both allene synthesis and cyclization. We wish to report
here the realization of such a concept with a palladium
catalyst working for both steps, providing a diverse and
efficient approach to indoles.
the indole product 6a following the allene formation step
via coupling;8À10 other metals such as Zn, Al, and Mg
together with NaI as the additive failed to execute such
a transformation (entries 6À8, Table 1). NaI may help to
generate the indium reagent and increase the group-trans-
fer ability of the in situ generated indium reagent. Further
screening led to the observation that LiCl, LiI, or KI failed
to show better performance (entries 9À11, Table 1).
Scheme 1. Cyclization of Functionalized Allenes and the Allene
SynthesisÀCyclization Approacha
Table 1. Palladium-Catalyzed Cross-Coupling Reaction and
Cyclization of 4a with 5aa
entry
metal
additive
yield of 6a (%)b
c
1
Zn
Al
À
À
a Nu = nucleophilic unit.
d
2
À
À
3
Mg
In
À
À
We first approached such a concept by applying the
coupling of organic halides with an amine functionality
with propargylic/allenylic metallic reagents.5,6 We were
initially attempting the Suzuki coupling reaction as well
as the Negishi coupling reaction of N-tosyl 2-iodoaniline
4a and allenylic/propargylic metallic reagents for the
synthesis of o-aminophenylallenes;7 however, the attempt
failed, most probably due to the presence of the o-amine
functionality (for details, see the Supporting Information).
Our further work began with the palladium(0)-catalyzed
coupling of N-tosyl 2-iodoaniline 4a with 1-bromobut-2-
yne 5a given the fact that propargylic bromide is much
more reactive toward metals forming allenylic/propargylic
organometallic reagents in situ. When the reaction was
carried out in N,N-dimethylformamide (DMF) at 100 °C
catalyzedby4mol%Pd(PPh3)4 inthepresenceof2.0equiv
of metal such as Zn, Al, Mg, and In, disappointing results
were obtained (entries 1À4, Table 1). Surprisingly, when
In was chosen as the reductant with the addition of NaI,
the indole product 6a was obtained directly in 81% yield
(entry 5, Table 1), and the presence of its allene precursor
7awas not detected, indicating smooth directcyclization to
4
À
À
5
In
Zn
Al
NaI
NaI
NaI
NaI
LiCl
LiI
KI
81
e
6
À
f
7
À
8
Mg
In
À
9
30
73
69
10
11
In
In
a The reaction was carried out using 4a (c = 0.17 M), 5a (3.0 equiv),
metal (2.0 equiv), additive (3.0 equiv), and Pd(PPh3)4 (4 mol %) at
100 °C in DMF. b Determined by 1H NMR analysis with nitromethane
as the internal standard. c 4a recovered in 71% yield as determined by
1H NMR analysis. d 4a recovered in 59% yield as determined by 1H
NMR analysis. e 4a recovered in 25% yield as determined by 1H NMR
analysis. f 4a recovered in 98% yield as determined by 1H NMR analysis.
Ts = 4-methylbenzenesulfonyl.
With the inspiring results in hand, we worked toward
further optimization of the reaction conditionsby applying
theligandeffect (Table2). Pd(OAc)2 together with different
phosphine ligands was screened (entries 2À6, Table 2), and
fortuitously, with the electron-rich tris(2-furyl)phosphine
(TFP) as the ligand, the yield of 6a was improved to
91% (entry 6, Table 2)! Thus, Pd(OAc)2 (4 mol %), TFP
(8 mol %), In (2.0 equiv), and NaI (3.0 equiv) in DMF at
100 °C were defined as the optimal reaction conditions for
further study.
(5) (a) Knochel, P. In Handbook of Functionalized Organometallics;
^
ꢀ
Wiley-VCH: Weinheim, 2005. (b) Lepretre, A.; Turck, A.; Ple, N.; Knochel,
ꢀ
P.; Queguiner, G. Tetrahedron 2000, 56, 265.
(6) For reviews, see: (a) Ma, S. Eur. J. Org. Chem. 2004, 1175.
(b) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 795.
(7) For unsuccessful attempted syntheses of o-aminoaryl allenes from
o-aminoarylacetylenes, see: (a) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N.
Angew. Chem., Int. Ed. 2007, 46, 2295. (b) Ohta, Y.; Chiba, H.; Oishi, S.;
Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052.
The scope of the reaction was then investigated by using
the optimal reaction conditions (Table 3). We first studied
the cyclization reaction of N-tosyl 2-iodoaniline 4a with
different propargylic bromides. When R2 is H, methyl,
n-Pr, allyl, or cinnamyl, the reaction showed moderate to
good results (entries 1À4 and 7, Table 3). Aryl-substituted
(8) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons:
New York, 1982.
(9) For reviews of indole synthesis, see: (a) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045. (b) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873. (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
(10) For the coupling reaction forming a CÀN bond from amine and
€
106, 2875. (d) Kuger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008,
o-haloarylallenes, see: (a) Liu, B.; Hong, X.; Yan, D.; Xu, S.; Huang, X.;
€
350, 2153. (e) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem.
2002, 2671. (f) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(g) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(h) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491. (i) Bandini,
M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (j) Shiri, M.
Chem. Rev. 2012, 112, 3508.
Xu, B. Org. Lett. 2012, 14, 4398. (b) Masters, K.-S.; Wallesch, M.; Brase,
S. J. Org. Chem. 2011, 76, 9060. (c) There is only one report for the
synthesis of such o-aminoaryl allenes using the not-readily available and
highly toxic allenyl preformed tin reagents; see: Mizutani, M.; Inagaki,
F.; Nakanishi, T.; Yanagihara, C.; Tamai, I.; Mukai, C. Org. Lett. 2011,
13, 1796.
B
Org. Lett., Vol. XX, No. XX, XXXX