Solid-phase syntheses of furopyridine and furoquinoline systems

Article abstract of DOI:10.1021/ol049762f

Syntheses of 2-substituted furo[3,2-b]pyridines and furo[3,2-h]quinolines have been achieved for the first time in the solid-phase mode. The central enabling steps involved concomitant deprotection/cyclization promoted by the mild base K₂CO

Full text of DOI:10.1021/ol049762f

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1405-1408
Solid-Phase Syntheses of Furopyridine
and Furoquinoline Systems
Pablo Cironi,†,‡,§ Judit Tulla-Puche,†,§, George Barany,
,†,|
,†,‡
Fernando Albericio,* and Mercedes AÄ lvarez*
Biomedical Research Institute, Barcelona Scientific Park,
Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Department of Organic Chemistry, UniVersity of Barcelona, 08028 Barcelona, Spain,
and Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
albericio@pcb.ub.es; malVarez@pcb.ub.es
Received February 10, 2004
ABSTRACT
Syntheses of 2-substituted furo[3,2-b]pyridines and furo[3,2-h]quinolines have been achieved for the first time in the solid-phase mode. The
central enabling steps involved concomitant deprotection/cyclization promoted by the mild base K2CO . Reactions were monitored “in situ”
3
in real time by a variety of spectroscopic techniques, which allowed full and accurate control of progress in these syntheses.
Completion of the Human Genome Program (HGP) in April
2003, along with accumulating DNA sequence information
from the genomes of an exponentially increasing number of
microbial, plant, or animal species, has led to a correspond-
ingly large number of protein targets that must be matched
with effective and selective organic molecule ligands identi-
fied through high-throughput screening.1 The demand for
potential ligands may best be met by combinatorial synthesis
onto diverse scaffolds, as expedited by a solid-phase mode
(SPOS) that has the advantages of being amenable to
automation and potentially giving products suitable for
further testing without going through time-consuming inter-
mediate purification steps.2
The focus of this report is to describe solid-phase syntheses
of furo[3,2-b]pyridines and furo[3,2-h]quinolines. The former
heterocycle is rarely found in nature,3 yet its heteroaromatic
unit is the nucleus of the pharmacophores of potent HIV
protease inhibitors such as L-754,3944 and PNU-142721.5
The latter tricyclic system has been encountered even fewer
times.6 Precedents for solution syntheses in these families
are relatively sparse,7 and to the best of our knowledge, their
(3) (a) Grundon, M. F. The Alkaloids; Academic Press: New York, 1979;
Vol. 17, pp 105-198. (b) Arruda, M. S. P.; Fernandes, J. B.; Vieira, P. C.;
Da Silva, M. F. D. G. F.; Pirani, J. R. Biochem. Syst. Ecol. 1992, 20, 173-
178.
(4) (a) Houpis, I. N.; Choi, W. B.; Reider, P. J.; Molina, A.; Churchill,
H.; Lynch, J.; Volante, R. P. Tetrahedron Lett. 1994, 35, 9355-9358. (b)
Bhupathy, M.; Conlon, D. A.; Wells, K. M.; Nelson, J. R.; Reider, P. J.;
Rossen, K.; Sager, J. W.; Volante, R. P.; Dorsey, B. D.; Hoffman, J. M.;
Joseph, S. A.; McDaniel, S. L. J. Heterocycl. Chem. 1995, 32, 1283-1287.
(5) (a) Wishka, D. G.; Graber, D. R.; Seest, E. P.; Dolak, L. A.; Han,
F.; Watt, W.; Morris, J. J. Org. Chem. 1998, 63, 7851-7859. (b) Wishka,
D. G.; Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis, J. M.; Hosley, J.
D.; Adams, W. J.; Seest, E. P.; Castle, T. M.; Dolak, L. A.; Keiser, B. J.;
Yagi, Y.; Jeganathan, A.; Schlachter, S. T.; Murphy, M. J.; Cleek, G. J.;
Nugent, R. A.; Poppe, S. M.; Swaney, S. M.; Han, F.; Watt, W.; White,
W. L.; Poel, T. J.; Thomas, R. C.; Voorman, R. L.; Stephanski, K. J.; Stehle,
R. G.; Tarpley, W. G.; Morris, J. J. Med. Chem. 1998, 41, 1357-1360. (c)
Uenishi, J.; Takagi, T.; Ueno, T.; Hiraoka, T.; Yonemitsu, O.; Tsukube, H.
Synlett 1999, 1, 41-44.
† Barcelona Scientific Park, University of Barcelona.
‡ Faculty of Pharmacy, University of Barcelona.
§ The first two authors have contributed similarly to the present work.
University of Minnesota.
| Department of Organic Chemistry, University of Barcelona.
(1) Current logic of the drug discovery field was reviewed by: Brein-
bauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int. Ed. 2002, 41,
2878-2890 and references therein.
(2) For examples of relatively complex natural products that can be
prepared efficiently by SPOS, see: (a) Nicolaou, K. C.; Winssinger, N.;
Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li,
T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268-272. (b) Myers,
A. G.; Lanman, B. A. J. Am. Chem. Soc. 2002, 124, 12969-12971. (c)
Cironi, P.; Manzanares, I.; Albericio, F.; AÄ lvarez, M. Org. Lett. 2003, 5,
2959-2962.
(6) For examples, see: (a) Beugelmans, R.; Bois-Choussy, M. Hetero-
cycles 1987, 26, 1863-1871 and references therein. (b) Yavari, I.; Anary-
Abbasinejad, M.; Alizadeh, A. Tetrahedron Lett. 2002, 43, 4503-4505.
10.1021/ol049762f CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004

solid-phase syntheses have not been described previously.8
A further feature of the present study is the monitoring of
all reactions “in situ” in real time, using FT-IR (KBr pellets),
13C gel-phase NMR, and 13C MAS NMR; this allowed full
and accurate control of progress in these syntheses.9
The enabling step of our overall process involves smooth
base-promoted deprotection, which is followed directly by
cyclization without a requirement for further catalysis
(Scheme 1). Cyclization is favored with electron-withdrawing
signals of any consequence were observed, suggesting that
within the limits of the monitoring technique, the reaction
had produced predominantly the desired product without
significant side reactions. In particular, premature loss of an
O-acetoxy protecting group in the presence of Pd(0) has been
mentioned elsewhere15 but does not appear to be occurring
in the present reactions.
Given our objective to establish the central furan ring by
addition of a phenol (or phenoxide) moiety to a triple bond
(Scheme 1), several trials were initiated to optimize deacety-
lation. Acidic conditions were avoided, due to the known
lability of alkynes. Of a number of bases tried under a variety
of conditions (solvent, temperatures, time), LiOH was
abandoned due to a complex pattern of products noted upon
gel-phase 13C NMR, whereas NaHCO3 was found to be
ineffective [only starting material was detected by the same
technique]. Instead, we treated the resin with 0.5 M 18-
crown-6 in DMF-H2O (19:1), in the presence of an excess
(saturating amount) of K2CO3, at 60 °C for 48 h.16 The
absence of IR stretches at 1765 and 2200 cm-1, and the
disappearance of methyl and carbonyl signals in the gel-
phase 13C NMR, confirmed the loss of the acetate group. In
addition, triple-bond signals at 94.9 and 82.9 ppm had
disappeared, and a new signal at 101.0 ppm was attributed
to the formation of a resin-bound furan ring. Finally,
treatment of the resin intermediate 4 with the Lewis acid
AlCl3 (10 equiv) in dry CH2Cl2 gave rather high-quality crude
product (Figure 1); after semipreparative HPLC, pure 2-(3-
hydroxy-4-methoxyphenyl)furo[3,2-b]pyridine (5) was ob-
tained in 45% overall yield based on the original loading of
the starting Merrifield-OH resin.
Scheme 1. Deprotection/Cyclization Step
substituents in the aromatic ring that includes the nucleophilic
phenoxide moiety.
In the first stage of this research, hydroxymethyl polysty-
rene resin (Merrifield-OH; 0.98 mmol/g) was used as the
solid support, due to its stability and robustness under
different conditions. The first synthetic step (Scheme 2)
involved incorporation of 5-iodo-2-methoxyphenol 1 onto
the resin under classic Mitsunobu conditions,10 which were
monitored by IR with the reaction endpoint indicated by
disappearance of hydroxyl stretches (3450 and 3580 cm-1).
Loading of the first building block was quantitative, within
the limit of detection of IR.
Next, a Sonogashira cross-coupling reaction11 between the
anchored iodophenol 2 and 3-acetoxy-2-ethynylpyridine
A12,13 established an aryl-pyridine acetylene 3.14 IR monitor-
ing revealed two intense signals (1765 and 2200 cm-1),
corresponding to the appearance, respectively, of resin-bound
acetoxy and acetylene functions. Gel-phase 13C NMR spectra
showed the expected chemical shifts corresponding to the
entire molecule being anchored to the resin. No additional
In a second stage of this research, we prepared on a parallel
synthesizer a pilot library, to gain a better appreciation of
the scope and limitations of this substituted furan-preparing
solid-phase methodology. In one dimension, activated as well
as deactivated iodophenols were tried, and the second
dimension explored acetylenes17 linked to three different
aromatic nuclei (pyridine, quinoline, aniline) [see Table 1].
While the hydroxyl substituents in the pyridine and quinoline
series A and B were protected as their O-acetoxy derivatives
as with the earlier work (Scheme 2), the aromatic ortho-
Scheme 2
1406
Org. Lett., Vol. 6, No. 9, 2004

Scheme 3
trichloroacetimidate18 resin 6 (maximum loading 0.82 mmol/
g) was readily loaded, in quantitative fashion, with each of
the three iodophenol building blocks (Scheme 3). Completion
of reactions was verified by disappearance of strong stretches
at 3339 cm-1 (N-H) and 1662 cm-1 (CdN). Sonogashira
cross-coupling reactions using each of three protected
acetylene derivatives provided the anticipated resin-bound
(7) Furopyridine synthesis has been reviewed by: (a) Shiotani, S.
Heterocycles 1997, 45, 975-1011. See also: (b) Arcadi, A.; Cacchi, S.;
Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Synlett 2002, 453-457. (c) Arcadi,
A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002,
4, 2409-2412. (d) Mathes, B. M.; Filla, S. A. Tetrahedron Lett. 2003, 44,
725-728.
(8) Even for the most common benzofuran system, there are few
published solid-phase methods. See: Macleod, C.; McKiernan, G. J.;
Guthrie, E. J.; Farrugia, L. J.; Hamprecht, D. W.; Macritchie, J.; Hartley,
R. C. J. Org. Chem. 2003, 68, 387-401 and references therein.
(9) Cironi, P.; AÄ lvarez, M.; Albericio, F. QSAR Comb. Sci. 2004, 23,
61-68.
Figure 1. HPLC-MS of crude 2-(3-hydroxy-4-methoxyphenyl)
furo[3,2-b]pyridine 5. (A) Total ion current. (B) UV (318 nm) trace.
(C) APCI-MS spectrum of the main component (tR ) 3.9 min)
amino group in series C was blocked by treatment with
trifluoroacetic anhydride in anticipation of a later base-
promoted deprotection step.
(10) (a) Review: Mitsunobu, O. Synthesis 1981, 1-28. See also: (b)
Richter, L. S.; Gadek, T. R.; Tetrahedron Lett. 1994, 35, 4705-4706. (c)
Krchnˇa´k, V.; Flegelova´, Z.; Weichsel, A. S.; Lebl, M. Tetrahedron Lett.
1995, 36, 6193-6196.
(11) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467-4470. (b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds; Wiley-VCH Verlag GmbH:
Weinheim, Germany, 1998, pp 203-229. (c) Sonogashira, K. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: Hoboken, NJ, 2002; pp 493-529.
Table 1. Exploratory Library to Generalize Chemistry of
Scheme 2a
(12) This known building block was made in three steps and 74% overall
yield from commercially available 3-hydroxy-2-bromopyridine, following
the procedure in: Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2,
2291-2293. The starting pyridinol was acetylated by treatment with acetic
anhydride (Ac2O), following which Pd(0)-catalyzed coupling with tri-
methylsilylacetylene established the carbon-arene bond, and final depro-
tection with tetrabutylammonium fluoride (TBAF) in THF completed the
process. See Supporting Information for experimental details.
(13) Requirement for protection of a phenol group for successful coupling
was suggested by a literature precedent that reported formation of significant
levels of 2,3-disubstituted byproducts when this is not performed: Arcadi,
A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280-9288.
(14) When carried out in solution, Sonogashira cross-coupling could be
accompanied by a homocoupling side reaction. For a precedent, see: (a)
Siemenes, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000,
39, 2634-2657 and references therein. (b) Liao, Y.; Fathi, R.; Reitman,
M.; Zhang, Y.; Yang, Z. Tetrahedron Lett. 2001, 42, 1815-1818. In the
methodology of the present study, the iodophenol component is anchored
on the solid phase, so homocoupled byproducts remain in solution and can
be washed away.
a Building blocks are on the top row and left column, outside of the
bold solid rules. Isolated yields after purification are indicated, along with
the structures of each product for which the chemistry was successful. All
results, including those relating to a ring C-alkylation side reaction as
described in the text and ref 19, were confirmed by both HPLC-MS and
1H NMR analyses [sometimes adding heterocorreletion analysis (gHSQC
and gHMBC)]. The failures of the right column are discussed in the text.
(15) Ajana, W.; Feliu, L.; AÄ lvarez, M.; Joule, J. A. Tetrahedron 1998,
54, 4405-4412.
(16) As previously reported for a related reaction, KOtBu-promoted
cyclization gave low yields of nitrobenzo[b]furans, presumably due to
instability of the products under the basic conditions. Dai, W.-D.; Lai, K.
W. Tetrahedron Lett. 2002, 43, 9377-9380
(17) Similar to ref 12, the required building blocks were made in three
steps and 74-83% overall yields from commercially available 2-bromo-
3-hydroxypyridine, 5-chloro-8-hydroxy-7-iodoquinoline, and o-iodoaniline.
See Supporting Information for experimental details.
Another aspect of this second-stage research was to replace
the Merrifield-OH resin by p-alkoxybenzyl alcohol (Wang)
resin, in anticipation of more facile final cleavage. Wang
(18) Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733-736.
Org. Lett., Vol. 6, No. 9, 2004
1407

bis(aryl)acetylenes, as evidenced by IR. The deprotection/
cyclization steps that followed were monitored by IR and
allowed to proceed until the characteristic bands (1765 and
2200 cm-1) were entirely abolished. Organic products were
released by treatments of the resins with TFA-CH2Cl2
(1:9) (2 × 2 h). The combined filtrates were combined with
5% (v/v) H2O and concentrated to dryness in vacuo.
Several of the library results were as hoped for, with very
respectable crude purities and final yields (Table 1). How-
ever, the chemistry did not work efficiently in series C, which
used ortho-ethynyltrifluoroacetanilide as a building block;
crude material obtained after cleavage was in each case a
complicated mixture. We attribute the differential results to
the fact that the aniline substituent donates electrons into
the triple bond, whereas the π-deficient pyridine or chloro-
quinoline rings withdraw electrons.
One class of byproducts was observed by HPLC-MS of
the crude materials19 and represents the principal yield-
diminishing alternative to formation of desired products in
series A and B. The undesired structures incorporate an extra
p-hydroxybenzyl moiety (mass 106) derived from the Wang
resin linker. Intramolecular rearrangement of a benzylic
carbocation with resultant C-ortho-alkylation of aromatic
rings that are activated as phenols is a well-known side
reaction from peptide chemistry20 and, in the present context,
relates to our recently described “linker leakage” problem.21
In summary, we have described an easy and efficient
methodology for synthesis of substituted furan-condensed
derivatives on hydroxypolystyrene-type solid supports. The
protocol should be readily generalizable for the rapid
synthesis of large libraries of related compounds, especially
in view of the relatively mild conditions for cyclization that
make it possible to accommodate a greater range of otherwise
labile diversity elements.
Acknowledgment. This work was supported in part by
CICYT (BQU2003-00089) and NIH (GM 42722 and 51628).
P.C. thanks MEC (Spain).
Supporting Information Available: General procedures,
description of syntheses, characterization of building blocks,
on-resin intermediates, final products, and byproducts, as well
as representative spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049762F
(19) The following C-alkylated derivatives were isolated and character-
ized by 1H NMR after purification (overall yields are next to the structures).
Further evidence for the structures was provided by masses 106 units higher
than anticipated for the desired products shown in Table 1.
(20) Erickson, B. W.; Merrifield, R. B. J. Am. Chem. Soc. 1973, 95,
3750-3755.
(21) Yraola, F.; Ventura, R.; Vendrell, M.; Colombo, A.; Ferna`ndez,
J.-C.; de la Figuera, N.; Ferna´ndez-Forner, D.; Royo, M.; Forns, P.;
Albericio, F. QSAR Comb. Sci. 2004, 23, in press.
1408
Org. Lett., Vol. 6, No. 9, 2004