498
LETTER
Lanthanide Triflates Catalyzed Reactions of Imines with Indole in Protic
Media
Wenhua Xie, Karen M. Bloomfield, Yafei Jin, Nicole Y. Dolney, and Peng George Wang*
Department of Chemistry, Wayne State University, Detroit, MI 48202- 3489, USA
Received 10 February 1999
product, the secondary indolyl amine, could be improved
Abstract: Lanthanide triflates Ln(OTf)3 were found to catalyze the
by performing the reaction at lower temperatures. For ex-
electrophilic substitution reactions of indole with a variety of imines
ample, when the reaction of N-benzylidene aniline was
in protic media, affording predominately secondary indolyl amines
as well as bisindolyl methanes as by-products.
carried out at 0 oC, the yield of 1a was increased to 83%.
Key words: lanthanide triflate, catalysis, imine, indole, protic
media
+
Ln(OTf)3
N
N
EtOH/H2O (4:1)
H
Mannich-type reactions of nucleophilic aromatic hetero-
cycles have been studied extensively for the synthesis of
heterocyclic compounds which are often biologically ac-
tive molecules.1 While secondary amines are used widely
in such reactions, the corresponding reactions of primary
amines usually give considerably lower yields due to var-
ious side reactions.2 For better results, an alternative
method has been reported by using the corresponding
imines (instead of primary amines) under acidic condi-
tions. For example, indole, a typical aromatic heterocycle,
reacted with a number of imines in the presence of a protic
acid to afford the desired secondary amines in moderate
yields.3
N
+
H
N
N
H
N
H
H
1a
1b
Scheme 1
The by-product phenyl bisindolyl methane initially ap-
peared to be the result of the corresponding reaction of
benzaldehyde,6 which might exist in the system due to the
hydrolysis of the imine in aqueous media. However, an-
other experiment showed that when the reaction was car-
ried out in dry acetonitrile, which minimized the
possibility of hydrolysis, the same by-product was also
isolated in an even slightly higher yield. The formation of
phenyl bisindolyl methane could then be better explained
by the following plausible pathway in which the first in-
dole-imine adduct underwent an elimination reaction to
generate 1c, which then reacted with a second molecule of
indole to result in 1b (Scheme 2). However it should be
pointed out that the hydrolysis pathway could not be ruled
out completely, especially for more reactive imines.
Organic reactions in protic and aqueous media are cur-
rently of great interest in chemical research.4 In the course
of our continuing investigation5-9 on using lanthanides as
stable Lewis acids in protic solvents,10, 11 we found that
lanthanide triflates effectively catalyzed the reaction of
indole with aldehydes or ketones in aqueous solution.6
The reactions afforded bisindolyl-methanes in high
yields. Similar to the corresponding carbonyl compounds,
imines are also electrophilic and can be effectively acti-
vated by Ln(OTf)3 as well. We recently examined the re-
actions of indole with a variety of imines in protic media.
Instead of protic acids, catalytic amounts of Ln(OTf)3
salts were utilized.
In a preliminary experiment, the reaction of indole with
equimolar N-benzylidene aniline was carried out in the
presence of Dy(OTf)3 (10% mol) using ethanol/water
(4:1) as solvent. The reaction proceeded smoothly at room
temperature to completion after 24 hours, affording a sec-
ondary amine, 3-(phenylamino benzylidene) indole 1a as
the main product in 57% yield, and phenyl bisindolyl
methane 1b as the by-product in 12% yield (Scheme 1).
Increasing the mole ratio of N-benzylidene aniline did not
Six other lanthanide triflates (La(OTf)3, Nd(OTf)3,
Eu(OTf)3, Gd(OTf)3, Yb(OTf)3 and Er(OTf)3) were also
tested and found to catalyze this reaction as well. More in-
terestingly, three lanthanide chlorides (NdCl3·6H2O,
DyCl3·6H2O and YCl3·6H2O) also worked well as cata-
lysts in this case. Among all of the lanthanides examined,
Dy(OTf)3 and Yb(OTf)3 gave the best results in terms of
yield.
affect the distribution of the products. However, when two Dy(OTf)3 was further tested in the reactions of indole with
equivalents of indole were used, the yield of 1a decreased other imines. The results are summarized in Table 1. The
to 41% while that of the by-product increased to 34%. In reactions of typical Schiff bases with either electron-do-
a control experiment, no reaction took place in the ab- nating or electron-withdrawing substituents proceeded in
sence of Dy(OTf)3. It was found that the yield of the major a similar manner as that of N-benzylidene aniline. How-
Synlett 1999, No. 4, 498–500 ISSN 0936-5214 © Thieme Stuttgart · New York