Tetrahedron Letters
Copper-catalyzed tandem intramolecular cyclization/coupling
reaction: solvent effect on reaction pathway
⇑
Mitsuaki Yamashita , Toshiaki Noro, Akira Iida
School of Agriculture, Kinki University, Nakamachi, Nara 631-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we developed direct methods for the synthesis of 3-substituted indoles from o-alkynylan-
ilines by utilizing a copper-catalyzed tandem intramolecular cyclization/coupling reaction under mild
and simple reaction conditions. Our investigation revealed that choice of the aprotic polar solvents and
additives such as camphorsulfonic acid is critical in this reaction.
Received 2 September 2013
Revised 30 September 2013
Accepted 3 October 2013
Available online 10 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Cyclization
Coupling reaction
Indoles
Indoles are interesting and valuable because they are widely
found in various biologically active natural and artificial com-
pounds.1 Therefore, the development of efficient methods to syn-
thesize these compounds continues to be an active research area.
In particular, the intramolecular cyclization of o-alkynylanilines,
which are typically prepared from o-haloanilines and terminal
acetylenes via the Sonogashira reaction, has been widely
reported.2,3 Despite early successes using Pd,4 Au,5 or other metals6
as catalyst, there are limited reports on the direct synthesis of 3-
substituted indoles from o-alkynylanilines using Cu as catalyst.7
However, much attention has been paid to Cu catalysis due to
the lower cost of copper catalysis.2a,b
Recently, we obtained preliminary results in our laboratory
when testing the copper-catalyzed cyclization of o-alkynylaniline
according to Shen’s procedure.7c Shen and Lu reported that indole
2a was obtained in 80% yield by the reaction of 1a in the presence
of CuCl (0.5 equiv) in DMSO at 50 °C for 1 h under nitrogen atmo-
sphere (Scheme 1a). We then tested Shen’s procedure, and 2a was
obtained in 70% yield as reported; surprisingly, trace amounts of 3-
chlorinated product 3a and homocoupling dimer 4a were also iso-
lated. Furthermore, when the reaction was conducted under open-
air conditions, 2a was still the major product, similar to the result
for the reaction conducted under an inert atmosphere; an increase
in the chemical yields of 3a and 4a was observed (Scheme 1b).
These results imply that the direct introduction of carbon func-
tional groups or halogens to the 3-position of indole is possible un-
der mild reaction conditions. Herein, we describe direct methods
for the synthesis of 3-substituted indoles from o-alkynylanilines
by utilizing a copper-catalyzed tandem intramolecular cycliza-
tion/coupling reaction under mild reaction conditions.
In initial studies, we investigated the reaction in various sol-
vents in air because the results of copper catalysis are known to
largely depend on the solvent.7c The results are shown in Table 1.
As a result, nonpolar and polar solvents such as toluene, CH2Cl2,
EtOAc, THF, acetone, and dioxane were ineffective in promoting
the reaction (Table 1, entries 1–6). In contrast, protic polar solvents
such as EtOH afforded 2a in 51% yield as a major product (Table 1,
entry 7). Alternatively, further interesting results were obtained
when aprotic polar solvents were used. Among them, when using
dimethylformamide (DMF) as a solvent, homocoupling product
4a was obtained as a major product, whereas when using N,N-
dimethyacetamide (DMA) as a solvent, 3-chlorinated indole 3a
was obtained as a major product. These results indicated that this
reaction should preferably be conducted in an aprotic polar
solvent, and that varying the aprotic polar solvent could affect
the reaction pathway.8
Recently, Pyne’s group reported CuCN-mediated cyclization/
cyanation reactions.7b However, this method has some drawbacks
for practical applications under reaction conditions (typical reac-
tion conditions: in DMF, at 100 °C and under oxygen atmosphere).
Thus, we attempted to perform the reaction with copper cyanide
under the developed reaction conditions. The results are shown
in Table 2. First, the reaction was tested under an air atmosphere
and with four aprotic polar solvents, DMA, dimethylsulfoxide
(DMSO), N-methylpyrrolidone (NMP), and DMF, which showed dif-
ferent tendencies under the reaction conditions shown in Table 1.
As expected, the reaction proceeded at room temperature to yield
⇑
Corresponding author. Tel./fax: +81 742 43 1770.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.