interesting 1,2-migration of the phenoxy group took place in
this C3-selective process. While the protective group was
CO2Me as the electron-withdrawing group, the substrate 2a
underwent a C2-site selective annulation, affording the
synthetically useful spiro-pseudoindoxyl derivative 4a and
the release of phenol.
To optimize the reaction conditions, a series of gold and
platinum catalysts were screened. We found that the use of
Au(PPh3)Cl/AgOTf (5 mol %) in CH2Cl2 (used as pur-
chased without further purification, containing about
0.05% H2O), at room temperature within 30 min, gave
the best results for either the N-Bn substrate (1a) or the
N-CO2Me substrate (2a), with high yields and short reac-
tion times (Table 1, entry 1). In contrast, using Au(PPh3)Cl/
AgSbF6 or Au(PPh3)Cl/AgBF4 as a catalyst gave low yields
of 4a, and the former catalyst was completely ineffective for
catalyzing the formation of 3a (Table 1, entries 2 and 3).
Figure 1. Representative indole alkaloids with spiro-pseudoin-
doxyl structure.
However, the direct elaboration of substituted THBCs
remains a challenge.10
Table 1. Optimization of Reaction Conditionsa
During our efforts examining the reactivity of alkynyl
indoles catalyzed by gold,11 we have developed an efficient
divergent strategy to construct both the spiro-pseudoin-
doxyl structure and THBC derivatives from 3-aryloxy alky-
nyl indoles. In particular, this gold-catalyzed regiodivergent
annulation can be tuned by protective groups on the indoles.
As shown in Scheme 1, in the presence of a gold(I) catalytic
system, a 3-phenoxy alkynyl indole model substrate with an
electron-donating group (benzyl (Bn), 1a) followed a C3-site
selective annulation to afford the spiro-THBC derivative 3a,
entry
1
yield (%)b/4a
catalyst
time
0.5 h
yield (%)b/3a
95
Au(PPh3)Cl/
AgOTf
80
2
3
41
65
Au(PPh3)Cl/
AgSbF6
10 h
ꢀ
Au(PPh3)Cl/
AgBF4
0.5 h
65
Scheme 1. Gold-Catalyzed Regiodivergent Annulations of 1a, 2a
4
12c
ꢀ
AuCl3
10 h
10 h
10 h
10d
ꢀ
5e
6e
PtCl2
PTSAf
ꢀ
ꢀ
a Reaction conditions: substrate 1aor 2a (0.1mmol),catalyst(5mmol%),
and CH2Cl2 (2 mL, used as purchased without further purification,
containing about 0.05% H2O) at rt under an Ar atmosphere. b Isolated
yield. c 55% of starting material was recovered. d 50% of starting
material was recovered. e No reaction. f PTSA = p-toluenesulfonic acid.
which contains a benzo[b]dihydrofuran subunit and an oxa-
quaternary carbon center embedded in the core. Notably, an
AuCl3 in CH2Cl2 gave the products 3a and 4a in very low
yields and required long reaction times (Table 1, entry 4).
Employment of nongold catalyst PtCl2 in CH2Cl2 resulted
in no reaction for both substrate 1a and 2a (Table1, entry5).
PTSA was used as a protic acid to catalyze the C2- and C3-
selective reaction, but none of the expected products could
be isolated (Table 1, entry 6).
(10) (a) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A.
J. Org. Chem. 2003, 68, 7126. (b) Bandini, M.; Alfonso, A.; Piccinelli, F.;
Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2003, 128,
1424. (c) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J.
Org. Lett. 2007, 9, 1847. (d) Rannoux, C.; Roussi, F.; Retailleau, P.;
ꢀ
Gueritte, F. Org. Lett. 2010, 12, 1240.
(11) For gold catalysis in indole chemistry, see: (a) Li, Z.; Shi, Z.; He,
C. J. Organomet. Chem. 2005, 690, 5049. (b) Zhang, L. J. Am. Chem. Soc.
2005, 127, 16804. (c) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2006, 45, 1105. (d) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M.
Chem.;Eur. J. 2007, 13, 1358. (e) Yang, T.; Campbell, L.; Dixon, D. J.
J. Am. Chem. Soc. 2007, 129, 12070. (f) England, D. B.; Padwa, A. Org.
Lett. 2008, 10, 3631. (g) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am.
Chem. Soc. 2008, 130, 1814. (h) Barluenga, J.; Fernandez, A.; Rodriguez,
F.; Fananas, J. J. Organomet. Chem. 2009, 694, 546. (i) Ferrer, C.;
Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009, 65, 9015. (j)
Li, G.; Liu, Y. J. Org. Chem. 2010, 75, 3526. (k) Lu, Y.; Du, X.; Jia, X.;
Liu, Y. Adv. Synth. Catal. 2009, 351, 1517. (l) Liu, Y.; Xu, W.; Wang, X.
Org. Lett. 2010, 12, 1448. (m) Verniest, G.; England, D.; Kimpe, N. D.;
Padawa, A. Tetrahedron 2010, 66, 1496.
Intrigued by the mild standard reaction conditions de-
scribed above, we then examined the generality of this gold-
catalyzed regiodivergent annulation. Various indole substrates
bearing different alkyl substituents on the aryloxy group
(1bꢀ1h) were subjected to the C3-selective reaction. Scheme
2 shows that all examples reacted smoothly within 30 min to
afford the desired products in moderate to high yields
(42ꢀ94%). It should be noted that the yields of the current
reactions were dependent, to some degree, on the position of
the substituents on the aryloxy group. For example, when
Org. Lett., Vol. 13, No. 13, 2011
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