32–6.36 (d, 1H, H-1ꢁꢁ,
J 1 -2 = 7.8 Hz), 7.25–8.05 (m, 10H, aromatic);13C NMR (CDCl3): δ 20.1
ꢁꢁ ꢁꢁ
(o-CH3), 20.8 (4 CH3), 62.3 (C-6ꢁꢁ), 68.6 (C-4ꢁꢁ), 70.6 (C-2ꢁꢁ), 72.9 (C-3ꢁꢁ),
73.0 (C-5ꢁꢁ), 94.7 (C-1ꢁꢁ), 96.1 (C-5), 114.0 (C-3), 116.5 (CN), 126.4–136.9
(aromatic), 157.8 (C-6), 158.5 (C-2), 162.0 (C-4), 170.9 (four acetoxy
carbonyl carbon); Anal.Calcd. for C33H32N2O10 (616.61): C, 64.28; H, 5.23;
N, 4.54%, found: C, 64.50; H, 5.23; N, 4.47%.
3-Cyano-6-phenyl-1-(2ꢁꢁ,3ꢁꢁ,4ꢁꢁ,6ꢁꢁ-tetra-O-acetyl-β-D-glucopyranosyl)-4-(thiophen-
2ꢁ-yl)-2-pyridone (5c). White crystals; yield 93% (method A), 64% (method
B); m.p. 188–189◦C, from ethanol; Rf = 0.92 (6:4 hexane/ethyl acetate), IR
(KBr, cm−1) 1680 (CO), 1752 (acetoxy carbonyl), 2354(CN); [α]25 = 7.1◦
1
(c = 4.28 mg/ml, chloroform); H NMR (CDCl3): δ 1.92–2.07 (4s, 12H,
4CH3), 4.06 (m, 1H, H-5ꢁꢁ), 4.21–4.22 (m, 2H, H-6ꢁꢁa, H-6ꢁꢁb) 5.18–5.50 (m,
3H, H-2ꢁꢁ,H-3ꢁꢁ, H-4ꢁꢁ), 6.29 (d, 1H, H-1ꢁꢁ, J
= 9.0 Hz), 7.20–7.56 (m, 5H,
1ꢁꢁ-2ꢁꢁ
aromatic), 7.69 (s, 1H, H-5), 7.98–8.06 (m, 2H, H-3ꢁ, 4ꢁ); 13C NMR (CDCl3):
δ 20.6–20.7 (4CH3), 62.0 (C-6ꢁꢁ), 68.4 (C-5ꢁꢁ), 70.3 (C-4ꢁꢁ), 72.98(C-3ꢁꢁ), 73.0

130
S. S. Al-Neyadi et al.
(C-2ꢁꢁ), 91.8 (C5), 94.4 (C-1ꢁꢁ), 114.2 (C-3), 114.5 (CN), 127.3–137.2, 148.6
(thienyl C-2), 158.0 (C-6), 162.9 (C-2), 168.9, 170.9, 170.4, and 170.6 (four
acetoxy carbonyl carbon); Anal.Calcd. for C30H28N2O10S (608.62): C, 59.20;
H, 4.64; N, 4.60; S, 5.27%, found: C, 59.02; H, 4.57; N, 4.63; S, 5.19%.
3-Cyano-6-(p-chlorophenyl)-1-(2ꢁꢁ,3ꢁꢁ,4ꢁꢁ,6ꢁꢁ-tetra-O-acetyl-β-D-glucopyranosyl)-4-
(thiophen-2ꢁ-yl)-2-pyridone (5d). White crystals; yield 81% (method A), 68%
(method B); m.p. 155–156◦C, from ethanol, Rf = 0.625(6:4 hexane/ethyl
acetate),), IR (KBr, cm−1) 1641 (C-2), 1752 (acetoxy carbonyl), 2330 (CN);
[α]25 = 17.9◦ (c = 9.2 mg/ml, chloroform); 1H NMR (CDCl3): δ 1.93–2.07
(4s, 12H, 4CH3), 4.00 (m, 1H, H-5ꢁꢁ), 4.19–4.25 (m, 2H, H-6ꢁꢁa, H-6ꢁꢁb),
5.20–5.25 (m, 1H, H-4ꢁꢁ), 5.39–5.45 (m, 2H, H-2ꢁꢁ, H-3ꢁꢁ), 6.25–6.30 (d,1H,
H-1ꢁꢁ, J 1 -2 = 8.2 Hz), 7.19–7.22 (d, 2H, J = 4.2 Hz), 7.45–7.51 (m, 1H,
ꢁꢁ ꢁꢁ
thienyl H-5ꢁ), 7.56–7.59 (d, 2H, J = 8.2 Hz), 7.63 (s, 1H, H-5), 7.94–7.99
(m, 2H, thienyl H-3ꢁ, H-4ꢁ); 13C NMR (CDCl3): δ 20.6–20.7 (4CH3), 61.7
(C-6ꢁꢁ), 67.1 (C-5ꢁꢁ), 67.8 (C-4ꢁꢁ), 70.9 (C-3ꢁꢁ), 71.7 (C-2ꢁꢁ), 95.0 (C-1ꢁꢁ),
91.9 (C-5), 113.9 (C-3), 114.5 (CN), 128.5–137.2 (aromatic), 148.7 (C-6),
156.7 (C-2), 163.1 (C-4), 168.9, 170.2, 170.3 and 170.4 (four acetoxy
carbonyl carbon). Anal.Calcd. for C30H27ClN2O10S (643.06): C, 56.03; H,
4.23; N, 4.36; S, 4.99%, found: C, 56.0; H, 4.20; N, 4.21; S, 4.89%.
3-Cyano-6-phenyl-1-(2ꢁꢁ,3ꢁꢁ,4ꢁꢁ,6ꢁꢁ-tetra-O-acetyl-β-D-glucopyranosyl)-4-(2ꢁ-trifluo-
romethylphenyl)-2-pyridone (5e). White crystals; yield 86% (method A), 58%
(method B); m.p. 167–168◦C, from ethanol, Rf = 0.86 (6:4 hexane/ethyl
acetate), IR (KBr, cm−1) 1660 (C-2), 1760 (acetoxy carbonyl), 2400 (CN);
[α]25 = 9.5◦ (c = 8.4 mg/mL, chloroform);1H NMR (CDCl3): δ 1.91, 2.05,
2.06, 2.08 (4s, 12H, 4CH3), 4.05–4.11 (m, 1H, H-5ꢁꢁ), 4.22–4.25 (m, 2H,
H-6ꢁꢁa,H-6ꢁꢁb), 5.18–5.27 (m, 1H, H-4ꢁꢁ), 5.42–5.47 (m, 2H, H-2ꢁꢁ, H-3ꢁꢁ),
6.33–6.37 (d, 1H, H-1ꢁꢁ, J 1 -2 = 8 Hz), 7.51 (m, 3H), 7.59 (s, 1H, H-5),
ꢁꢁ ꢁꢁ
7.77 (m, 4H), 8.05 (m, 2H);13C NMR (CDCl3): δ 20.5–20.6 (4s, 4CH3),
62.0 (C-6ꢁꢁ), 68.3 (C-5ꢁꢁ), 70.3 (C-4ꢁꢁ), 72.7 (C-3ꢁꢁ), 94.2 (C-2ꢁꢁ), 94.4 (C-1ꢁꢁ),
113.6 (C-5), 115.3 (C-3), 116.5 (CN), 126.1 (CF3), 127.3–139.3 (aromatic),
162.3 (C-6), 155.7 (C-2), 158.4 (C-4), 168.9–170.6 (four acetoxy carbonyl
carbon); Anal.Calcd. for C33H29F3N2O10 (670.59): C, 59.11; H, 4.36; N,
4.18%, found: C, 59.18; H, 4.30; N, 4.12%.
Ammonolysis of (5a–e). Dry gaseous ammonia was passed through a so-
lution of acetylated nucleoside (5a–e, 0.5 g) in dry methanol (10 mL) at 0◦C
for about 0.5 hours. The mixture was stirred at 0◦C until the reaction was
judged complete by TLC. Then the residue was purified using column chro-
matography eluting with 2% CH3OH in CH2Cl2 to give after crystallization
in MeOH a white crystalline product (6a–e).
3-Cyano-1-(β-D-glucopyranosyl)-4-phenyl-2-pyridone (6a). White crystals;
yield 89%; m.p. 182◦C, from methanol; Rf = 0.35 (CH2Cl2), IR (KBr, cm−1)
1590 (CO), 2230 (CN), 3430 sugar-OH; [α]25 = 116.8◦ (c = 10.4 mg/ml,
methanol);1H NMR (DMSO-d6): δ 3.26–3.67 (m, 6H, H-2ꢁ, H-3ꢁ, H-4ꢁ, H-5ꢁ,
H-6ꢁa,H-6ꢁb), 4.57, 5.08, 4.15, 5.43 (4 sugar OH, exchangeable with D2O),

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
131
6.13–6.16 (d, 1H, H-1ꢁ, J = 7.4 Hz), 7.51–7.60 (m, 6H, aromatic), 7.73–7.76
(m, 2H), 7.88 (s, 1H, H-5), 8.22–8.27 (m, 2H);13C NMR (DMSO-d6): δ 60.6
(C-6ꢁ), 69.7 (C-5ꢁ), 72.9 (C-4ꢁ), 77 (C-3ꢁ), 78.0(C-2ꢁ), 96.6 (C-1ꢁꢁ), 92.8 (C-5),
114.9 (C-3), 115.0 (CN), 127.6–136.5 (aromatic), 156.8 (C-6), 157.4 (C-2),
162.9(C-4). Anal. Calcd. for C24H22N2O6 (434.44): C, 66.35; H, 5.10; N,
6.45; found: C, 65.99; H, 4.98; N, 6.41%.
3-Cyano-1-(β-D-glucopyranosyl)-6-phenyl-4-(2ꢁ-tolyl-2-pyridone
(6b). White
crystals; yield 95%; m.p. 163◦C, from methanol; Rf = 0.51 (CH2Cl2), IR
(KBr, cm−1) 1585 (CO), 2450 (CN), 3400 sugar-OH; [α]25 = 88◦ (c = 6.52
mg/ml, methanol);1H NMR (DMSO-d6): δ 2.52 (s, 3H, CH3), 3.36–3.66
(m, 6H, H-2ꢁꢁ H-3ꢁꢁ, H-4ꢁꢁ, H-5ꢁꢁ, H-6ꢁꢁa,H-6ꢁꢁb), 4.65, 4.95, 5.27(4 sugar OH,
exchangeable with D2O), 6.12–6.15 (d, 1H, H-1ꢁꢁ, J 1 -2 = 7.8 Hz), 7.39–7.57
ꢁꢁ ꢁꢁ
(m, 7H), 7.87 (s, 1H, H-5), 8.24–8.28 (m, 2H);13C NMR (DMSO-d6): δ 21.7
(s, CH3), 61.0 (C-6ꢁꢁ), 68.8 (C-5ꢁꢁ), 70.6 (C-4ꢁꢁ), 74.2 (C-3ꢁꢁ), 77.1 (C-2ꢁꢁ), 93.4
(C-1ꢁꢁ), 97.8 (C-5), 115.4 (C-3), 115.7 (CN), 126.4–139.0 (aromatic), 157.5
(C-6), 157.9 (C-2), 163.7 (C-4). Anal. Calcd. for C25H24N2O6 (448.47): C,
66.95; H, 5.39; N, 6.25%; found: C, 66.89; H, 5.37; N, 6.31%.
3-Cyano-1-(β-D-glucopyranosyl)-6-phenyl-4-(thiophen-2ꢁ-yl)-2-pyridone
(6c).
White crystals; yield 92%; m.p. 219◦C, from methanol; Rf = 0.34 (CH2Cl2),
IR (KBr, cm−1) 1595 (CO), 2300 (CN), 3445 sugar-OH; [α]25 = 202◦
1
(c = 8.4 mg/ml, methanol); H NMR (DMSO-d6): δ 3.25–3.68 (m, 6H,
H-2ꢁꢁ, H-3ꢁꢁ, H-4ꢁꢁ, H-5ꢁꢁ, H-6ꢁꢁa, H-6ꢁꢁb), 4.59, 5.09, 5.18, 5.42 (4 sugar OH,
exchangeable with D2O), 6.11–6.15 (d, 1H, H-1ꢁꢁ, J 1 -2 = 7.8 Hz), 7.32–7.37
ꢁꢁ ꢁꢁ
(dd, 1H, H-4ꢁ, J = 5.0 Hz, J = 3.4 Hz), 7.54–7.56 (m, 3H, aromatic), 7.97 (s,
1H, H-5), 7.98–7.99 (d, 1H, H-3ꢁ, J = 3.4 Hz), 8.03–8.06 (d, 1H, H-5ꢁ, J = 5.0
Hz), 8.22–8.27 (m, 2H, aromatic); 13C NMR (DMSO-d6): δ 60.5 (C-6ꢁꢁ), 69.6
(C-5ꢁꢁ), 72.7 (C-4ꢁꢁ), 76.9 (C-3ꢁꢁ), 78.0 (C-2ꢁꢁ), 90.4 (C-3), 96.7(C-1ꢁꢁ), 113.4
(C-5), 115.3 (CN), 127.6, 128.7, 129.0, 130.6, 130.9, 131.1, 136.3, 148.3
(C-6), 157.4 (C-2), 163.5 (C-4). Anal. Calcd. for C22H20N2O6S (440.47): C,
59.99; H, 4.58; N, 6.36; S, 7.28%; found: C, 60.10; H, 4.59; N, 6.20; S, 7.32%.
3-Cyano-6-(4ꢁ-chlorophenyl)-1-(β-D-glucopyranosyl)-4-(thiophen-2ꢁ-yl)-2-pyridone
(6d). White crystals; yield 86%; m.p. 250◦C, from methanol; Rf = 0.38
(CH2Cl2), IR (KBr, cm−1) 1645 (CO), 2240 (CN), 3440 sugar-OH; [α]25
=
331.2◦ (c = 8.8 mg/ml, methanol);1H NMR (DMSO-d6): δ 3.24–3.68 (m,
6H, H-2ꢁꢁ H-3ꢁꢁ, H-4ꢁꢁ, H-5ꢁꢁ, H-6ꢁꢁa,H-6ꢁꢁb), 4.59, 5.13, 5.19, 5.44 (4 sugar OH,
exchangeable with D2O), 6.08–6.12 (d, 1H, H-1ꢁꢁ, J 1 -2 = 7.4 Hz), 7.32–7.37
ꢁꢁ ꢁꢁ
(dd, 1H, H-4ꢁ, J = 5.0 Hz, J = 3.8 Hz), 7.59–7.63 (d, 2H, J = 10.6 Hz),
7.98–8.05 (m, 3H, H-5, H-3ꢁ, H-5ꢁ), 8.26–8.28 (d, 2H, J = 10.6 Hz); 13C NMR
(DMSO-d6): δ 60.6 (C-6ꢁꢁ), 69.6 (C-5ꢁꢁ), 72.8 (C-4ꢁꢁ), 76.9(C-3ꢁꢁ), 78.0 (C-2ꢁꢁ),
90.7 (C-5), 96.8 (C-1ꢁꢁ), 113.3(C-3), 115.2 (CN), 128.6, 129.1, 129.5, 130.8,
131.3, 135.2, 135.8, 136.4, 148.5 (C-6), 156.1 (C-2), 163.5 (C-4). Anal. Calcd.
for C22H19ClN2O6S (474.91): C, 55.64; H, 4.03; N, 5.90; S, 6.75%; found: C,
55.59; H, 3.99; N, 6.01; S, 6.64%.

132
S. S. Al-Neyadi et al.
3-Cyano-1-(β-D-glucopyranosyl)-6-phenyl-4-(2ꢁ-trifluoromethylphenyl)-2-pyridone
(6e). White crystals; yield 88%; m.p. 168◦C, from methanol; Rf = 0.87
(CH2Cl2), IR (KBr, cm−1) 1650 (CO), 2220 (CN), 3445 sugar-OH;
[α]25 = 100.6◦ (c = 8 mg/ml, methanol); 1H NMR (DMSO-d6): δ 3.24–3.69
(m, 6H, H-2ꢁꢁ H-3ꢁꢁ, H-4ꢁꢁ, H-5ꢁꢁ, H-6ꢁꢁa,H-6ꢁꢁb), 4.58, 5.10, 5.18, 5.44 (4
sugar OH, exchangeable with D2O), 6.15–6.18 (d, 1H, H-1ꢁꢁ, J 1 -2 = 7.4
ꢁꢁ ꢁꢁ
Hz), 7.54–7.55 (m, 3H), 7.97–7.99 (m, 5H, aromatic), 8.28–8.29 (m, 2H);
13C NMR (DMSO-d6): δ 60.5 (C-6ꢁꢁ), 69.6 (C-5ꢁꢁ), 72.7 (C-4ꢁꢁ), 76.9 (C-3ꢁꢁ),
78.0(C-2ꢁꢁ), 92.9 (C-3), 96.7(C-1ꢁꢁ), 114.7(C-5), 115.0 (CN), 125.7–139.8 (aro-
matic), 155.3 (C-6ꢁ), 157.7 (C-2), 162.8 (C-4). Anal. Calcd. for C25H21F3N2O6
(502.44): C, 59.76; H, 4.21; N, 5.58%; found: C, 59.65; H, 4.30; N, 5.59%.
Cell Viability Assay[18–21]
The human promyelocytic leukemia HL-60 cell line (ATCC, Manassas,
VA, USA) was grown in the DMEM medium (Gibco) supplemented with
20% fetal calf serum (Gibco, Carlsbad, CA, USA), 100 units/ml penicillin-
streptomycin (Gibco) and non-essential amino acid (Gibco). The cells were
maintained at 37◦C in 5% CO2 incubator. After reaching confluency, the
cells were subcultured into 96 wells culture plates, allowed to grow for
24 hours to a density of 4 × 103 cells and treated with different concen-
trations of compounds. The human promyelocytic leukemia HL-60 cells
were propagated by spinning at 1500 rpm for 3 minutes, changing the old
medium and then subcultured.
The effects of compounds (4a–i, 5a–d, and 6a–d) on cell viability was eval-
uated by the MTT [3-(4ꢁ,5ꢁ-dimethylthiazol-2ꢁ-yl)-2,5-diphenyltetrazolium
bromide] assay as described previously[18–21] and according to the manufac-
turer (Promega, Madison, WI, USA) instructions. Cells were plated in 96-well
plates at a density of 4× 103 cells/well/100 µL and incubated overnight in
DMEM medium with and without the compounds (4a–i, 5a-d, and 6a–d) at
concentrations of 100 and 200 µM for 24 hours. In parallel, the cells were
treated with 0.1% of SDS and DMSO as controls then, 10 nM of MTT (final
concentration of 0.5 mg/ml) was added to each well and incubated for 2–4
hours at 37◦C. This assay is a colorimetric assay for cell viability based on
the cellular cleavage of the yellow tetrazolium salt, MTT, into the purple
formazan crystals that is soluble in cell culture medium and the absorbance
is measured at 550 nm. Absorbance is directly proportional to the number
of living cells in culture. Cell viability was calculated as percent of the control
(untreated) cells.
CONCLUSION
This work led us to investigate three different ways to obtain 4,6-
disubistituted-3-cyano-2(1H)-pyridone and their glucosides (4–6a–e). We

Microwave Synthesis of 2(1H)-Pyridones and Their Glucosides
133
have reported one-pot synthesis using microwave to produce pyridine ana-
logues as an environmental and economically improved method. The sily-
ated method was used to produce nucleosides in competitive yields and
remains one of the best nucleosides’ synthetic strategies. Spectroscopic
techniques such as infrared and NMR were used to confirm structures
of the obtained products. The biological results done in vitro and have
shown that compounds containing trifluoromethyl or heteroaryl groups
at the 4-position possessed the highest anti-proliferation activities among
all synthesized analogues. In addition, different aryl groups at the 6-
position had similar activities. For example, 3-cyano-6-phenyl-4-(thiophen-
2ꢁ-yl)-2(1H)-pyridone (4d) and 3-cyano-6-(p-chlorophenyl)-4-(thiophen-2ꢁ-
yl)-2(1H)-pyridone (4e) have shown similar activities on cell viability. In
summary, the results presented in this paper indicate that compounds with
heteroaryl or trifluoromethyl groups substituted at the 4-position of the pyri-
dine ring may lead to a novel nucleosides with better bioactivity.
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