Palladium-mediated three-component synthesis of furo[2,3-b]pyridones by one-pot coupling of 3-lodopyridones, alkynes, and organic halides

Article abstract of DOI:10.1021/ol034644y

(Matrix presented) The one-pot assembly of 4-alkoxy-3-iodo-2-pyridones, terminal alkynes, and organic halides has been achieved by integration of two sequential palladium-mediated cross-coupling reactions - Sonogashira and Wacker-type heteroannulation pro

Full text of DOI:10.1021/ol034644y

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2441-2444
Palladium-Mediated Three-Component
Synthesis of Furo[2,3-b]pyridones by
One-Pot Coupling of 3-Iodopyridones,
Alkynes, and Organic Halides
Emmanuel Bossharth,† Philippe Desbordes,‡ Nuno Monteiro,† and
,†
Genevie`ve Balme*
Laboratoire de Chimie Organique 1, CNRS UMR 5622, UniVersite´ Claude Bernard,
Lyon I, CPE. 43, Bd du 11 NoVembre 1918, 69622 Villeurbanne, France, and
Bayer CropScience, 14/20 rue Baizet, 69623 Lyon, France
balme@uniV-lyon1.fr
Received April 15, 2003
ABSTRACT
The one-pot assembly of 4-alkoxy-3-iodo-2-pyridones, terminal alkynes, and organic halides has been achieved by integration of two sequential
palladium-mediated cross-coupling reactions−Sonogashira and Wacker-type heteroannulation processes−and subsequent deprotection of the
alkoxy group to afford furo[2,3-b]pyridones.
Chemical processes that allow assembly of several flexible,
readily available building blocks in a single operation are
drawing increasing attention in the search for new efficient,
diversity-oriented synthetic methodologies, and particularly
those directed toward heterocycles. Such processes are highly
desirable for the rapid generation of libraries of small drug-
like molecules for high-throughput screaning.1 The design
of multicomponent syntheses often relies on the integration
of multiple individual reactions to give a one-pot synthetic
operation, a new concept that also addresses important eco-
nomical and environmental issues.2,3 As part of a program
aimed at evaluating the synthetic potential of 4-alkoxy-2-
pyridones (1) as precursors of new drug-like heterocycles,
we envisioned that their halogenated analogues 2 could be
particularly attractive substrates for the development of a
Pd-mediated three-component synthesis of furo[2,3-b]pyri-
dones 7. The strategy would consist of assembling various
iodopyridones, alkynes, and organic halides by means of two
sequential cross-coupling reactions (Scheme 1).4 Hence, the
unprecedented cross-coupling of 3-alkynylpyridones 4sob-
tained in situ from 2 by Sonogashira coupling reactions
with organic halides, if successful, should produce furopy-
(2) The concept of integrated chemical processes has been recently
introduced by Otera: Orita, A.; Yoshioka, N.; Struwe, P.; Braiser, A.;
Beckmann, A.; Otera, J. Chem. Eur. J. 1999, 5, 1355-1363.
† Universite´ Claude Bernard.
‡ Bayer CropScience.
(3) For leading references on Pd-based multicomponent reactions relying
on integrated chemical processes, see: (a) Grigg, R.; Liu, A.; Shaw, D.;
Sunganthan, S.; Washington, M.; Woodall, D.; Yoganathan, G. Tetrahedron
Lett. 2000, 41, 7129-7133. (b) Braun, R.; Zeitter, K.; Mu¨ller, T. Org. Lett.
2001, 3, 3297-3300. (c) Clique, B.; Vassiliou, S.; Monteiro, N.; Balme,
G. Eur. J. Org. Chem. 2002, 1493-1499.
(1) For reviews, see: (a) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144.
(b) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000,
6, 3321-3329. (c) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168-3210. (d) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366-
374. (e) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem.
1999, 6, 255-270. (f) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131.
(4) A similar strategy had been previously applied to o-iodophenols:
Chaplin, J. H.; Flynn, B. L. Chem. Commun. 2001, 1594-1595.
10.1021/ol034644y CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003

easily prepared in high yields through iodination of the
corresponding alkoxypyridones using N-iodosuccinimide in
MeCN at room temperature (Scheme 2).10,11
Scheme 1. Retrosynthetic Analysis of Furo[2,3-b]pyridones
Scheme 2. Preparation of 4-Alkoxy-3-iodo-2-pyridones 2
ridinium salts of type 6. The latter would then collapse to
the desired pyridones through subsequent cleavage of the
oxygen protecting group. In contrast to their benzannulated
homologuessthe furo[2,3-b]quinolinesswhich are wide-
spread in nature and have been the subject of numerous
synthetic and biological studies,5 the chemistry and biological
properties of furo[2,3-b]pyridones have been much less
documented.6
The cyclization of nucleophiles bearing a tethered alkyne
with organopalladium reagents has been developed by us
and other groups into a versatile and efficient method to
access diversely substituted carbo- and heterocyclic systems7,8
and has already contributed to the development of new
multicomponent reactions.9 To date, howeVer, N-substituted
2-pyridones, and N,N-disubstituted amides in general, haVe
not been used as nucleophilic partners in this process which
remains essentially based on the use of anionic nucleophiles.
To test the feasibility of our concept, we first prepared a
series of 4-alkoxy-3-iodo-2-pyridones 2a-c. These were
Preliminary studies of the integrated process focused on
the separate optimization of each step under the same set of
conditions and, preferably, using the same Pd catalyst.12
Reactions were conducted using 4-benzyloxy-N-methyl-2-
pyridone 2a, (p-MeO2C)phenyl acetylene 3a, and (p-MeO2C)-
phenyl iodide 5a as model substrates. Sonogashira coupling
of 2a with 3a was found particularly effective when
conducted under PdCl2(PPh3)2/CuI catalysis in MeCN/Et3N
(9:1) at 60 °C, which afforded the desired 3-alkynylpyridone
4a in 75% isolated yield. The participation of 4a in the
cyclization-coupling reaction was then probed using 4 mol
% PdCl2(PPh3)2 reduced by n-BuLi, as Pd0 catalyst,13 and
MeCN as solvent under neutral conditions as no base should
be needed in this process. Pleasingly, upon heating 4a for
24 h under these conditions in the presence of 1.4 equiv of
5a as coupling partner, the desired furopyridinium 6a (27%)-
was obtained together with the corresponding furopyridone
7a (22%) and a substantial amount of unreacted 4a (29%).
Conversion of 4a into the targeted pyridone as the sole
bicyclic heterocycle was optimized by extending the reaction
time to 48 h, which yielded 7a in a satisfactory 67% isolated
yield (78% based on recovered 4a) (Scheme 3).
(5) For recent reports, see: (a) Pirrung, M. C.; Blume, F. J. Org. Chem.
1999, 64, 3642-3649 and references therein. (b) Chang, G.-J.; Wu, M.-
H.; Chen, W.-P.; Kuo, S.-C.; Su, M.-J. Drug DeV. Res. 2000, 50, 170-
185. (c) Butenscho¨n, I.; Mo¨ller, K.; Ha¨nsel, W. J. Med. Chem. 2001, 44,
1249-1256. (d) Michael, J. P. Nat. Prod. Rep. 2001, 543-559 and previous
annual reports.
The facile debenzylation of pyridinium iodide 6a under
our reaction conditions was somewhat unexpected.14 Interest-
ingly, while 6a proved stable when heated in MeCN for
prolonged reaction times (up to 3 days), it was found that
its complete conversion into 7a could be achieved within
24 h by simply adding a catalytic amount of a PdII complex,
for instance PdCl2(MeCN)2. We reasoned that palladium was
probably not only acting as an organometallic reagent in the
(6) (a) Snyder, H.; Ebetino, F. J. Heterocycl. Chem. 1966, 3, 202-205.
(b) Prankerd, R.; Stella, V. Int. J. Pharm. 1989, 52, 71-78. (c) Bhupathy,
M.; Conlon, D.; Wells, K.; Nelson, J.; Reider, P.; Rossen, K.; Sager, J.;
Volante, P.; Dorsey, B. J. Heterocycl. Chem. 1995, 32, 1283-1287.
(7) For reactions involving carbonucleophiles, see: Balme, G.; Monteiro,
N.; Bouyssi, D. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley & Sons: New York, 2002; pp 2245-
2265. For oxygen nucleophiles, see: Cacchi, S.; Arcadi, A. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
Wiley & Sons: New York, 2002; pp 2193-2210. For nitrogen nucleophiles,
see: Cacchi, S.; Marinelli, F. in Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., Ed.; Wiley & Sons: New York, 2002;
pp 2227-2244.
(8) The methodology has already been successfully applied to the
synthesis of other fused furans. Benzo[b]furans: (a) Arcadi, A.; Cacchi,
S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61,
9280-9288. (b) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett 1998, 741-745.
(c) Monteiro, N.; Balme, G. Synlett 1998, 746-747. (d) Cacchi, S.; Fabrizi,
G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101-5104. (e) Monteiro, N.;
Arnold, A.; Balme, G. Synlett 1998, 1111-1113. (f) Flynn, B. L.; Hamel,
E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670-2673. (g) Hu, Y.; Zhang,
Y.; Yang, Z.; Fathi, R. J. Org. Chem. 2002, 67, 2365-2368. Furo[2,3-d]-
pyrimidin-2-ones: Carangio, A.; McGuigan, C.; Andrei, G.; Snoeck, R.;
De Clercq, E.; Balzarini, J. AntiViral Chem. Chemother. 2001, 187-197.
(9) (a) Inoue, Y.; Itoh, Y.; Yen, I. F.; Imaizumi, S. J. Mol. Catal. 1990,
60, L1-L3. (b) Wei, L.-M.; Lin, C.-F.; Wu, M.-J. Tetrahedron Lett. 2000,
41, 1215-1218. (c) Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro,
N.; Balme, G. J. Org. Chem. 2001, 66, 175-179. (d) Garc¸on, S.;
Cavicchioli, M.; Vassiliou, S.; Hartmann, B.; Monteiro, N.; Balme, G. J.
Org. Chem. 2001, 66, 4069-4073. See also ref 8f.
(10) For the preparation of N-substituted 4-alkoxy-2-pyridones, see: (a)
Katigiri, N.; Sato, M.; Yoneda, N.; Saikawa, S.; Sakamoto, T.; Muto, M.;
Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1986, 1289-1296. (b) Buck, J.;
Madeley, J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1995, 67-73.
(11) For the iodination of analogous 4-alkoxy-2-pyridones, see: Devagas,
B.; Rogers, T. E.; Gray, S. H. Synth. Commun. 1995, 25, 3199-3210.
(12) The one-pot realization of two consecutive, independent Pd-mediated
reactions based on the use of a single Pd catalyst are rare. For recent
examples related to multicomponent reactions, see: Grigg, R.; Mariani,
E.; Sridharan, V. Tetrahedron Lett. 2001, 42, 8677-8680. Organ, M. G.;
Arvanitis, E. A.; Dixon, C. E.; Cooper, J. T. J. Am. Chem. Soc. 2002, 124,
1288-1294. See also ref 8f.
(13) Negishi, E.; Takahashi, T.; Akiyoshi, K. Chem. Commun. 1986,
1339. We have already reported the high efficiency of this Pd0 source in
similar reactions; see ref 9c.
(14) Based on literature precedents, we had anticipated that further
treatment of the reaction mixture with a source of halide would have been
necessary. Sekar, M.; Prasad, J. R. J. Nat. Prod. 1998, 294-296.
2442
Org. Lett., Vol. 5, No. 14, 2003

Scheme 3
Table 1. One-Pot versus Two-Step Coupling of
4-Alkoxy-3-iodo-2-pyridones with Alkynes and Organic Halides
cyclization process but also as a Lewis acid15 in making the
benzyloxypyridinium intermediate more prone to cleavage
of the benzyl ether through complexation to the alkoxy
group.16,17 Indeed, when 6a was heated in MeCN in the
presence of 4 mol % Pd(PPh3)4 as a source of Pd0 and (p-
MeO2C)phenyl iodide (5 mol %) clean debenzylation was
achieved within 48 h.
A sequential addition, one-pot protocol for the conversion
of iodopyridone 2a into furo[2,3-b]pyridone 7a was then
optimized as follows: 2a (1.0 equiv) and (p-MeO2C)phenyl
acetylene (3a) (1.2 equiv) underwent the Sonogashira coup-
ling reaction under the conditions previously used (4 mol %
PdCl2(PPh3)2, 4 mol % CuI, MeCN-Et3N, 60 °C). After 24
h, (p-MeO2C)phenyl iodide (5a) (1.4 equiv) was added and
the reaction was left to stir for 48 h at 60 °C to afford 7a in
83% isolated yield. As a comparison, the same compound
was obtained in only 50% overall yield when the reactions
were conducted independently. This probably reflects another
advantage of the concept which follows from the simplifica-
tion of experimental procedures: loss of material during the
isolation and purification of intermediates is avoided.
The generality of the process was then explored with
various iodopyridones, alkynes, and organic halides. Results
have been compared with those obtained with the stepwise
procedure (Table 1). With only a few exceptions, an increase
in oVerall yields was obserVed with the integrated protocol.
Moderate to good yields were generally obtained with arylic
halides bearing electron-withdrawing groups. In contrast, as
illustrated with the reaction of p-methoxyphenyl iodide
(Table 1, entry 6), the presence of an electron-donating group
a Isolated yields (single runs). There was essentially no material loss as
unreacted alkynylpyridones 4 were generally recovered. b Numbers in
parentheses refer to yields of the cyclization-coupling reaction (4 f 7).
c See text for reaction conditions.
on the arylic coupling partner had a negative effect on the
heteroannulation process,18 the intermediate 3-alkynylpyri-
done being recovered as the main product of the reaction. It
should be noted that, in this case, best results were achieved
using the stepwise protocol. Remarkably, bis-iodobenzene
5c did not produce any product of double cyclization-coup-
ling reaction even when used in substoichiometric quantities
(Table 1, entry 3).19 It was also found that 4-methoxy- and
(15) Examples of Lewis acid catalysis using PdII complexes are quite
rare; see: Strukul, G. Top. Catal. 2002, 1, 33-42. Deacetalizations may
be induced by palladium catalysts: Lipshutz, B. H.; Pollart, D.; Monforte,
J.; Kotsuki, H. Tetrahedron Lett. 1985, 26, 705-708.
(16) The possibility that an arylpalladium halide may serve as a Lewis
acid has been suggested recently. Rutherford, J. L.; Rainka, M. P.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 15168-15169.
(17) Another palladium-catalyzed process where PdII acts simultaneously
as transition-metal catalyst and Lewis acid has been reported recently. Asao,
N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 764.
(18) A similar trend was recently reported by Larock in the cyclization
of o-alkynyl benzaldimines: Dai, G.; Larock, R. C. J. Org. Chem. 2003,
68, 920-928.
Org. Lett., Vol. 5, No. 14, 2003
2443

4-benzyloxypyridones participate equally well in this process,
affording the same reaction product after cleavage (Table 1,
entries 1 and 11).
Scheme 4. Working Mechanism for the
Cyclization-Coupling-Deprotection Process
Although the NMR spectroscopic data support the forma-
tion of furopyridones 7, the structure was unambiguously
secured by an X-ray crystal structure analysis of compound
7i (Figure 1).20
by the halide counterion induces intermediate D to collapse
to furopyridone 7.
In conclusion, we have shown that hitherto unknown,
diversely substituted furo[2,3-b]pyridones can be prepared
in a single, practical operation through the sequential coup-
ling of three readily available starting materials, 3-iodo-2-
pyridones, terminal alkynes, and aryl iodides. In this process,
a single palladium catalyst interVenes in three different
transformations acting alternatiVely as an organometallic
reagent or as a Lewis acid: Sonogashira coupling, cycliza-
tion, and fragmentation. The successful participation of
N-substituted 3-alkynyl-2-pyridones in the Pd-catalyzed
cyclization with organic halides prefigures future extensions
of this chemistry to the synthesis of other bis-heterocyclic
compounds of interest.
Figure 1. ORTEP representation of compound 7i.
A plausible mechanism accounting for the cyclization-
coupling-deprotection process is depicted in Scheme 4.
Oxidative addition of the organic halide to the Pd0 catalyst
generates a σ-arylPdIIX complex (A) which activates, through
coordination, the alkyne triple bond of 4 toward nucleophilic
attack of the amide. Complexation of the metal to the
o-alkoxy group may contribute to stabilize intermediate B
and facilitate the cyclization process to give the Pd-containing
furopyridinium C. Reductive elimination liberates the cy-
clization product 6 and recycles the catalyst. Finally, attack
of the alkoxy function, supposedly activated by a PdII species,
Acknowledgment. This research was assisted financially
by a grant to E.B. from Bayer CropScience and the Centre
National de la Recherche Scientifique. We thank Dr. C.
Bavoux for the X-ray crystallographic analysis and Dr. J. P.
Vors (Bayer CropScience, Lyon) for his interest in this work.
Supporting Information Available: Experimental pro-
cedures, characterization for all compounds, and X-ray data
for compound 7i (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) For multicomponent syntheses of symmetrical compounds involving
bis-iodobenzene, see: (a) de Meijere, A.; Nu¨ske, H.; Es-Sayed, M.; Labahn,
T.; Schroen, M.; Bra¨se, S. Angew. Chem., Int. Ed. Engl. 1999, 38, 3669-
3672. (b) Azoulay, S.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2002,
43, 9311-9314.
(20) See the Supporting Information for data of the X-ray single-crystal
structure determination of compound 7i.
OL034644Y
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Org. Lett., Vol. 5, No. 14, 2003