An efficient approach to 3,4-disubstituted pyridin-2-ones. Formal synthesis of mappicine ketone

Article abstract of DOI:10.1021/jo034042s

Treatment of 3,4-dihydro-3-tosylpyridin-2-one 5 with sodium hydride and then alkyl halides gave various 3,4-disubstituted pyridin-2-ones 6. Formal synthesis of mappicine ketone (1) was also reported.

Full text of DOI:10.1021/jo034042s

An Efficien t Ap p r oa ch to 3,4-Disu bstitu ted P yr id in -2-on es. F or m a l
Syn th esis of Ma p p icin e Keton e
Ching H. Lin, Min R. Tsai, Yung S. Wang, and Nein C. Chang*
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan 804, Republic of China
ncchang@mail.nsysu.edu.tw
Received J anuary 14, 2003
Treatment of 3,4-dihydro-3-tosylpyridin-2-one 5 with sodium hydride and then alkyl halides gave
various 3,4-disubstituted pyridin-2-ones 6. Formal synthesis of mappicine ketone (1) was also
reported.
SCHEME 1
Six-membered nitrogen containing heterocycles has
been intensively studied in the synthesis of alkaloids, and
a great number of them have significant biological
activities.1,2 It is well-known that the pyridin-2-one ring
system is a valuable building block in natural product
synthesis.3 Numerous methods for the preparation of
substituted pyridin-2-one had been reported in the
literature.4
In this paper, we described an efficient access to a
variety of 3,4-disubstituted pyridin-2-ones 6, which ex-
isted in many alkaloids such as mappicine ketone 15 and
camptothecin 2.6 A formal synthesis of mappicine ketone
1 is also reported.
3 with sodium hydride and then with lithium aluminum
hydride could regioselectively reduce various 3-sulfonyl
glutarimides 3 to hydroxy piperidones 4, which were
further dehydrated to 3,4-dihydro-3-tosylpyridin-2-one 5
in the presence of boron trifluoride (Scheme 1).8
Herein, we further developed an efficient approach to
3,4-disubstituted pyridin-2-ones 6 starting from 5. As
shown in Scheme 2, reaction of 3,4-dihydro-3-tosylpyri-
din-2-one 5 with 2.2 equiv of sodium hydride at 25 °C in
THF for 5 min, the resulting anion reacted with a variety
of alkyl halides to afford the corresponding 3,4-disubsti-
tuted pyridin-2-ones 6 in good yield, presumably after
alkylation, and dehydrosulfonation then followed (Scheme
2). Several examples were examined, and the results are
listed in Table 1.
Previously, we reported an efficient route to the
unsymmetrical glutarimides 3 with a sulfonyl group at
the C-3 position.7 We further discovered that reaction of
* To whom correspondence should be addressed. Telephone: (+886)-
75253913. Fax: (+886)-75253913.
(1) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure, Prepara-
tion, Reactivity, and Synthetic Applications of Piperidine and its
Serivatives; Elsevier: Amsterdam, 1991.
(2) Strunz, G. M.; Findlay, J . A. The Alkaloids; Academic Press:
New York, 1985; Vol. 26, p 89. Southon, I. W.; Buckingham, J .
Dictionary of Alkaloids; Chapman and Hall: London, 1989. Daly, J .
W. J . Nat. Prod. 1998, 61, 162.
(3) (a) Comins, D. L.; Hong, H.; Saha, J . K.; J ianhua, G. J . Org.
Chem. 1994, 59, 5120. (b) Comins, D. L.; Hong, H.; J ianhua, G.
Tetrahedron Lett. 1994, 35, 5331. (c) Bernstein, P. R.; Gomes, B. C.;
Kosmider, B. J .; Vacek, E. P.; Williams, J . C. J . Med. Chem. 1995, 38,
212. (d) Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.; Saxena,
A.; Doctor, B. P. J . Am. Chem. Soc. 1996, 118, 11357. (e) Williams, D.
R.; Lowder, P. D.; Gu, Y.-G. Tetrahedron Lett. 1997, 38, 327.
(4) For recent examples of the synthesis of functionalized 2-pyri-
dones, see: (a) Bondavalli, F.; Bruno, O.; Presti, E. L.; Menozzi, G.;
Mosti, L. Synthesis 1999, 1169. (b) Perrin, S.; Monnier, K.; Laude, B.;
Kubicki, M.; Blacque, O. Eur. J . Org. Chem. 1999, 297, 7. (c) Furukawa,
I.; Fujisawa, H.; Kawazome, M.; Nakai, Y.; Ohta, T. Synthesis 1998,
1715. (d) Ciufolini, M. A.; Bouchu, D.; Rousset, L.; Penlou, S.;
Narkunan, K.; Carles, L. J . Org. Chem. 2002, 67, 4304. (e) Shimizu,
M.; Ogura, K.; Hachiya, I. Org. Lett. 2002, 4 (16), 2755.
(5) For recent examples of the synthesis of mappicine ketone, see:
(a) Comins, D. L.; Saha, J . K. J . Org. Chem. 1996, 61, 9623. (b) J osien,
H.; Curran, D. P. Tetrahedron 1997, 53, 8881. (c) Boger, D. L.; Hong,
J . J . Am. Chem. Soc. 1998, 120, 1218. (d) Yadav, J . S.; Sarkar, S.;
Chandrasekhar, S. Tetrahedron 1999, 55, 5449.(e) Greene, A. E.; Leue,
S.; Genisson, Y.; Mekouar, K. J . Org. Chem. 2000, 65, 5212. (f)
Ciufolini, M. A.; Bouchu, D.; Rousset, L.; Penlou, S.; Narkunan, K.;
Carles, L. J . Org. Chem. 2002, 67, 4304.
(6) The Camptothecins: Unfolding their Anticancer Potential; Liehr,
J . G., Giovanella, B. C., Verschraegen, C. F., Eds. Ann. N. Y. Acad.
Sci. 2000, 922. Du, W.; Curran, D. P. Org. Lett. 2002, 4 (19), 3215.
(7) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C. Tetrahedron
Lett. 2000, 41, 10273.
(8) Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett. 2002,
43, 3233.
10.1021/jo034042s CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/17/2003
5688
J . Org. Chem. 2003, 68, 5688-5691

An Efficient Approach to 3,4-Disubstituted Pyridin-2-ones
TABLE 1. Rea ction of 5 w ith Excess Na H a n d Va r iou s
Alk yl Ha lid e
SCHEME 3
SCHEME 4
obtained as the major product accompanied with a small
amount of 9a .
To avoid this over reduction problem, we chose PMB
as the N-protecting group. Following the same procedures
as described above, pyridinone 10b was prepared in 43%
overall yield starting from 6b. Finally, reaction of 10b
with TFA in a sealed tube at 100 °C provided the desired
ketopyridinone 12 in 80% yield (Scheme 4).10
Since compound 12 had already been transformed into
mappicine ketone (1),5a a formal synthesis of 1 was
accomplished.
a
b
Reaction at room temperature. Reaction at reflux tempera-
ture.
SCHEME 2
In summary, we have successfully developed an ef-
ficient approach to 3,4-disubstituted pyridin-2-ones 6.
This methodology provides greater flexibility for incor-
poration of an alternative functionality at the 3- and
4-position and proved to be applicable for the synthesis
of mappicine ketone (1). Further application of these
results in the synthesis of analogues of the mappicine
and camptothecin is currently underway in our labora-
tory.
The synthesis of mappicine ketone was carried out as
depicted in Scheme 3. Debenzylation of 6a with BCl3 at
-20 °C to 0 °C obtained alcohol 7a in 85% yield, and
treatment of 7a with PCC furnished the corresponding
aldehyde 8a in 87% yield. Addition of ethylmagnesium
bromide to 8a in the presence of CeCl3 gave alcohol 9a
in 71% yield,9 which was further oxidized with PCC to
give ketone 10a in 95% yield. Unfortunately, while we
tried to debenzylate pyridinone 10a with hydrogen gas
at 1 atm in the presence of palladium hydroxide catalyst,
the unexpected over reduced compound 11 (81%) was
Exp er im en ta l Section
Before use, THF was distilled from a deep blue solution
resulting from sodium and benzophenone under nitrogen. All
reagents and solvents were obtained from commercial sources
and used without further purification. Thin-layer chromatog-
raphy (TLC) analysis was performed with precoated silica gel
(9) Direct adding of ethylmagnesium bromide to 8a gave complex
results.
(10) Padwa, A.; Heidellbaugh, T. M.; Kuethe, J . T. J . Org. Chem.
2000, 65, 2368.
J . Org. Chem, Vol. 68, No. 14, 2003 5689

Lin et al.
(60 f254 plates), and column chromatography was carried out
on silica (70-230 mesh). All reactions were performed under
an atmosphere of nitrogen in dried (except those concerned
with aqueous solutions) spherical flasks and stirred with
magnetic bars.
cm-1) 1731, 1652; 1H NMR (500 MHz, CDCl3) δ 7.35-7.26 (m,
10 H), 7.22 (d, J ) 7.5 Hz, 1 H), 6.37 (d, J ) 7.5 Hz, 1 H), 5.14
(s, 2 H), 4.55 (s, 2 H), 4.42 (s, 2 H), 4.12 (q, J ) 7.0 Hz, 2 H),
3.65 (s, 2 H), 1.22 (t, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 170.8, 162.1, 147.9, 137.4, 136.2, 135.1, 128.8 (2C),
128.4 (2C), 128.1 (2C), 127.9 (2C), 127.8, 127.7, 123.3, 105.8,
72.8, 68.4, 60.8, 52.3, 32.0, 14.0; MS (EI, 30 eV); 391 (M+,
3.3%), 91 (100%).
1,3-Dib e n zyl-4-(3-b e n zyloxy-p r op yl)-1H -p yr id in -2-
on e (6f). 81% yield; IR (CDCl3, cm-1) 1602; 1H NMR (500 MHz,
CDCl3) δ 7.34-7.22 (m, 15 H), 7.11 (d, J ) 7.0 Hz, 1 H), 6.02
(d, J ) 7.0 Hz, 1 H), 5.14 (s, 2 H), 4.47 (s, 2 H), 4.04 (s, 2 H),
3.43 (t, J ) 6.0 Hz, 2 H), 2.61 (t, J ) 8.0 Hz, 2 H), 1.76 (m, 2
H); 13C NMR (125 MHz, CDCl3) δ 162.8, 150.8, 140.6, 138.3,
136.7, 134.0, 129.2, 128.8 (2C), 128.4 (2C), 128.3 (2C), 128.2
(2C), 128.1 (2C), 127.9, 127.6 (2C), 127.6, 125.8, 108.1, 72.9,
69.2, 52.3, 32.1, 29.6, 29.4; HRMS calcd for C29H29NO2 (M+)
423.2193, found 423.2197.
Gen er a l P r oced u r e of Regioselective Red u ction of
Glu ta r im id es 3 to 3,4-Dih yd r o-3-tosylp yr id in -2-on es 5.
To a suspension of sodium hydride (1.2 mmol, 60% dispersion
in oil, was washed 3 times with dry hexane) in dry THF (10
mL) was added glutarimides 3 (1.0 mmol) at 25 °C for 5 min,
and then 2.0 mmol equiv of LAH was added in one portion
and further stirred for 0.5-1.0 h. The reaction was quenched
with ammonium chloride solution (1 mL). The layers were
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried, filtered, and concentrated. Without purification, crude
4 was treated with boron trifloride (catalyst) in 20 mL of CH2-
Cl2 at 0 °C for 1 day and quenched with saturated aqueous
sodium bicarbonate. The layer was separated, and aqueous
layer was extracted with dichloromethane. The combined
organic layers were washed with brine, dried, filtered, and
concentrated. The crude product was purified by flash chro-
matography (hexane/AcOEt ) 4:1) to afford dehydration
product 5.
Gen er a l P r oced u r e to 3,4-Disu bstitu ted P yr id in -2-on e
6. A solution of 5 (1.0 mmol) in THF (20 mL) was added to a
rapidly stirred suspension of sodium hydride (60% dispersion
in mineral oil, 2.2 mmol). After the reaction mixture was
stirred at room temperature for 10 min, 1.2 mmol of alkyl
halide was then added to the suspension mixture. The mixture
was stirred for 12 h, quenched with water (5 mL), and
extracted with AcOEt (3 × 20 mL). The organic layers were
washed with brine, dried with anhydrous MgSO4, filtered, and
evaporated. The residue was purified by column chromatog-
raphy on silica gel (elution with hexane/ethyl acetate ) 2:1)
to give pyridin-2-one 6.
4-(3,4-Dim eth oxtp h en yl)-1-(4-m eth oxyben zyl)-3-m eth -
yl-1H-p yr id in -2-on e (6g). 86% yield; IR (CDCl3, cm-1) 1647,
1
1513; H NMR (500 MHz, CDCl3) δ 7.32 (d, J ) 8.5 Hz, 2 H),
7.17 (d, J ) 7.0 Hz, 1 H), 6.92-6.83 (m, 4 H), 6.79 (d, J ) 2.0
Hz, 1 H), 6.10 (d, J ) 7.0 Hz, 1 H), 5.10 (s, 2 H), 3.91 (s, 3 H),
3.87 (s, 3 H), 3.78 (s, 3 H), 2.13 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 163.0, 159.2, 148.8, 148.7, 148.5, 132.7, 132.0, 129.8
(2C), 128.6, 126.1, 120.8, 114.1 (2C), 111.5, 110.8, 108.5, 55.8,
55.8, 55.2, 51.8, 14.6; HRMS calcd for C22H23NO4 (M+) 365.1623,
found 365.1625.
3-Allyl-4-(3,4-d im eth oxyp h en yl)-1-(4-m eth oxyben zyl)-
1H-p yr id in -2-on e (6h ). 82% yield; IR (CDCl3, cm-1) 1644,
1614, 1513; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J ) 8.5 Hz,
2 H), 7.20 (d, J ) 6.5 Hz, 1 H), 6.90-6.86 (m, 5 H), 6.12-6.03
(m, 2 H), 5.12 (s, 2 H), 5.05-4.95 (m, 2 H), 3.92 (s, 3 H), 3.86
(s, 3 H), 3.80 (s, 3 H), 3.29 (d, J ) 5.5 Hz, 2 H); 13C NMR (125
MHz, CDCl3) δ 162.4, 159.3, 150.0, 148.8, 148.4, 136.7, 133.5,
131.7, 129.8 (2C), 128.6, 127.6, 120.4, 114.8, 114.1 (2C), 111.4,
1-Ben zyl-4-[(ben zyloxy)m eth yl]-3-m eth yl-1H-p yr id in -
110.8, 108.6, 55.8, 55.8, 55.2, 51.7, 32.7; HRMS calcd for C24H25
-
1
2-on e (6a ). 85% yield; IR (CDCl3, cm-1) 1649; H NMR (500
NO4 (M+) 391.1784, found 391.1783.
MHz, CDCl3) δ 7.35-7.25 (m, 10 H), 7.15 (d, J ) 7.0 Hz, 1 H),
6.37 (d, J ) 7.0 Hz, 1 H), 5.11 (s, 2 H), 4.56 (s, 2 H), 4.40 (s, 2
H), 2.08 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 162.4, 145.7,
137.4, 136.4, 133.4, 128.5 (2C), 128.2 (2C), 127.9 (2C), 127.7,
127.6 (2C), 127.5, 125.6, 105.4, 72.6, 68.2, 52.2, 11.8; HRMS
calcd for C21H21NO2 (M+) 319.4024, found 319.4033.
3-Allyl-1-ben zyl-4-p h en yl-1H-p yr id in -2-on e (6i). 81%
yield; IR (CDCl3, cm-1) 1649; 1H NMR (500 MHz, CDCl3) δ
7.43-7.26 (m, 10 H), 7.21 (d, J ) 7.0 Hz, 1 H), 6.11 (d, J ) 7.0
Hz 1 H), 6.05-5.97 (m, 1 H), 5.20(s, 2 H), 4.96 (m, 2 H), 3.27
(d, J ) 6.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 162.5, 149.3,
139.6, 136.6, 133.1, 132.32, 128.8 (2C), 128.4 (2C), 128.3 (2C),
127.9 (2C), 127.8 (2C), 127.7, 108.7, 52.3, 21.6, 13.5; HRMS
calcd for C21H19NO (M+) 301.1467, found 301.1470.
4-[(Ben zyloxy)m eth yl]-1-(4-m eth oxyben zyl)-3-m eth yl-
1H-p yr id in -2-on e (6b). 88% yield; IR (CDCl3, cm-1) 1648; 1H
NMR (500 MHz, CDCl3) δ 7.36-7.30 (m, 5 H), 7.26 (d, J ) 8.5
Hz, 2 H), 7.16 (d, J ) 7.5 Hz, 1 H), 6.85 (d, J ) 8.5 Hz, 2 H),
6.37 (d, J ) 7.5 Hz, 1 H), 5.07 (s, 2 H), 4.58 (s, 2 H), 4.41 (s, 2
H), 3.78 (s, 3 H), 2.08 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
162.6, 159.2, 145.8, 137.6, 133.4, 129.7 (2C), 128.6, 128.4 (2C),
127.8, 127.7 (2C), 125.8, 114.1 (2C), 105.5, 72.8, 68.4, 55.2, 51.9,
11.9; HRMS calcd for C22H23NO3 (M+) 349.1678, found 349.1675.
3-Allyl-1-b en zyl-4-[(b en zyloxy)m et h yl]-1H -p yr id in -2-
on e (6c). 84% yield; IR (CDCl3, cm-1) 1647; 1H NMR (500
MHz, CDCl3) δ 7.36-7.26 (m, 10 H), 7.19 (d, J ) 7.0 Hz, 1 H),
6.41 (d, J ) 7.0 Hz, 1 H), 5.91-5.83 (m, 1 H), 5.14 (s, 2 H),
4.99-4.95 (m, 2 H), 4.56 (s, 2 H), 4.44 (s, 2 H), 3.35 (d, J ) 6.0
Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 162.1, 146.9, 137.6,
136.5, 134.8, 134.4, 128.8 (2C), 128.4 (2C), 128.1 (2C), 127.9,
127.8 (2C), 127.7, 127.3, 115.1, 105.5, 72.9, 67.8, 52.3, 30.5;
HRMS calcd for C23H23NO2 (M+) 345.1729, found 345.1731.
1,3-Diben zyl-4-ben zyloxym eth yl-1H-pyr idin -2-on e (6d).
83% yield; IR (CDCl3, cm-1); 1H NMR (500 MHz, CDCl3) δ
7.39-7.14 (m, 16 H), 6.42 (d, J ) 7.0 Hz, 1 H), 5.17 (s, 2 H),
4.51 (s, 1 H), 4.43 (s, 2 H), 3.97 (s, 2 H); 13C NMR (125 MHz,
CDCl3) δ 162.6, 147.2, 139.7, 137.5, 136.5, 134.6, 128.8 (2C),
128.7, 128.6, 128.5 (2C), 128.4 (2C), 128.3 (2C), 128.1 (2C),
127.9, 127.8 (2C), 125.9, 105.6, 72.9, 68.2, 52.5, 31.8; MS (EI,
30 eV); 395 (M+, 6.4%), 91 (100%).
1-Ben zyl-3-et h yl-4-p h en yl-1H-p yr id in -2-on e (6j). 82%
yield; IR (CDCl3, cm-1) 1647; 1H NMR (500 MHz, CDCl3) δ
7.35-7.18 (m, 10 H), 7.08 (d, J ) 7.0 Hz, 1 H), 5.98 (d, J ) 7.0
Hz, 1 H), 5.10 (s, 2 H), 2.45 (q, J ) 7.5 Hz, 2 H), 1.03 (t, J )
7.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 162.5, 149.2, 139.5,
136.6, 133.1, 132.2, 128.8 (2C), 128.4 (2C), 128.3, 127.9 (2C),
127.8, 127.7 (2C), 108.6, 52.2, 21.5, 13.4; HRMS calcd for
C
20H19NO (M+) 289.1448, found 289.1461.
1-Ben zyl-4-(h yd r oxym et h yl)-3-m et h yl-1H -p yr id in -2-
on e (7a ). A solution (1.0 M) of BCl3 in CH2Cl2 (0.95 mL) was
added to a cooled solution (-20 °C) of 6a (200.0 mg, 0.63 mmol)
in CH2Cl2 (20 mL). The reaction mixture was then warmed
slowly to 0 °C (4 h) and quenched with saturated aqueous
sodium bicarbonate. The layers were separated, and the
aqueous layer was extracted with dichloromethane. The
organic layers were washed with brine, dried, filtered, and
concentrated. Flash chromatography (hexane/ethyl acetate )
1:1) of the residue followed by filtration through a silica gel
column gave 122.8 mg of 7a (85%). IR (CDCl3, cm-1) 1721,
1
1643; H NMR (500 MHz, CDCl3) δ 7.34-7.26 (m, 5 H), 7.19
(d, J ) 7.0 Hz, 1 H), 6.42 (d, J ) 7.5 Hz, 1 H), 5.14 (s, 2 H),
4.58 (s, 2 H), 2.08 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 162.6,
148.2, 136.5, 133.8, 128.8 (2C), 128.0 (2C), 127.8, 124.9, 104.9,
61.4, 52.4, 11.7; HRMS calcd for C14H15NO2 (M+) 229.1096,
found 229.1097.
(1-Ben zyl-4-ben zyloxym eth yl-2-oxo-1,2-d ih yd r o-p yr i-
d in -3-yl)a cetic Acid Eth yl Ester (6e). 82% yield; IR (CDCl3,
4-(Hyd r oxym eth yl)-1-(4-m eth oxyben zyl)-3-m eth yl-1H-
5690 J . Org. Chem., Vol. 68, No. 14, 2003

An Efficient Approach to 3,4-Disubstituted Pyridin-2-ones
p yr id in -2-on e (7b). 86% yield; IR (CDCl3, cm-1) 1711, 1643;
1H NMR (500 MHz, CDCl3) δ 7.25 (d, J ) 8.5 Hz, 2 H), 7.18
(d, J ) 7.0 Hz, 1 H), 6.85 (d, J ) 8.5 Hz, 2 H), 6.39 (d, J ) 7.0
Hz, 1 H), 5.06 (s, 2 H), 4.57 (s, 2 H), 3.78 (s, 3 H), 2.07 (s, 3 H);
13C NMR (125 MHz, CDCl3) δ 162.6, 159.3, 148.0, 133.6, 129.6
(2C), 128.6, 124.9, 114.1 (2C), 104.9, 61.5, 55.2, 52.0, 11.7;
HRMS calcd for C15H17NO3 (M+) 259.1208, found 259.1202.
1-Ben zyl-3-m et h yl-2-oxo-1,2-d ih yd r o-p yr id in e-4-ca r -
ba ld eh yd e (8a ). To a stirred solution of alcohol 7a (200.0 mg,
0.87 mmol) in 20 mL of dichloromethane at 25 °C under
nitrogen was added Celite, pyridium chlorochromate (226.3
mg, 1.05 mmol). The reaction mixture was stirred for 1 day.
The mixture was filtered through silica gel, and the solid was
washed with hexane/ethyl acetate ) 2:1. The filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (elution hexane/ethyl acetate )
2:1) to give ketone 8a (172.0 mg, 87%). IR (CDCl3, cm-1) 1716,
1-Ben zyl-3-m eth yl-4-p r op ion yl-1H-p yr id in -2-on e (10a ).
A solution of 9a (130.2 mg, 0.51 mmol) in CH2Cl2 (10 mL) was
added to a mixture of PCC (131.4 mg, 0.61 mmol) and Celite
in CH2Cl2 (10 mL). The reaction mixture was stirred overnight
at room temperature and then filtered over a short pad of silica
gel with hexane/ethyl acetate ) 1:1 to provide 123.7 mg (95%)
1
of pyridone 10a . IR (CDCl3, cm-1) 1716, 1641; H NMR (500
MHz, CDCl3) δ 7.37-7.27 (m, 5 H), 7.22 (d, J ) 7.5 Hz, 1 H),
6.06 (d, J ) 7.5 Hz, 1 H), 5.14 (s, 2 H), 2.74 (q, J ) 7.5 Hz, 2.0
H), 2.16 (s, 3 H), 1.17 (t, J ) 7.5 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 205.5, 162.9, 147.1, 135.9, 134.4, 128.8 (2C), 128.2
(2C), 128.1, 126.6, 102.9, 52.6, 35.8, 13.9, 7.6; HRMS calcd for
C
16H17NO2 (M+) 255.1252, found 255.1254.
1-(4-Meth oxyben zyl)-3-m eth yl-4-pr op ion yl-1H-p yr id in -
2-on e (10b). 91% yield; IR (CDCl3, cm-1) 1717, 1643; 1H NMR
(500 MHz, CDCl3) δ 7.27 (d, J ) 8.5 Hz, 2 H), 7.20 (d, J ) 7.0
Hz, 1 H), 6.87 (d, J ) 8.5 Hz, 2 H), 6.04 (d, J ) 7.0 Hz, 1 H),
5.07 (s, 2 H), 3.74 (s, 3 H), 2.73 (q, J ) 7.5 Hz, 2 H), 2.15 (s, 3
H), 1.17 (t, J ) 7.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
205.6, 162.9, 159.4, 147.0, 134.2, 129.8 (2C), 128.0, 126.6, 114.2
1
1648; H NMR (500 MHz, CDCl3) δ 10.30 (s, 1 H), 7.26-7.19
(m, 5 H), 7.18 (d, J ) 7.5 Hz, 1H), 6.45 (d, J ) 7.0 Hz, 1 H),
5.07 (s, 2 H), 2.42 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 190.7,
163.4, 139.2, 135.7, 135.1, 134.3, 128.8 (2C), 128.1, 128.0 (2C),
101.7, 52.8, 11.02; HRMS calcd for C14H13NO2 (M+) 227.0946,
found 227.0947.
(2C), 102.8, 55.2, 52.1, 35.8, 13.9, 7.6; HRMS calcd for C17H19
-
NO3 (M+) 285.1357, found 285.1359.
3-Meth yl-4-p r op yl-1H-p yd id in -2-on e 11. To a solution of
60.1 mg (0.23 mmol) of pyridinone 10a in 7 mL of acetic acid
was added a catalytic amount of Pd(OH)2, and the reaction
mixture was stirred under hydrogen overnight. After filtration
of the catalyst, the solution was extracted with CH2Cl2 and
washed with water. The organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chroma-
tography to give 28.2 mg (81%) of 11 as a white solid: mp 108-
109 °C. IR (CDCl3, cm-1) 3020, 1616; 1H NMR (500 MHz,
CDCl3) δ 7.24 (d, J ) 6.5 Hz, 1 H), 6.17 (d, J ) 6.5 Hz, 1 H),
2.51 (t, J ) 7.5 Hz, 2 H), 2.14 (s, 3 H), 1.59 (q, J ) 7.5 Hz, 2
H), 0.98 (t, J ) 7.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
164.6, 153.1, 130.1, 125.4, 109.7, 35.5, 22.4, 13.9, 11.7; HRMS
calcd for C9H13NO (M+) 151.0997, found 151.0998.
1-(4-Meth oxyben zyl)-3-m eth yl-2-oxo-1,2-d ih yd r o-p yr i-
d in e-4-ca r ba ld eh yd e (8b). 87% yield; IR (CDCl3, cm-1) 1701,
1
1619; H NMR (500 MHz, CDCl3) δ 10.39 (s, 1 H), 7.28-7.24
(m, 3 H), 6.87 (d, J ) 8.5 Hz, 2 H), 6.52 (d, J ) 7.0 Hz, 1 H),
5.09 (s, 2 H), 3.79 (s, 3 H), 2.51 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 190.8, 163.5, 159.5, 139.2, 135.2, 134.2, 129.8 (2C),
127.8, 114.3 (2C), 101.7, 55.2, 52.4, 11.0; HRMS calcd for
C
15H15NO3 (M+) 257.1052, found 257.1052.
1-Ben zyl-4-(1-h yd r oxyp r op yl)-3-m eth yl-1H-p yr id in -2-
on e (9a ). A solution of 8a (150.1 mg, 0.66 mmol) in anhydrous
THF (10 mL) under N2 was added to anhydrous CeCl3 (325.5
mg, 1.32 mmol). After 30 min, EtMgBr (3.0 M in THF, 0.33
mL) was added to the mixture and stirred at 25 °C for 1 h.
The reaction mixture was quenched with the addition of
saturated aqueous NH4Cl (5 mL) and extracted with EtOAc
(3 × 20 mL); the organic layer was dried MgSO4 and concen-
trated under reduced pressure. Chromatography (SiO2, hex-
ane/ethyl acetate ) 1:2) afforded 9a (120.6 mg, 71%). IR
(CDCl3, cm-1) 3021, 1617; 1H NMR (500 MHz, CDCl3) δ 7.34-
7.27 (m, 5 H), 7.13 (d, J ) 7.5 Hz, 1 H), 6.40 (d, J ) 7.5 Hz, 1
H), 5.08 (dd, J ) 15.3, 8.7 Hz, 2 H), 4.68 (dd, J ) 7.5, 5.5 Hz,
1 H), 2.01 (s, 3 H), 1.67-1.60 (m, 2 H), 0.93 (t, J ) 7.5 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 162.7, 152.1, 136.3, 133.5,
128.7 (2C), 128.2 (2C), 127.8, 124.7, 104.3, 70.8, 52.4, 29.9, 12.0,
9.9; HRMS calcd for C16H19NO2 (M+) 257.1402, found 257.1410.
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.63; H, 7.19; N, 5.18.
3-Meth yl-4-p r op ion yl-1H-p yr id in -2-on e 12. A solution of
50.3 mg (0.17 mmol) of 10b in 12 mL of trifluoroacetic acid
was heated in a sealed tube at 100 °C for 4 h. The mixture
was cooled, the solvent was removed under reduced pressure,
and the residue was chromatographed on silica gel to give 22.5
mg (80%) of pyridinone 12 as a white solid: mp 128-129 °C.
IR (CDCl3, cm-1) 3690, 1706; 1H NMR (500 MHz, CDCl3) δ
7.34 (d, J ) 6.5 Hz, 1 H), 6.19 (d, J ) 6.5 Hz, 1 H), 2.77 (q, J
) 7.0 Hz, 2 H), 2.14 (s, 3 H), 1.92 (t, J ) 7.0 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 205.6, 165.4, 149.5, 131.8, 125.9,
103.9, 35.9, 13.1, 7.6; HRMS calcd for C9H11NO2 (M+) 165.0790,
found 165.0791.
4-(1-H yd r oxyp r op yl)-1-(4-m et h oxyb en zyl)-3-m et h yl-
1H-p yr id in -2-on e (9b). 87% yield; IR (CDCl3, cm-1) 3020,
Ack n ow led gm en t. The authors would like to thank
the National Science Council of the Republic of China
for financial support
1
1613; H NMR (500 MHz, CDCl3) δ 7.26 (d, J ) 8.5 Hz, 2 H),
7.16 (d, J ) 7.0 Hz, 1 H), 6.86 (d, J ) 8.5 Hz, 2 H), 6.37 (d, J
) 7.0 Hz, 1 H), 5.08 (d, J ) 14.0 Hz, 1 H), 5.01 (d, J ) 14.0
Hz, 1 H) 4.74 (t, J ) 7.0 Hz, 1 H), 3.79 (s, 3 H), 2.08 (s, 3 H),
1.68-1.63 (m, 2 H), 0.95 (t, J ) 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 162.7, 159.3, 151.4, 133.5, 129.8 (2C), 128.5,
124.8, 114.1 (2C), 103.8, 71.1, 55.2, 51.9, 29.9, 12.0, 9.9; HRMS
calcd for C17H21NO3 (M+) 287.1512, found 287.1523. Anal.
Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C,
71.33; H, 7.08; N, 4.74.
Su p p or tin g In for m a tion Ava ila ble: Additional spectro-
scopic data for compounds 12, 10b, 9b, 8b, 7b, and 6b (1H
NMR in CDCl3). This material is available free of charge via
the Internet at http://pubs.acs.org.
J O034042S
J . Org. Chem, Vol. 68, No. 14, 2003 5691