Synthesis of 6-substituted-4-hydroxy-2-pyridinones via intramolecular ketene trapping of functionalized enamine-dioxinones

Article abstract of DOI:10.1021/ol202028t

The synthesis of various 6-substituted-4-hydroxy-2-pyridinones is reported. The functionalized keto-dioxinones were constructed via a diethylzinc mediated crossed Claisen condensation reaction and subsequent enamine formation, thermolysis, and cyclization

Full text of DOI:10.1021/ol202028t

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5156–5159
Synthesis of 6-Substituted-4-Hydroxy-
2-pyridinones via Intramolecular Ketene
Trapping of Functionalized
Enamine-Dioxinones
Bhavesh H. Patel,† Andrew M. Mason,‡ and Anthony G. M. Barrett*,†
Department of Chemistry, Imperial College, London SW7 2AZ, U.K., and
GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
agm.barrett@imperial.ac.uk
Received July 27, 2011
ABSTRACT
The synthesis of various 6-substituted-4-hydroxy-2-pyridinones is reported. The functionalized keto-dioxinones were constructed via a
diethylzinc mediated crossed Claisen condensation reaction and subsequent enamine formation, thermolysis, and cyclizationÀaromatization
providing the pyridinone unit.
The pyridinone structural motif is present in a range of
natural products1 and biologically active molecules,2 with
6-substituted-4-hydroxy-2-pyridinones being key inter-
mediates in their synthesis. Notably these heterocycles
are used as templates in drug discovery,2,3 used in the total
synthesis of natural products including novel human chy-
mase inhibitors produced by Penicillium sp.,4 and em-
ployed in the preparation of related heteroaromatics.5
The synthesis of 4-hydroxy-6-methyl-2-pyridinone was
first reported by Collie via treatment of triacetic lactone (4-
hydroxy-6-methyl-2-pyrone) with ammonia.6 Soon after,
the same pyridinone was synthesized using a condensation
reaction between a malonic ester and a β-aminocrotonate
followed by decarboxylation.7 Since then, several other
routes with varying yields have been reported for the
construction of 6-substituted-4-hydroxy-2-pyridinones.
These include reactions of functionalized enamines with
carbon suboxide (C3O2),8 condensation of ethyl acetoace-
tate with benzonitrile followed by cyclization,9 acid-
mediated rearrangement of 2-amino-4-pyrones,10 and re-
action of Schiff’s bases with diphenyl malonate and sub-
sequent retro-ene reaction.11
Following on from our preceding work utilizing
dioxinones,12 we envisaged a versatile route toward 6-sub-
stituted-4-hydroxy-2-pyridinones 1 via cyclization of
enamine-keto-ketenes 2 (Scheme 1). Such reactive inter-
mediates2 should be available from enamine-dioxinones3,
which could be prepared from functionalized keto-dioxinones
† Imperial College.
‡ GlaxoSmithKline R&D.
(1) Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27, 1168.
(2) Groutas, W. C.; Stanga, M. A.; Brubaker, M. J.; Huang, T. L.;
Moi, M. K.; Carroll, R. T. J. Med. Chem. 1985, 28, 1106.
(3) Demuner, A. J.; Valente, V. M. M.; Barbosa, L. C. A.; Rathi,
A. H.; Donohoe, T. J.; Thompson, A. L. Molecules 2009, 14, 4973.
(4) (a) Shimatani, T.; Hosotani, N.; Ohnishi, M.; Kumagai, K.; Saji,
I. J. Antibiot. 2006, 59, 29. (b) Vegi, S. R.; Boovanahalli, S. K.; Sharma,
A. P.; Mukkanti, K. Tetrahedron Lett. 2008, 49, 6297.
(5) (a) Findlay, J. A.; Krepinsky, J.; Shum, F. Y.; Tam, W. H. J. Can.
J. Chem. 1976, 54, 270. (b) Hajdok, S.; Conrad, J.; Leutbecher, H.;
Strobel, S.; Schleid, T.; Beifuss, U. J. Org. Chem. 2009, 74, 7230.
(6) (a) Collie, J. N. J. Chem. Soc. 1891, 59, 607. For other examples
(7) Knovenagel, E.; Fries, A. Chem. Ber. 1898, 31, 767.
(8) Ziegler, E.; Hradetzky, F. Monatsh. Chem. 1964, 95, 1247.
(9) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343.
(10) Kato, T.; Kubota, Y.; Tanaka, M.; Takahashi, H.; Chiba, T.
Heterocycles 1978, 9, 841.
(11) Ito, K.; Miyajima, S. J. Heterocyclic Chem. 1992, 29, 1037.
(12) Patel, B. H.; Heath, S. F .A.; Mason, A. M.; Barrett, A. G. M.
Tetrahedron Lett. 2011, 52, 2258.
€
using a similar procedure, see:(b) Wislicenus, W.; Schollkopf, K.
J. Prakt. Chem. 1917, 95, 269. (c) Kato, T.; Yamamoto, Y.; Takeda,
S. Chem. Pharm. Bull. 1973, 21, 1047. (d) Giddens, A. C.; Nielsen, L.;
Boshoff, H. I.; Tasdemir, D.; Perozzo, R.; Kaiser, M.; Wang, F.;
Sacchettini, J. C.; Copp, B. R. Tetrahedron 2008, 64, 1242.
r
10.1021/ol202028t
Published on Web 08/31/2011
2011 American Chemical Society

4, which in turn could be generated from the parent
dioxinone 5 and commercially available acids 6 via C-
acylation of the derived enolate.
Table 1. Acyl Imidazolide Formation Followed by Claisen
Condensation with Dioxinone 5
Scheme 1. Retrosynthetic Strategy
Herein, we report our initial results in the facile three-step
synthesis of diversely substituted pyridinones 1 using a key
intramolecular ketene trappingÀcyclizationÀaromatiza-
tion sequence.
The procedure for our previously reported synthesis of
methyl keto-dioxinone 4a13 (Scheme 2) using a crossed
Claisen condensation reaction was applied to the synthesis
of other derivatives 4bÀg (Table 1). Acids 6bÀg were
allowed to react with carbonyl diimidazole (CDI) at 0 °C
to give imidazolides 7bÀg in 76À96% yield.14 The lithium
enolate of dioxinone 5 was treated with diethylzinc and
following transmetalation,15 to presumably a less basic
alkylzincate species, allowed to react with imidazolides
7bÀg at À10 °C to provide the functionalized keto-
dioxinones in 58À73% yield with no byproduct forma-
tion (Table 1). We successfully synthesized dioxinones
with an isobutyl 4b (entry 1) and benzyloxymethyl 4c
(entry 2) ketone. Furthermore, the protected amino-
methyl-ketone 4d (entry 3) and piperidine-3-ketone 4e
(entry 4) derivatives were efficiently applied in this
chemistry. The 4-methoxy-phenyl 4f (entry 5) and the
inherently reactive furanyl 4g (entry 6) derivatives were
slightly less efficient in the C-acylation step. However,
subsequent heterocyclization was comparably efficient
to the other examples.
a Isolated yield of crude 7 following aqueous workup. b Isolated yield
following chromatography.
Scheme 2. Formation of Enamine-Dioxinone 3a
complete conversion to the methyl enamine-dioxinone was
achieved with ammonium acetate in ethanol at room
temperature.17
Keto-dioxinones 4aÀh18 were successfully converted to
the enamine-dioxinone derivatives 3aÀh (Scheme 3).19
Direct thermolysis of these intermediates proceeded
by addition to toluene at reflux to generate the
Initially we investigated the generation of methyl enam-
ine-dioxinone 3a from keto-dioxinone 4a (Scheme 2). It
was hoped that the dioxinone moiety would be stable upon
treatment with ammonium acetate as this had previously
been used to form β-enamine-esters from β-keto-esters.16
Fortunately, in this case, heating was not required and
(17) Formation of the enamine-dioxinones was confirmed by 1H
NMR spectroscopy in d6-acetone; enamine-dioxinones were not purified
by chromatography due their instability and hydrolysis back to the keto-
derivative in the presence of silica.
(18) For procedure to prepare keto-dioxinone 4h, see analogous
procedure for allyl ester keto-dioxinone: Navarro, I.; Basset, J.-F.;
Hebbe, S.; Major, S. M.; Werner, T.; Howsham, C.; Brackow, J.;
Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130, 10293.
(19) It was essential to store the enamine-dioxinones in the freezer
and use as soon as possible in the subsequent step. A‘one-pot’ procedure
using keto-dioxinone 4a and NH4OAc in PhMe (0.012 M) was at-
tempted; however, this gave a mixture of pyridinone and pyranone
products (2:1, 84%).
(13) Patel, B. H.; Mason, A. M.; Patel, H.; Coombes, R. C.; Ali, S.;
Barrett, A. G. M. J. Org. Chem. 2011, 76, 6209.
(14) Compounds 7bÀg were characterized by 1H and 13C NMR
spectroscopy, and HRMS for those that were stable, and then used
immediately in the next step; commercially available 7a was used.
(15) Morita, Y.; Masaaki, S.; Noyori, R. J. Org. Chem. 1989, 54,
1785.
(16) (a) Perlman, N.; Etinger, M.; Niddam-Hildesheim, V.; Abramov,
M. WO Patent 2009, 064476. (b) Tang, W.; Wu, S.; Zhang, X J. Am.
Chem. Soc. 2003, 125, 9570.
Org. Lett., Vol. 13, No. 19, 2011
5157

Scheme 3. Enamine Formation and Pyridinone Synthesis via Intramolecular Ketene Trappinga
a Analysis by 1H NMR spectroscopy showed disappearance of the CH2 protons (singlet peak at ∼4.1À3.3 ppm) R to the ketone, and the appearance of
the CH enamine proton (singlet peak at ∼4.6À4.4 ppm), and an upfield shift of the dioxinone CH proton (singlet peak from ∼5.5À5.3 ppm to ∼4.9À
4.7 ppm).b Isolated yield.
enamine-acyl-ketenes 2aÀh in situ,20 which underwent
intramolecular cyclization to give the aromatic pyr-
Table 2. Synthesis of N-Benzyl-4-hydroxy-6-methyl-2-pyridi-
idinones 1aÀh (Scheme 3). High dilution was essential
none 8
to avoid intermolecular reaction, and slow addition to
toluene at reflux was optimal in ensuring clean
conversion.21
The pyridinones 1aÀh were isolated as solids following
trituration, without the need for chromatography, in
84À93% yield (Scheme 3). Protected alcohol, amine, and
ester functionalities were all successfully applied in the
transformation (see 1cÀe,h) thereby allowing for the in-
corporation of alternative groups away from the pyridi-
none ring, in analogue synthesis.
Keto-dioxinone 4a was allowed to react with benzyl-
amine in a similar fashion.22 However, under reaction
conditions in ethanol used in the synthesis of enamines
3, subsequent trapping gave only acyclic adduct 9 and
none of the desired N-benzyl-pyridinone 8 (Table 2,
entry 1). Even with the use of stoichiometric amounts
of the amine (Table 2, entries 2 and 3), byproduct 9 was
obtained presumably due to the presence of water in
the reaction mixture. This was overcome by prepara-
tion of the enamine in the presence of molecular sieves
in dichloromethane and subsequent intramolecular
PhCH2NH2
(equiv)
yield of 8a yield of 9a
entry
conditions
EtOH
(%)
(%)
1b
2.5
1.0
1.0
1.0
0
0
82
45
48
0
2b
EtOH
3c
À
0
4b,d
MS 4 A, CH2Cl2
75
˚
a Isolated yield following trituration with Et2O. b Initial treatment
with benzylamine and subsequent thermolysis. c Addition of 4a to a
mixture of PhCH2NH2 and PhMe at reflux. d EtOAc was added to
solubilize the enamine dioxinone.
trapping, which gave the pyridinone 8 in 75% yield
over the two steps (Table 2, entry 4).
(20) Hyatt., J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984,
49, 5105.
In conclusion, we have extended the use of dioxinones to
develop a general methodology for the synthesis of 6-sub-
stituted-4-hydroxy-2-pyridinones in 45À64% overall yield
from inexpensive starting materials, with only one purifi-
cation required. Enamine-dioxinones were successfully
used as cyclization precursors containing both electrophi-
lic and nucleophilic entities. Further applications are in
(21) Typical experimental procedure: Keto-dioxinone 4aÀh (0.60
mmol) and NH4OAc (0.23 g, 3.00 mmol) were stirred in absolute EtOH
(2.5 mL). After 2À3 h, the solvent was evaporated, EtOAc (10 mL)
added, and the resultant solid filtered. The solvent was evaporated to
provide crude enamine-dioxinone 3aÀh, which in PhMe (5 mL) were
added to PhMe (50 mL) at reflux over 30 min. After 4 h, the solvent was
evaporated and the residue triturated with Et2O (25 mL) to provide the
desired pyridinone 1aÀh.
(22) We thank one of the referees for suggesting this experiment.
5158
Org. Lett., Vol. 13, No. 19, 2011

progress toward the synthesis of alternative pyridinone
derivatives and will be reported in due course.
GlaxoSmithKlineforgrant support throughthecollabora-
tive EPSRC-Pharma Synthesis Programme (to B.H.P.).
Acknowledgment. We thank P. R. Haycock and R. N.
Sheppard (Imperial College London) for high-resolution
NMR spectroscopy, GlaxoSmithKline for the generous
endowment (to A.G.M.B.), and the Engineering and
Physical Sciences Research Council (EPSRC) and
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra corre-
sponding to all isolated and purified compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5159