A new complex of palladium-thiourea and carbon tetrabromide catalyzed carbonylative annulation of o-hydroxylarylacetylenes: Efficient new synthetic technology for the synthesis of 2,3-disubstituted benzo[b]furans

Article abstract of DOI:10.1021/ol991327b

(matrix presented) A highly effective cocatalysis system (Pdl₂-thiourea and CBr₄) was developed for carbonylative cyclization of both electron-rich and electron-deficient o-hydroxylarylacetylenes to the corresponding methyl benzo[b]f

Full text of DOI:10.1021/ol991327b

ORGANIC
LETTERS
2000
Vol. 2, No. 3
297-299
A New Complex of Palladium−Thiourea
and Carbon Tetrabromide Catalyzed
Carbonylative Annulation of
o-Hydroxylarylacetylenes: Efficient New
Synthetic Technology for the Synthesis
of 2,3-Disubstituted Benzo[b]furans
Yang Nan, Hua Miao, and Zhen Yang*
HarVard Institute of Chemistry and Cell Biology, HarVard UniVersity,
250 Longwood AVenue, SGM 604, Boston, Massachusetts 02115-5731
zhen_yang@hms.harVard.edu
Received November 10, 1999
ABSTRACT
A highly effective cocatalysis system (PdI2−thiourea and CBr4) was developed for carbonylative cyclization of both electron-rich and electron-
deficient o-hydroxylarylacetylenes to the corresponding methyl benzo[b]furan-3-carboxylates.
During the development of a chemical genetic approach to
analyzing biological systems by using small molecules in
an appropriate cell-based assay,1 we became interested in
developing a general synthetic method for combinatorial
synthesis of a 2,3-disubstituted benzo[b]furan library.
Benzo[b]furan derivatives are of interest because of their
frequent occurrence in nature2 and their wide range of
biological effects.3
has centered on the use of palladium catalysts for carbon-
carbon bond formation leading to the benzofuran structures.
Largely due to the efforts of Richard C. Larock and
co-workers, an extremely versatile method for the synthesis
of a wide variety of heterocycles and carbocycles by the
palladium-catalyzed carbo- and heteroannulation of 1,2-
dienes,5 1,3-dienes,6 1,4-dienes,7 and vinyllic cyclopropanes
or cyclobutanes8 by aromatic halides bearing functional
groups in the ortho position has been developed.
Although various methods are known in the literature for
the synthesis of benzo[b]furan,4 recent research, however,
(4) (a)Yang, Z,; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C.
J. Org. Chem. 1992, 57, 7248-7257, and references therein. (b) Larock,
R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29, 4687. (c) Iwasaki, M.;
Kobayashi, Y.; Li, J.-P.; Matsuzaka, H.; Ishii, Y.; Hidai, M. j. Org. Chem.
1991, 56, 1922. (d) Kondo, Y.; Sakamoto, T.; Yamanaka, H. Heterocycles
1989, 29, 1013. (e) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K.
J. Chem. Soc., Chem. Commun. 1992, 41.
(5) Larock, R. C.; Berrios-Pena, N. G.; Narayanan, K. J. Org. Chem.
1991, 56, 2615.
(6) (a) Larock, R. C.; Berrios-Pena, N. G.; Narayanan, K. J. Org. Chem.
1990, 55, 3447. (b) Larock, R. C.; Fried, C. A. J. Am. Chem. Soc. 1990,
112, 5882. (c) O′Connor, J. M.; Stallman, B. J.; Clark, W. G.; Shu, A. Y.
L.; Spada, R. E.; Stevenson, T. M.; Dieck, H. A. J. Org. Chem. 1983, 48,
807. (d) Larock, R. C.; Guo, L. Synlett 1995, 465.
(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. Scinece 1999, 286, 971-974.
(2) (a) Cagniant, P.; Carniant, D. AdV. Hetercycl. Chem. 1975, 18, 337.
(b) Donnelly, D. M. X.; Meegan, M. J. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 4; pp 657-712.
(3) (a) Felder, C. C.; Joyce, K. E.; Briley, E. M.; et al. J. Pharmacol.
Exp. Ther. 1998, 284, 291-297. (b) Yang, Z.; Hon, P. M.; Chui, K. Y.;
Chang, H. M.; Lee, C. M.; Cui, Y. X.; Wong, H. N. C. Poon, C. D.; Fung,
B. M. Tetrahedron Lett. 1991, 32, 2061-2064. (c) Carter, G. A.;
Chamberlain, K. Wain, R. L. Ann. Appl. Biol. 1978, 88, 57-64. (d) Ingham,
J. L.; Dewick, P. M. Phytochemistry 1978, 17, 535-538. (e) Takasugi,
M.; Nagao, S.; Masamune, T. Tetrahedron Lett. 1979, 4675-4678. (f)
Davies, W.; Middleton, S. Chem. Ind. (London) 1957, 599-600.
(7) Larock, R. C.; Berrios-Pena N. G.; Fried, C. A.; Yum, E. K.; Tu, C.;
Leong, W. J. Org. Chem. 1993, 58, 4509.
10.1021/ol991327b CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/06/2000

For the synthesis of benzo[b]furan-3-carboxylates, the
palladium-catalyzed carbonylative cyclization of arylacetyl-
enes bearing hydroxyl groups in the ortho position (1) has
proven to be a useful method for the synthesis of these
heterocycles (2) (Figure 1).9
the complex B, followed by nucleophilic addition of the
phenolic oxide to the XPdII(CO)OR-activated arylacetylene
B to give intermediate C. Reductive elimination of C
produces ester D and palladium(0). The palladium(0) is then
oxidized to palladium(II), completing the cycle.
In this catalytic cycle, the nature of the base (B-),
palladium(II) complex (XPdII(CO)OR), and oxidative agent
(XY) [which promotes the turnover of Pd0 to PdII] is
paramount to the success of the reaction. The base should
allow the desired catalytic cycle to proceed while minimizing
the unwanted direct cyclization of A to E (see Figure 2).
The XPdII(CO)OR complex has to be active enough to
coordinate with acetylene to form B, and the oxidative agent
(XY) has to efficiently promote the turnover of the palladium
catalyst from Pd0 to PdII without disrupting the carbonylative
cyclization.
Figure 1. General scheme for palladium-catalyzed carbonylative
heteroannulation.
The palladium-catalyzed carbonylative cyclization of o-
hydroxylarylacetylenes to generate benzo[b]furan-3-carboxyl-
ates has been recently utilized by Scammells in his synthesis
of XH14.9a,b Unfortunately, we were not able to reproduce
the cyclization reported in ref 9a utilizing the published
conditions. The best yields we could obtain were in the range
of 10-15% due to decomposition of starting material and
autocyclization, where Scammells reports a 68% yielding.
We then carried out a systematic study to identify the
appropriate base (B-), catalyst (XPdII(CO)OR), and oxidative
agent (XY) that would effect carbonylative heteroannulation
of electron-deficient substrates and tolerate silyl-protecting
groups. We evaluated palladium catalysts, such as PdCl2,
PdCl2(PPh3)2, Pd(OAc)2, PdI2, and PdI2-thiourea.11 All the
catalysts tested gave low yields when electron-deficient
substrates were used with CuCl2 as an oxidative agent. In
addition, the silyl protecting group was cleaved under the
reaction conditions (CuCl2, MeOH).
There are however limitations associated with this meth-
odology: (1) low yields of the benzo[b]furan-3-carboxylates
when electron-deficient substrates are used9b,c and (2) the
incompatibility of reaction conditions with silyl protecting
groups.10 The later limitation is of particular concern since
our proposed library synthesis is to be carried out on a silyl
linker to allow efficient high throughput screening. Therefore,
we needed to find reaction conditions that will allow us to
use both electron-rich and electron-deficient substrates while
not cleaving silyl groups.
Mechanistically, the formation of benzo[b]furan-3-car-
boxylates starting from o-hydroxylarylacetylenes presumably
proceeds via the multistage process shown in Figure 2.11
We finally focused our attention on oxidative agents (XY
in Figure 2). Our goal was to find a reagent that not only
efficiently converts the Pd0 to PdII but also promotes the
annulation of electron-deficient substrates while tolerating
silyl groups. Some oxidative agents can convert the Pd0 to
PdII,9c,12 but they are not compatible with the conditions of
our 2,3-disubstituted benzo[b]furan synthesis. Although
organic halides, such as bromobenzene and iodobenzene,
have been used effectively to reoxidize palladium(0),13 they
cannot be applied to our catalytic process owing to competi-
tive reductive elimination of the phenyl group.14
Figure 2. Mechanism of palladium-catalyzed carbonylative cy-
clization of o-hydroxylarylacetylenes.
After considerable experimentation, it was found that
electron-deficient substrates 3 could be carbonylatively
heteroannulated with PdI2-thiourea, CBr4, and Cs2CO3 as
the base, in methanol at 40 °C and balloon pressure of CO
The overall process may involve attack of a carboalkoxy-
palladium(II) intermediate on the arylacetylene A to generate
(12) (a) Tamaru, Y. Yamada, Y.; Yamamoto, Y. Yoshida, Z.-I. J. Org.
Chem. 1983, 48, 1286-1292. (b) Nagashima, H. Sato, K.; Tsuji, J.
Tetrahedron 1985, 41, 5645-5651. (c) B. M.; Reddy, N. P.; Kantam, M.
L. Tetrahedron Lett. 1985, 26, 6257-6258. (d) Ba¨ckvall, J. E.; Awasthi,
A. K.; Renko, Z. D. J. Am. Chem. Soc. 1987, 109, 4750-4752. (e) Sakurai,
Y. Sakaguchi, S.; Ishii, Y. Tetahedron lett. 1999, 40, 1701-1704.
(13) (a) Tamaru, Y. Yamada, Y.; Yamamoto, Y. Yoshida, Z.-I. Yoshida,
Z.-I. Tetrahedron Lett. 1979, 16, 1401-1403. (b) Choudary, B. M.;
Prabhakar Reddy, N.; Lakshmi Kantam, M. Tetrahedron Lett. 1985, 26,
6257-6258.
(8) Larock, R. C.; Yum, E. K. Synlett 1990, 529.
(9) Lu¨tjens, H.; Scammells, P. J. Tetrahedron Lett. 1998, 39, 6581-
6584. (b) Lu¨tjens, H.; Scammells, P. J. Synlett 1999, 7, 1079-1081. Kondo,
Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994,
50, 11803-11812. (c) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V.
Carbonylation: Direct Synthesis of Carbonyl compounds; Pleamum: New
York, 1991.
(10) Cort, A. D. Synth. Commun. 1990, 20, 757.
(11) Choudary, Gabriele, B.; Salerno, G.; Cosat, M.; Chiusoli, G. P. J.
Organomet. Chem. 1995, 503, 21-28.
(14) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437-452.
298
Org. Lett., Vol. 2, No. 3, 2000

Scheme 1. Synthesis of Benzo[b]furan-3-carboxylate 3a
Table 1. Palladium-Thiourea-Catalyzed Carbonylative
Annulation of o-Hydroxylarylacetylenes
(Scheme 1), to give 84% yield of the desired product 3a.
The reaction was also complete in less than a half-hour.
To assess the generality of this procedure, other o-
hydroxylarylacetylenes were prepared by Sonogashira cou-
pling15 [Scheme 2] and annulated. The detailed experimental
Scheme 2. Synthesis of o-Hydroxylarylacetylenes from the
Corresponding Iodolphenol Acetates and Acetylenes
data are summarized in the Supporting Information.
Remarkably, with all the substrates (both electron-rich and
electron-deficient) the reaction gave satisfactory yields (see
Table 1) and went to completion in less than a half-hour
using the same conditions as described above. Furthermore,
the TBS protecting group (see compound 5a in Table 1) was
found to be stable under these reaction conditions.
In summary, we have developed a highly effective
cocatalysis system (PdI2-thiourea and CBr4) for carbonyl-
ative cyclization of both electron-rich and electron-deficient
o-hydroxylarylacetylenes to the corresponding methyl benzo-
[b]furan-3-carboxylates. We have introduced, for the first
time, carbon tetrabromide (CBr4) as a superior oxidative
agent for the turnover of palladium(0) to palladium(II). This
result has the potential to be used in other types of palladium
chemistry, such as oxidation of an alcohol to an aldehyde
or a ketone.13
proved to be as effective as in solution phase, and a
combinatorial synthesis of a benzo[b]furan library is currently
underway in our laboratory.
Acknowledgment. We thank professors Stuart L.
Schreiber, Timothy J. Mitchison, and Rebecca Ward for their
invaluable advice during the course of this research. Financial
support from the NIH (Grant 1PO1 CA78048) and Merck
Co. (Grant MCI97MITC804) is gratefully acknowledged.
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.
The application of this cocatalyst system to a silyl linker-
based solid-phase benzo[b]furan-3-carboxylate synthesis
(15) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. (b) Sonogashira, K. In ComprehesiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, p 521.
OL991327B
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