A Pd-Catalyzed heteroannulation approach to 2,3-Disubstituted furo[3,2-c]coumarins

Article abstract of DOI:10.1021/ol902189q

The Pd-catalyzed cyclofunctionalization of 3-alkynyl-4-methoxycoumarins with aryl halides resulted in the selective formation of 3-arylfuro[3,2c] coumarins in lieu of the expected regioisomeric 3-arylfuro[2,3-b]chromones. A mechanism involving the linear

Full text of DOI:10.1021/ol902189q

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5254-5257
A Pd-Catalyzed Heteroannulation
Approach to 2,3-Disubstituted
Furo[3,2-c]coumarins
Guillaume Raffa, Marion Rusch, Genevie`ve Balme, and Nuno Monteiro*
ICBMS, Institut de Chimie et Biochimie Mole´culaire et Supramole´culaire, CNRS UMR
5246, UniVersite´ Lyon 1, ESCPE Lyon 43, BouleVard du 11 NoVembre 1918,
69622 Villeurbanne, France
monteiro@uniV-lyon1.fr
Received September 22, 2009
ABSTRACT
The Pd-catalyzed cyclofunctionalization of 3-alkynyl-4-methoxycoumarins with aryl halides resulted in the selective formation of 3-arylfuro[3,2-
c]coumarins in lieu of the expected regioisomeric 3-arylfuro[2,3-b]chromones. A mechanism involving the linear to angular rearrangement of
a Pd-containing furan intermediate was proposed.
The furan structure is a ubiquitous subunit in a variety of
bioactive natural products and synthetic materials, including
agrochemicals and pharmaceuticals.1 Thus, the development
of efficient and concise synthetic methods that allow access
to functionalized furan derivatives, and particularly furan-
fused heterocyclic compounds, remains an important task
in modern organic chemistry. Significant advances in this
area have resulted from the design and discovery of flexible
electrophilic heteroannulations of R-alkynyl carbonyl com-
pounds that allow the single-step construction and function-
alization of the furan ring.2 Our recent contributions to this
field have targeted the synthesis of furo[2,3-b]pyridin-4(1H)-
ones and related furoquinolinones (II) through Pd-catalyzed
or iodonium-promoted cyclofunctionalization of 3-alkynyl-
4-alkoxy(benzo)pyridin-2-ones (I) followed by in situ dealky-
lation of the resulting, and otherwise stable, (benzo)pyridin-
ium salts (Scheme 1, eq 1).3 In an effort to broaden the scope
of this class of annulations, we envisioned that similar
chemistry would also apply to the heteroannulation of alkynyl
coumarins (III) and would thereby enable access to the so
far poorly documented4 furo[2,3-b]chromones (IV) (Scheme
1, eq 2). In this paper, we report our preliminary results
toward this goal.
The participation of alkynylcoumarins in our Pd-catalyzed
cyclofunctionalization process3a was first investigated. To
this end, a range of starting 3-alkynyl-4-methoxycoumarins
2a-d were readily prepared by Pd-catalyzed cross-coupling
(3) (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.
(1) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b) Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955. (c) Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 2001, 2491.
(4) A limited number of 3-unsubstituted furo[3,2-b]chromones have been
recently reported; see, for instance: (a) Lee, Y. R.; Suk, J. Y. Tetrahedron
2002, 58, 2359. (b) Tollari, S.; Palmisano, G.; Cenini, S.; Cravotto, G.;
Giovenzana, G. B.; Penoni, A. Synthesis 2001, 735. (c) Kobayashi, K.;
Sakashita, K.; Akamatsu, H.; Tanaka, K.; Uchida, M.; Uneda, T.; Kitamura,
T.; Morikawa, O.; Konishi, H. Heterocycles 1999, 51, 2881. (d) Lee, Y. R.;
Kim, B. S.; Wang, H. C. Tetrahedron 1998, 54, 12215. (e) Lee, Y. R.;
Byun, M. W.; Kim, B. S. Bull. Korean Chem. Soc. 1998, 19, 1080.
(2) For leading references, see: (a) Rao, M. S.; Esho, N.; Sergeant, C.;
Dembinski, R. J. Org. Chem. 2003, 68, 6788. (b) Yao, T.; Zhang, X.;
Larock, R. C. J. Org. Chem. 2005, 70, 7679. (c) Liu, Y.; Zhou, S. Org.
Lett. 2005, 7, 4609. (d) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org.
Lett. 2005, 7, 1769. (e) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008,
47, 1903. (f) Zhao, L.; Cheng, G.; Hu, Y. Tetrahedron Lett. 2008, 49, 7364.
10.1021/ol902189q CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

cyclization compound that had incorporated the aryl frag-
ment. Surprisingly, however, IR and NMR experiments
suggested that we had in fact isolated the angularly fused
furo[3,2-c]coumarin 4a (Scheme 3), the structure of which
Scheme 1. Heteroannulative Strategies toward Fused Furans
Scheme 3. Coupling-Heteroannulation of 2a with 3a
reactions of 3-iodo-4-methoxycoumarins with terminal acety-
lenes under amine-free conditions (Scheme 2).5
Scheme 2
.
Synthesis of 3-Alkynyl-4-methoxycoumarins
was confirmed by X-ray analysis (Figure 1). Pd(PPh3)4 was
found to be a particularly effective catalyst for this trans-
formation when used in DMF at 100 °C. Under these
Preliminary studies were conducted using 4-methoxycou-
marin 2a and (p-MeO2C)-phenyl iodide 3a as model sub-
strates. Initially, the cyclization reaction was probed using
our previous conditions, that is to say cat. PdCl2(PPh3)2
reduced by n-BuLi, as Pd(0) catalyst, in refluxing MeCN.
However, no reaction was observed under these conditions
even after prolonged reaction times (24 h). Pleasingly, a rapid
screening of Pd catalysts and solvents led us to isolate a
Figure 1. X-ray analysis of 4a.
conditions, 4a was obtained in a satisfactory 64% yield
within 2 h reaction time. Furo[3,2-c]coumarins as well as
the structurally related dihydrofurocoumarins and coumestans
are valuable compounds endowed with many interesting
biologically properties.6,7 We therefore sought to investigate
the unexpected behavior of alkynyl coumarins in this
cyclization process more deeply.
The generality of the process was first explored with
various organic halides (Table 1). Moderate to good yields
were generally obtained with aryl halides bearing electron-
withdrawing groups. Conversely, as illustrated with the
reaction of p-methoxyphenyl iodide, the presence of an
electron-donating group on the aryl coupling partner resulted
in poor yields of the desired furocoumarins, probably
reflecting a decreased electrophilicity of the organoPd(II)
complex (Table 1, entry 5). A range of substituted aryl as
well as alkyl groups on the alkyne were also successfully
employed in the cyclization-coupling reaction (Table 1,
entries 7-10 and 11, respectively).
(5) This avoids undesired amine-induced demethylation of the resulting
acetylenic coumarins; see: (a) Conreaux, D.; Belot, S.; Desbordes, P.;
Monteiro, N.; Balme, G. J. Org. Chem. 2008, 73, 8619. (b) Le Bras, G.;
Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud, V.; Stella,
B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189.
(6) (a) Wang, X.; Nakagawa-Goto, K.; Kozuka, M.; Tokuda, H.; Nishino,
H.; Lee, K.-H. Pharm. Biol. 2006, 44, 116. (b) Mulholland, D. A.; Iourine,
S. E.; Taylor, D. A. H.; Dean, F. M. Phytochemistry 1998, 47, 1641. (c)
Motai, T.; Kitanaka, S. Chem. Pharm. Bull. 2004, 52, 1215. (d) Lee, Y. R.;
Kim, B. S.; Wang, H. C. Tetrahedron 1998, 54, 12215. (e) Poˆc¸as, E. S. C.;
Lopes, D. V. S.; da Silva, A. J. M.; Pimenta, P. H. C.; Leita˜o, F. B.; Netto,
C. D.; Buarque, C. D.; Brito, F. V.; Costa, P. R. R.; Noe¨l, F. Bioorg. Med.
Chem. 2006, 14, 7962.
(7) From a synthetic point of view, 2,3-disubstituted furocoumarins have
been the focus of recent attention. For leading references, see: (a) Cheng,
G.; Hu, Y. Chem. Commun. 2007, 3285. (b) Cadierno, V.; Diez, J.; Gimeno,
J.; Nebra, N. J. Org. Chem. 2008, 73, 5852. (c) Cheng, G.; Hu, Y. J. Org.
Chem. 2008, 73, 4732. (d) Huang, W.; Wang, J.; Shen, Q.; Zhou, X.
Tetrahedron 2007, 63, 11636. (e) Nair, V.; Menon, R. S.; Vinod, A. U.;
Viji, S. Tetrahedron Lett. 2002, 43, 2293. (f) Risitano, F.; Grassi, G.; Foti,
F.; Bilardo, C. Tetrahedron Lett. 2001, 42, 3503. (g) Lee, Y. R.; Suk, J. Y.;
Kim, B. S. Org. Lett. 2000, 2, 1387. (h) Ahluwalia, V. K.; Adhikari, R.;
Singh, R. P. Synth. Commun. 1985, 15, 1191. In many cases, mixtures of
isomeric furo[3,2-c]coumarins and furo[3,2-b]chromones have been previ-
ously obtained: see ref 4.
Interestingly, 3-methylfurocoumarin 6 was often isolated
as a side product (<30% isolated yield). It is likely that
Org. Lett., Vol. 11, No. 22, 2009
5255

Table 1. Synthesis of 3-Arylfuro[3,2-c]coumarinsa
Scheme 4. MeI-Initiated Cycloisomerization of 2a
group to give a linearly fused furan intermediate which, at
some point, would rearrange to its angularly fused isomeric
form.8 To investigate this hypothesis, we first needed to seek
a method for preparing furochromones of type 5 so as to
probe their stability under the cyclization reaction conditions.
We thus turned our attention to the alternative iodocyclization
approach to 3-substituted furan derivatives.3b Pleasingly, it
was found that 3-alkynylcoumarin 2a reacted with 2 equiv
of I2 in refluxing 1,2-dichloroethane to directly afford9 the
expected 3-iodofurochromone 7 in 85% isolated yield as the
sole reaction product.10 Interestingly, Suzuki-Miyaura cross-
coupling of 7 with p-fluorophenyl boronic acid using the
system Pd(OAc)2/TPPMS/i-Pr2NH in aqueous MeCN pro-
duced a 1:1 mixture of regioisomeric furan derivatives 4c
and 5c isolated in 42% and 41% yield, respectively.
Importantly, this isomeric ratio did not evolve with time.
Besides, 5c proved stable when subjected to reaction
conditions similar to those previously used for the synthesis
of 4c from 2a (2 equiv of p-FPhI, 10 mol % of Pd(PPh3)4,
DMF, 100 °C), which indicated that 5c is probably not an
intermediate in the synthesis of 4c (Scheme 5).
Scheme 5. Access to Furochromone 5c via Iodocyclization
a All reactions were run on a 0.2 mmol scale using 2 equiv of aryl
iodide in 2 mL of DMF. b Isolated yields. c Not isolated as a pure compound.
Contains small amounts of inseparable 4,4′-dinitro-1,1′-biphenyl.
cycloisomerization of 2a occurred via competitive activation
of the triple bond by a methylpalladium(II) iodide complex,
resulting in methylation of the furan ring following cycliza-
tion. This complex would be generated by oxidative addition
of methyl iodide, produced in the demethylation step (vide
infra), to Pd(0). Remarkably, reaction of 2a under the
previous conditions in the presence of only 0.2 equiv of MeI
as an initiator of the cyclization process led to the production
of 6 in 65% isolated yield (Scheme 4).
From a mechanistic point of view, we believed that the
alkynyl coumarins behave similarly to alkynyl pyridones3a
in the first steps of the cyclization process, undergoing
intramolecular attack by the carbonyl oxygen of the ester
In light of the previous observations, we may propose the
mechanistic pathway described in Scheme 6 to explain the
formation of angularly fused furan derivatives either via Pd-
catalyzed cyclization or Suzuki-Miyaura cross-coupling. In
the cyclization process, the σ-arylPd(II) iodide complex
generated in situ by oxidative addition of the organic iodide
to the Pd(0) catalyst would activate the alkyne triple bond
of 2a toward nucleophilic attack of the ester carbonyl oxygen
5256
Org. Lett., Vol. 11, No. 22, 2009

Scheme 6
.
Mechanistic Proposal
Scheme 7. Heteroannulation of Alkynyl Quinolinone 8
X-ray analysis. It is likely that in this case reductive
elimination would be faster than demethylation possibly due
to a better stability of the putative linearly fused furoquino-
linium salt intermediate (not shown).
In summary, we have unraveled the flexibility provided
by electrophilic heteroannulation reactions of 3-alkynyl-4-
alkoxycoumarins, which hold the synthetic potential to access
either furo[3,2-c]coumarins or the regioisomeric furo[2,3-
b]chromones. Further studies into the scope and limitations
as well as the mechanistic understanding of this chemistry
are currently underway in our laboratories and will be
reported as events merit.
to give the intermediate furochromenylium salt A. Dem-
ethylation of the latter would proceed rapidly through attack
of the methoxy group by the halide counterion before
reductive elimination takes place to give the corresponding
Pd-containing furochromone B as a key intermediate along
with iodomethane as side product.11 Intermediate B is also
expected to be produced in the Suzuki-Miyaura cross-
coupling reaction. It may evolve through reductive elimina-
tion to furnish the linearly fused furan derivatives 5 or
possibly rearrange to the isomeric Pd-containing furocou-
marin C via a furan ring-opening12-furan ring-closure
pathway involving palladium enolate intermediates. Reduc-
tice elimination would then afford the angularly fused furan
derivatives 4.13
Acknowledgment. This research was assisted financially
by a grant to G.R. from the French Ministry of Higher
Education and Research (MESR). We thank Dr. E. Jeanneau
(Centre de Diffractome´trie Henri Longchambon, Universite´
Lyon 1) for the X-ray crystallographic analyses. S. Belot
(Universite´ Lyon 1) is acknowledged for preliminary experi-
ments.
Supporting Information Available: Experimental pro-
cedures, characterization for all compounds, and X-ray data
for compounds 4a and 9 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
It is worth noting that, under identical cyclization reaction
conditions, alkynyl quinolinone 8 reacted uneventfully with
aryl iodide 3b to furnish the linearly fused furoquinolinone
9 as the sole cyclization-coupling product in 86% isolated
yield (Scheme 7), the structure of which was secured by
OL902189Q
(12) Ring-opening processes have already been observed in the case of
3-lithiobenzofurans and 3-lithiofuropyridines; see, respectively: (a) Barton,
T. J.; Groh, B.; L, J. Org. Chem. 1985, 50, 158, and references therein. (b)
Shiotani, S.; Morita, H. J. Heterocycl. Chem. 1992, 29, 413. See also: (c)
Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48, 607. (d) Frejd, T.;
Karlsson, J. O.; Gronowitz, S. J. Org. Chem. 1981, 46, 3132. Interestingly,
treatment of iodofurochromone 7 with 1.1 equiv of n-BuLi (THF at -78
°C, 3 h) followed by quenching with saturated aq NH4Cl at rt led to the
formation of furocoumarin 12 (20% conversion as determined by 1H NMR).
It is likely that 12 resulted from ring-opening of 3-lithiofurochromone 10
leading to enolate intermediate 11 which then underwent anionic cyclization
as previously observed (see ref 5a).
(8) Linear to angular rearrangements have been previously reported,
especially in the case of dihydrofuroquinolinones: (a) James, K. J.; Grundon,
M. F. J. Chem. Soc., Perkin Trans. 1 1979, 1467. (b) Butenscho¨n, I.; Mo¨ller,
K.; Ha¨nsel, W. J. Med. Chem. 2001, 44, 1249. (c) Bar, G.; Parsons, A. F.;
Thomas, C. B. Tetrahedron 2001, 57, 4719. (d) Pirrung, M. C.; Blume, F.
J. Org. Chem. 1999, 64, 3642. The rearrangement of dihydrofurochromones
to thermodynamically more stable dihydrofurocoumarins has also been
documented. (e) Majumdar, K. C.; Choudhury, P. K.; Nethaji, M. Tetra-
hedron Lett. 1994, 35, 5927.
(9) The formation of the putative furochromenylium salt intermediate
could not be observed under these conditions probably due to low
stability.
(10) Interestingly, 2a was shown to undergo simple trans-addition of I2
to the triple bond at room temperature. However, formation of the desired
iodofuran was found to occur at higher temperatures, suggesting that this
addition reaction may then become reversible: Miller, S. I.; Noyes, R. M.
J. Am. Chem. Soc. 1952, 74, 3403. This process is currently under
investigation and details will be reported in a forthcoming paper.
(11) At the present time, we cannot unequivocally rule out the possibility
that demethylation may occur prior to cyclization. However, the starting
coumarin 2a proved stable when heated in DMF at 100 °C for several hours,
even in the presence of Pd(PPh3)4 or PdII salts.
(13) Further work will be undertaken to investigate factors that may
influence the product distribution in the Suzuki reaction so as to possibly
drive this reaction toward the selective formation of the desired linearly
fused products. This would also provide additional information concerning
the isomerization process.
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