A novel synthesis of 2,3-disubstituted-4-pyridones from 4-methoxypyridine

Article abstract of DOI:10.1246/cl.2006.712

Novel 2,3-disubstituted 4-pyridone derivatives were prepared from 4-methoxypyridine through aldol condensation and isomerization of exo-olefin as key reactions, in fairly good to high yields. Copyright

Full text of DOI:10.1246/cl.2006.712

712
Chemistry Letters Vol.35, No.7 (2006)
A Novel Synthesis of 2,3-Disubstituted-4-pyridones from 4-Methoxypyridine
Hideo Kitagawa,ꢀ Ko Kumura, and Kunio Atsumi
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567
(Received April 3, 2006; CL-060391; E-mail: hideo kitagawa@meiji.co.jp)
Novel 2,3-disubstituted 4-pyridone derivatives were pre-
Cl
Cl
Cl
Cl
O
N
OMe
N
OTBS
N
O
N
pared from 4-methoxypyridine through aldol condensation and
isomerization of exo-olefin as key reactions, in fairly good to
high yields.
a, b
d
c
CO2Bn
CO2Bn
2
3
Cl
4
Cl
Cl
4-Pyridone derivatives are important as synthetic intermedi-
ates for the preparation of natural products and as biologically
active compounds.1 We have been screening our compound li-
brary for enoyl-ACP reductase (FabI)2 inhibitors as antibacterial
agents. And we found a novel 4-pyridone derivative 1 as a FabI
inhibitor. Compound 1 exhibited not only FabI-inhibitory activ-
ity, but also antibacterial activity against Staphylococcus aureus.
For structure optimization studies, we required a convenient
and accessible method to synthesize a range of 4-pyridone deriv-
atives. The conventional methods can be roughly classified as
follows: (1) cyclization of triketones,3 (2) reaction of primary
and secondary enamines with diketene,4 and (3) conversion of
natural products, such as maltol or kojic acid, in the presence
of an appropriate amine.5 Though a number of synthetic methods
have been reported for 4-pyridone derivatives, it is still difficult
to prepare 2,3-disubstituted 4-pyridones because the methods
generally need multiple steps or involve troublesome intermedi-
ates, such as triketones. Here, we would like to report a conven-
ient method for synthesizing a wide range of 2,3-disubstituted
4-pyridone derivatives.
We planned to use N-acylated 2,3-dihydropyridine-4(1H)-
ones as synthetic intermediates.6 The racemic 2,3-dihydropyri-
dine-4(1H)-ones can be easily prepared by the addition of orga-
nometallics such as Grignard reagent to 1-acyl-4-methoxypyri-
dinium salts.7 2,3-Dihydropyridine-4(1H)-one 28 was prepared
in 94% yield from commercially available 4-methoxypyridine,
by introduction of the methyl group into 4-methoxypyridine
via nucleophilic addition using methylmagnesium bromide in
the presence of carbobenzyloxy chloride.9 Compound 3 was
prepared from the lithium enolate of 2 with 2,6-dichlorobenzyl
bromide. Although we examined several methods for oxidation
of compound 3, aromatization reaction did not occur. We finally
found that dehydrogenation of the TBS enol ether of compound
4 with DDQ afforded compound 5 in 34% yield. 4(1H)-Pyridone
5 was treated with benzyl bromide in the presence of NaH in
DMF, to afford 1 in 37% yield. The overall yield was only 8%
from compound 2 (Scheme 1). Since these synthetic methods
have multiple steps and low overall yield, we considered the syn-
thesis of 3-(1-hydroxyalkyl)-2,3-dihydro-4-pyridone 6 by using
the aldol reaction with 2. The reaction of 2 with 2,6-dichloro-
benzaldehyde was carried out in THF at ꢁ78 ꢂC in the presence
of lithium hexamethyldisilazide and the corresponding aldol ad-
duct 6 was obtained in 95% yield. The hydroxy group of com-
pound 6 was converted into methanesulfonylate by treatment
with methanesulfonyl chloride under ice cooling in 94% yield.
Elimination of the methanesulfonyloxy group and isomerization
O
O
e
f
Cl
N
N
H
Bn
5
1
Reagents: (a) BnOCOCl (1 equiv.), CH3MgBr (1.2 equiv.), THF, -25
°C; (b) 3 M HCl, r.t. (94% for two steps); (c) 2,6-
dichlorobenzyl bromide (1.5 equiv.), LiHMDS (1.2 equiv.), THF, 0 °C
(95%); (d) TBSOTf (1.5 equiv.), Et3N (2 equiv.), CH2Cl2, 0 °C to r.t.
(71%); (e) DDQ (1.2 equiv.), NaHCO3 (1.2 equiv.), 1,4-dioxane, r.t.
(34%); (f) BnBr (1.5 equiv.), NaH (1.5 equiv.), DMF, r.t. (37%);
Overall yield was 8% from compound 2 to 5 (4 steps).
Scheme 1. Synthesis of compound 1.11
of the exo-olefin by using potassium tert-butoxide gave the
desired 4(1H)-pyridone 5 in 82% yield (two steps).
As described previously, the 1-benzyl-4-pyridone was ob-
tained in 37% yield, together with 4-benzyloxypyridine in
25% yield, using DMF in the presence of sodium hydride
(Scheme 1). The desired 1-benzylated 4-pyridone was prepared
in 92% yield by changing the reaction solvent from DMF
to THF. Compound 1 was obtained in 67% overall yield
(Scheme 2).
However, when the above methods were applied to aliphatic
aldehydes, the desired 4(1H)-pyridones were not obtained at all.
Since the exo-olefin 810 was isolated from the reaction mixture
(E:Z = 1:4), we examined isomerization of the exo-olefin to
form the 4(1H)-pyridone. The desired 4(1H)-pyridone 9 was ob-
tained in high yield through isomerization of 8 by using catalytic
palladium under a hydrogen atmosphere (Scheme 3). Therefore,
it was possible to prepare a wide range of 2,3-disubstituted
4(1H)-pyridones by using the two procedures.
Finally, these methods were applied to prepare the 2,3-di-
substituted 4(1H)-pyridone derivatives listed in Table 1. The
Cl
Cl
Cl
Cl
Cl
O
O
O
O
HO
d
b, c
a
Cl
N
N
H
N
N
Bn
CO2Bn
CO2Bn
2
6
5
1
Reagents: (a) 2,6-dichlorobenzaldehyde (1.3 equiv.), LiHMDS (1.1
equiv.), THF, -78 °C (98%); (b) MsCl (2 equiv.), pyridine, 0 °C to r.t.
(94%); (c) tBuOK (3 equiv.), THF, 0 °C (87%); (d) BnBr (1.3 equiv.),
NaH (1.3 equiv.), THF, r.t. (92%); Overall yield was 67% from
compound 2 to 5 (4 steps).
Scheme 2. Improved synthesis method of compound 1.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.7 (2006)
713
Yasue, N. Kawamura, J. Sakakibara, Yakugaku Zasshi
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O
O
O
OH
a, b
c
N
H
N
N
CO2Bn
8
CO2Bn
9
7
Reagents: (a) MsCl (2 equiv.), pyridine, 0 °C to r.t. (94%); (b) DBU (1.5
6
7
equiv.), THF, r.t. (85%); (c) H2, 10%Pd/C (cat.), r.t. (93%).
Scheme 3. Isomerization of 8 to 9 by using Pd/C.
Table 1. Synthesis of 3-substituted 4(H)-pyridone derivatives
O
O
OH
O
LiHMDS
(1.1 equiv.)
1)MsCl (2 equiv.), Py
2)tBuOK (3 equiv.)
or DBU(1.5 equiv.),
Pd/C (cat.), H2
R
R
+
8
9
RCHO
(1.3 equiv.)
N
N
N
H
B
CO2Bn
CO2Bn
A
When the other Grignard reagents such as ethylmagnesium
or butylmagnesium bromide were used for addtion of 4-
methoxypyridine, desired 2,3-dihydropyridines were ob-
tained 81 or 99%, respectively. Each 4-pyridone derivative
obtained through aldol condensation and isomerization of
exo-olefin in 11 or 22% total yield.
Yield/%c
Yield/%c
A
Entry
R
Entry
R
A
B
B
1a
2a
N
36, 75
48, 77
6a
7a
S
97, 79
79, 37
Cl
N
N
Cl
10 The aldol adduct 7 that was similarly prepared (Scheme 2)
was treated with DBU under mild reaction conditions to
afford compound 8.
3a
4a
5a
98, 82
Cl
Me
8b
9b
97, 57
11 A typical experimental procedure is as follows; to a solution
of 28 (5.0 g, 20.4 mmol) in THF (60 mL) at ꢁ78 ꢂC was add-
ed 1 M lithium bis(trimethylsilyl)amide in THF (22.4 mL).
The resulting mixture was stirred at 0 ꢂC for 30 min and
cooled to ꢁ78 ꢂC, then a solution of 2,6-dichlorobenzalde-
hyde (4.64 g, 26.5 mmol) was added and stirring was contin-
ued at ꢁ78 ꢂC for 1 h. The mixture was poured into saturated
NH4Claq (200 mL). Usual work-up and separation by
column chromatography on silica gel afforded 3 (8.4 g,
98%) as a colorless oil. Next, to a solution of the prepared
3 (1.61 g, 3.83 mmol) in pyridine (10 mL) at 0 ꢂC was added
mesyl chloride (0.445 mL, 5.75 mmol). The resulting mix-
ture was stirred at room temperature for 3 h then poured into
water (150 mL). Usual work up and separation by column
chromatography on silica gel gave 4 (1.79 g, 94%) as a
colorless oil. To a solution of 4 (1.00 g, 2.01 mmol) in
THF (35 mL) was added potassium tert-butoxide (1.13 g,
10.0 mmol). The resulting solution was stirred at room tem-
perature for 10 min then poured into 5% NH4Claq (100 mL).
Usual work up and separation by column chromatography on
silica gel afforded 5 (469 mg, 87%) as a white powder. Final-
ly, to a solution of 5 (100 mg, 0.373 mmol) in THF (3 mL)
was added sodium hydride (19.4 mg, 0.485 mmol as a 60%
dispersion in mineral oil), followed by benzyl bromide
(0.0577 mL, 0.485 mmol). The reaction mixture was stirred
at room temperature for 3 h, then diluted with ethyl acetate
and washed with 5% NaClaq. Usual work up and separation
by column chromatography on silica gel gave 1 (123 mg,
90, 41
78, 32
Me
nPr
quant, 70
N
aPotassium tert-butoxide was used. bDBU and Pd/C, H2 was
used. Isolated yield.
c
desired 2,3-disubstituted 4(1H)-pyridones were obtained in fair-
ly good yields.
Thus, we have developed a new and efficient method to pre-
pare various 2,3-disubstituted 4-pyridones from 4-methoxypyri-
dine through aldol condensation and isomerization of exo-olefin
as key reactions, in good to high yields. Further studies on 4-
pyridones, including 5- and 6-substituted derivatives, are in
progress.
References and Notes
1
2
3
H. Tieckelmann, in Pyridine and its Derivatives, ed. by R. A.
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1963, 28, 725. b) M. L. Miles, T. M. Harris, C. R. Hauser,
J. Org. Chem. 1965, 30, 1007. c) T. M. Harris, S. Boatman,
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E. Ziegler, I. Herbst, T. Kappe, Monatsh. Chem. 1969, 100,
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For examples: a) M. A.-F. Elkaschef, M. H. Nosseir, A.
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H. C. Smitherman, J. Org. Chem. 1961, 26, 2987. d) M.
4
5
1
92%) as a white solid: H NMR (400 MHz, CDCl3) ꢀ 1.98
(3H, s), 4.36 (2H, s), 5.01 (2H, s), 6.38 (1H, d, J ¼
7:6 Hz), 6.96–7.06 (3H, m), 7.21–7.39 (6H, þm): HRMS
(FABþ) m=z: calcd for C20H18Cl2NO ðM þ HÞ : 358.0765,
found: 358.0775.
Published on the web (Advance View) May 30, 2006; doi:10.1246/cl.2006.712