Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation

Article abstract of DOI:10.1021/ol052998e

Polycyclic ring-fused 2-pyridones (5a-e and 9a-e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting from 3,4-dihydroisoquinolines (4a-b) or 3,4-dihydroharman (8), fused 2-pyridones could be prepared in a one-step pr

Full text of DOI:10.1021/ol052998e

ORGANIC
LETTERS
2006
Vol. 8, No. 5
935-938
Synthesis of Multi Ring-Fused
2-Pyridones via an Acyl-Ketene Imine
Cyclocondensation
Nils Pemberton, Lotta Jakobsson, and Fredrik Almqvist*
Organic Chemistry, Umeå UniVersity, SE-901 87 Umeå, Sweden
fredrik.almqVist@chem.umu.se
Received December 12, 2005
ABSTRACT
Polycyclic ring-fused 2-pyridones (5a
from 3,4-dihydroisoquinolines (4a b) or 3,4-dihydroharman (8), fused 2-pyridones could be prepared in a one-step procedure. By using either
Meldrum’s acid derivatives (1a d) or 1,3-dioxine-4-ones (7a b) as acyl-ketene sources, mono- or disubstitution of the fused 2-pyridone ring
could be accomplished. As an application of the method, a formal synthesis of the indole alkaloid sempervilam was performed.
−e and 9a−e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting
−
−
−
The 2-pyridone core structure is an important heterocyclic
framework that can be found in numerous biologically active
compounds. It is also a versatile synthon that can be further
transformed to pyridine, piperidine, quinolizidine, and in-
dolizidine alkaloids.1 The broad range of applications of the
2-pyridone structural motif has resulted in several synthetic
methods.2 The most common and general approaches rely
not only on conversion of suitably functionalized pyridines3
but also on different variations of the Guareschi-Thorpe
condensation, where condensations between 1,3-dicarbonyls
and amides yield functionalized 2-pyridones.4 Previously, we
have shown that bicyclic 2-pyridones, 3, possess novel
antibacterial properties, as they target periplasmic chaper-
ones,5 essential for bacterial pathogenesis in uropathogenic
Escherichia coli. An effective synthesis of these bicyclic
systems was developed, and the key step in this route is an
acyl-ketene imine cyclocondensation (Figure 1). Thus, by
reacting acyl-ketenes generated from Meldrum’s acid deriva-
tives 1 with ∆2-thiazolines 2 under acidic conditions,
2-pyridones 3 were synthesized in excellent yields.6 This
reaction has been further developed using solid-phase
techniques7 and microwave irradiation8 (MWI), allowing the
bicyclic 2-pyridones to be prepared in a fast and parallel
manner. However, many biologically interesting 2-pyridones
are natural products that contain multi ring-fused systems.
Recently reported examples include the yohimbane alkaloid
sempervilam9 (Figure 2) and the antineoplastic agent camp-
(1) (a) Scriven, E. F. V. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol.
2. (b) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1981; Vol. 5, pp
1-54.
(2) Reviews: (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, pp 167-243. (b) Torres, M.; Gil, S.; Parra, M. Curr.
Org. Chem. 2005, 9, 1757-1779.
(3) (a) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623-9624.
(b) Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem.-Eur. J. 1998, 4,
67-83. (c) Wijtmans, M.; Pratt, D. A.; Brinkhorst, J.; Serwa, R.; Valgimigli,
L.; Pedulli, G. F.; Porter, N. A. J. Org. Chem. 2004, 69, 9215-9223.
(4) Baron, H.; Renfry, F.; Thorpe, J. J. Chem. Soc. 1904, 85, 1726.
(5) (a) Svensson, A.; Larsson, A.; Emtenas, H.; Hedenstrom, M.; Fex,
T.; Hultgren, S. J.; Pinkner, J. S.; Almqvist, F.; Kihlberg, J. Chembiochem
2001, 2, 915-918. (b) Aberg, V.; Hedenstrom, M.; Pinkner, J. S.; Hultgren,
S. J.; Almqvist, F. Org. Biomol. Chem. 2005, 3, 3886-3892. (c) Heden-
strom, M.; Emtenas, H.; Pemberton, N.; Aberg, V.; Hultgren, S. J.; Pinkner,
J. S.; Tegman, V.; Almqvist, F.; Sethson, I.; Kihlberg, J. Org. Biomol. Chem.
2005, 3, 4193-4200.
(6) Emtenas, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, 6756-
6761.
(7) Emtenas, H.; Ahlin, K.; Pinkner, J. S.; Hultgren, S. J.; Almqvist, F.
J. Comb. Chem. 2002, 4, 630-639.
(8) Emtenas, H.; Taflin, C.; Almqvist, F. Mol. DiVersity 2003, 7, 165-
169.
10.1021/ol052998e CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/01/2006

different Meldrum’s acid derivatives 1a-d14 in combination
with the simple preparation of 3,4-dihydroisoquinolines 4
(via the Bischler-Napieralski reaction) would provide a
direct and simple procedure to a variety of different
2-substituted benzo[a]quinolizine-4-ones 5.
Thus, the commercially available 3,4-dihydroisoquinolines
4a and 4b were reacted with acyl Meldrum’s acid derivatives
1a and 1b using the previously developed conditions (64
°C in 1/2-saturated HCl(g) solution of 1,2-dichloroethane or
irradiated at 140 °C in 1/8-saturated HCl(g) solution of 1,2-
dichloroethane) as a starting point. This resulted in moderate
to excellent yields of the 2-substituted benzo[a]quinolizine-
4-ones 5a-c (Table 1, entries 1-6). To further improve this
Figure 1. Synthesis of bicyclic sulfur containing 2-pyridones via
an acyl-ketene imine cyclocondensation.
tothecin (Figure 2), the latter of which has attracted great
interest from synthetic chemists resulting in a large number
of synthetic routes.10
Table 1. Synthesis of Benzo[a]quinolizine-4-ones 5a-d
The benzo[a]quinolizine ring system constitutes the struc-
tural framework of many naturally occurring alkaloids, e.g.,
berberine (Figure 2), and can also be found in compounds
targeting sleep disorder.11 Several methods to prepare this
structural framework have been developed,12 and recently,
Roy et al. demonstrated an elegant procedure to benzo[a]-
quinolizine-4-ones 5.13 Hence, by reacting 3,4-dihydroiso-
quinoline 4a with different â-oxodithioesters, benzo[a]-
quinolizine-4-thiones were obtained. These could be further
converted to benzo[a]quinolizine-4-ones 5 via methylation
of the sulfur followed by hydrolysis with NaOH (aqueous),
resulting in overall yields of 54-64% over three steps.
yield
entry
R1
Ph
Ph
Ph
Ph
Me
Me
Me
R
method equiv of 1 time product (%)a
1
2b
3
4
5
6
7
8
9
OMe
H
A
A
B
B
B
B
C
C
D
3
14 h
19 h
120 s
240 s
240 s
360 s
4 h
5a
5b
5a
5a
5c
5c
5c
5d
5d
65
64
91
98
54
55
86
49
69
3c
3
OMe
OMe
OMe
OMe
OMe
3.5
3.5
3.5d
3
3
3
C6H11 OMe
C6H11 OMe
2 h
120 s
a Isolated yield. b Imine 4b was used as the commercially available
hydrochloride salt. c 1a was added portionwise 2 + 1 equiv over 14 h. d 1b
was added portionwise 3 + 0.5 equiv over 240 s.
Figure 2. Examples of 2-pyridone containing natural products and
the alkaloid berberine containing the tricyclic benzo[a]quinolizine
ring system.
method, it was desirable to avoid the cumbersome use of
HCl(g). Thus, by using trifluoroacetic acid (TFA) instead
of HCl(g), a more practical procedure with better control of
the amount of acid would be obtained. Rewardingly, com-
pound 5c could be isolated in 86% yield by using 1.5%
(v/v) of TFA (3 equiv) in refluxing toluene (Table 1, entry
7), which corresponds to an increased isolated yield of 31%
(Table 1, entries 6 and 7). In addition, by exchanging 1,2-di-
chloroethane for toluene and applying MWI, it was possible
to shorten the reaction time substantially and compound 5d
could be prepared in 69% yield after irradiating for only 120 s.
In a recent study, it was shown that acyl Meldrum’s acid
derivatives react with nucleophiles via the R-oxoketene
intermediate (Figure 3) and not via a protonated species as
Provided that we could find conditions to use other imines
than thiazolines, we envisioned that our earlier developed
acyl-ketene imine cyclocondensation would be ideal to
construct multi ring-fused 2-pyridones and still allow vari-
ability in the substitution pattern. Indeed, the easy access to
(9) Kogure, N.; Nishiya, C.; Kitajima, M.; Takayama, H. Tetrahedron
Lett. 2005, 46, 5857-5861.
(10) Review: Du, W. Tetrahedron 2003, 59, 8649-8687.
(11) (a) Spurr, P. R. Tetrahedron Lett. 1995, 36, 2745-2748. (b)
Benovsky, P.; Stille, J. R. Tetrahedron Lett. 1997, 38, 8475-8478.
(12) Reviews: (a) Saraf, S.-U. Heterocycles 1981, 16, 803-841. (b)
Popp, F. D.; Watts, R. F. Heterocycles 1977, 6, 1189-1228. For a related
cyclocondensation, see: (c) Gulyakevich, O. V.; Kurman, P. V.; Mikhal-
′chuk, A. L. Chem. Nat. Compd. 2002, 38, 598-601.
(13) Roy, A.; Nandi, S.; Ila, H.; Junjappa, T. Org. Lett. 2001, 3, 229-
232.
(14) 1a-d were prepared according to a published procedure: Raillard,
S. P.; Chen, W. W.; Sullivan, E.; Bajjalieh, W.; Bhandari, A.; Baer, T. A.
J. Comb. Chem. 2002, 4, 470-474.
936
Org. Lett., Vol. 8, No. 5, 2006

formed via a [4+2] cycloaddition.17 Basic conditions favored
the formation of the 1,3-oxazine-4-one 6, and by using
conventional heating, it was formed almost exclusively
resulting in an isolated yield of 87% (Table 2, entry 3).
We theorized that one role of the acid could be to convert
preformed 1,3-oxazine-4-one 6 to the more acid-stable
dehydrated 2-pyridone 5. This was confirmed when pure 6
was subjected to MWI at 160 °C for 120 s with 1.5% (v/v)
TFA in 1,2-dichloroethane. 1,3-Oxazine-4-one 6 was thus
converted to a mixture of the 2-pyridone 5a and the 3,4-
dihydroisoquinoline 4a in a 2:3 ratio (Figure 3). In summary,
the role of the acid is not only to facilitate the dehydration
step in the formation of the 2-pyridone framework, but also
to provide a possibility to convert formed 1,3-oxazine-4-
one 6 to 2-pyridone 5a.
So far, acyl Meldrum’s acids 1 have been used as an acyl-
ketene source, but there are several other ways to generate
acyl-ketenes.18 We were now interested in exploring the
possibility to further widen the scope of the reaction by using
disubstituted acyl-ketenes and thereby obtaining 2-pyridones
with a different substitution pattern. 5,6-Disubstituted-1,3-
dioxine-4-ones 7 are a well-known acyl-ketene source that
can be used to generate disubstituted acyl-ketenes, and they
are readily available from â-ketoacids.19 Thus, 5,6-disubsti-
tuted-1,3-dioxine-4-one 7a was prepared from methyl 2-eth-
ylacetoacetate and then reacted with 3,4-dihydroisoquinoline
4a. This resulted in 69% yield of the 2,3-substituted benzo-
[a]quinolizine-4-one 5e (Scheme 1). To challenge the reac-
Table 2. Reaction of Dihydroisoquinoline 4a with Meldrum’s
Acid Derivative 1a under Different Reaction Conditions
ratioa
entry
method
TFA
solvent
5a/6
1
2
3
4
5
6
toluene (∆)
toluene (∆)
toluene (∆)
DCE (MWI)
DCE (MWI)
DCE (MWI)
100:0
3:14
1:19b
100:0
5:8
TEA
TFA
TEA
3:7
a Ratio determined by analysis of the crude mixture with 1H NMR.
b Isolated in 87% yield.
previously suggested.15 It was also shown that the 2-pyridone
could be prepared without addition of acid. From a practical
point of view, it would be ideal if neutral conditions could
be used. Therefore, to study this further, imine 4a was reacted
with acyl Meldrum’s acid 1a under acidic, neutral, and basic
conditions (Table 2, entries 1-6). This study showed that
Scheme 1
Figure 3. Conversion of isolated 1,3-oxazine-4-one 6 to 2-pyridone
5a and the 3,4-dihydroisoquinoline 4a.
the formation of 2-pyridone was clearly favored by acidic
conditions (Table 2, entries 1 and 4). Neutral conditions
resulted in more complex product mixtures, but both 2-pyr-
idone 5a and 1,3-oxazine-4-one 6 were observed by NMR
analysis of the crude mixtures (Table 1, entries 2 and 5).
1,3-Oxazine-4-ones are known products in the reaction
between imines and acyl-ketenes16 and are believed to be
tion further, unprotected 3,4-dihydroharmane 820 was reacted
with acyl-ketenes generated from both Meldrum’s acid
derivatives 1b-d and 5,6-disubstituted-1,3-dioxine-4-one 7a.
This resulted in good to moderate yields of the fused
tetracyclic 2-pyridones 9a-d (Scheme 1).
(15) Xu, F.; Armstrong, J. D.; Zhou, G. X.; Simmons, B.; Hughes, D.;
Ge, Z. H.; Grabowski, E. J. J. J. Am. Chem. Soc. 2004, 126, 13002-13009.
(16) (a) Pemberton, N.; Emtenas, H.; Bostrom, D.; Domaille, P. J.;
Greenberg, W. A.; Levin, M. D.; Zhu, Z. L.; Almqvist, F. Org. Lett. 2005,
7, 1019-1021. (b) Yamamoto, Y.; Watanabe, Y. Chem. Pharm. Bull. 1987,
35, 1871-1879. (c) Yamamoto, Y.; Watanabe, Y.; Ohnishi, S. Chem.
Pharm. Bull. 1987, 35, 1860-1870. (d) Masayuki, S.; Hiromichi, O.;
Tetsuzo, K. Chem. Pharm. Bull. 1984, 32, 2602-2608.
(18) Review: Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994,
1219-1248.
(19) Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull. 1983,
31, 1896-1901.
(17) Sato, M.; Ogasawara, H.; Yoshizumi, E.; Kato, T. Chem. Pharm.
Bull. 1983, 31, 1902-1909.
(20) Compound 8 was prepared via a Bischler-Napieralski reaction; see
Supporting Information.
Org. Lett., Vol. 8, No. 5, 2006
937

This tetracyclic ring system is also the basic structural core
of several different indole alkaloids. Recently, Kogure et al.
isolated a new indole alkaloid named sempervilam (Figure
2).9 They also described a synthetic route starting from 3,4-
dihydroharman, which was converted to dihydrosempervilam
9e in 23% over three steps. Aromatization of the C-ring then
yielded the desired alkaloid. Knowing that 3,4-dihydrohar-
man 8 worked well in the acyl-ketene imine cycloconden-
sation for the preparation of the tetracyclic compounds 9a-
d, we aimed for a direct approach to the analogous
pentacyclic dihydrosempervilam 9e. The precursor to the
desired cyclic R-oxoketene, 5,6-disubstituted-1,3-dioxine-4-
one 7b, was easily prepared according to a published
procedure.19 Dihydrosempervilam 9e was then obtained in
56% yield by reacting 7b with 3,4-dihydroharman 8 under
MWI for 5 min. By simply increasing the reaction time to
23 min and adding the acyl-ketene source 7b portionwise,
this could be improved to 77% (Scheme 2). This simple short
procedure to dihydrosempervilam clearly demonstrates the
efficiency of this method as a route to multi ring-fused
2-pyridones.
Scheme 2
the 1,3-oxazine-4-one 6 was selectively obtained in a high
yield. Further investigations regarding the scope and limita-
tions of the synthesis of 2-pyridones and 1,3-oxazinones via
acyl-ketenes and imines are ongoing in our research group.
In conclusion, we have reported a short, fast, and simple
pathway to substituted multi ring-fused 2-pyridones 5a-e
and 9a-e, via an acyl-ketene imine cyclocondensation.
Different conditions were investigated, and the use of TFA
instead of solutions containing dry HCl(g) proved to be more
efficient and practical. The methodology worked well with
different sources of acyl-ketenes and with different types of
ring-fused imines, thus providing an excellent platform for
future library synthesis of various 2-pyridone-containing
heterocycles. In addition, by switching to basic conditions,
Acknowledgment. We thank the Swedish Natural Sci-
ence Research Council and the Knut and Alice Wallenberg
foundation for financial support.
Supporting Information Available: Experimental pro-
cedures and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052998E
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Org. Lett., Vol. 8, No. 5, 2006