of limited structural diversity. We envisage that if we were
able to prepare o-iodoaryl vinyl ethers via a conjugate
addition procedure from o-iodophenols and activated
alkynes, the subsequent intramolecular Heck reaction
would regiospecifically provide us the corresponding
2-substituted-3-functionalized benzofurans. Herein, we re-
port the versatile route to 2-substituted-3-functionalized
benzofurans and its application to the total synthesis of
Daphnodorin B (Figure 1).
Pd(OAc)2/PPh3 ≈ Pd(OAc)2/P(o-tol)3 > PdBr2/PPh3 ≈
Pd(PPh3)4 > Pd(OAc)2/dppf ≈ Pd(OAc)2/BINAP > Pd-
(OAc)2/PBu3 ≈ Pd(PPh3)4/Et3N > Pd2(dba)3/BINAP
(Table 1, entries 1À9). It is evident that PPh3 and P(o-tol)3
could accelerate the reaction, while P(o-tol)3 was not
utilized in this work due to its air sensitivity and higher
cost compared to PPh3.
Table 1. Effect of Palladium/Ligand and Base on the Reactiona
entry
palladium/ligand
yield(%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PBu3
Pd(OAc)2/dppf
Pd(OAc)2/PPh3
Pd(OAc)2/P(o-tol)3
Pd(OAc)2/BINAP
Pd2(dba)3/BINAP
PdBr2/PPh3
29
52
75
73
47
11
68
28
63
Figure 1. Bioactive compounds containing 2-substituted-3-
functionalized benzofuran scaffold.
Pd(PPh3)4/Et3Nb
Pd(PPh3)4
Our initial studies focused on the synthesis of a model
substrate (o-iodoaryl vinyl ether 4a, Table 1), which was
available from a conjugate addition procedure employing
o-iodophenol with ynone 3a in the presence of a base at
75 °C in CH3CN. Different bases such as DBU, t-BuOK,
Pyridine, DIPEA, K3PO4, Et3N, DABCO, Ag2CO3, and
K2CO3 were tried to promote the conjugate addition, and
K3PO4 (100 mol %) gavethe highest yield (>99%) of 4aas
a pair of Z/E isomers mixture (≈ 1:1). Fortunately, the
subsequent intramolecular Heck reaction of 4a proceeded
smoothly without separation of the Z- and E-isomers.
We next screened the effect of the palladium source and
ligand on the intramolecular Heck reaction of the model
substrate by using Ag2CO3 as base at 115 °C in CH3CN,
and the results are summarized in Table 1. The model
reaction could be catalyzed by PdII or Pd0 complexes,
such as Pd(OAc)2, PdBr2, Pd(PPh3)2Cl2, Pd2(dba)3, and
Pd(PPh3)4 in the absence of additional ligand. From
Table 1, the reactivity of the Pd catalytic system decreases
in the following order for the cyclization reaction:
a Optimal reaction conditions: 2a/3a 1:1 (1 equiv), Pd (5 mol %),
Ligand (10 mol %), Ag2CO3 (1 equiv), CH3CN, 115 °C, 15 h. Isolated
yields. b Et3N was employed instead of Ag2CO3.
Next, the substrate scope of the reaction was explored
with a range of o-iodophenols with ynones. Under our
optimized conditions, substrates with electron-donating or
-withdrawing groups or electron-neutral substituents were
successfully transformed into the corresponding 2-substi-
tued-3-aroyl-benzofurans (5aÀk) in good to excellent
yields (Scheme 1). A chloro substituent on the aryl part
of the o-iodophenols (5i/j) was tolerated in this transfor-
mation. In the case of 5a and 5iÀk, lower yields were
obtained, which might be attributed to the large steric
effect of bulky ynones (3a/b) and 3-chloro-2-iodophenol.
With these encouraging results in hand, we decided to
further probe the reaction scope by employing other alkynes
bearing electron-withdrawing substituents, such as cyano
or carboalkoxy groups. To our delight, all the substrates
employed yielded corresponding 2-substitued-3-functio-
nalized benzofurans (8aÀi) in high yields (Scheme 2).
Finally, we note that the aryl chloride moieties in5i/j and
8b/h can be exploited in a subsequent synthetic modifica-
tion. For example, SuzukiÀMiyaura cross-coupling reac-
tions can enable further diversification.5c,6 The nitrile
group can be utilized for further transformations.7
(5) For selected papers on the synthesis of benzofurans, see: (a) Ye,
S.-Q.; Liu, G.; Pu, S.-Z.; Wu, J. Org. Lett. 2012, 14, 70. (b) Yin, B.-L.;
Cai, C.-B.; Zeng, G.-H.; Zhang, R.-Q.; Li, X.; Jiang, H.-F. Org. Lett.
2012, 14, 1098. (c) Liu, Y.; Ma, S.-M. Org. Lett. 2012, 14, 720. (d)
ꢀ
Schevenels, F.; Marko, I. E. Org. Lett. 2012, 14, 1298. (e) Li, C.-L.;
Zhang, Y.-C.; Li, P.-H.; Wang, L. J. Org. Chem. 2011, 76, 4692. (f)
Markina, N. A.; Chen, Y.; Larock, R. C. Tetrahedron 2013, 69, 2701. (g)
Henke, B. R.; Aquino, C. J.; Birkemo, L. S.; Croom, D. K.; Dougherty,
R. W., Jr.; Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.; James, M. K.;
Johnson, M. F.; Queen, K. L.; Sherrill, R. G.; Sugg, E. E.; Suh, E. M.;
Szewczyk, J. W.; Unwalla, R. J.; Yingling, J.; Willson, T. M. J. Med.
Chem. 1997, 40, 2706. (h) Ma, D.-W.; Cai, Q.; Xie, X.-A. Synlett 2005,
1767. (i) Stork, G.; Yamashita, A.; Adams, J.; Schulte, G. R.; Chesworth,
R.; Miyazaki, Y.; Farmer, J. J. J. Am. Chem. Soc. 2009, 131, 11402. (j)
Liao, Y.; Smith, J.; Fathi, R.; Yang, Z. Org. Lett. 2005, 7, 2707. (k) Liao,
Y.; Reitman, M.; Zhang, Y.; Fathi, R.; Yang, Z. Org. Lett. 2002, 4, 2607.
(l) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.
With a set of new synthetic methodologies in hand, we
turned our attention to the total synthesis of Daphnodorin B.
(6) Kudo, M.; Perseghini, G.; Fu, C. Angew. Chem., Int. Ed. 2006, 45,
1282.
(7) Rappoport, Z., Ed. Chemistry of the Cyano Group; John Wiley &
Sons: London, 1970.
B
Org. Lett., Vol. XX, No. XX, XXXX