Hydroxyterphenylphoshine-palladium catalyst for benzo[ b ]furan synthesis from 2-chlorophenols. Bifunctional ligand strategy for cross-coupling of chloroarenes

Article abstract of DOI:10.1021/jo1007948

(Figure presented) A catalyst composed of Pd and hydroxyterphenylphosphine was found to be effective for one-pot benzo[b]furan synthesis from 2-chlorophenols and alkynes.

Full text of DOI:10.1021/jo1007948

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various types of cross-coupling of chloroarenes,4 which
Hydroxyterphenylphoshine-Palladium Catalyst for
Benzo[b]furan Synthesis from 2-Chlorophenols.
Bifunctional Ligand Strategy for Cross-Coupling of
Chloroarenes
are cheaper and more widely available than iodo- and
bromoarenes, chloroarenes with an electron-donating sub-
stituent are still challenging substrates because of their low
reactivity. The lack of examples of benzo[b]furan synthesis
from 2-chlorophenol probably results from slow oxida-
tive addition of the C-Cl bond, which is deactivated by
the o-hydroxy group, to Pd.
Recently, we found that bifunctional hydroxyterphenyl-
phosphines such as 15 dramatically accelerated cross-
coupling of 2-chlorophenols with Grignard reagents in the
presence of a Pd source.6 This catalytic system offers a new
strategy to activate chloroarenes. This acceleration is as-
sumed to be the result of transition state stabilization by the
Mg-phenoxide moiety of the bifunctional ligand in the rate-
determining oxidative-addition step of the catalytic cycle.6a
We envisioned that this accelerating effect would also be
applicable to one-pot synthesis of benzo[b]furans from
2-chlorophenols. Here we report the first Pd-catalyzed one-
pot synthesis of benzo[b]furans from 2-chlorophenols and
terminal alkynes (eq 1).
Jia-Rui Wang† and Kei Manabe*,†,‡
†RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako
351-0198, Japan, and School of Pharmaceutical Sciences,
‡
University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka
422-8526, Japan
manabe@u-shizuoka-ken.ac.jp
Received April 22, 2010
A catalyst composed of Pd and hydroxyterphenylpho-
sphine was found to be effective for one-pot benzo[b]-
furan synthesis from 2-chlorophenols and alkynes.
First, we searched reaction conditions to obtain benzo[b]-
furan 2 from 2-chlorophenol and 1-dodecyne, and found that
4d
the catalyst derived from 1 HBF4 and PdCl2(CH3CN)2
The benzo[b]furan framework is ubiquitous in natural
products and pharmaceuticals.1 Various methods have been
developed for the synthesis of benzo[b]furans, and among
those methods, Pd-catalyzed one-pot synthesis from 2-
halophenols and terminal alkynes by a Sonogashira coupling-
cyclization sequence is a useful and reliable way to construct
2-substituted benzo[b]furans.2 2-Iodo- and 2-bromophenols
have been widely used as the 2-halophenols.3 However, there
are no examples of 2-chlorophenols except one example in
which a benzofuran was obtained in a low yield (<10%).3h
Although recent progress in the field of Pd catalysis realizes
3
gave the desired product in good yield (Table 1, entry 1). The
use of t-BuOLi as a base is the key for this reaction, and other
bases as shown in entries 2-6 resulted in much lower yields.
Phosphines such as t-Bu3P HBF4,7 3,8 and 4,9 which have
3
often been used for cross-coupling of chloroarenes, did not
work well (entries 7-9). Bidentate ligand 510,11 also failed to
(4) Examples of Sonogashira coupling of chlorobenzenes, see: (a) Eberhard,
M. R.; Wang, Z. H.; Jensen, C. M. Chem. Commun. 2002, 8, 818. (b) Choudary,
B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem.
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(1) (a) Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry
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1996; Vol. 2, p 395. (b) Hou, X.-L.; Yang, Z.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Elsevier: Oxford,
UK, 2002; Vol. 14, p 139.
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Sussex, UK, 2004; p 211. (b) Shea, K. M. In Palladium in Heterocyclic
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2007; p 303. (c) Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65, 7761.
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N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997,
2815. (d) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017.
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Legros, J.-V.; Fiaud, J.-C. J. Organomet. Chem. 2003, 687, 353. (g) Sanz, R.;
Int. Ed. 2003, 42, 1056. (d) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed.
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C.; Wang, X. Eur. J. Org. Chem. 2007, 3445. (g) Huang, H.; Liu, H.; Jiang, H.;
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S.; Manabe, K. Chem. Lett. 2007, 36, 1304. (c) Manabe, K.; Ishikawa, S.
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(11) Ligand 5 was very effective for the reaction of 2-bromophenol (see
the Supporting Information).
ꢀ
~
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5340 J. Org. Chem. 2010, 75, 5340–5342
Published on Web 06/28/2010
DOI: 10.1021/jo1007948
r
2010 American Chemical Society

Wang and Manabe
JOCNote
TABLE 1. Optimized Reaction Conditions and Effects of Reaction
Parameters
TABLE 2. Benzo[b]furan Synthesis from Various 2-Chlorophenols and
Alkynesa
entry
variation of the standard conditions
none
t-BuOK instead of t-BuOLi
K3PO4 instead of t-BuOLi
Cs2CO3 instead of t-BuOLi
yield (%)
1
2
3
82
6
5
4
7
5
6
7
8
EtMgBr (2.6 equiv) instead of t-BuOLi
i-Pr2NEt instead of t-BuOLi
t-Bu3P HBF4 instead of 1 HBF4
0
trace
3
8
17
0
28
72
3
3
3 instead of 1 HBF4
4 instead of 1 HBF4
3
3
9
10
11
12
5 (2.4 mol %) instead of 1 HBF4
3
DMF instead of t-BuOH
toluene instead of t-BuOH
give the product (entry 10). In the reactions in entries 2-10,
large amounts of 2-chlorophenol remained after 22 h, indicat-
ing that the first Sonogashira coupling step did not proceed
well. Among the solvents tested, t-BuOH was found to be the
best (entries 11 and 12).
aConditions: PdCl2(CH3CN)2 (2 mol %), 1 HBF4 (4 mol %),
t-BuOLi (3.6 equiv), t-BuOH, 22 h.
3
The optimized reaction conditions were applied to other
substrates as shown in Table 2. A chlorophenol with an
electron-donating methoxy group slowly reacted to give the
desired product 6a in a modest yield (entry 1), while a chloro-
phenol with a fluoro group reacted faster to give 6b in a
higher yield (entry 2). 2-Chloro-3-hydroxypyridine also re-
acted under these conditions, producing furo[3,2-b]pyridine
6c in good yield (entry 3).
SCHEME 1. Formation of Proposed Intermediate A
This catalytic system could also be used for synthesis of
chloro-substituted benzo[b]furans 6d-f from dichlorophe-
nols through site-selective Sonogashira coupling. As shown
in Table 2, entries 4-6, dichlorophenols gave the desired
benzo[b]furans in modest to high yields. Although small
amounts of 4-(1-dodecynyl)-2-decylbenzo[b]furan (3%) and
6-(1-dodecynyl)-2-decylbenzo[b]furan (10%) were produced
in the reactions of 2,3-dichlorophenol (entry 4) and 2,5-dichloro-
phenol (entry 6), respectively, such a byproduct was not obtained
at all in the reaction of 2,4-dichlorophenol (entry 5). The
success in the synthesis of chlorobenzo[b]furans indicates that
the first Sonogashira coupling step site-selectively occurred
at the 2-position, the more sterically hindered position espe-
cially in the case of 2,3-dichlorophenol, emphasizing the effect
of the present catalytic system to accelerate cross-coupling at
the 2-chloro group.12 In previous examples of Pd-catalyzed
synthesis of chlorobenzo[b]furans, chloro-substituted 2-iodo-
and 2-bromophenols were used as the starting compounds.3e,f
Now, our method enables the use of dichlorophenols, which are
much cheaper than chloroiodo- or bromochlorophenols. These
results exemplify the importance of the present catalytic system.
The benzo[b]furan formation consists of two steps: the
Sonogashira coupling of 2-chlorophenols with alkynes and
the subsequent cyclization of the corresponding 2-alkynylphe-
nols presumably catalyzed by Pd(II). The present catalytic sys-
tem improves the first Sonogashira coupling step probably due
to acceleration of oxidative addition of the starting 2-chloro-
phenols. Although we do not have clear evidence for the
mechanism of the acceleration, the following scheme is pro-
posed: (1) both the hydroxy groups of 1 and chlorophenol are
deprotonated to generate Li phenoxides under the reaction
conditions, and (2) these Li phenoxides are in equilibrium with
a heteroaggregate13 such as A (Scheme 1) in which the 2-chloro
group is easily accessed by the Pd atom located nearby.
€
(12) Reviews on site-selective cross-coupling: (a) Schroter, S.; Stock, C.;
Bach, T. Tetrahedron 2005, 61, 2245. (b) Fairlamb, I. J. S. Chem. Soc. Rev.
2007, 36, 1036. (c) Wang, J.-R.; Manabe, K. Synthesis 2009, 1405.
(13) De Vries, T. S.; Goswami, A.; Liou, L. R.; Gruver, J. M.; Jayne, E.;
Collum, D. B. J. Am. Chem. Soc. 2009, 131, 13142.
J. Org. Chem. Vol. 75, No. 15, 2010 5341

Wang and Manabe
JOCNote
In summary, we developed a method of one-pot benzo-
[b]furan synthesis from 2-chlorophenols catalyzed by Pd
bearing bifunctional ligand 1. Thanks to progress in transi-
tion metal catalysis, chloroarenes are becoming widely
used coupling partners. The acceleration induced by the
bifunctional catalyst shown here provides another strategy
to improve the usability of chloroarenes in cross-coupling
chemistry.
was stirred at 110 °C for 22 h. The resulting suspension was
quenched with aq NH4Cl at rt and extracted with ethyl ace-
tate (2 Â 15 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated, and then the residue was
purified by preparative thin-layer chromatography (SiO2,
hexane) to give 2-decylbenzofuran14 (106 mg, 82% yield) as a
colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.45 (d, 1H, J = 7.5
Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.18-7.14 (m, 2H), 6.34 (d, 1H,
J = 1.0 Hz), 2.73 (t, 2H, J =7.5Hz), 1.72 (quint, 2H, J = 7.5 Hz),
1.31-1.26 (m, 14H), 0.88 (t, 3H, J = 7.0 Hz) ppm; 13C NMR
(CDCl3, 125 MHz) δ 159.8, 154.7, 129.1, 123.0, 122.4, 120.2,
110.7, 101.8, 32.0, 29.7, 29.6, 29.5, 29.4, 29.3, 28.5, 27.8, 22.8,
14.2 ppm;
Experimental Section
Typical Experimental Procedure of Benzofuran Synthesis
(Table 1, Entry 1). t-BuOH (1.0 mL) was added to PdCl2-
(CH3CN)2 (2.6 mg, 0.01 mmol), 1 HBF4 (10.6 mg, 0.02 mmol),
3
Acknowledgment. This work was partly supported by
Takeda Science Foundation.
t-BuOLi (144 mg, 1.8 mmol), and 2-chlorophenol (64.3 mg,
0.5 mmol) in a sealable tube under argon. The reaction mixture
was stirred at rt for 45 min, and then 1-dodecyne (125 mg, 0.75
mmol) was added. The tube was sealed, and the reaction mixture
Supporting Information Available: Experimental proce-
dures, characterization data, and a result of benzofuran synth-
esis from 2-bromophenol with 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Kitamura, T.; Zheng, L.; Fukuoka, T.; Fujiwara, Y.; Taniguchi, H.;
Sakurai, M.; Tanaka, R. J. Chem. Soc., Perkin Trans. 2 1997, 1511.
5342 J. Org. Chem. Vol. 75, No. 15, 2010