Synthesis of 2-(polyfluoroaryl)benzofurans via a copper(I)-catalyzed reaction of 2-(2,2-dibromovinyl)phenol with polyfluoroarene

Article abstract of DOI:10.1021/ol202858f

A novel and efficient route for the synthesis of 2-(polyfluoroaryl) benzofurans via a copper(I)-catalyzed tandem reaction of 2-(2,2-dibromovinyl) phenol with polyfluoroarene is reported. The corresponding products are generated in good yields. During the

Full text of DOI:10.1021/ol202858f

ORGANIC
LETTERS
2012
Vol. 14, No. 1
70–73
Synthesis of 2-(Polyfluoroaryl)benzofurans
via a Copper(I)-Catalyzed Reaction of
2-(2,2-Dibromovinyl)phenol with
Polyfluoroarene
Shengqing Ye,† Gang Liu,†,‡ Shouzhi Pu,*,‡ and Jie Wu*,†,§
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology
Normal University, Nanchang 330013, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
jie_wu@fudan.edu.cn; pushouzhi@yahoo.com.cn
Received October 23, 2011
ABSTRACT
A novel and efficient route for the synthesis of 2-(polyfluoroaryl)benzofurans via a copper(I)-catalyzed tandem reaction of 2-(2,2-
dibromovinyl)phenol with polyfluoroarene is reported. The corresponding products are generated in good yields. During the reaction process,
a copper-catalyzed intramolecular CÀO bond formation and a CÀH activation are involved.
As a prominent structural motif, compounds with a
polyfluorinated aromatic structure have found applica-
tions in medicinal chemistry1 and material science.2 For
example, molecules containing the polyfluoroarene struc-
ture serve as active materials in electronic devices, such as
organic light-emitting diodes and field-effect transistors.2
As a privileged scaffold, the benzofuran core structure is
found in a wide variety of natural products3 and biologi-
cally important molecules.4 Additionally, its application in
† Fudan University.
‡ Jiangxi Science & Technology Normal University.
§ Chinese Academy of Sciences.
(1) Zahn, A.; Brotschi, C.; Leumann, C. J. Chem.;Eur. J. 2005, 11,
2125.
(4) For selected examples, see: (a) Felder, C. C.; Joyce, K. E.; Briley,
E. M. J. Pharmacol. Exp. Ther. 1998, 284, 291. (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. (c)
Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Naruto, S.;
Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 455. (d) Fukai, T.; Oku,
Y.; Hano, Y.; Terada, S. Planta Medica 2004, 70, 685. (e) Tsuji, E.;
Ando, K.; Kunitomo, J.-i.; Yamashita, M.; Ohta, S.; Kohno, S.; Ohishi,
Y. Org. Biomol. Chem. 2003, 1, 3139.
(2) For selected recent reviews and papers, see: (a) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Babudri, F.; Farinola,
G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, 1003. (c) Tang, M. L.;
Reichardt, A. D.; Miyaki, N.; Stoltenberg, R. M.; Bao, Z. J. Am. Chem.
Soc. 2008, 130, 6064. (d) Wang, Y.; Watson, M. D. J. Am. Chem. Soc.
2006, 128, 2536. (e) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew.
ꢀ
Chem., Int. Ed. 2003, 42, 1210. (f) Murphy, A. R.; Frechet, J. M. J. Chem.
Rev. 2007, 107, 1066.
(3) For selected examples, see: (a) Maximo, P.; Lourenc-o, A.; Feio,
(5) Hwu, J. R.; Chuang, K.-S.; Chuang, S. H.; Tsay, S.-C. Org. Lett.
2005, 7, 1545.
ꢀ
S. S.; Roseiro, J. C. J. Nat. Prod. 2002, 65, 175. (b) Song, K.-S.; Raskin, I.
J. Nat. Prod. 2002, 65, 76. (c) Sritularak, B.; Likhitwitayawuid, K.;
Conrad, J.; Vogler, B.; Reeb, S.; Klaiber, I.; Kraus, W. J. Nat. Prod.
2002, 65, 589. (d) Lin, Y.-L.; Chang, Y.-Y.; Kuo, Y.-H.; Shiao, M.-S.
J. Nat. Prod. 2002, 65, 745. (e) Pacher, T.; Seger, C.; Engelmeier, D.;
Vajrodaya, S.; Hofer, O.; Greger, H. J. Nat. Prod. 2002, 65, 820. (f)
Muriithi, M. W.; Abraham, W.-R.; Addae-Kyereme, J.; Scowen, I.;
Croft, S. L.; Gitu, P. M.; Kendrick, H.; Njagi, E. N. M.; Wright, C. W.
J. Nat. Prod. 2002, 65, 956. (g) 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 657À712.
(6) For recent selected examples: (a) Li, S.; Wu, J. Org. Lett. 2011, 13,
712. (b) Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848. (c) Luo, Y.;
Pan, X.; Wu, J. Org. Lett. 2011, 13, 1150. (d) Ren, H.; Luo, Y.; Ye, S.;
Wu, J. Org. Lett. 2011, 13, 2552. (e) Li, S.; Luo, Y.; Wu, J. Org. Lett.
2011, 13, 3190. (f) Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011, 13, 4312. (g)
Luo, Y.; Wu, J. Org. Lett. 2011, 13, 5858. (h) Luo, Y.; Hong, L.; Wu, J.
Chem. Commun. 2011, 47, 5298. (i) Pan, X.; Luo, Y.; Wu, J. Chem.
Commun. 2011, 47, 8967. (j) Luo, Y.; Wu, J. Chem. Commun. 2011, 47,
11137. (k) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem. Commun. 2011, 47,
5623. (l) Qiu, G.; Hu, Y.; Ding, Q.; Peng, Y.; Hu, X.; Wu, J. Chem.
Commun. 2011, 47, 9708.
r
10.1021/ol202858f
Published on Web 12/02/2011
2011 American Chemical Society

material science has been demonstrated.5 In our labora-
tory, we have been interested in the synthesis of natural
product-like compounds with privileged scaffolds.6
Prompted by the importance of polyfluorinated com-
pounds and benzofurans, we envisioned that the benzofur-
an-incorporated polyfluorinated compounds would be
beneficial for various biological assays. Thus, we initiated
a program for method development and library construc-
tion of 2-(polyfluoroaryl)benzofurans.
much attention.8,9 In the meantime, gem-dihaloolefins
have served as a versatile building block in organic synth-
esis with good stereoselectivity.10À12 We also used gem-
dibromoolefins as substrates for the synthesis of indene
derivatives.11kÀm Encouraged by these results, we con-
ceived that 2-(polyfluoroaryl)benzofurans could be pre-
pared via a transition-metal-catalyzed reaction of 2-(2,2-
dibromovinyl)phenol12l with polyfluoroarene (Scheme 1).
Therefore, we started to explore the possibility of this
transformation.
Scheme 1. Proposed Route for the Transition-Metal-Catalyzed
Reaction of 2-(2,2-Dibromovinyl)phenol 1 with Polyfluoroar-
ene 2
Table 1. Initial Studies for the Copper(I)-Catalyzed Reaction of
2-(2,2-Dibromovinyl)phenol 1a with Polyfluoroarene 2a
[Cu]
yield
(%)a
entry
(mol %)
base
solvent
Recently, the synthesis of polyfluorinated aromatic
compounds using a CÀH activation strategy7 has attracted
1
CuI (10)
CuI (20)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (20)
CuI (10)
CuI (20)
CuBr (20)
CuCl (20)
CuI (20)
CuI (20)
CuI (20)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
Ag2CO3
1,4-dioxane
1,4-dioxane
DMF
40
2b
NR
NR
NR
trace
38
3
4
DMPU
(7) For reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174. (b) Giri, R.; Shi, B. F.; Engle, K. M.; Maugel,
N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (c) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(e) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (f) Bras,
J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (g) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Rev. 2011, 111, 1293. (i) Ackermann, L. Chem. Rev. 2011, 111,
1315. (j) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(k) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (l)
Kuninobu, Y.; Takai, K. Chem. Rev. 2011, 111, 1938.
5
xylene
6c
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
7d
57
8e
52
9d,e
10d,e
11d,e
12 d,e
13 d,e
14
72
38
27
74
94
NR
(8) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Lafrance, M.; Shore, D.; Fagnou, K.
Org. Lett. 2006, 8, 5097. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 1128. (d) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 15185. (e) Do, H.-Q.; Daugulis, O. Chem.
Commun. 2009, 6433. (f) Rene, O.; Fagnou, K. Org. Lett. 2010, 12, 2116.
(9) (a) Wei, Y.; Kan, J.; Wang, M.; Su, W.; Hong, M. Org. Lett. 2009,
11, 3346. (b) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem.
Soc. 2010, 132, 2522. (c) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min,
Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (d) He,
C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. (e) Nakao,
Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008,
130, 16170. (f) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. (g) Li,
H.; Liu, J.; Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2011, 13, 276.
(10) For reviews of gem-dihaloolefins, see: (a) Handbook of Orga-
nopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; p 650. (b) Xu, B.; Ma, S. Chin. J. Org.
Chem. 2001, 21, 252.
(11) For selected examples, see: (a) Zeng, X.; Qian, M.; Hu, Q.;
Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259. (b) Molander, G. A.;
Yokoyama, Y. J. Org. Chem. 2006, 71, 2493. (c) Knorr, R.; Pires, C.;
Freudenreich, J. J. Org. Chem. 2007, 72, 6084. (d) Sun, C.; Xu, B. J. Org.
Chem. 2008, 73, 7361. (e) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H.
J. Am. Chem. Soc. 2008, 130, 1820. (f) Ma, S.; Xu, B. J. Org. Chem. 1998,
63, 9156. (g) Ma, S.; Xu, B.; Ni, B. J. Org. Chem. 2000, 65, 8532.
(h) Ye, W.; Mo, J.; Zhao, T.; Xu, B. Chem. Commun. 2009, 3246. (i)
Bandyopadhyay, A.; Varghese, B.; Hopf, H.; Sankararaman, S.
Chem.;Eur. J. 2007, 13, 3813. (j) Gholami, M.; Melin, F.; McDonald,
R.; Ferguson, M. J.; Echegoyen, L.; Tykwinski, R. R. Angew. Chem.,
Int. Ed. 2007, 46, 9081. (k) Ye, S.; Ren, H.; Wu, J. J. Comb. Chem. 2010,
12, 670. (l) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 2950. (m)
Ye, S.; Wu, J. Org. Lett. 2011, 13, 5980. (n) Zeng, F.; Alper, H. Org. Lett.
2011, 13, 2868. (o) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H.
Org. Lett. 2008, 10, 4899. (p) Arthuis, M.; Pontikis, R.; Florent, J. C.
Org. Lett. 2009, 11, 4608.
a Isolated yield based on 2-(2,2-dibromovinyl)phenol 1a. b Without
the addition of 1,10-phenanthroline. c In the presence of 4.0 equiv of
K3PO4. d In the presence of 20 mol % of 1,10-phenanthroline. e Using 4.0
equiv of pentafluorobenzene 2a.
Since a copper(I) catalyst showed high efficiency in the
CÀO coupling reaction13 as well as in the arylation and
alkenylation of polyfluoroarene CÀH bonds,8c,d at the
(12) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Yuen,
J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (c) Fayol, A.; Fang,
Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (d) Fang, Y.-Q.; Karisch,
R.; Lautens, M. J. Org. Chem. 2007, 72, 1341. (e) Nagamochi, M.; Fang,
Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955. (f) Fang, Y.-Q.; Lautens, M.
J. Org. Chem. 2008, 73, 538. (g) Bryan, C. S.; Lautens, M. Org. Lett.
2008, 10, 4633. (h) Bryan, C. S.; Lautens, M. Org. Lett. 2010, 12, 2754. (i)
Bryan, C. S.; Braunger, J. A.; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 7064. (j) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M.
Chem. Commun. 2009, 5236. (k) Chai, D. I.; Lautens, M. J. Org. Chem.
2009, 74, 3054. (l) Qin, X.; Cong, X.; Zhao, D.; You, J.; Lan, J. Chem.
Commun. 2011, 47, 5611.
(13) For selected examples, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400. (b) Shafir, A.; Lichtor, P. A.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 3490. (c) Altman, R. A.; Shafir, A.;
Choi, A.; Lichtor, P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73, 284. (d)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096. (e)
Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423. (f)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (g)
Kabir, M. S.; Lorenz, M.; Namjoshi, O. A.; Cook, J. M. Org. Lett. 2010,
12, 464. (h) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
Org. Lett., Vol. 14, No. 1, 2012
71

outset we selected copper(I) salts as the catalysts for
reaction development. 2-(2,2-Dibromovinyl)phenol 1a
and pentafluorobenzene 2a were chosen as the model
substrates (Table 1). In an initial attempt, the reaction
was catalyzed by copper(I) iodide (10 mol %) and 1,10-
phenanthroline (10 mol %) in the presence of K3PO4
(3.0 equiv) as the base in 1,4-dioxane at 125 °C (Table 1,
entry 1). To our delight, the expected 2-(polyfluoroaryl)
benzofuran 3a was formed and isolated in 40% yield. No
reaction occurred without the addition of 1,10-phenan-
throline in a control experiment (Table 1, entry 2). The
reaction could not proceed when the reaction was per-
formed in DMF or DMPU (Table 1, entries 3 and 4). A
trace amount of product was detected when the solvent
was replaced by xylene (Table 1, entry 5). No better result
was generated when the amount of base was increased
(38% yield, Table 1, entry 6). The yield could be improved
when 20 mol % of copper(I) iodide and 1,10-phenanthro-
line were employed in the reaction (57% yield, Table 1,
entry 7). A similar outcome was observed when the
amount of pentafluorobenzene 2a was increased to 4.0
equiv (52% yield, Table 1, entry 8). Thus, an investigation
was conducted for a combination of the above two condi-
tions in the model reaction. As expected, the desired
product 3a was formed in 72% yield (Table 1, entry 9).
The result was inferior when the catalyst was changed to
copper(I) bromide or copper(I) chloride (Table 1, entries
10 and 11). Other bases were examined subsequently,
which showed that K2CO3 was the best choice (94% yield,
Table 1, entry 13).
Table 2. Synthesis of 2-(Polyfluoroaryl)benzofurans 3 via a
Copper(I)-Catalyzed Reaction of 2-(2,2-Dibromovinyl)phenol
1 with Polyfluoroarene 2
With the optimized conditions in hand [CuI (10 mol %),
1,10-phenanthroline (20 mol %), K2CO3 (3.0 equiv),
1,4-dioxane, 125 °C], we then investigated the general-
ity of this copper(I)-catalyzed tandem reaction of
2-(2,2-dibromovinyl)phenol 1 with polyfluoroarene 2.
The results are presented in Table 2. Usually, the
solution turned black after the reaction was stirred
overnight. Noticeably, 2-(2,2-dibromovinyl)phenols
1 with different substitutions on the aromatic ring
were all compatible under the standard conditions.
For instance, 2-(2,2-dibromovinyl)-5-methoxyphenol
1b reacted with pentafluorobenzene 2a leading to the
corresponding product 3b in 93% yield (Table 2, entry 2).
An almost quantitative yield was obtained when
2-(2,2-dibromovinyl)-6-methoxyphenol 1c was used
as a substrate in the reaction of pentafluorobenzene
2a (98% yield, Table 2, entry 3). 2,3,5,6-Tetrafluor-
obenzonitrile 2b was a suitable partner as well, which
afforded the desired product 3d in 68% yield (Table 2,
entry 4). Interestingly, reaction of 2-(2,2-dibromovinyl)-
6-methoxyphenol 1c with 2,3,5,6-tetrafluoropyri-
dine 2c worked well to furnish 2,3,5,6-tetrafluoro-
4-(7-methoxybenzofuran-2-yl)pyridine 3e in 92%
yield (Table 2, entry 5). 1,2,4,5-Tetrafluoro-3-(trifluoro-
methyl)benzene 2d or 1,2,4,5-tetrafluoro-3-methoxyben-
zene 2e served as a reactant in the reaction of 2-(2,2-
dibromovinyl)phenol 1f (Table 2, entries 11 and 12). It
seems that the reactivity is superior when trifluoromethyl-
substituted polyfluoroarene 2d was employed in the reaction.
a Isolated yield based on 2-(2,2-dibromovinyl)phenol 1.
A similar result was observed when 2-(2,2-dibromovinyl)
phenol 1g was utilized in the reaction of polyfluoroarene 2d
or 2e (Table 2, entries 14 and 15). Reaction of 2-(2,2-
dibromovinyl)phenol 1d with 1,2,4,5-tetrafluorobenzene 2f
was investigated subsequently (Scheme 2). It was not surpris-
ing that two products (compounds 3p and 3q) were isolated
under the standard conditions. Although we do not have
clear evidence to support the mechanism currently, we con-
sider that the reaction may proceed through an initial cupra-
tion of polyfluoroarenes by copper(I) iodide,14 followed by a
cross-coupling reaction of the (E)-bromoethenyl moiety.
Subsequently, the intramolecular copper(I)-catalyzed
(14) Kanyiva, K. S.; Kashihara, N.; Nakao, Y.; Hiyama, T.; Ohashi,
M.; Ogoshi, S. Dalton Trans. 2010, 39, 10483 and references cited
therein.
72
Org. Lett., Vol. 14, No. 1, 2012

CÀO coupling13 occurs to afford the benzofuran
of 2-(2,2-dibromovinyl)phenol with polyfluoroarene.
During the reaction process, a copper-catalyzed intramo-
lecular CÀO bond formation and an alkenylation of the
polyfluoroarene CÀH bond were involved. Currently,
using polyfluoroarene as a substrate for the formation
of N-heterocycles is under investigation in our laboratory,
and the results will be reported in due course.
scaffold.
Scheme 2. Copper(I)-Catalyzed Reaction of
2-(2,2-Dibromovinyl)phenol 1d with 1,2,4,5-Tetrafluorobenzene 2f
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 21032007,
21172038) and Jiangxi Key Laboratory of Organic Chem-
istry, Jiangxi Science & Technology Normal University is
gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, we have described a novel and effi-
cient route for the generation of 2-(polyfluoroaryl)
benzofurans via a copper(I)-catalyzed tandem reaction
Org. Lett., Vol. 14, No. 1, 2012
73