1522
Published on the web December 5, 2013
Tantalum(V) Fluoride-catalyzed N-Alkylation of Arylamines with Benzyl Alcohols
Sathaiah Gangaram, Chandra Shekhar Adimulam, Ravi Kumar Akula, Raju Kengiri,
Shanthan Rao Pamulaparthy,* Sridhar Madabhushi, and Narsaiah Banda
Fluoroorganics Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007, India
(Received August 8, 2013; CL-130727; E-mail: psrao@iict.res.in)
CN
CN
This paper describes a simple and efficient protocol for the
N-alkylation of arylamines with benzyl alcohols using tanta-
lum(V) fluoride as the catalyst.
TaF5 (10 mol%)
HO
H2O
Toluene,
reflux, 2h
NH2
N
H
1a
3a
2a
The formation of C-C and C-N bonds is important reactions
in organic synthesis. N-Alkylated amines are good synthons for
drug intermediates, agrochemicals, natural products, and various
biologically active compounds.1 Conventional N-alkylation of
amines was performed with alkyl halides2 in the presence of
stoichiometric amounts of base, or with carbonyl compounds3
using strong reducing agents. Over a period of time, alternate
methods were developed such as hydroamination of olefins4 or
alkynes.5
Alcohols are interesting alkylating agents for the selective
monoalkylation of amines, though the reactions are somewhat
sluggish. Classical methods for the N-alkylation of amines with
alcohols using catalysts such as iridium,6 rhodium,7 and ru-
thenium8 complexes have been reported. These transition-metal
complexes act as redox reagents for N-alkylation based on the
hydrogen autotransfer mechanism. The initial reaction was the
oxidation of alcohols followed by imine formation with amine.
The subsequent reduction of imine leads to the N-monoalkylated
product. Heterogeneous catalysis9 received attention for the N-
alkylation of amines using alcohols. Zhao and co-workers
developed new ligands10 for the N-alkylation of amines using
alcohols in the presence of iron, which proceeds via a
nucleophilic substitution (SN) type reaction.
Scheme 1. Reaction of 2-aminobenzonitrile with benzyl
alcohol.
alkylation with benzyl alcohols 2a-2j furnished corresponding
N-alkylamines 3a-3j as exclusive products in 65-86% yields.
We did not find any dialkylated product. Aliphatic alcohols such
as propargyl alcohol (2k), isoamyl alcohol (2l), and allylic
alcohol (2m) remained unreactive as shown in Table 1.
We studied the N-alkylation of a variety of amines 1a-1o
with 4-methoxybenzyl alcohol using TaF5 as the catalyst in
refluxing toluene. Arylamines 1a-1m were found to undergo N-
alkylation and furnished the corresponding N-alkylamines 4a-
4m in 56-96% yields, as shown in Table 2. Aliphatic amines
such as morpholine 1n and butylamine 1o remained unreactive
under these reaction conditions.
TaF5 might form a complex with alcohol (Scheme 2). Then,
amine, acting as a nucleophile, replaces the OH functional group
in the form of H2O and TaF5. We observed that amino-
containing electron-withdrawing groups were more favorable for
this reaction. However, greater electron density on the nitrogen-
containing compounds (aliphatic amines) did not give the
desired product as the amine first formed a complex with TaF5
instead of alcohol.
In accordance with our goal to develop new synthetic
procedures such as the Lewis acid-catalyzed N-formylation
of amines with formic acid under microwave irradiation,11 we
have developed for the first time an elegant method for the
monoalkylation of amines with alcohols using tantalum(V)
fluoride as the catalyst. Lewis acid catalysts have been
extensively used for various chemical transformation reactions
previously.
We have investigated the reaction of 2-aminobenzonitrile
and benzyl alcohol in the presence of Lewis acids such as zinc(II)
chloride, aluminum(III) chloride, aluminum(III) fluoride, cop-
per(II) fluoride, copper(II) triflate, lanthanum(III) triflate, gado-
linium(III) triflate, titanium(IV) chloride, and tantalum(V)
fluoride under refluxing toluene. With the exception of tanta-
lum(V) fluoride, none of the other Lewis acids induced any
reaction. Therefore, tantalum(V) fluoride has been identified as a
suitable catalyst for the formation of 2-(benzylamino)benzoni-
trile from 2-aminobenzonitrile and benzyl alcohol (Scheme 1).12
Tantalum(V) fluoride is volatile but exists as an oligomer in the
solid state and is used for some fluorination reactions.13
The versatility of the alkylation reaction was proved by
employing a variety of alcohols 2a-2l, and using TaF5 as the
catalyst in refluxing toluene. In this study, the efficient N-
The nucleophilic displacement mechanism was further
confirmed by carrying out the reaction of aniline (1b) with
2-(2-methoxyphenyl)propan-2-ol (2n) under the same reaction
conditions, furnished N-[2-(2-methoxyphenyl)propan-2-yl]ani-
line (4p) in good yield (Scheme 3).
It was further supported by the reaction of 4-methoxyaniline
(1d) with 9-methyl-9H-fluoren-9-ol (2o), which yielded N-(4-
methoxyphenyl)-9-methyl-9H-fluoren-9-amine (4q) (Scheme 4).
The above-mentioned products 4p and 4q were character-
ized based on 1H NMR and ESI-Mass spectral data. The
formation of compounds 4p and 4q indicate that the benzylation
reaction followed the nucleophilic substitution type mechanism
and not the hydrogen autotransfer mechanism.
In conclusion, the present work shows that tantalum(V)
fluoride-catalyzed the efficient N-alkylation of arylamines with
benzyl alcohols. In this study, a variety of arylamines and benzyl
alcohols were shown to react efficiently to give N-alkylamines in
high yields in the presence of tantalum(V) fluoride as the catalyst.
We are thankful to the Director, IICT for constant
encouragement and we are also thankful to Council of Scientific
and Industrial Research (CSIR), India for the financial assistance
in the form of SRF fellowship.
Chem. Lett. 2013, 42, 1522-1524
© 2013 The Chemical Society of Japan