Published on the web April 16, 2011
489
Ruthenium-catalyzed Formation of Tertiary Amines from Nitriles and Alcohols
Saiwen Liu, Ru Chen, and Guo-Jun Deng*
Key Laboratory of Environment-Friendly Chemistry and Applications of Ministry of Education,
College of Chemistry, Xiangtan University, Xiangtan 411105, P. R. China
(Received February 25, 2011; CL-110158; E-mail: gjdeng@xtu.edu.cn)
A ruthenium-catalyzed tertiary-amine formation was devel-
oped using the borrowing hydrogen strategy. Various tertiary
amines were obtained efficiently from nitriles and primary
alcohols. Two possible pathways were found for the tertiary-
amine formation under RuCl3/dppf catalytic conditions. The
nitriles mainly act as a nitrogen source in this kind of
transformation.
R'
borrowing
hydrogen
borrowing
hydrogen
R
CH2NH2
N
1
R' CH2OH
R
R'
R
CN
R
COOH
+
R'
borrowing
hydrogen
hydrolysis
+
NH3 (or NH4
)
N
2
R' CH2OH
R'
R'
Scheme 1. Possible pathways of nitrile reacting with alcohol.
Tertiary and secondary amines are of great importance as
building blocks for pharmaceuticals, agrochemicals, dyes, and
ligands.1 A number of catalytic and noncatalytic procedures,2 for
example, 1) direct amination of amines with alkyl and aryl
halides,3 2) reductive amination of ketones and aldehydes,4 3)
hydroamination of unsaturated hydrocarbons with amines,5 and
4) direct C-H amination,6 have been developed for the synthesis
of tertiary and secondary amines in the past decades. In recent
years, there has been significant interest in the transition-metal-
catalyzed alkylation of amines by alcohols as a more benign
alternative to potentially genotoxic alkyl halides. Alcohols are
cheap, stable, and commercially available organic compounds.7
Most alcohols are poorly electrophilic and not suitable as direct
alkylating agents for amines. However, alcohols can be readily
activated by oxidizing to aldehydes and used as direct alkylating
agents. In a typical amination of alcohol with amine, the alcohol
can be activated by the transfer of hydrogen to metal catalyst,
generating an aldehyde, followed by in situ imine formation.
Reduction of the imine by return of the hydrogen affords the
tertiary or secondary amine. The overall process is termed as the
“borrowing hydrogen” methodology (Williams et al.) or “hydro-
gen autotransfer” reaction (Yus et al.) and widely employed for
C-C and C-N bond construction.8
The first homogeneous alkylation of amines by alcohols
under harsh conditions was developed independently by Grigg
and Watanabe,9 and several ruthenium10 and iridium11 catalysts
have been developed subsequently. Milder conditions have been
employed by Yamaguchi and co-workers with [Cp*IrCl2],12 and
by Beller13 and Williams14 with ruthenium and iridium. In recent
years, the borrowing hydrogen methodology has been used in
the synthesis of primary amines, secondary amines, tertiary
amines, and N-alkylated sulfonamides in high yields under mild
conditions.15 Amines, ammonia, ammonium salts, and even
urea16 are used as the nitrogen sources in this kind of
transformation.
in acidic or basic aqueous solutions. The amine formation from
ammonium or ammonium salts is well developed recently.12b,14a
Therefore, we hypothesized that there are two possible pathways
for the formation of tertiary amines when nitriles react with
alcohols (Scheme 1): 1) nitrile is reduced to primary amine by
hydrogen generated from the alcohol oxidation step, and the
primary amine reacts with alcohol to form the “normal” tertiary
amine via borrowing hydrogen (pathway 1), 2) nitrile is
hydrolyzed to ammonia and reacted with alcohol to generate
symmetric tertiary amine (pathway 2). In the second pathway,
nitrile only acts as a nitrogen source. Herein, we report a
ruthenium-catalyzed tertiary-amine formation from nitriles and
alcohols using borrowing hydrogen methodology.
We began our investigation by examining the reaction of
benzonitrile (1a) and 4-methoxybenzyl alcohol (2a) under
various conditions using toluene as a solvent. As shown in
Table 1, the choice of ligand was very important for this kind of
reaction using RuCl3¢3H2O as catalyst, and the reaction,
monitored by GC-MS, did not take place in the absence of
ligand (Table 1, Entry 1). After screening several phosphine
ligands, dppf [1,1¤-bis(diphenylphosphino)ferrocene] was found
to give the best result (Entry 6). Tris(4-methoxybenzyl)amine
(3a) was obtained in 90% yield (via pathway 2) together with
7% N-benzylbis(4-methoxybenzyl)amine (4a) (via pathway 1).
Ruthenium complexes such as [Ru(CO)HCl(PPh3)3] and [Ru-
(CO)(H)2(PPh3)3] were inefficient catalysts for tertiary-amine
formation (Entries 7 and 8). [Ru(cod)Cl2]/dppf was found to be
efficient catalyst for tertiary-amine formation, albeit with lower
selectivity (Entry 10). Good combination yield was obtained
when the catalyst loading decreased to 2.5 mol % (Entry 11).
Decreasing the amount of 2a decreased the product yield
(Entry 12). To our delight, excellent yield was observed when an
equivalent of water was added (Entry 13). Under the optimized
reaction conditions, the amine formation mainly took pathway 2
and symmetric amine was the major product. If we remove part
of the water (mainly generated from the imine formation step)
from the reaction system, the reaction might take pathway 1. To
prove our deduction, molecular sieves were added to the
reaction. Indeed, the yield of 4a improved to 45% when 100 mg
of molecular sieves was added (Entry 14).19
Recently, we17 and others18 developed direct alkylation of
nitroarenes with alcohols using the borrowing hydrogen meth-
odology. We are also interested in employing this procedure
for other unsaturated nitrogen-containing compounds such as
nitriles. Nitriles are useful reagents and can be readily trans-
ferred into primary amines by reducing reagents, and can be
hydrolyzed to carboxylic acids and ammonia or ammonium salts
Chem. Lett. 2011, 40, 489-491
© 2011 The Chemical Society of Japan
Liu, Saiwen
