Electrophilic cyclization of o-acetoxy- and o-benzyloxyalkynylpyridines: An easy entry into 2,3-disubstituted furopyridines

Article abstract of DOI:10.1021/ol0261581

(Matrix Presented) 2,3-Disubstituted furo[3,2-b]pyridines, 2,3-disubstituted furo[2,3-to]pyridines, and 2,3-disubstituted furo[2,3-c]pyridines are readily prepared under mild conditions via the palladium-catalyzed cross-coupling of 1-alkynes with o-iodoac

Full text of DOI:10.1021/ol0261581

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2409-2412
Electrophilic Cyclization of o-Acetoxy-
and o-Benzyloxyalkynylpyridines: An
Easy Entry into 2,3-Disubstituted
Furopyridines
,†
,‡
Antonio Arcadi,* Sandro Cacchi,* Sabrina Di Giuseppe,† Giancarlo Fabrizi,‡ and
Fabio Marinelli†
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta` di Scienze,
UniVersita` di L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy, and
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received May 8, 2002
ABSTRACT
2,3-Disubstituted furo[3,2-b]pyridines, 2,3-disubstituted furo[2,3-b]pyridines, and 2,3-disubstituted furo[2,3-c]pyridines are readily prepared under
mild conditions via the palladium-catalyzed cross-coupling of 1-alkynes with o-iodoacetoxy- or o-iodobenzyloxypyridines, followed by electrophilic
cyclization by I2 or by PdCl2 under a balloon of carbon monoxide.
The furopyridine nucleus represents a useful pharmacophore
in a variety of therapeutic areas.1 Recently, this structural
unit has been incorporated into HIV protease inhibitor
candidates.2 Despite its importance, however, synthetic
methodologies for its construction remain limited, and the
provision of sufficient amounts of these substances may
represent the bottleneck for further studies and development
in medicinal chemistry.3 Our palladium-catalyzed coupling-
cyclization of o-iodopyridinols with terminal alkynes4,5 and
of o-alkynylpyridinols with aryl and vinyl halides or triflates6
are among the most general and versatile synthetic method-
ologies for the preparation of a variety of 2-substituted
furopyridines. The synthesis of 3-substituted furopyridines
is carried out by the palladium-catalyzed cyclization of
iodopyridinyl allyl ethers.7 However, the preparation of 2,3-
disubstituted furopyridines still remains a synthetic challenge.
* Email for A.A.: arcadi@univaq.it.
† Universita` di L’Aquila.
‡ Universita` degli Studi “La Sapienza”.
(1) (a) Rapoport, H.; Van Sickle, A. P. J. Org. Chem. 1990, 55, 895. (b)
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115159m.
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39, 5375.
(4) Arcadi, A.; Cacchi, S.; Marinelli, F. Synthesis 1986, 749.
(5) For some applications of our palladium-catalyzed coupling-cyclization
of o-iodopyridinols with terminal alkynes, see: (2-substituted furo[2,3-b]-
pyridines) ref 2b and 2c, (2-substituted furo[2,3-c]pyridines) Wishka, D.
G.; Graber, D. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Watt, W.; Morris, J.
J. Org. Chem. 1998, 63, 7851. Reference 2a.
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F.; Watt, W.; Morris, J. J. Org. Chem. 1998, 63, 7851. (b) Wishka, D. G.;
Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis, J. M.; Hosley, J. D.;
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W. B.; Houpis, I. N.; Churchill, H. R. O.; Molina, A.; Lynch, J. E.; Volante,
R. P.; Reider, P. G.; King, A. O. Tetrahedron Lett. 1995, 36, 4571. (c)
Houpis, I. N.; Choi, W. B.; Reider, P. J.; Molina, A.; Churchill, H.; Lynch,
J.; Volante, R. P. Tetrahedron Lett. 1994, 35, 9355.
(6) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G., Marinelli, F.
Synlett 2002, 453.
10.1021/ol0261581 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/21/2002

There are only a few reports concerning the synthesis of this
class of compounds,8 and the development of new, more
versatile procedures appears desirable. Our success in
preparing 2,3-disubstituted benzo[b]furans via iodocycliza-
tion of o-alkynylphenols9,10 followed by palladium-catalyzed
reactions of the resultant 2-substituted 3-iodobenzo[b]furans
encouraged us to employ related chemistry for the prepara-
tion of 2,3-disubstituted furopyridines. We were also stimu-
lated by our involvement in a program devoted to the
development of more potent Aâ aggregation inhibitors, based
on the synthesis of isosteres of related benzofurans. Recently,
a number of benzofurans have been identified as efficient
Aâ aggregation inhibitors.11 The formation of fibrillar protein
aggregates is an important pathological feature of neuro-
degenerative diseases such as Alzheimer’s disease, Parkin-
son’s disease, and the prion diseases.12
Table 1. Preparation of 2-Substituted 3-Iodofuropyridines 2
and 2,3-Disubstituted Furopyridines 7
In analogy to our previous work,9 o-akynylpyridinols were
initially selected as the starting alkynes. However, under the
conditions used by us for the preparation of o-alkynylphenols
from o-alkynylphenylacetates,13 o-acetoxyalkynylpyridines
produced o-akynylpyridinols in low yield, 2-substituted
furopyridines being the main reaction products. For example,
removal of the protective acetyl group from 1a (acetone/2
N HCl, 4 h, 60 °C) gave 2-phenyl-furo[3,2-b]pyridine in 68%
yield. The desired 2-phenylethynyl-pyridin-3-ol was isolated
only in 25% yield and showed a strong tendency to cyclize
on storage.
After some experimentation, we were very pleased to find
that o-acetoxyalkynylpyridines 1 could be directly employed
in the preparation of 2-substituted 3-iodofuropyridines via
iodocyclization, with the advantage of replacing a stepwise
synthesis with a domino process.14 Compounds 1a-e,
bearing electron-donating and moderately electron-withdraw-
ing substituents in the pyridine fragment, were prepared by
using a procedure based on the palladium-catalyzed reaction
of 1-alkynes with o-acetoxyhalopyridines in THF at room
temperature in the presence of a catalytic amount of CuI15
(see Table 1).
(7) Cho, S. Y.; Kim, S. S.; Park, K. H.; Kang, S. K.; Choi, J.-K.; Hwang,
K.-J.; Yum, E. K. Heterocycles 1996, 43, 1641.
(8) (a) Desideri, N.; Manna, F.; Stein, M. L. J. Heterocycl. Chem. 1988,
25, 333. (b) Shiotani, S.; Morita, H.; Ishida, T.; In, Y. J. Heterocycl. Chem.
1988, 25, 1205.
(9) Arcadi, A.; Cacchi, S.; Fabrizi, G., Marinelli, F.; Moro, L. Synlett
2000, 1432.
(10) For other examples of iodine-promoted cyclization of alkynes to
give heterocycles, see: (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J.
Chem. Soc., Perkin Trans. 1 2002, 622. (b) Huang, Q.; Hunter, J. A.; Larock,
R. C. Org. Lett. 2001, 3, 2973. (c) Flynn, B. L.; Verdier-Pinard, P.; Hamel,
E. Org. Lett. 2001, 3, 651. (d) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi,
R. Tetrahedron Lett. 2001, 42, 2859. (e) Bellina, F.; Biagetti, M.; Carpita,
A.; Rossi, R. Tetrahedron 2001, 57, 2857. (f) Djuardi, E.; McNelis, E.
Tetrahedron Lett. 1999, 40, 7193. (g) Marshall, J. A.; Yanik, M. M. J.
Org. Chem. 1999, 64, 3798. (h) Knight, D. W.; Redfern, A. L.; Gilmore, J.
J. Chem. Soc. Chem. Commun. 1998, 2207. (i) Redfern, A. L.; Gilmore, J.
Synlett 1998, 731. (j) Ren, X.-F., Konaklieva, M. I.; Shi, H.; Dicy, H.;
Lim, D. V.; Gonzales, J.; Turos, E. J. Org. Chem. 1998, 63, 8898. (k) Bew,
S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996, 1007.
(11) (a) Allsop, D.; Howlett, D.; Christie, G., Karran, E. Biochem. Soc.
Trans. 1998, 26, 459. (b) Howlett, D.; Allsop, D.; Karran, E. Neurobiology
of Alzheimer’s Disease; Dawbarn, D., Allen, S. J., Eds.; Bios Scientific
Publishers: Oxford, 1999; pp 9-49.
a Procedure A. 1/I2/NaHCO3 ) 1:3:3 in MeOH at rt (0.51-3.38 mmol
scale). Procedure B. 1/K2CO3/NaOAc/CuCl2‚2H2O/PdCl2 ) 1:2:2:3:0.05
in MeOH at rt, under a balloon of carbon monoxide (0.47-2.72 mmol scale).
Procedure C. 3/I2/NaHCO3 ) 1:3:3 in EtOH at rt (0.62-1.23 mmol scale).
b Yields refer to single runs and are given for isolated products.
(12) Kakizuka, A. Trends Genet. 1998, 14, 396.
Iodocyclization of o-acetoxyalkynylpyridines 1a-e gener-
ates, under the conditions shown in Scheme 1, the corre-
sponding 2-substituted 3-iodo-furo[3,2-b]pyridines and 2-sub-
(13) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F.
J. Org. Chem. 1996, 61, 9280.
(14) Tietze, L. F. Chem. ReV. 1996, 96, 115.
2410
Org. Lett., Vol. 4, No. 14, 2002

Though removal of the acetyl group before formation of
4 cannot be excluded, a deacetylation step following the
formation of 4 appears more likely. Premature removal would
be expected to generate 2-substituted furopyridines in
significant yield, whereas the formation of 2-substituted
furopyridines has been observed only in trace amounts under
iodocyclization conditions. Isolation of 2-phenylfuro[3,2-b]-
pyridine 5 in 45% yield together with 2-(phenylethynyl)-
pyridin-3-ol (52% yield) after subjecting 1a to our standard
conditions for 4 h, omitting I2, gives support to this
hypothesis. The possibility that the formation of 2 may
proceed through (1) deacetylation, (2) cyclization, and (3)
iodination of the resultant 2-substituted furopyridines is ruled
out by the following experiment: 2-phenyl-furo[3,2-b]
pyridine 5 was recovered essentially unchanged (90%) after
treatment with I2 and NaHCO3 in CH3OH at room temper-
ature for 24 h (Scheme 4).
Scheme 1
stituted 3-iodo-furo[2,3-c]pyridines 2 in good yields (Table
1, entries 1, 3, 6, 8).
The preparation, according to the above procedure,15 of
o-acetoxyalkynylpyridines containing strongly electron-
withdrawing substituents in the pyridine ring was prevented
by the instability of the corresponding o-acetoxyhalo-
pyridines. The latter, in fact, whose preparation was at-
tempted via acetylation of o-halopyridinols, were found to
undergo a deacetylation reaction under workup conditions,
thus making them unsuitable as partners in the coupling step.
The use of other protecting groups was explored, and the
benzyl group proved to give satisfactory results. The benzyl
derivatives 3a,b, prepared in high yield through the pal-
ladium-catalyzed coupling of the corresponding o-iodo-
benzyloxy derivative and phenylacetylene, afforded the
furo[2,3-b]pyridines 2e,f in good yield (Scheme 2) (Table
1, entries 10 and 11).
Scheme 4
With benzyl derivatives, the reaction may proceed through
an alternative reaction pathway involving the nucleophilic
attack of the oxygen to the activated carbon-carbon triple
bond before the cleavage of the O-Cbenzyl bond. Accordingly,
the benzyl derivative 3a was recovered unchanged after
treatment under reaction conditions omitting I2.
Scheme 2
The potential of 2-substituted 3-iodofuropyridines 2 as
precursors for increasing molecular complexity via pal-
ladium-catalyzed reactions16 has been briefly investigated
using 2a as the model compound. Some examples are shown
in Scheme 5.
As for the reaction mechanism of o-acetoxyalkynyl-
pyridines (Scheme 3), a tentative rationale considers the
following steps: (1) initial formation of the bridged-ion
intermediate 4, (2) nucleophilic attack of methanol to the
carbonyl group to free the pyridinolic oxygen, and (3)
intramolecular nucleophilic attack of the oxygen across the
activated carbon-carbon triple bond to give the target
furopyridine product.
Scheme 5
Scheme 3
Compound 2a, however, failed to give the corresponding
2-phenyl-3-carboxymethylfuropyridine 7a in satisfactory
yield under alkoxycarbonylation conditions. For example,
Org. Lett., Vol. 4, No. 14, 2002
2411

treatment of 2a (0.79 mmol) with methanol (5 mL) under a
balloon of CO in the presence of triethylamine (15.8 mmol)
and Pd(PPh3)4 (0.04 mmol) at 60 °C for 24 h led to the
formation of 7a in only 13% yield.
Scheme 6
A nice solution to this came up when we discovered that
electrophilic activation by PdCl2 can allow the direct for-
mation of 2-substituted 3-carboxymethylfuro[3,2-b]pyridines
and 2-substituted 3-carboxymethylfuro[2,3-c]pyridines 7
from o-acetoxyalkynylpyridines 1. Reactions were carried
out by subjecting 1 to PdCl2 in methanol, under a balloon
of carbon monoxide, in the presence of NaOAc and K2CO3
as the bases and CuCl2 as the oxidative agent (Scheme 6).
Our preparative results are summarized in Table 1 (entries
2, 4, 5, 7, 9).
temperature. Further work is in progress to extend the
synthetic ease of the present methodology to the preparation
of more complex molecular structures.
Acknowledgment. This work was supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica (MURST) and Consiglio Nazionale delle Ricerche
(C.N.R.).
In summary, we have shown that employment of o-
acetoxy- and o-benzyloxyalkynylpyridines in sequential
O-deprotection/electrophilic cyclization reactions can provide
an easy entry into 2,3-disubstituted furopyridines at room
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291.
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