Published on the web September 5, 2011
1041
Iron-catalyzed Oxidative Coupling of Alkylamines
with Arenes, Nitroalkanes, and 1,3-Dicarbonyl Compounds
Eiji Shirakawa,* Tomoki Yoneda, Kohei Moriya, Kensuke Ota,
Nanase Uchiyama, Ryo Nishikawa, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
(Received July 13, 2011; CL-110599; E-mail: shirakawa@kuchem.kyoto-u.ac.jp)
FeCl3 in combination with t-BuOOt-Bu as an oxidant was
found to catalyze oxidative coupling of alkylamines with arenes,
nitroalkanes, and 1,3-dicarbonyl compounds to give arylmethyl-
amines, ¢-nitroalkylamines, and 2-(aminomethyl)-1,3-dicarbon-
yl compounds, respectively.
A sequence consisting of oxidation of a C-H bond adjacent
to a nitrogen atom and substitution reaction of the resulting
oxidation product with a carbon nucleophile is useful for
introduction of carbon substituents into nitrogen-containing
compounds. From operational simplicity, methods of conducting
the sequence in one batch have recently attracted attention. In
this context, we have reported that a combination of FeCl3
and t-BuOOt-Bu as a catalyst and an oxidant, respectively, is
effective for oxidative coupling of alkylamides with arenes,
where FeCl3 works efficiently in both the oxidation and
electrophilic aromatic substitution (SEAr) steps (Scheme 1).1
In contrast to the fact that only a few examples are available for
alkylamides,2,3 more readily oxidizable alkylamines have been
used for oxidative couplings with heteroarenes,4 nitroalkanes,5
and 1,3-dicarbonyl compounds.6,7 However, a single oxidation
system applicable to a wide range of nucleophiles has not been
reported. Here we report that the FeCl3-t-BuOOt-Bu system is
effective for oxidative coupling of alkylamines with arenes,
nitroalkanes, and 1,3-dicarbonyl compounds.
Scheme 1.
Table 1. Oxidative coupling of alkylamines with arenesa
Entry 1
2
Cond.a Time/h Yield/% Product
1
1a 2a
A
9
95
The reaction of N-methylindole (1a: 1 equiv) with 2-phenyl-
1,2,3,4-tetrahydroisoquinoline (2a: 4 equiv) using FeCl3 (10
mol %) and t-BuOOt-Bu (2 equiv) in 1,2-dichloroethane (DCE)
at 80 °C for 9 h gave 1-(1-methyl-3-indolyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (3a) in 95% yield (Entry 1 of Table 1).8
Saturated alkylamines also underwent the oxidative coupling
with 1a, though a higher temperature (110 °C) was required
(Entries 2 and 3). To the best of our knowledge, there have been
no reports that amines having no unsaturated bonds are used for
oxidative coupling with arenes. The coupling proceeded also
with N,N-dimethylbenzylamine (2d) (Entry 4). Amines having
methyl groups on the nitrogen atom were arylated selectively
on the methyl group. The present iron-catalyzed reaction is
applicable to a benzene derivative (Entries 5 and 6), contrasting
with the previous methods.4,9 The yields were higher by use of
FeCl2 instead of FeCl3 in these cases.
2
3
4
1a 2b
1a 2c
1a 2d
B
B
C
2
8
2
70
52
63
5
6
1b 2e
1b 2f
D
D
48
30
74
78
Addition of N-methylindole (1a) to a reaction mixture of
tetrahydroisoquinoline 2a, FeCl3, and t-BuOOt-Bu after full
consumption of t-BuOOt-Bu gave 71% of coupling product 3a
(Scheme 2).15 Although we were not able to identify any
intermediates derived from oxidation of 2a, the result shows that
the present oxidative coupling consists of oxidation of alkyl-
amines and SEAr with the oxidized intermediate as is the case
with alkylamides shown in Scheme 1. A higher yield observed
aThe reaction was carried out in a solvent (1.0 mL) under a
nitrogen atmosphere using an arene 1 (0.25 mmol), an amine 2,
and t-BuOOt-Bu in the presence of FeCl3 (0.025 mmol).
Conditions (solvent, temperature, 1/2/t-BuOOt-Bu) are as
follows. A: 1,2-dichloroethane, 80 °C, 1/4/2. B: 1,2-dichloro-
2-methylpropane, 110 °C, 1/6/3. C: DMSO, 80 °C, 1/5/2.
D: DMSO, 80 °C, 1/6/3; use of FeCl2 instead of FeCl3.15
Chem. Lett. 2011, 40, 1041-1043
© 2011 The Chemical Society of Japan
Shirakawa, Eiji
