Scheme 1
Table 1. Survey of Reaction Conditions for the Preparation of
Benzofuran 8a
time
(h) yieldc
conditionsb
1d Pd(PPh3)4, Et3N (5), LiCl (4), THF, air, 60 °C 20
11
20
2d Pd(OAc)2,e PPh3,f LiCl (5), K2CO3 (7), DMF,
air, Cu(OAc)2 (2.1), rt
5
3
4
Pd(PPh3)4,e Et3N (10), DMF, air, rt
Pd(PPh3)4,e Et3N (10), toluene, air, rt
8
24
11
20
10
34
60g
62
5d Pd2(dba)3, PPh3,f Et3N (10), DMF, air, rt
nucleopalladation followed by Heck reaction,5,6 only one of
them involving the preparation of a fully aromatic furan
nucleus.6 In that particular case, however, the buta-1,2,3-
triene carbinol cyclization precursors had to be generated in
situ for good yields, and the reactions of R,ꢀ-unsaturated
ketones were complicated by the competing formation of
conjugate addition (hydroarylation-type) products. A limita-
tion was also found in that the coupling reaction did not
tolerate substitution at the ꢀ-alkene position of the R,ꢀ-
unsaturated carbonyl compound.6
With these precedents, we initiated a study directed at the
efficient formation of benzofurans using the general ideas
depicted in Scheme 1. At the outset, one of the foreseeable
benefits of this strategy, besides simplicity, was the attain-
ment of structural diversity, emanating from variations in
the starting phenol (1) and alkyne components as well as
from the use of a variety of alkene coupling partners.
Reported below are the preliminary results of the successful
realization of these ideas.
6
PdCl2, KI (0.5), DMF, air, 80 °C
a Unless otherwise stated, 5 mol % of a Pd complex and 6 equiv of
n-butyl acrylate were used relative to 7a. b Within brackets, number of
equivalents relative to 7a. c Isolated yield (%). d 4 equiv of n-butyl acrylate.
e 10 mol %. f Pd/PPh3 ratio ) 1:2. g Product was 2-hexylbenzofuran (9).
employed with R-allenols in a related process5d were also
disappointing (entry 2), as were other combinations of
solvent, catalyst, and base (entries 3-5). Interestingly, the
use of Pd2(dba)3 resulted in efficient formation of benzofuran
9, the product of cycloisomerization of the starting alky-
nylphenol 7a, and no 8 was detected (Figure 1). Eventually,
conditions reported for allenoic acids in other oxidative
coupling processes7 proved successful, and benzofuran 8 was
obtained in good yield (entry 6).
Application of the reaction conditions reported to be
successful with buta-1,2,3-triene carbinols6 to the coupling
between alkynylphenol 7a and n-butyl acrylate afforded the
desired product 8, but the yield was not satisfactory (Table
1, entry 1). Similarly, conditions inspired in those previously
Figure 1. Byproduct obtained in the preparation of 8.
(4) Compounds 2 have also been employed as starting materials in the
alternative Pd-catalyzed cyclization/coupling with R-halocyclohexenones,
but this procedure is limited by the availability of the required halo-
derivatives. See: (a) Chaplin, J. H.; Flynn, B. L. Chem. Commun. 2001,
159, 4–1595. (b) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004, 6,
457–460. (c) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew.
Chem., Int. Ed. 2006, 45, 944–947. (d) Nakamura, M.; Ilies, L.; Otsubo,
S.; Nakamura, E. Org. Lett. 2006, 8, 2803-2805. For other Pd-catalyzed
cyclization/coupling sequences between 2 and organic halides or pseudoha-
lides, see: (e) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli,
F. J. Org. Chem. 1996, 61, 9280–9288. (f) Cacchi, S.; Fabrizi, G.; Moro,
L. Synlett 1998, 741–745.
As shown in Table 2, the same conditions were applied
successfully to other 2-alkynylphenols, incorporating varia-
tions at both the terminal alkynyl position (entries 3-5) and
the phenol moiety (entries 2, 4, and 5). The data illustrate
the use of both aryl- (entries 3-5) and alkyl-substituted
alkynes (entries 1 and 2) as efficient precursors, as well as
good tolerance to the presence of electron-withdrawing
(entries 4 and 5) and electron-donating groups (entries 3-5)
alike in the aryl groups at either alkyne termini.
Particular attention was paid to the possibility of applying
this cyclization/coupling reaction to olefins other than n-butyl
acrylate, as this would allow a significant increase in
structural diversity (Table 3). In fact, a wide variety of olefins
were found to participate efficiently, and this included R,ꢀ-
(5) Formation of 2-substituted tetrahydrofurans: (a) Semmelhack, M. F.;
Epa, W. R. Tetrahedron Lett. 1993, 34, 7205-7208. Formation of
3-substituted indoles: (b) Yasuhara, A.; Kaneko, M.; Sakamoto, T. Het-
erocycles 1998, 48, 1793–1799. (c) Yasuhara, A.; Takeda, Y.; Suzuki, N.;
Sakamoto, T. Chem. Pharm. Bull. 2002, 50, 235-238. Formation of
4-substituted isoquinolines: (d) Huang, Q. H.; Larock, R. C. J. Org. Chem.
2003, 68, 980-988. Formation of 3-substituted dihydrofurans: (e) Alcaide,
B.; Almendros, P.; Rodriguez-Acebes, R. Chem. Eur. J. 2005, 11,
5708-5712. Formation of 4-substituted 2,5-dihydro-1,2-oxaphosphole
derivatives: (f) Yu, F.; Lian, X. D.; Ma, S. Org. Lett. 2007, 9, 1703–1706.
(6) Aurrecoechea, J. M.; Durana, A.; Pe´rez, E. J. Org. Chem. 2008, 73,
3650–3653.
(7) Ma, S.; Yu, Z. Q.; Gu, Z. H. Chem.-Eur. J. 2005, 11, 2351–2356.
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