Palladium-mediated intramolecular carbonylative annulation of o-alkynylphenols to synthesize benzo[b]furo[3,4-d]furan-1-ones.

Article abstract of DOI:10.1021/ol010033z

[reaction in text] The carbonylative annulation of o-alkynylphenols mediated by PdCl(2)(PPh(3))(2) and dppp in the presence of CsOAc at 55 degrees C in acetonitrile under a balloon pressure of CO generates functionalized benzo[b]furo[3,4-d]furan-1-ones in

Full text of DOI:10.1021/ol010033z

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1387-1390
Palladium-Mediated Intramolecular
Carbonylative Annulation of
o-Alkynylphenols To Synthesize
Benzo[b]furo[3,4-d]furan-1-ones
Youhong Hu and Zhen Yang*
HarVard Institute of Chemistry and Cell Biology, HarVard Medical School,
250 Longwood AVenue, SGM 604, Boston, Massachusetts 02115-5731
zhen_yang@hms.harVard.edu
Received February 23, 2001
ABSTRACT
The carbonylative annulation of o-alkynylphenols mediated by PdCl2(PPh3)2 and dppp in the presence of CsOAc at 55 °C in acetonitrile under
a balloon pressure of CO generates functionalized benzo[b]furo[3,4-d]furan-1-ones in good yields. This novel synthetic approach provides a
highly efficient method for diversification of the benzofuran scaffold for combinatorial synthesis.
As a result of recent advances in chemical biology,1 there is
a strong desire to develop efficient methods and strategies
for combinatorial syntheses of small molecule libraries based
on naturally occurring products.2 Therefore, development of
a truly practical and efficient method3 for combinatorial
synthesis of these natural product libraries is both essential
and necessary. One of the best ways to address this objective
is to develop processes that afford enhancement of target-
relevant molecular complexity at minimal cost.4 Among the
many effective ways to reach the goal, the tandem process,5
which integrates multistep processes in a single operation,
is very attractive.
In this Letter, we would like to report our recent efforts
for the tandem synthesis of benzo[b]furo[3,4-d]furan-1-ones
by palladium-mediated intramolecular carbonylative annu-
lation of o-alkynylphenols.
(1) (a) Stockwell, B. R.; Haggarty, S. J.; Schreiber, S. L. Chem. Biol.
1999, 6, 71-83. (b) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King,
R. W.; Schreiber, S. L.; Mitchison, T, J. Science 1999, 286, 971-974.
(2) (a) http://sbweb.med.harvard.edu/∼iccb. (b) Tan, D. S.; Foley, M.
A.; Stockwell, B. R.; Shair, M. D.; Schreiber, S. L. J. Am. Chem. Soc.
1999, 121, 9073. (c) Schreiber, S. L. Science 2000, 287, 1964. (d) Lindsley,
C. W.; Chan, L. K.; Goess, B. C.; Joseph, R.; Shair, M. D. J. Am. Chem
Soc. 2000, 122, 422. (e) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A.
J.; Cao, G.-O.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122,
9939. (f) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A.
J.; Barluenga, S.; Cao, G.-O.; Affleck, R. L.; Lillig, J. E. J. Am. Chem.
Soc. 2000, 122, 9954.
(3) (a) Hudlicky, T.; Natchus, M. G. In Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2,
p 1. (b) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and
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Oxford, 1991; Vol. 5, Chapter 7.3. (d) Parsons, P. J.; Penkett, C. S.; Shell,
A. J. Chem. ReV. 1996, 96, 196.
(6) (a) Cagniant, P.; Cagniant, D. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1975;
Vol. 18, pp 337-482. (b) Pandey, G.; Muralikrishna, C.; Bhalerao, U. T.
Tetrahedron 1989, 45, 6867. (c) Chauder, B. A.; Kalinin, A. V.; Taylor,
N. J.; Snieckus, V. Angew. Chem. 1999, 111, 413. (d) Kraus, G. A.; Zhang,
N. J. Org. Chem. 2000, 65, 5644.
(7) (a) Endocrine Disrupters: A Scientific PerspectiVe. The American
Council on Science and Health, July 1999. (b) Gaido, K. W.; Leonard, L.
S.; Lovell, S. Toxicol. Appl. Pharmacol. 1997, 143, 205-212. (c) Solomon,
G. L. EnViron. Health Perspect. 1994, 102, Number 8. (d) Pereira, N. A.;
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10.1021/ol010033z CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/07/2001

Benzo[b]furo[3,4-d]furan-1-ones share a common scaffold
with many naturally occurring products,6 which have a wide
range of biological effects.7
Scheme 2. Proposed Mechanism of the Palladium-Catalyzed
Carbonylative Cyclization of o-Alkynylphenols
Several methods are known for synthesizing this type of
molecule;8 however, all of them focused on individual targets.
Consequently, there is a need for new and powerful methods
that offer greater flexibility and synthetic ease to diversity-
oriented synthesis9 of this type of molecule.
The transition metal-catalyzed carbonylative annulation of
alkynols or alkeneols provides convenient and effective one-
step processes for the syntheses of pyran or furan carboxy-
lates, lactones, and other interesting scaffolds, and significant
progress has been made in this fertile area.10
We previously demonstrated that palladium-thiourea is
an effective cocatalyst for the syntheses of 2,3-disubstituted
benzo[b]furans by carbonylative annulation of o-alkynylphe-
nols under very mild conditions (at 45 °C under a balloon
pressure of CO) [see Scheme 1].11
We therefore set up the experiments to pursue this
proposed cascade reaction. The reaction of o-alkynylphenols
1 in the presence of palladium-thiourea and CBr4 in
acetonitrile under conditions similar to those of our previous
annulation conditions11 resulted in formation of the desired
product 2 in 17% yield (Scheme 3).
Scheme 1. Palladium-Catalyzed Carbonylative Annulation
Scheme 3. Synthesis of Benzo[b]furo[3,4-d]furan-1-one 2
Our continuing interest in this field grew out of a desire
to create a cascade reaction which would exhibit broad
versatility with maximum toleration of diversified functional
groups for a combinatorial synthesis of benzo[b]furo[3,4-d]-
furan-1-ones from o-alkynylphenols.
To find the optimal reaction conditions, we studied the
effect of various reaction parameters (palladium catalyst,
solvent, base, etc.) on the outcome of the reaction. It was
found that among the catalysts tested [PdCl2, PdI2, Pd(OAc)2,
PdCl2(PPh3)2, PdCl2(PPh3)2-thiourea, PdI2-thiourea, PdCl2-
(PPh3)2-dppp], PdCl2(PPh3)2-dppp proved to be the most
efficient. Among the solvents used [THF, benzene, DMF,
CH3CN], CH3CN was the best choice. Between the bases
CsOAc and Cs2CO3, CsOAc gave a better result. Taken
together, a 68% yield of compound 2 was eventually obtained
when a stoichiometric amount of PdCl2(PPh3)2-dppp (1:1)
was utilized at 55 °C under a balloon pressure of CO.
Although a variety of oxidative agents, such as CuCl2 and
CBr4, were tested for the turnover of Pd(0) to Pd(II) in order
to carry out a palladium-catalyzed process, current results
using these oxidative agents gave only a 38% yield of the
desired product 2 under conditions identical to those
discussed above. Further investigation to find other oxidative
agents is being carried out in our lab.
On the basis of our previous mechanistic interpretation
for the palladium-catalyzed carbonylative annulation to
synthesize 2,3-disubstituted benzo[b]furans,11 we envisage
that benzo[b]furo[3,4-d]furan-1-ones could also be generated
from o-alkynylphenols A via the following multistage process
shown in Scheme 2.
We speculated that the overall process may involve attack
of alcohol A on the PdIIXYLn to generate complex B,
followed by insertion of CO to give intermediate C.
Intramolecular nucleophilic addition of the phenolic oxide
to the resulting acyl-palladium complex C leads to forma-
tion of intermediate D, which might undergo reductive
elimination to produce the five-membered lactone E and
palladium(0). The palladium(0) is then oxidized to palladium-
(II), completing the cycle.
(9) (a) Schreiber, S. L. Science 2000, 287, 1964-1969. (b) Nicolaou,
K. C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.;
Cao, G.-Q. J. Am. Chem Soc. 2000, 122, 9968-9976.
(10) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106,
1496. (b) Tamaru, Y.; Kobayashi, T.; Kawamura, S.; Ochiai, H.; Hojo, M.;
Yoshida, Z. Tetrahedron Lett. 1985, 26, 3207. (c) Tamaru, Y.; Hojo, M.;
Yoshida, Z. Tetrahedron Lett. 1987, 28, 325. (d) Tamaru, Y.; Hojo, M.;
Yoshida, Z. J. Org. Chem. 1991, 56, 1099. (e) Paddon-Jones, G. C.;
Hungerford, N. L.; Hayes, P.; Kitching, W. Org. Lett. 1999, 1, 1905. (f) EI
Ali, B.; Alper, H. Synlett 2000, 2, 161.
To assess the generality of the optimal reaction conditions,
other o-alkynylphenols were prepared by Sonogashira cou-
pling12 (see Scheme 4) and annulated.
(12) Sonogashira, K.; Tohda, Y,; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(11) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297-299.
1388
Org. Lett., Vol. 3, No. 9, 2001

acetonitrile, followed by treatment with DIPEA, and then
stirring the solution at 25 °C for 24 h to give the o-
alkynylphenol acetate, which was treated with NH2NH2 in
THF to afford the desired product o-alkynylphenol. The
detailed experimental data are summarized in the Supporting
Information.
Scheme 4. Synthesis of o-Alkynylphenols from the
Corresponding Iodophenol Acetate and Terminal Acetylenes
To delineate the scope of this annulation, particularly in
regard to our future combinatorial library construction, we
investigated the annulation of various o-alkynylphenols with
more complex and sterically hindered substitutes, and most
of them have a side chain attached to the TBS silyl protecting
group. As we expected, all the selected substrates gave
The Sonogashira reaction was carried out by mixing
phenyl iodide, acetylene, CuI ,and PdCl2(Ph3P)2 in dry
Table 1. PdCl2(PPh3)2-dppp Promoted Carbonylative Annulation of o-Alkynylphenols
a Pure product after flash chromatography and refers to a single run.
Org. Lett., Vol. 3, No. 9, 2001
1389

satisfactory yields and the reaction went to completion at
55 °C in less than 12 h using the conditions described.14
Furthermore, the TBS protecting group (see products 4c-
4n) was found to be stable under these reaction conditions.
This result is particularly important since we plan to build
up a benzo[b]furo[3,4-d]furan-1-one library on silyl linker
based polystyrene macrobeads.13,14
From the results in Table 1, we can make the following
observations. (1) Considering the substitution effects of a
five-membered ring (see 4e, 4h, 4j, and 4n in Table 1) and
a six-membered ring (compound 2 in Scheme 2 and 4c in
Table 1) on the outcome of the cyclization, it is interesting
to note that the five-membered ring based substrates give
higher yields of cyclization products than that of the six-
membered ring based substrates. (2) In comparison to tertiary
propargylic alcohols (see 3c, 3e-h, 3j, and 3l-n in Table
1), secondary propargylic alcohols (3a, 3d, 3i, and 3k in
Table 1) gave lower yields of cyclization products, a result
presumably due to the oxidation of the secondary propargylic
alcohols to ketones (see Scheme 5).
D (Path A) or be converted to a ketone by deprotonation of
the R hydrogen in the propargylic alcohol portion of the
molecule (Path B).
To prove this assumption, we selected two types of
propargylic alcohol based o-alkynylphenols (Scheme 6) to
Scheme 6. Oxidation of Primary and Secondary Alcohols with
Palladium(II) Species
carry out the annulations under conditions identical to those
listed in Table 1. As expected, these two easily oxidized
propargylic alcohols (primary propargylic alcohol 5 and
benzylic alcohol 6) gave unidentified complex reaction
mixtures, presumably due to the decomposition of the newly
generated aldehyde or ketone.
Scheme 5. Oxidation of the Secondary Propargylic Alcohols
In summary, we have developed a highly efficient
synthetic methodology for carbonylative cyclization of
o-alkynylphenols to construct the corresponding benzo[b]-
furo[3,4-d]furan-1-ones, and all the products listed in Table
1 were synthesized, for the first time, with good to excellent
yields. Such an efficient manipulation of multiple steps (three
carbon-oxygen bonds and one carbon-carbon bond) in this
particular reaction cycle combined with mild reaction condi-
tions will make this method a general approach to the
syntheses of benzo[b]furo[3,4-d]furan-1-ones.
We reasoned that two competitive paths would account
for these low yields. Accordingly, the secondary propargylic
alcohol based acyl-palladium complex C (see Scheme 5)
could either undergo an intramolecular nucleophilic addition
of a phenolic oxide to the acetylene to provide intermediate
Acknowledgment. We thank Professors Stuart L. Schreiber
and Timothy J. Mitchison and Rebecca Ward for their
invaluable advice during the course of this research and Dr.
Reza Fathi for helpful assistance and comments for the
preparation of the manuscript. Financial support from NIH
(Grant 1PO1 CA78048), Merck & Co. (Grant MCI97-
MITC804), and Merck KGaA is gratefully acknowledged.
(13) Liao, Y.; Fathi, R.; Reitman, M.; Zhang, Y.; Yang, Z. Tetrahedron
Lett. 2001, 42, 1815-1818.
(14) Typical procedure used in the synthesis of benzo[b]furo[3,4-d]-
furan-1-ones: A mixture of o-alkylnylphenol (1.0 mmol), dppp (1.0 mmol),
CsOAc (4.0 mmol), and PdCl2(PPh3)2 (1.0 mmol) was dissolved in dry
acetonitrile (5.0 mL), and the reaction mixture was degassed by CO for 10
min and then stirred at 55 °C under a balloon pressure of CO for 12 h. The
reaction mixture was concentrated and the residue was filtered through a
pad of silica gel and washed by EtOAc. The filtrate was concentrated, and
the residue was purified by silica gel flash chromatography.
Supporting Information Available: Experimental pro-
cedures and 1H and C13 NMR spectra for all the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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