A synthetic entry to furo[2,3-b]pyridin-4(1H)-ones and related furoquinolinones via iodocyclization

Article abstract of DOI:10.1021/ol053048w

N-Methyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo iodine-promoted 5-endo-heteroannulation under mild conditions to 3-iodofuropyridinium triiodide salts in moderate to good yields. The latter may be dealkylated in situ upon exposure to an iodid

Full text of DOI:10.1021/ol053048w

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1113-1116
A Synthetic Entry to
Furo[2,3-b]pyridin-4(1H)-ones and
Related Furoquinolinones via
Iodocyclization
Isabelle Aillaud,† Emmanuel Bossharth,† David Conreaux,† Philippe Desbordes,‡
Nuno Monteiro,*,† and Genevie`ve Balme*,†
Laboratoire de Synthe`se Organome´tallique et Mole´cules BioactiVes, CNRS UMR 5181,
UniVersite´ Claude Bernard-Lyon I, ESCPE Lyon. 43, Bd 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
Received December 16, 2005
ABSTRACT
N-Methyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo iodine-promoted 5-endo-heteroannulation under mild conditions to 3-iodofuro-
pyridinium triiodide salts in moderate to good yields. The latter may be dealkylated in situ upon exposure to an iodide anion to provide the
corresponding 3-iodofuro[2,3-b]pyridin-4(1H)-ones. The same strategy applies to the formation of furo[2,3-b]quinolin-4(9H)-ones.
Heteroannulation processes involving acetylenic compounds
bearing a tethered nucleophilic substituent are among the
most versatile and efficient synthetic methods toward ring-
fused heterocycles, of which many rely on transition-metal
catalysis.1 For instance, organopalladium complexes have
been extensively used as electrophilic partners which allow
the selective formation of functionalized heterocyclic com-
pounds via cyclo-palladation-reductive elimination se-
quences.2 On the other hand, iodonium-promoted heteroan-
nulations are also highly attractive since they offer an
alternative tactic to similar structures upon subsequent
transformation of the iodide functional group into other
substituents that are not always accessible by the aforemen-
tioned organometallic methods. This has been particularly
well illustrated in recent syntheses of benzo[b]furans,3
furopyridines,4 furo-pyrimidines,5 benzo[b]thiophenes,6 in-
doles,7 isoquinolines and naphthyridines,8 isoindolinones,9
isochromenes,10 isocoumarins,11phosphaisocoumarins,12 and
coumestans.13,14
(3) (a) Banwell, M. G.; Flynn, B. L.; Willis, A. C.; Hamel, E. Aust. J.
Chem. 1999, 52, 767. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Moro, L. Synlett 1999, 1432. (c) Colobert, F.; Castanet, A.-S.; Abillard, O.
Eur. J. Org. Chem. 2005, 3334. (d) Yue, D.; Yao, T.; Larock, R. C. J. Org.
Chem. 2005, 70, 10292.
(4) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli F.
Org. Lett. 2002, 4, 2409.
(5) Rao, M. S.; Esho, N.; Sergeant, C.; Roman, D. J. Org. Chem. 2003,
68, 6788.
(6) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (b) Hessian,
K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377.
† Universite´ Claude Bernard-Lyon I.
‡ Bayer CropScience.
(1) For representative illustrations, see the following reviews: (a)
Nakamura, I.; Yamamoto, Y. Chem. ReV 2004, 104, 2127. (b) Zeni, G.;
Larock, R. C. Chem. ReV 2004, 104, 2285. (c) Alonso, F.; Beletskaya, I.
P.; Yus, M. Chem. ReV 2004, 104, 3079. (d) Vizer, S. A.; Yerzhanov, K.
B.; Al Aziz Al Quntar, A.; Dembitsky V. M. Tetrahedron 2004, 60, 5499.
(2) For a review, see: Lomberget, T.; Bossharth, E.; Bouyssi, D.;
Monteiro, N.; Balme, G. Synthesis 2003, 2407.
(7) (a) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037. (b) Barluenga,
J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem., Int. Ed. 2003,
42, 2406. (c) Yao, D.; Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7,
809.
(8) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437
(9) Yao, T.; Larock R. C. J. Org. Chem. 2005, 70, 1432.
10.1021/ol053048w CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/24/2006

In conjunction with a recent drug development program,
we became interested in the furopyridinone ring system, a
key structural subunit prevalent in numerous natural products
and structural analogues associated with interesting biological
activities.15 Pursuant to our longstanding interest in Pd-
catalyzed cyclization processes, we have recently reported
the construction of 2,3-disubstituted furo[2,3-b]pyridin-
4(1H)-ones from 3-alkynylpyridin-2(1H)-ones (3-alkynyl-
2-pyridones) and aryl halides.16 As a complement to this
chemistry, we have now investigated the reactivity of the
alkynylpyridones toward iodonium reagents.
alkyl group from the remote alkyl ether on the 2-pyridone
nucleus to afford the desired 3-iodofuro[2,3-b]pyridin-4(1H)-
ones 3 (Scheme 1, eq 2). The alternative heteroannulative
pathway that would lead to the regioisomeric furo[3,2-c]-
pyridin-2(1H)-ones (4) via preferential attack of the triple
bond by the alkoxy group17 could also be expected (Scheme
1, eq 3). The iodocyclization precursors 1 were prepared from
the corresponding 3-iodo-2-pyridones via Pd-catalyzed cross-
coupling reaction with terminal alkynes. Gratifyingly, pre-
liminary experiments conducted with 2-pyridone 1a as a
model substrate have shown that iodine could indeed promote
the expected iodocyclization, whereas other iodonium sources
(ICl, NIS) proved rather inefficient. The reaction proceeded
cleanly at room temperature in CH2Cl2 in the presence of 2
equiv of I2 to afford within 5 h the corresponding pyridinium
triiodide salt 2a exclusively, in 79% isolated yield (eq 4).
Iodonium-promoted cyclizations often require a removable
functional group on the nucleophile, which implies a stepwise
electrophilic addition/dealkylation sequence involving cat-
ionic intermediates (Scheme 1, eq 1). Recent methods have
Scheme 1. Heteroannulative Strategies toward Fused
Heterocycles
The generality of the cyclization process was then explored
with other N,O-dialkylated pyridones. The results sum-
marized in Table 1 demonstrate that I2 was efficient in most
cases and a variety of annulated 3-iodofurans were obtained
under the standard conditions. Best results have been
achieved with aryl-substituted alkynes 1a-e (Table 1, entries
1-5), which provided the corresponding 2-aryl-3-iodofurans
in good yields. Alkyl-substituted alkyne 1f participated less
efficiently in the cyclization process (Table 1, entry 6),
whereas acetylene 1g bearing a SiMe3 group led to a complex
mixture of products (Table 1, entry 7). Finally, to explore
the scope and generality of the reaction, we further examined
the cyclization of the benzo-homologated substrate 1h. If
successful, this would open access to analogous derivatives
of the linearly fused furoquinoline alkaloids, of which some
important members are substituted at the nitrogen atom,
either in the form of 4-methoxyquinolinium methosalts or
N-alkylated quinolin-4-ones.18 To our satisfaction, 1h af-
forded the desired furoquinolinium triiodide 2h under identi-
cal reaction conditions, albeit in a moderate 56% isolated
yield (Table 1, entry 8).
been mainly focused on the cyclization of readily available
ortho-functionalized aryl (or heteroaryl) acetylenes. Notably,
o-benzyloxyalkynylpyridines have been shown to yield
3-iodofuro[2,3-b]pyridines upon exposure to iodine in basic
medium.4 In contrast, and in analogy to our previous work,
we anticipated that 4-alkoxy-1-methyl-2-pyridones (1) would
generate pyridinium salts 2 as intermediates and that,
hopefully, the counterion would subsequently displace the
Having examined the scope of the iodocyclization process,
we sought an effective method to convert the pyridinium
and quinolinium triiodide salts into the corresponding pyri-
dinones and quinolinone, respectively.19 Various methods
have been reported to effect the O-dealkylation of 4-alkoxy-
(10) (a) Barluenga, J.; Va´zquez-Villa, H.; Ballesteros, A.; Gonza´lez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (b) Yue, D.; Della Ca`, N.; Larock
R. C. Org. Lett. 2004, 6, 1581.
(11) (a) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (b) Rossi,
R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59,
2067.
(12) Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2004, 6, 1119.
(13) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985.
(14) For other recent examples of iodonium-promoted heterocyclizations
of acetylenic compounds, see: (a) Sniady, A.; Wheeler, K. A.; Dembinski,
R. Org. Lett. 2005, 7, 1769. (b) Liu, Y.; Song, F.; Cong, L. J. Org. Chem.
2005, 70, 6999. (c) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005,
70, 7679. (d) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609. (e) Waldo, J. P.;
Larock R. C. Org. Lett. 2005, 7, 5203.
(17) An example of such an outcome, albeit not involving activation by
iodonium species, has been reported: Gaston, J. L.; Greer, R. J.; Grundon,
M. F. J. Chem. Res., Miniprint 1985, 1873.
(18) (a) Pirrung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642 and
references therein. (b) Wu, T.-S.; Li, C.-Y.; Leu, Y.-L.; Hu, C.-Q.
Phytochemistry 1999, 50, 509. (c) Chang, G.-J.; Wu, M.-H.; Chen, W.-P.;
Kuo, S.-C.; Su, M.-J. Drug DeV. Res. 2000, 50, 170. (d) Boyd, D. R.;
Sharma, N. D.; Barr, S. A.; Carroll, J. G.; Mackerracher, D.; Malone, J. F.
J. Chem. Soc., Perkin Trans. 1 2000, 3397. (e) Bar, G.; Parsons, A. F.;
Thomas, C. B. Tetrahedron 2001, 57, 4719.
(15) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627 and previous annual
reports.
(16) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett.
2003, 5, 2441.
1114
Org. Lett., Vol. 8, No. 6, 2006

same reaction vessel without isolation of the triiodide salts.
A test experiment was conducted on pyridone 1a using
MeCN as solvent for both steps,23 which allowed access to
3a in 79% isolated yield. Accordingly, a range of 3-iodo-
furans 3b-d were obtained in good to excellent yields from
the corresponding O-methylated acetylenic precursors (Table
2).
Table 1. Iodocyclization of 4-Alkoxy-3-alkynyl-2-pyridonesa
Table 2. One-Pot Synthesis of 3-Iodofuransa
a All reactions were run on 0.2 mmol of the acetylenic compounds using
2 equiv of I2 in 2 mL of MeCN at 20 °C (5 h), followed by addition of 1.5
equiv of NaI and refluxing overnight. b Isolated yields (single runs).
A plausible mechanism for the formation of the furopy-
ridinones is shown in Scheme 2. Cyclizations are believed
Scheme 2. Mechanism for the Cyclization-Dealkylation
a All reactions were run on 0.2 mmol of the acetylenic compounds using
2 equiv of I2 in 2 mL of CH2Cl2. b Isolated yields (single runs).
Process
pyridinium (and quinolinium) salts, which include treatment
with a halide salt,20 methanolic sodium hydroxide,21 or Pd-
(II) complexes16 or upon heating in pyridine.22 After some
experimentation, the desired transformation was successively
achieved upon simple exposure of the triiodide salts to an
external source of iodide. For instance, treatment of 2a with
1.5 equiv of NaI in refluxing MeCN gave 3a in 75% isolated
yield (eq 5).
to proceed via activation of the carbon-carbon triple bond
by coordination to I+ and subsequent intramolecular attack
of the carbonyl oxygen (A) to give the pyridinium-fused
(19) The triiodide salts proved remarkably stable, withstanding treatment
with aqueous Na2S2O3.
(20) Sekar, M.; Rajendra Prasad, K. J. J. Nat. Prod. 1998, 61, 294.
(21) Gaston, J. L.; Grundon, M. F. J. Chem. Soc., Perkin Trans. 1 1989,
905.
We next considered the possibility of conducting the
heteroannulation and dealkylation steps sequentially in the
Org. Lett., Vol. 8, No. 6, 2006
1115

furan. Upon exposure to iodide, the latter undergoes removal
of the protective methyl group via SN2 displacement (B) to
liberate the desired pyridinone. Importantly, these reactions
only produced volatile (MeI) and water-soluble (NaI3)
byproducts, thus rendering purification of the products very
simple.24
As mentioned in the Introduction, the presence of the
iodide functional group on the furan ring provides an
opportunity for further functionalization (Scheme 3). For
nylfuropyridinone 5 in 51% yield. In addition, Suzuki
coupling of 3a with 4-methoxyphenyl boronic acid afforded
the bisarylic furan 6a in 66% isolated yield. This result is
particularly interesting in view of the fact that direct
cyclofunctionalization of 3-alkynyl-2-pyridones via our cy-
clopalladation/reductive elimination sequence16 proved rather
difficult using electron-rich aryl halides. On the other hand,
the coupling reaction of 3a with 4-fluorophenylboronic acid
furnished, under identical conditions, the previously re-
ported16 compound 6b (89% yield), which gave us a chemical
confirmation of the furo[2,3-b]pyridinone structure (X-ray).
In summary, the scope of our furo[2,3-b]pyridin-4(1H)-
one synthesis via electrophilic heteroannulation of N-al-
kylated-3-alkynyl-2-pyridones has been expanded to include
iodine as electrophile. The presence of the halogen func-
tionality on the heterocyclic products further makes them
useful substrates for derivatization, most probably via metal-
catalyzed C-C bond formation. Interestingly, the intermedi-
ate iminium salts are stable compounds that can be easily
isolated. This is of particular importance in the furoquino-
linium series due to the occurrence of this subunit in natural
products. Further studies into the scope and limitations of
this chemistry are currently underway in our laboratories.
Future investigations will also focus on the development of
other electrophilic cyclizations of alkynyl-2-pyridones and
their benzo-fused homologues.
Scheme 3
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
M. Trosset for preliminary experiments.
example, 3a underwent Sonogashira coupling with 4-meth-
oxycarbonylphenylacetylene to give the corresponding 3-alky-
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Neville, C. F.; Grundon, M. F.; Ramachandran, V. N.; Reisch, J. J.
Chem. Soc., Perkin Trans. 1 1991, 259.
(23) MeCN was found as effective as CH2Cl2 in the cyclization process.
(24) See the Supporting Information. It should be noted that the
4-benzyloxypyridinium salts undergo debenzylation in the same manner.
However, purification of the products required chromatography.
OL053048W
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