Flexible strategy for differentially 3,5-disubstituted 4-oxypyridin-2(1H)- ones based on site-selective Pd-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ol062721u

(Chemical Equation Presented) 3,5-Dihalogeno-4-methoxy-N-methylpyridin- 2(1H)-ones have been shown to undergo single Suzuki coupling reactions in a site-selective fashion. Monoarylations occur at the C-5 position preferentially, thus leaving the remaining

Full text of DOI:10.1021/ol062721u

ORGANIC
LETTERS
2007
Vol. 9, No. 2
271-274
Flexible Strategy for Differentially
3,5-Disubstituted
4-Oxypyridin-2(1H)-ones Based on
Site-Selective Pd-Catalyzed
Cross-Coupling Reactions†
David Conreaux,‡ Emmanuel Bossharth,‡ Nuno Monteiro,*,‡ Philippe Desbordes,§
Jean-Pierre Vors,*,§ and Genevie`ve Balme*,‡
Laboratoire de Synthe`se Organome´tallique et Mole´cules BioactiVes, CNRS UMR 5181,
UniVersite´ Claude Bernard- Lyon 1, ESCPE Lyon 43, BouleVard du 11 NoVembre
1918, 69622 Villeurbanne, France, and Bayer CropScience, 14/20 rue Baizet,
BP9163, 69623 Lyon Cedex 09, France
balme@uniV-lyon1.fr; monteiro@uniV-lyon1.fr; jean-pierre.Vors@bayercropscience.com
Received November 7, 2006
ABSTRACT
3,5-Dihalogeno-4-methoxy-N-methylpyridin-2(1H)-ones have been shown to undergo single Suzuki coupling reactions in a site-selective fashion.
Monoarylations occur at the C-5 position preferentially, thus leaving the remaining C-3 halide free for further functionalization, to finally
access differentially 3,5-disubstituted 2-pyridones. This two-step strategy has been applied to the elaboration of the 3-acyl-5-aryl-4-oxy-2-
pyridone subunit that is prevalent in numerous bioactive natural products.
The 3,5-disubstituted 4-oxypyridin-2(1H)-one system is
found in several structurally and biologically interesting
alkaloids which include a small group of antibiotic fungal
metabolites featuring a p-hydroxyphenyl (or phenyl) moiety
at the C-5 position (Figure 1). These natural products have
been shown to display a wide range of biological properties,
including antifungal, antiinsecticidal, and antitumoral proper-
ties.1 From a synthetic point of view, this class of compounds
has aroused a significant amount of interest, and various
strategies have already been developed to access the central
5-aryl-2-pyridone nucleus to be further elaborated to the
natural products. The arylpyridone nucleus was generally
built up via condensation of preassembled acyclic precursors
already bearing the requisite aryl moiety.2 Occasionally, Pd-
catalyzed cross-coupling reactions have been used to install
the aryl group on precyclized intermediates, although, to the
best of our knowledge, the latter were in all cases hetero-
aromatic precursors of the desired 4-oxy-2-pyridones.3
(1) (a) Jayasinghe, L.; Abbas, H. K.; Jacob, M. R.; Herath, W. H. M.
W.; Nanayakkara, N. P. D. J. Nat. Prod 2006, 69, 439. (b) Gutierrez-Cirlos,
E. B.; Merbitz-Zahradnik, T.; Trumpower, B. L. J. Biol. Chem. 2004, 279,
8708. (c) Zhang, C.; Jin, L.; Mondie, B.; Mitchell, S. S.; Castelhano, A.
L.; Cai, W.; Bergenhem, N. Bioorg. Med. Chem. Lett. 2003, 13, 1433. (d)
Schmidt, K.; Riese, U.; Li, Z.; Hamburger, M. J. Nat. Prod. 2003, 66, 378.
(e) Sakemi, S.; Bordner, J.; DeCosta, D. L.; Dekker, K. A.; Hirai, H.;
Inagaki, T.; Kim, Y.-J.; Kojima, N.; Sims, J. C.; Sugie, Y.; Sugiura, A.;
Sutcliffe, J. A.; Tachikawa, K.; Truesdell, S. J.; Wong, J. W.; Yoshikawa,
N.; Kojima, Y. J. Antibiot. 2002, 55, 6. (f) Hirano, N.; Kohno, J.; Tsunoda,
S.; Nishio, M.; Kishi, N.; Okuda, T.; Kawano, K.; Komatsubara, S.;
Nakanishi, N. J. Antibiot. 2001, 54, 421. (g) Takahashi, S.; Uchida, K.;
Kakinuma, N.; Hashimoto, R.; Yanagisawa, T.; Nakagawa, A. J. Antibiot.
1998, 51, 1051.
† Dedicated to the memory of Marcial Moreno-Man˜as.
‡ Universite´ Lyon 1.
§ Bayer CropScience.
10.1021/ol062721u CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/23/2006

different substituents to the pyridone ring in a highly
convergent and flexible manner.6 We envisioned this ap-
proach being particularly useful for the rapid generation of
libraries of simplified analogues of bioactive natural 5-aryl-
2-pyridone alkaloids. We report herein our preliminary results
toward this goal.
As we began to assess our strategy, we required a method
to effect the dihalogenation of N-alkyl-4-alkoxy-2-pyridones
I at the C-3 and C-5 positions. Although scattered dibromi-
nations of the related aromatic 2,4-dioxypyridines had been
previously reported,3c,7 no general method was available from
the literature to achieve the dihalogenation of the corre-
sponding N-substituted pyridones. With this backdrop, there
was an opportunity for us to develop an effective, scalable
method for the preparation of these potentially useful 3,5-
dihalogeno-2-pyridones (II). Our initial efforts focused on
the preparation of the diiodo derivatives, and the reactivity
of N,O-dimethylpyridone 1, as a model substrate, was first
investigated toward a series of iodination reagents and
reaction conditions. Although the expected iodination at the
C-3 position4a,8 was observed in the presence of various
iodonium generating systems (i.e., NIS; ICl/AcOH; or bis-
Figure 1. Some representative, naturally occurring 5-aryl-4-
oxypyridin-2(1H)-ones.
9
In connection with our ongoing program devoted to the
synthesis of structurally diversified pyridone derivatives in
a search for new drug candidates,4 we became interested in
the synthetic utility of 3,5-dihalogenated 4-alkoxy-2-pyri-
dones for the synthesis of differentially difunctionalized
2-pyridones by means of site-selective Pd-catalyzed C-C
bond forming processes (Scheme 1).5 Indeed, the probable
(sym-collidine)iodine(I), PF6 ), further iodination at the C-5
position proved to be extremely troublesome. After consider-
able effort, we found that the desired transformation could
be achieved by using superelectrophilic iodine(I) trifluoro-
acetate generated in situ from NIS and catalytic TFA.10 On
the basis of this, we devised a convenient, mild, and high-
yielding procedure for the preparation of milligram to
multigram quantities of diiodopyridone 2a. Interestingly, the
method was also effective for the preparation of the di-
brominated pyridone 2b by simply using NBS in lieu of NIS
(Scheme 2).
Scheme 1. Convergent Approach to Differentially
3,5-Disubstituted 4-Alkoxy-2-pyridones
Scheme 2. Dihalogenation of N-Alkyl-4-alkoxy-2-pyridone 1
difference in reactivity between the C-3 and C-5 positions
was expected to allow the successive introduction of two
(2) For selected examples, see: (a) Williams, D. R.; Sit, S. Y. J. Org.
Chem. 1982, 47, 2846. (b) Williams, D. R.; Bremmer, M. L.; Brown, D.
L.; D’Antuono, J. J. Org. Chem. 1985, 50, 2807. (c) Rigby, J. H.; Burkhardt,
F. J. J. Org. Chem. 1986, 51, 1374. (d) Rigby, J. H.; Qabar, M. J. Org.
Chem. 1989, 54, 5852. (e) Buck, J.; Madeley, J. P.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1992, 67. (f) Snider, B. B.; Lu, Q. J. Org. Chem.
1996, 61, 2839. (g) Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217.
(h) Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc. 2002, 124,
5774. (i) Fu¨rstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Tetrahedron
2004, 60, 9543. (j) Snider, B. B.; Che, Q. Org. Lett. 2004, 6, 2877.
(3) (a) Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller, K. A. M.; Dunn,
S. H. J. Chem. Soc., Perkin Trans. 1 1999, 765. (b) Rao Irlapati, N.; Baldwin,
J. E.; Adlington, R. M.; Pritchard, G. J.; Cowley, A. Org. Lett. 2003, 5,
2351. (c) Rao Irlapati, N.; Adlington, R. M.; Conte, A.; Pritchard, G. J.;
Marquez, R.; Baldwin, J. E. Tetrahedron 2004, 60, 9307.
(4) For previous reports from this group, see: (a) Bossharth, E.;
Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003, 5, 2441. (b) Aillaud,
I.; Bossharth, E.; Conreaux, D.; Desbordes, P.; Monteiro, N.; Balme, G.
Org. Lett. 2006, 8, 1113.
(5) For an excellent review on site-selective cross-coupling reactions of
multiple halogenated heterocycles, see: Schro¨ter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
Having secured a reliable preparative method to the
dihalogenopyridones, we next focused our attention on their
(6) Previously, the simple 3,5-dibromo-2-pyridone (3,5-dibromo-2-
hydroxypyridine) failed to undergo Suzuki bis-coupling with p-methoxy-
phenylboronic acid: Bracher, F.; Daab, J. Eur. J. Org. Chem. 2002, 2288.
(7) (a) den Hertog, H. J. Recl. TraV. Chim. 1945, 64, 85. (b) Kolder, C.
R.; den Hertog, H. J. Recl. TraV. Chim. 1953, 72, 853. (c) den Hertog, H.
J.; Combe, W. P.; Kolder, C. R. Recl. TraV. Chim. 1954, 73, 704. (d) Wang,
C.-S.; McGee, T. W. U.S. Patent (1972), US 3637722.
(8) Devadas, B.; Rogers, T. E.; Gray, S. H. Synth. Commun. 1995, 25,
3199.
(9) This reagent is known to effect the diiodination of pyridinols:
Rousseau, G.; Robin, S. Tetrahedron Lett. 1997, 38, 2467.
(10) This reagent was introduced by Colobert and co-workers: Castanet,
A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron Lett. 2002, 43, 5047. Note
that the group of Olah had previously introduced iodine(I) trifluoromethane-
sulfonate as a powerful reagent for the iodination of deactivated aromatics:
Olah, G. A.; Wang, Q.; Sandford, G.; Surya Prakash, G. K. J. Org. Chem.
1993, 58, 3194.
272
Org. Lett., Vol. 9, No. 2, 2007

application in Pd-catalyzed cross-coupling reactions. At this
point, predictions regarding the C-3/C-5 selectivity were not
obvious. We could nevertheless hypothesize that steric factors
may intervene in the relative rates of coupling and possibly
favor cross-coupling at the less-hindered C-5 position.11 We
thus selected the reaction of 2a with p-methoxyphenylboronic
acid under Suzuki-type conditions as a model system.
Pleasingly, early experiments conducted with various catalyst
systems have established the coupling reaction to proceed
essentially at C-5, giving the desired 5-aryl-2-pyridone 3 as
the only monocoupled product.12 After further exploration
of the reaction parameters, we determined that the system
Pd/TPPTS/i-Pr2NH13 in aqueous MeCN was the most effec-
tive to achieve the desired coupling reaction in reasonably
good yield (72%) (Scheme 3). Small amounts (ca. 15%) of
excellent yields (Table 1). Remarkably, both electron-rich
and electron-poor boronic acids were found to be suitable
partners in this process.
Table 1. Suzuki Monocoupling of 3-Bromo-5-iodo-2-pyridone
6 with Various Boronic Acidsa
Scheme 3. Site-Selective Suzuki Coupling of 2a
a Conditions: 1.4 equiv of boronic acid, 5 mol % of Pd(OAc)2, 15 mol
% of TPPTS, i-Pr2NH (2.5 equiv), MeCN/H2O (3:1), 80 °C, 16 h. b Isolated
yields.
the bis-arylated 2-pyridone (4) were also formed as a slight
excess of the boronic acid was needed to ensure complete
conversion of the diiodo compound.14
We then briefly explored the reactivity of the remaining
halogen atom at C-3 with the aim of further diversifying the
5-aryl-2-pyridones (Scheme 5). For example, Pd-catalyzed
reduction of 3-bromo-2-pyridone 7a by sodium formate
provided access to the corresponding monosubstituted alkoxy-
pyridone 8, a potential precursor of naturally occurring
4-oxy-2-pyridones.2e The bromine atom acts here as a
removable blocking group that allows regioselective mono-
substitution of the pyridone at C-5.15 Pd-catalyzed C-C bond
forming processes have also been investigated. As illustrated
by the synthesis of 3-(p-chloro)-phenyl-2-pyridone 9 (81%
isolated yield), Suzuki cross-coupling reactions of bromine
derivative 7a with arylboronic acids proved very successful
As an alternative, and a potentially enhanced site-selective
approach to the 5-aryl-2-pyridones, we next examined the
reactivity of 3-bromo-5-iodo-2-pyridone 6 with the hope that
the lower capability of the C-Br bond to oxidative addition
to palladium would avoid formation of the bis-arylated side
product. Thus, 6 was prepared in two high-yielding steps
from 1 as depicted in Scheme 4 and subjected to the previous
Scheme 4. Synthesis of 2-Pyridone 6 Bearing Two
Distinguishable Halides
(11) In a study toward pyridovericin, Baldwin and co-workers have
examined the Suzuki coupling of the isomeric 3,5-dibromo-2,4-dimethoxy-
pyridine with p-methoxyphenylboronic acid, which afforded a 3:1 ratio of
the C5-C3 isomers. See ref 3c.
(12) The structure of 3 has been secured by X-ray analysis. See
Supporting Information.
(13) TPPTS: tris(3-sulfonatophenyl)phosphane trisodium salt.
(14) It should be noted that reaction of 3,5-dibromo-2-pyridone 2b under
identical conditions proved rather sluggish and afforded inseparable mixtures
of mono- and bis-arylated adducts.
(15) It is worth mentioning that the related C-5 (or C-3) monoarylated
4-methoxy-2-pyrones have previously been prepared by Suzuki coupling
of the corresponding monohalogenated pyrones: (a) Cerezo, S.; Moreno-
Man˜as, M.; Pleixats, R. Tetrahedron 1998, 54, 7813. (b) Marrison, L. R.;
Dickinson, J. M.; Fairlamb, I. J. S. Bioorg. Med. Chem. Lett. 2003, 13,
2667.
cross-coupling reaction. Gratifyingly, displacement of the
iodine atom took place selectively, affording the desired
monosubstituted product 7a, exclusively, in 88% isolated
yield. Accordingly, application of this strategy to a series of
arylboronic acids furnished the corresponding 5-aryl-3-
bromo-2-pyridones as single products in good to
Org. Lett., Vol. 9, No. 2, 2007
273

Scheme 5. Diversification of 5-Aryl-3-halo-2-pyridones
Scheme 6. TFA-Promoted Hydration of Alkynylpyridone 10
on sequential, site-selective, Pd-catalyzed cross-coupling
reactions on dihalogenated 2-pyridone scaffolds.
The chemistry described herein should find useful ap-
plications most probably in the production of simplified
analogues of natural alkaloids or, potentially, in total
synthesis. Further studies into the synthetic potential of 3,5-
dihalogenated 2-pyridones are currently underway in our
laboratories.
Acknowledgment. This research was assisted financially
by a grant to E.B. and D.C. from Bayer CropScience and
the Centre National de la Recherche Scientifique. We thank
Dr. E. Jeanneau (Centre de Diffractome´trie Henri Long-
chambon, Universite´ Claude Bernard, Lyon 1) for the X-ray
crystallographic analysis.
with the system Pd/PPh3/K2CO3 in toluene/EtOH, thereby
opening access to unsymmetrically bis-arylated pyridones.16
On the other hand, 7a did not undergo facile cross-coupling
reactions with terminal acetylenic compounds. For example,
attempts to couple 7a with trimethylsilylacetylene under
classical Sonogashira conditions only afforded low yields
(<15%) of the corresponding 3-alkynyl-2-pyridone 10.
However, the iodine derivative 3 could alternatively be
successfully used in place of 7a to furnish 10 in a satisfactory
96% isolated yield.
Supporting Information Available: Experimental pro-
cedures, characterization for all compounds, and CIF file for
compound 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL062721U
(16) Symmetrically 3,5-diarylated 2-hydroxypyridines had been previ-
ously prepared from 3,5-dihalopyridines and then converted to the corre-
sponding pyridones: Tagat, J. R.; McCombie, S. W.; Barton, B. E.; Jackson,
J.; Shortall, J. Bioorg. Med. Chem. Lett. 1995, 5, 2143. See also ref 6.
(17) It is likely that the trimethylsilyl group is initially cleaved from the
alkyne which then undergoes acidic hydrolysis to the corresponding
3-acetylpyridone. The acid-induced desilylation of silylacetylenes has been
documented: Siehl, H.-U.; Kaufmann, F.-P.; Hori, K. J. Am. Chem. Soc.
1992, 114, 9343.
(18) Usually, acid-promoted hydrations of alkynes require metal catalysis,
typically Hg(II) salts. For a review, see: Beller, M.; Seayad, J.; Tillack,
A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. For metal-free methods,
see: Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett
2004, 2175 and references therein.
As an additional synthetic application of this work, it was
found that trimethylsilylacetylenic compound 10 could be
easily converted to the corresponding 3-acetyl-2-pyridone
11 upon concomitant desilylation and regioselective hydra-
tion of the alkyne in TFA (Scheme 6).17,18 3-Acetyl-5-aryl-
4-oxy-2-pyridones have been the focus of considerable
interest, notably as potential precursors of the more elaborate
natural 3-acyl-2-pyridones.19
(19) 3-Acetyl-4-oxypyridones have been used as intermediates in the
syntheses of tenellin and ilicicolin H. See refs 2a,b. For other approaches
to 3-acetyl-5-aryl-4-oxypyridones, see refs 2c and 3a,b.
In conclusion, we have developed a new, convergent
synthetic entry to 3,5-disubstituted 4-oxy-2-pyridones based
274
Org. Lett., Vol. 9, No. 2, 2007