annulation reactions of 2-alkynylphenols has been described.
Here, we report a novel and selective palladium-catalyzed
annulation of 2-alkynylphenols method for the synthesis of
2
respectively (entry 2). When 3 equiv of CuBr was added,
substrate 1a was converted completely to 2a and 3a in 84
and 10% GC yields, respectively, for 5 h (entry 3). Identical
2
-substituted 3-halobenzo[b]furans.5a,h,i Furthermore, the
results were observed when the amount of CuBr
increased to 5 equiv (entry 4). The results also demonstrated
that PdBr played a crucial role in the reaction (entry 5).
Without PdBr , no benzo[b]furans were observed. Another
catalytic system (PdCl /CuCl ) was also tested (entry 6). It
was found that PdCl was also effective for the annulation
reaction of 1a. The addition of PdCl and CuCl gave a 90%
isolated yield of 2a together with a 5% GC yield of 2-octyl
2
was further
method affords products with a halide (Cl or Br) at the 3
position, which provides an attractive and useful route to
introduce new groups for the synthesis of natural products
2
2
(Scheme 1).
2
2
2
2
2
Scheme 1
3
-chlorobenzo[b]furan (4a).
Although 2-octyl benzo[b]furan (2a) was obtained in good
yields, our interest is focused on the synthesis of 2-substituted
-halobenzo[b]furans, the side products 3a and 4a in the
above transformations. Accidentally, we found that HEt NI
3
3
could shift the selectivity of the reaction from 2-substituted
benzo[b]furan toward 2-substituted 3-halobenzo[b]furan (en-
As shown in Table 1, 2-(2-n-octylethynyl)phenol (1a) was
tries 3 and 7-9). In the presence of 5 mol % of PdBr
equiv of CuBr , and 0.1 equiv of HEt NI, the ratio of 2a to
a was 1:1 (40 and 43% GC yields, respectively; entry 7),
whereas in the presence of 0.2 equiv of HEt NI, a 77% GC
yield of 3a was obtained as the major product together with
a 10% GC yield of 2a (entry 8). Surprisingly, further
2
, 3
2
3
3
3
Table 1. Screening the Effect of Additives on the Palladium
Bromide-Catalyzed Annulation of 2-(2-n-Octylethynyl)phenol
a
(
1a)
increasing the loading of HEt
reaction (entry 9). Other reagents, including HEt
NBr, TBAB, KI, Et N, and PPh , were also evaluated, and
3
NI to 0.5 equiv led to no
3
NCl, HEt -
3
3
3
the results demonstrated that they affected the selectivity
slightly (entries 10-15).
yield (%)b
Under the optimized reaction conditions, palladium-
catalyzed annulations of 2-alkynylphenols 1a-g provided
good yields of the corresponding 2-substituted 3-halobenzo-
entry
1c
additive (equiv)
2a
3a
6
97 (91)
50
84 (81)
85
0
4
d
2
3
4
5
6
7
8
9
1
1
1
1
1
1
[
b]furans 3 and 4 selectively, and the results are summarized
in Table 2. For example, treatment of 2-alkynylphenol (1b)
with 5 mol % of PdBr , 3 equiv of CuBr , and 0.2 equiv of
HEt NI afforded a 92% isolated yield of 2-phenyl 3-bro-
10
e
f
8
0
0
2
2
g
95 (90)
40
10
5 (4a)
43
77 (75)
3
HEt3NI (0.1)
HEt3NI (0.2)
HEt3NI (0.5)
HEt3NCl (0.2)
HEt3NBr (0.2)
TBAB (0.2)
KI (0.2)
(4) For representative papers on the synthesis of benzo[b]furans via
0
0
palladium-catalyzed annulations of 2-alkynylphenols, see: (a) Arcadi, A.;
Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996,
1, 9280. (b) Chaplin, J. H.; Flynn, B. L. Chem. Commun. 2001, 1594. (c)
0
1
2
3
4
5
75
69
83 (80)
81
81
14
17
8
10
9
6
Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670. (d)
Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org.
Chem. 2004, 69, 2235 and references therein. (e) Kondo, Y.; Shiga, F.;
Murata, N.; Sakamoto, T.; Yamanaka, Tetrahedron 1994, 50, 11803. (f)
Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297. (g) Hu, Y.; Yang, Z.
Org. Lett. 2001, 3, 1387. (h) Liao, Y.; Reitman, M.; Zhang, Y.; Fathi, R.;
Yang, Z. Org. Lett. 2002, 4, 2067. (i) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi,
R. J. Org. Chem. 2002, 67, 2365. (j) Liao, Y.; Fathi, R.; Yang, Z. Org.
Lett. 2003, 5, 909. (k) Liao, Y.; Fathi, R.; Yang, Z. J. Comb. Chem. 2003,
5, 79.
(5) For recent selected papers on palladium-free synthesis of benzo[b]-
furans, see: (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
Synlett 1999, 1432 and references therein. (b) Bates, C. G.; Saejueng, P.;
Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727 and references
therein. (c) Baker, S. R.; Cases, M.; Keenan, M.; Lewis, R. A.; Tan, P.
Tetrahedron Lett. 2003, 44, 2995. (d) Dahl e´ n, A.; Petersson, A.; Hilmersson,
G. Org. Biomol. Chem. 2003, 1, 2423. (e) McKiernan, G. J.; Hartley, R. C.
Org. Lett. 2003, 5, 4389. (f) Serra, S.; Fuganti, C. Synlett 2003, 2005. (g)
Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761. (h) Yue, D.;
Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292. (i) Yao, T.; Yue,
D.; Larock, R. C. J. Comb. Chem. 2005, 7, 809. (j) Kao, C.-L.; Chern,
J.-W. J. Org. Chem. 2002, 67, 6772.
PPh3 (0.2)
Et3N (1.0)
78
12
a
Reaction conditions: 1 (0.3 mmol), PdBr2 (5 mol %), and CuBr2 (3
b
equiv) in DCE (5 mL) at room temperature for 5 h. GC yield. Isolated
yield is given in parentheses. Without CuBr2. CuBr2 (1 equiv). Conver-
sion of 1a was 60% as determined by GC analysis. CuBr2 (5 equiv).
c
d
e
f
Without PdBr2. 2-(1,2-Dibromo-2-phenylvinyl)phenol was isolated in 10%
g
yield. PdCl2 (5 mol %) and CuCl2 (3 equiv) instead of both PdBr2 and
CuBr2.
annulated smoothly to afford a 95% isolated yield of the
desired 2-octyl benzo[b]furan (2a) in the presence of 5 mol
%
of PdBr
CuBr affected the reaction, and 2-octyl bromobenzo[b]furan
3a), a byproduct, was observed (entries 1-4). In the
presence of 1 equiv of CuBr , the reaction was slow, resulting
in the formation of 2a and 3a in 50% and 4% GC yields,
2
(entry 1). It is noteworthy that the presence of
2
(
6) 2-Alkynylphenols 1a-d were prepared from the reactions of the
(
corresponding 2-iodophenols with terminal alkynes directly, and substrates
2
1
e-g were obtained via three steps including O-protection, Sonogashira
coupling, and O-deprotecting by known procedures, see: refs 3a and 4a.
3018
Org. Lett., Vol. 8, No. 14, 2006