A facile solid-phase synthesis of 3,4,6-trisubstituted-2-pyridones using sodium benzenesulfinate as a traceless linker

Article abstract of DOI:10.1016/j.tetlet.2004.07.051

A facile and traceless solid-phase synthesis of 3,4,6-trisubstituted-2- pyridones has been developed using polystyrene sodium benzenesulfinate resin. The chemistry is applicable to combinatorial library synthesis.

Full text of DOI:10.1016/j.tetlet.2004.07.051

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6545–6547
A facile solid-phase synthesis of 3,4,6-trisubstituted-2-
pyridones using sodium benzenesulfinate as a traceless linker
Weiwei Li, Yu Chen and Yulin Lam*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 3 June 2004; revised 5 July 2004; accepted 13 July 2004
Abstract—A facile and traceless solid-phase synthesis of 3,4,6-trisubstituted-2-pyridones has been developed using polystyrene
sodium benzenesulfinate resin. The chemistry is applicable to combinatorial library synthesis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
One of the challenges of solid-phase synthesis of com-
pounds for drug discovery is developing synthetic routes
that provide access to the target compound without
leaving any trace of the tether that was used to link
the starting reagent to the solid support. This is because
complications may arise if these appendages are redun-
dant and affect the activities of the compounds. In this
regard, one of our interests is to develop the sulfone lin-
ker via polystyrene/1% divinylbenzene sodium sulfinate
1 as a traceless linker and to explore its new applications
in solid-phase organic synthesis (SPOS). Earlier reports
from other laboratories1 and ours2 have demonstrated
the use of 1 as a solid support for SPOS and have shown
the resulting sulfone linker derived from 1 to be a versa-
tile and robust tether that offers a variety of on-resin
functionalization or cleavage with additional changes.
our knowledge, only one of these reports concerns the
traceless preparation of these compounds. In this report,
4-pyridones were prepared through condensation of
resin-bound acylpyridiniums with Grignard reagents.11e
We herein report the application of 1 for the convenient
traceless syntheses of 2-pyridones. The key steps in our
synthesis include (i) sulfinate S-alkylation, (ii) sulfone
anion alkylation with an epoxide, (iii) c-hydroxyl sulf-
one!c-ketosulfone oxidation and (iv) traceless product
release by a one-pot elimination–cyclization process
(Scheme 1).
Polystyrene/1% divinylbenzene sodium benzenesulfinate
(1) in NBu4I/KI/DMF was reacted with an alkyl or aryl
bromide at room temperature. The formation of 2 was
easily monitored by IR spectroscopy for the appearance
of the sulfone stretches (2a: masym 1313.5cmꢀ1 and
msym 1150.4cmꢀ1). Alkylation of 2 with an alkyl or aryl
epoxide gave 3, which could not be reliably analyzed by
IR spectroscopy. Hence we proceeded to oxidize 3 with
the JonesÕ reagent to give resin 4. This transformation
was monitored by IR spectroscopy for the appearance
of the carbonyl stretch (4a: mmax 1687.7cmꢀ1). Treat-
ment of 4 with potassium tert-butoxide/DMSO and 2-
cyanoacetamide in air at 50ꢁC gave 3-cyano-2-pyridones
in 28–48% overall yields.12 Similarly, reactions with mal-
onamide or methyl malonate monoamide gave pyridine-
3-carboxylic acids and pyridine-3-carboxylic acid
amides in 20–49% overall yields. However, in the cases
of 4f and 4i, where R1 and R2 are both alkyl groups,
it was observed that reactions at 50ꢁC gave the interme-
diates, 6-hydroxy-6-methyl-2-oxo-4-propyl-piperidine-
3-carbonitrile13 and 6-hydroxy-6-methyl-2-oxo-4-propyl-
piperidine-3-carboxylic acid, respectively. Aromatization
2-Pyridones represent a unique class of pharmacophore,
which are observed in various therapeutic agents3 and
antibiotics.4 They are also versatile precursors for the
construction of complex natural products,5 pyridines6
and larger pyridone systems such as those found in the
nitroguanidine insecticide Imidacloprid7 and subtype
selective GABAA receptor agonists.8 Consequently,
methodologies for the preparation of pyridones have at-
tracted much attention from both industry and acade-
mia, and various solution-phase syntheses of these
compounds have been reported.9,10 In recent years, syn-
thetic methods for the preparation of 2- and 4-pyridones
on solid-phase have also been examined.11 To the best of
Keywords: 2-Pyridones; Sodium benzenesulfinate; Traceless.
*
Corresponding author. Tel.: +65-6874-2688; fax: +65-6779-1691;
e-mail: chmlamyl@nus.edu.sg
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.051

6546
W. Li et al. / Tetrahedron Letters 45 (2004) 6545–6547
O
O
O
O
O
BrCH2R1
NBu4I, KI,
DMF, rt
LiCH2SCH3
R1
OH
R2
R1
S
S
SO2Na
O
1
R2
3
2
O
Jones' reagent,
acetone, 0oC
O
O
t-BuOK, DMSO
X
R1
S
HN
R2
O
O
R1
X
H2N
R2
4
5
X = CN, COOH, CONH2
Scheme 1.
was achieved only when the reaction mixtures were
heated at 70ꢁC. It was noted that for combinations
where R2 is an alkyl group, the corresponding 2-pyr-
idones were obtained in lower yields. This would be
expected as the protons on these methyl groups are
acidic and could readily be removed under basic condi-
tions to generate enolates which, in turn, could undergo
side-reactions.
gents can be used in steps (i), (ii) and (iv), the overall
strategy is applicable for library generation.
References and notes
1. (a) Cheng, W. C.; Kurth, M. J. J. Org. Chem. 2002, 67,
4387–4391; (b) Cheng, W. C.; Wong, M.; Olmstead, M.
M.; Kurth, M. J. Org. Lett. 2002, 4, 741–744; (c) Cheng,
W. C.; Lin, C. C.; Kurth, M. J. Tetrahedron Lett. 2002, 43,
2967–2970; (d) Cheng, W. C.; Olmstead, M. M.; Kurth,
M. J. J. Org. Chem. 2001, 66, 5528; (e) Cheng, W. C.;
Halm, C.; Evarts, J. B.; Olmstead, M. M.; Kurth, M. J. J.
Org. Chem. 1999, 64, 8557; (f) Halm, C.; Evarts, J.; Kurth,
M. J. Tetrahedron Lett. 1997, 38, 7709–7712; (g) Huang,
W.; Cheng, S.; Sun, W. Tetrahedron Lett. 2001, 42,
1973–1974; (h) Farrall, M. J.; Frechet, J. M. J. Org. Chem.
1976, 41, 3877; (i) Fyles, T. M.; Leznoff, C. C. Can. J.
Chem. 1976, 54, 935; (j) Fyles, T. M.; Leznoff, C. C. Can.
J. Chem. 1978, 56, 1031.
To provide an additional diversity in this library, we
carried out the elimination–cyclization process under
nitrogen. Decyanative aromatization due to Ôoxygen
starvationÕ occurred and 2-pyridones (5l–o) were
obtained exclusively (Table 1).
In summary, this letter demonstrates a general protocol
for the regiospecific solid-phase synthesis of 3,4,6-trisub-
stituted-2-pyridone derivatives using polystyrene/1%
divinylbenzene sodium sulfinate as a traceless linker.
Product 5 precipitated from water under acidic condi-
tions and could be expediently purified without the need
for column chromatography.12 Since a variety of rea-
2. (a) Chen, Y.; Lam, Y. L.; Lai, Y. H. Org. Lett. 2003, 5,
1067–1069; (b) Chen, Y.; Lam, Y. L.; Lai, Y. H. Org. Lett.
2002, 4, 3935–3937; (c) Chen, Y.; Lam, Y. L.; Lee, S. Y.
Chem. Lett. 2001, 3, 274–275.
3. (a) Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.;
Bromidge, F. A.; Quirk, K.; Atack, J. R.; McKernan, R.
M.; Thompson, S. A.; Wafford, K.; Dawson, G. R.; Pike,
A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro, J. L. J.
Med. Chem. 2002, 45, 1887–1900; (b) Saiki, A. Y. C.;
Shen, L. L.; Chen, C. M.; Baranowski, J.; Lerner, C. G.
Antimicrob. Agents Chemother. 1999, 43, 1574–1577; (c)
Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. Rev. 2000,
231–293.
4. Brickner, S. Chem. Ind. 1997, 131.
5. Kawato, Y.; Terasawa, H. Prog. Med. Chem. 1997, 34,
69–109.
6. Murray, T.; Zimmerman, S. Tetrahedron Lett. 1995, 36,
7627–7630.
7. Werbitzky, O.; Studer, P. U.S. Patent 6,022,974, Feb 9,
2000; Chem. Abstr. 2095953.
8. Harrison, T.; Moyes, C. R.; Nadin, A.; Owens, A. P.;
Lewis, R. T. PCT WO 98/50384.
9. Charles, L.; Kesavaram, N.; Penlou, S.; Rousset, L.;
Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67,
4303–4308.
Table 1. Solid-phase synthesis of 3,4,6-trisubstituted-2-pyridones
Entry
X
R1
R2
% Yielda
5a
5b
5c
5d
5e
5f
CN
CN
Ph
Ph
Ph
43
45
48
29
28
14b
46
20
12b
49
26
49
44c
28
25
p-BrPh
p-MeOPh
Ph
CN
CN
Ph
Me
Me
Me
Ph
CN
CN
p-MeOPh
CH3CH2CH2
Ph
5g
5h
5i
COOH
COOH
COOH
CONH2
CONH2
H
Ph
Me
Me
Ph
CH3CH2CH2
Ph
Ph
5j
5k
5l
Me
Ph
Ph
5m
5n
5o
H
p-BrPh
Ph
p-BrPh
Ph
H
Me
Me
H
ˆ
10. Cherry, K.; Abarbri, M.; Parrain, J.-L.; Duchene, A.
a Purified yield calculated based on original loading of the resin.
Purities were >97% as evaluated by NMR.
b Yield obtained after further purification by flash chromatography.
c Crystallographic data (excluding structure factors) of 5m have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 239935.
Tetrahedron Lett. 2003, 44, 5791–5794, and references
cited therein.
11. (a) Katritzky, A. R.; Chassaing, C.; Barrow, S. J.; Zhang,
Z.; Vvedensky, V.; Forood, B. J. Comb. Chem. 2002, 4,
249–250; (b) Wang, Y.; Wilson, S. R. Tetrahedron Lett.
1997, 38, 4021–4024; (c) Chen, C.; McDonald, I. A.;

W. Li et al. / Tetrahedron Letters 45 (2004) 6545–6547
6547
Munoz, G. Tetrahedron Lett. 1998, 39, 217–220; (d) Far,
A. R.; Tidwell, T. T. J. Org. Chem. 1998, 63, 8636–8637;
(e) Chen, C.; Munoz, B. Tetrahedron Lett. 1998, 39,
6781–6784; (f) Gorsche, P.; Ho¨ltzel, A.; Walk, T. B.;
Trautwein, A. W.; Jung, G. Synthesis 1999, 1961–1970.
12. Typical experimental procedure: Resin 1 (2.1mmol/g, 100–
200 mesh) was obtained from Tianjin Nankai Hecheng
Science and Technology Co Ltd, China. The resin (1g)
was swollen under nitrogen in 20mL DMF for 30min.
Alkyl or aryl bromide (5equiv), KI (5equiv) and tetrabut-
ylammonium iodide (1equiv) were added and the mixture
was shaken at room temperature for 24h. The resin was
then filtered and washed sequentially with DMF
(20mL · 2), H2O (20mL · 2), ethanol (20mL · 2),
CH2Cl2 (20mL · 2) and diethyl ether (20mL · 2), and
dried overnight in a vacuum oven at 40ꢁC to afford resin
2. n-BuLi (5equiv) was added to DMSO (10equiv) in THF
(10mL), at 0ꢁC, and the mixture was stirred for 5min. The
resulting dimsyl anion solution was transferred to a
suspension of resin 2 (0.3g, 1equiv) in THF (8mL) at
room temperature and the mixture was shaken for 1h.
Epoxide (8equiv) was added and the mixture was shaken
for a further 12h, after which, the reaction was quenched
with 10% HCl and filtered. The resin was washed
sequentially with DMF (20mL · 2), H2O (20mL · 2),
ethanol (20mL · 2), CH2Cl2 (20mL · 2) and diethyl ether
(20mL · 2), and dried overnight in a vacuum oven at
40ꢁC to afford resin 3. JonesÕ reagent (10equiv) was added
to a suspension of resin 3 (0.3g, 1equiv) in acetone (8mL),
at 0ꢁC, and the mixture was shaken for24 h. The resin was
filtered and washed sequentially with H2O (20mL · 2),
CH2Cl2 (20mL · 2) and diethyl ether (20mL · 2), and
dried overnight in a vacuum oven at 40ꢁC to afford resin 4
as light green coloured beads. Resin 4 (1g) was swollen in
20mL DMSO for 1h. t-BuOK (9equiv) and the amide
(12equiv) were added and the resulting mixture was
heated at 50ꢁC in air for a further 8h, after which the resin
was filtered and washed with DMF (5mL · 2) and H2O
(5mL · 2). The combined washings were diluted with H2O
(80mL) and 2M HCl was added until pH2 was achieved.
The precipitate formed was filtered, washed with water
and dried under vacuum to give 5. Compounds 5a,14 5e14
and 5l9 have been reported previously.14 5b: 1H NMR
(300MHz, DMSO-d6): d 6.83 (s, 1H, CH), 7.53 (m, 3H,
ArH), 7.69 (m, 2H, ArH), 7.76 (m, 2H, ArH), 7.87 (m, 2H,
ArH), 12.60 (br, 1H, NH). 13C NMR (500MHz, DMSO-
d6): 162.1, 160.9, 131.4, 130.1, 128.6, 127.5, 126.7, 123.7,
116.5, 103.7, 95.4. HRMS (EI): Calcd for C18H11BrN2O
350.0055, Found 350.0050. 5c: 1H NMR (300MHz,
DMSO-d6): d 3.85 (s, 3H, OCH3), 6.79 (s, 1H, CH), 7.12
(d, J = 8.7Hz, 2H, MeOArH), 7.55 (m, 3H, ArH), 7.74 (d,
J = 8.7Hz, 2H, MeOArH), 7.90 (m, 2H, ArH), 12.70 (br,
1H, NH). 13C NMR (500MHz, DMSO-d6): 162.2, 161.1,
159.2, 151.0, 132.3, 131.1, 129.9, 128.9, 127.7, 116.8, 114.2,
105.9, 97.5, 55.4. HRMS (EI): Calcd for C19H14N2O2
302.1055, Found 302.1052. 5d: 1H NMR (300MHz,
DMSO-d6): d 2.31 (s, 3H, CH3), 6.33 (s, 1H, CH), 7.55
(m, 5H, ArH), 12.5 (br, 1H, NH). 13C NMR (500MHz,
DMSO-d6): 161.4, 160.1, 152.2, 136.1, 130.3, 128.8, 127.9,
116.6, 106.5, 97.3, 19.1. HRMS (EI): Calcd for
C13H10N2O: 210.0793, Found 210.0789. 5f: 1H NMR
(300MHz, CDCl3): d 0.98 (t, J = 7.3Hz, 3H, CH3), 1.68
(m, 2H, CH2), 2.39 (s, 3H, CH3), 3.11 (m, 2H, CH2), 6.27
(s, 1H, CH), 13.1 (br s, 1H, NH). 13C NMR (500 MHz,
CDCl3): 160.7, 160.5, 152.1, 135.9, 106.8, 97.6, 36.9, 24.1,
19.4, 14.8. HRMS (EI): Calcd for C10H12N2O 176.0950,
Found 176.0951. 5g: 1H NMR (300MHz, DMSO-d6): d
6.71 (s, 1H, CH), 7.46 (m, 8H, ArH), 7.87 (m, 2H, ArH),
12.99 (br, 1H, COOH). 13C NMR (500MHz, DMSO-d6):
166.5, 162.5, 153.0, 148.1, 138.4, 132.9, 130.4, 128.9, 128.3,
127.6, 127.4, 118.3, 107.9. HRMS (EI): Calcd for
C18H13NO3 291.0895, Found 291.0894. 5h: 1H NMR
(300MHz, DMSO-d6): d 1.89 (s, 3H, CH3), 6.41 (s, 1H,
CH), 7.45 (m, 3H, ArH), 7.65 (m, 2H, ArH), 12.78 (br,
1H, COOH). 13C NMR (500MHz, DMSO-d6): 164.1,
163.1, 161.2, 136.9, 136.5, 126.7, 126.5, 126.1, 117.4, 103.9,
21.2. HRMS (EI): Calcd for C13H11NO3 229.0739, Found
229.0738. 5i: 1H NMR (300MHz, CDCl3): d 1.05 (t,
J = 7.3Hz, 3H, CH3), 1.75 (m, 2H, CH2), 2.29 (s, 3H,
CH3), 3.21 (m, 2H,CH2), 6.92 (s, 1H, CH), 11.28 (br, 1H,
NH), 15.13 (br s, 1H, COOH). 13C NMR (500MHz,
CDCl3): 166.9, 165.4, 165.1, 138.3, 116.5, 110.5, 37.5, 23.8,
19.5, 14.9. HRMS (EI): Calcd. for C10H13NO3 195.0895,
1
Found 195.0897. 5j: H NMR (300MHz, DMSO-d6): d
4.87 (m, 2H, NH2), 6.66 (s, 1H, CH), 7.49 (m, 6H, ArH),
7.73 (m, 2H, ArH), 7.81 (m, 2H, ArH), 11.95 (br, 1H,
NH). 13C NMR (500MHz, DMSO-d6): 167.4, 163.7,
161.2, 151.8, 149.6, 138.5, 129.9, 128.8, 128.7, 128.5,
128.2, 127.8, 127.0, 106.8. HRMS (EI): Calcd for
C18H14N2O2 290.1055, Found 290.1053. 5k: 1H NMR
(300MHz, DMSO-d6): d 2.19 (s, 3H, CH3), 4.91 (m, 2H,
NH2), 6.50 (s, 1H, CH), 7.41 (m, 3H, ArH), 7.58 (m, 2H,
ArH), 11.83 (br, 1H, NH). 13C NMR (500MHz, DMSO-
d6): 167.4, 164.8, 161.1, 137.5, 136.9, 128.7, 128.5, 128.1,
127.9, 104.6, 19.3. HRMS (EI): Calcd for C13H12N2O2
228.0899, Found 228.0894. 5m: 1H NMR (300MHz,
DMSO-d6): d 6.68 (m, 1H, CH), 7.00 (m, 1H, CH), 7.49
(m, 3H, ArH), 7.67 (m, 2H, ArH), 7.70 (m, 2H, ArH), 7.89
(m, 2H, ArH), 11.7 (br, 1H, NH). 13C NMR (500MHz,
DMSO-d6): 167.0, 155.4, 148.1, 137.1, 133.3, 131.6, 130.3,
129.9, 127.9, 125.3, 114.6, 107.4. HRMS (EI): Calcd for
C17H12BrNO 325.0102, Found 325.0101. 5n: 1H NMR
(300MHz, DMSO-d6): d 2.22 (s, 3H, CH3), 6.34 (m, 1H,
CH), 6.37 (m, 1H, CH), 7.47 (m, 3H, ArH), 7.65 (m, 2H,
ArH), 11.6 (br, 1H, NH). 13C NMR (500MHz, DMSO-
d6): 163.3, 151.9, 145.8, 137.5, 129.3, 128.9, 126.6, 112.7,
103.1, 18.8. HRMS (EI): Calcd for C12H11NO 185.0841,
Found 185.0839. 5o: 1H NMR (300MHz, DMSO-d6): d
2.22 (s, 3H, CH3), 6.33 (m, 2H, CH), 7.64 (m, 4H, ArH),
11.6 (br, 1H, NH). 13C NMR (500MHz, DMSO-d6):
163.2, 150.5, 146.0, 136.6, 131.8, 128.7, 122.7, 112.7, 102.7,
18.7. HRMS (EI): Calcd for C12H10BrNO 262.9946,
Found 262.9945.
13. Crystallographic data (excluding structure factors) of the
intermediate, 6-hydroxy-6-methyl-2-oxo-4-propyl-piper-
idine-3-carbonitrile, have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication number CCDC 239936.
14. Jain, R.; Roschangar, F.; Ciufolini, M. A. Tetrahedron
Lett. 1995, 36, 3307–3310.