Construction of 5,6-ring-fused 2-pyridones: An effective annulation tactic achieved in water

Article abstract of DOI:10.1055/s-0029-1217749

An efficient protocol to annulate the 5,6-fused 2-pyridone ring system, exploiting a tandem condensation of propiol-amide and cyclic -keto methyl esters in water, followed by acid- or base-promoted intramolecular ring closure and decarboxylation, has been

Full text of DOI:10.1055/s-0029-1217749

LETTER
2643
Construction of 5,6-Ring-Fused 2-Pyridones: An Effective Annulation Tactic
Achieved in Water
C
onstruction of 5,
m
d
2-Pyr
o
idones s B. Smith, III *a Onur Atasoylu,a Douglas C. Beshoreb
a
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter,
University of Pennsylvania, Philadelphia, PA 19104, USA
Fax +1(215)8985129; E-mail: smithab@sas.upenn.edu
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
b
Received 19 June 2009
covery of starting materials. Increasing the reactivity of
the ketone by conversion into the b-keto ester (cf. 3), em-
ploying propiolamide, a tactic similar to that used in the
Mulzer synthesis of huperzine A,10 followed by modified
conditions for the cyclization and decarboxylation (cf.
Me4NOAc, MeCN) permitted completion of the total syn-
thesis of (+)-lyconadin A (4).8
Abstract: An efficient protocol to annulate the 5,6-fused 2-pyri-
done ring system, exploiting a tandem condensation of propiol-
amide and cyclic b-keto methyl esters in water, followed by acid- or
base-promoted intramolecular ring closure and decarboxylation,
has been developed.
Key words: heterocycles, condensation, fused-ring systems, tan-
dem reactions, Michael additions
CONH2
O
O
The 2-pyridone ring system comprises the central struc-
tural element in numerous important biologically active
natural products and related congeners, including the
camptothecins,1 drug candidates active against leuke-
mia,1b Huperzine A,2 a potent acetylcholine esterase in-
hibitor,2b and Merck’s L-697,661,3 an HIV-1 reverse
transcriptase inhibitor. In addition, the similarity of the 2-
pyridone ring system to nucleoside bases, in conjunction
with the aromatic nature of the ring, permitting π–π stack-
ing interactions, as well as the availability of two tauto-
meric forms capable of participating in multidirectional
hydrogen bonds, raises the 2-pyridone ring system to that
of a ‘privileged structure’4 in the context of drug design
and development.
CONH2, acid or base
N
N
or
Me
Me
COMe, NH3
1
2
O
CONH2
Cs2CO3
DMSO, r.t., 82%
1)
CO2Me
2)
O
HN
Me4NOAc, MeCN
N
N
135 °C, 16 h, 71 %
Me
Me
(+)-lyconadin A
3
4
Scheme 1 Installation of the 2-pyridone ring in the total synthesis
of (+)-lyconadin A
To date, most protocols for the construction and/or annu-
lation of the 2-pyridone ring are by-and-large limited to
the conversion of 2-pyrones employing ammonia,5 the ox-
idation of pyridines6 and the Guareschi–Thorpe7 conden-
sation of acyclic precursors such as cyanoacetamide with
1,3-diketones. Given the importance of the 2-pyridone
ring system, there is clearly a need for alternative, effi-
cient synthetic tactics to access this system.
In this letter, we report the culmination of a study aimed
at exploring the scope and utility of this tactic as a general
protocol for the construction of 5,6-fused 2-pyridones.
We first examined the Michael addition of a-car-
bomethoxy-cyclopentanone with propiolamide (Table 1).
When the lyconadin conditions8 (cf. Cs2CO3 in DMSO)
were employed, no reaction was observed at room tem-
perature (entry 1); elevated temperatures were also not
profitable, leading instead to extensive polymerization
(entry 2). Given the low electrophilicity as well as the
poor ability of the amide carbonyl to effectively stabilize
the resulting carbanion, acetylenic amides are recognized
to be poor Michael acceptors.11
In conjunction with our recently achieved enantiospecific
syntheses of (+)-lyconadin A and (–)-lyconadin B8
(Scheme 1), we envisioned late-stage installation of the
requisite 2-pyridone ring, employing advanced amino ke-
tone 1. We initially selected the Kozikowski one-pot tac-
tic, employed in the syntheses of huperzine A and
analogues,9 which entails the condensation of methyl pro-
piolate and ammonia with a ketone or b-keto ester. The
poor Michael acceptor ability of the unsaturated amide, in
our case however, precluded addition, resulting in the re-
Indeed, to the best of our knowledge, there is only one re-
port wherein a propiolamide has proven to be a competent
Michael acceptor.12 Not withstanding this lack of litera-
ture precedent, careful screening of a variety of conditions
quickly revealed that Na2CO3 in water at room tempera-
ture furnished Michael adduct 6 in 88% yield (entry 7).13
Use of K2CO3 in acetone at 50 °C also provided the requi-
site addition product (6), albeit in somewhat lower yield
(entry 6).
SYNLETT 2009, No. 16, pp 2643–2646
x
x
.x
x
.2
0
0
9
Advanced online publication: 04.09.2009
DOI: 10.1055/s-0029-1217749; Art ID: S06709ST
© Georg Thieme Verlag Stuttgart · New York

2644
A. B. Smith III. et al.
LETTER
complex mixtures consisting of hydrolyzed and decarboxy-
lated substrates, spirobicyclic and 3-substituted glutarim-
ides and polymers in conjunction with decomposition
products were observed. We reasoned that use of the acid-
ic conditions might suppress these alternative pathways,
in particular, intramolecular attack of the amide nitrogen
on the ester to yield the spiro-glutarimides,15 as well as al-
dol reactions leading to polymeric byproducts. Initially,
weakly acidic conditions proved somewhat promising, al-
beit providing the desired 2-pyridone 8 in low yield (18%)
along with recovered starting material and enamide 7.
Strongly acidic conditions (cf. concd HCl), on the other
hand, not only accelerated the reaction but, pleasingly, led
to the desired pyridone 8 in nearly quantitative yield
(Table 2).16
Table 1 Conditions Examined for Michael Addition
CONH2
O
O
conditions
CONH2
CO2Me
CO2Me
5
6
Entry Base
Solvent
Time
(h)
Temp Result
(°C)
1
2
3
4
5
6
7
Cs2CO3
DMSO
DMSO
DMF
12
2
r.t.
80
r.t.
60
r.t.
50
r.t.
no reaction
Cs2CO3
NaH
polymerization
no reaction
polymerization
polymerization
76%
12
2
NaH
DMF
Table 2 Optimization of the Cyclization Conditions
NaOH
K2CO3
Na2CO3
MeOH
acetone
H2O
12
1
O
O
CONH2
CO2Me
O
HN
HN
conditions
1
88%
CO2Me
Having achieved an effective Michael addition process,
we turned to the development of a one-pot protocol to
generate the 2-pyridone ring. Here we called upon a tan-
dem reaction sequence, involving cyclization, ester hy-
drolysis and decarboxylation (Scheme 2).
6
7
8
Reagent
Solvent
Time Temp Result
(h)
(°C)
130
130
130
120
130
130
130
Me4NOAc
Me4NOAc
NaOH
MeCN
MeCN
3
no desired product
polymerization
polymerization
no desired product
polymerization
7 (24%) + 8 (18%)
8 (99%)
12
O
O
O
CONH2
1.
H2O–DMSO 12
HN
Na2CO3, H2O or
K2CO3, acetone, reflux
OMe
LiI
DMF
12
12
24
6
2. conditions
R
R
TBAI, LiI
HCl (1 M)
HCl (concd)
DMF–H2O
H2O
addition
H2O
– CO2
Having achieved the tandem cyclization/decarboxylation
reaction sequence with 6, we next applied the conditions
to substrates possessing different ring sizes (Table 3).
Substrates possessing five- and six-membered rings fur-
nished good yields upon addition of propiolamide, where-
as reduced yields, accompanied by modest amounts of
polymerization, was observed with the seven-membered
substrate 13. Interestingly the eight-membered ring ana-
logue 16 did not lead to the desired product under the
strongly acidic conditions. However, strong base15 was ef-
fective in furnishing 2-pyridone 17 in 44% yield.
O
O
O
NH2
1. olefin
isomerization
HN
O
O
HN
– MeOH
COOMe
2. – H2O
OMe
COOH
R
R
R
Scheme 2 Proposed formation of fused 2-pyridones
In our (+)-lyconadin A synthesis, tetrabutylammonium
acetate proved optimal, given that stronger nucleophilic
reagents such as sodium cyanide or thiophenol led to sec-
ondary conjugate addition of the basic anion to the initial-
ly derived Michael adduct to furnish 4-substituted 2-
pyridones.8 However, when this reagent was applied to 6
(Table 2), only polymerization was observed. Examina-
tion of other Krapcho decarboxylation conditions14 ex-
ploring a variety of substrates, including six- and seven-
membered rings possessing a-carboethoxy substituents,
revealed the sensitivity of such substrates to nucleophilic
attack. We also observed that, at elevated temperatures,
We also explored the effect of a-substitution on the six-
membered ring. Not surprisingly, both electron-with-
drawing and electron-donating substituents led to lower
yields in the Michael addition step, possibly due to steric
hindrance. Particularly noticeable, however, was the drop
in the yield of 22, bearing an a-bromine, most likely due
a Favorskii reaction17 leading to polymerization (Table 4).
Ring-closure, hydrolysis and decarboxylation then pro-
ceeded in good to excellent yield to furnish the 5,6-ring
fused 2-pyridones similar to the unsubstituted system.
Synlett 2009, No. 16, 2643–2646 © Thieme Stuttgart · New York

LETTER
Construction of 5,6-Ring Fused 2-Pyridones
2645
Table 3 Effect of Ring Size
Starting material
Addition product
Yield (%)
Final product
Yield (%)
O
O
CO2NH2
CO2Me
O
O
HN
HN
5
9
6
88
85
8
99
99
CO2Me
CO2Me
CO2NH2
CO2Me
O
O
10
11
14
17
O
CO2NH2
CO2Me
O
O
HN
CO2Me
12
15
13
67
65
76
O
CO2NH2
O
O
HN
44a
CO2Me
16
CO2Me
a Strongly basic conditions used (0.5 equiv t-BuOH, 0.15 equiv 18-crown-6, THF, 60 °C).15
Finally, we examined systems having different distal ring also tested with 34, a substrate lacking the ability to eno-
fusions (Table 5). Substrates leading to structures pos- lize (Table 6). Although the acidic protocol provided 35 in
sessing increased ring-strain, not surprisingly, led to 69% yield, basic and neutral conditions also delivered the
somewhat lower yields in both the Michael addition and product in modest yield, thus demonstrating that alterna-
subsequent annulation and decarboxylation processes tive protocols are available for substrates with base- or
(30–32). Basic and neutral (NH4OAc) conditions were acid-sensitive functional groups.
Table 4 Effect of a-Substitution on Six-Membered Rings
Starting material
Addition product
Yield (%)
85
Final product
Yield (%)
99
O
CO2NH2
CO2Me
O
O
HN
CO2Me
9
10
11
O
CO2NH2
O
O
HN
CO2Me
18
19
75
44
20
23
82
68
CO2Me
O
CO2NH2
CO2Me
O
O
HN
Br
CO2Me
21
22
Br
Br
O
CO2NH2
O
O
HN
MeO
CO2Me
24
25
62
26
71
MeO
CO2Me
MeO
Synlett 2009, No. 16, 2643–2646 © Thieme Stuttgart · New York

2646
A. B. Smith III. et al.
LETTER
Table 5 Substrates Having Different Ring Fusions
Starting material
Addition product
Yield (%) Final product
Yield (%)
76
CO2NH2
CO2Me
CO2Me
27
28
71
42
29
32
HN
O
O
O
CO2NH2
CO2Me
30
31
34
44
69
CO2Me
HN
O
O
O
CO2NH2
CO2Me
O
O
O
HN
CO2Me
33
52
35
D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J.
P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(5) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9,
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(6) Decker, H. Ber. Dtsch. Chem. Ges. 1892, 25, 443.
(7) Baron, H.; Renfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904,
85, 1726.
Table 6 Effect of pH on the Cyclization of 34
CO2NH2
O
O
HN
conditions
CO2Me
(8) Beshore, D. C.; Smith, A. B. III. J. Am. Chem. Soc. 2007,
129, 4148.
34
35
(9) Kozikowski, A. P.; Reddy, E. R.; Miller, C. P. J. Chem. Soc.,
Perkin Trans. 1 1990, 195.
(10) Högenauer, K.; Baumann, K.; Enz, A.; Mulzer, J. Bioorg.
Reagent
Solvent
MeCN
Time (h) Temp (°C) Yield (%)
Me4NOAc
NaOH
40
18
6
150
150
130
42
50
69
Med. Chem. Lett. 2001, 11, 262.
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H2O–DMSO
H2O
HCl (concd)
(13) Representative procedure for Michael addition: To a
solution of propiolamide (325 mg, 4.70 mmol) and Na2CO3
(270 mg, 2.75 mmol) in H2O (5 mL) at 0 °C, methyl 2-
oxocyclopentanecarboxylate (5; 390 mg, 2.75 mmol) was
added dropwise. The reaction mixture was warmed to r.t.
over 2 h and then extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. Purification by
flash column chromatography (EtOAc–hexane, 1:1; Rf =
0.2) afforded 6 as a white solid (511 mg, 88% yield).
(14) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P.
Synthesis 1982, 893.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Support for this project was provided by the National Institutes of
Health through Grant GM-081253, under the Pilot-Scale Libraries
for HTS Program.
(15) Popović-Ðorđević, J. B.; Ivanović, M. D.; Kiricojević, V. D.
Tetrahedron Lett. 2005, 46, 2611.
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tube, containing a stir bar methyl 1-(3-amino-3-oxoprop-1-
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carefully opened and the reaction mixture poured onto ice
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saturated aqueous NaHCO3 and then the mixture was
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dried over MgSO4, filtered and concentrated under reduced
pressure to furnish a white solid. Purification through a short
pad of silica gel (EtOAc, 100%) afforded 8 as a white
amorphous solid (97.4 mg, 99% yield).
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Synlett 2009, No. 16, 2643–2646 © Thieme Stuttgart · New York