Angewandte
Chemie
DOI: 10.1002/anie.200803229
Homogeneous Catalysis
Selective Synthesis of Primary Amines Directly from Alcohols and
Ammonia**
Chidambaram Gunanathan and David Milstein*
[
18]
Amines are a very important family of compounds in
chemistry and biology. They are widely used in the production
of pharmaceuticals, fine chemicals, agrochemicals, polymers,
amines, as well as alkene and alkane side products. Thus,
selective, catalytic synthesis of primary amines directly from
alcohols and ammonia with elimination of water [Eq. (1)],
under relatively mild conditions, without producing waste is
highly desirable economically and environmentally.
[1]
dyestuffs, pigments, emulsifiers, and plasticizing agents.
Among the amines, the terminal primary amines are the
most useful, but their selective synthesis is challenging, due to
their high reactivity.
catalyst, D
RCH OH þ NH ! RCH NH þ H O
ð1Þ
2
3
2
2
2
R¼alkyl, aryl
Existing methods for the preparation of primary amines
generally utilize stoichiometric amounts of toxic reagents and
Atom-economical methods to activate alcohols (replacing
the Mitsunobu protocol) for the direct nucleophilic substitu-
tion and “N centered” chemistry that precludes azides and
hydrazine are among the most required processes in pharma-
ceutical industries. Selective catalytic synthesis of primary
amines is a challenge, as the primary amines are more
nucleophilic than ammonia and compete with it in reaction
with electrophiles such as alkyl halides or aldehydes, produc-
ing secondary amines, which can also react, leading to the
formation of mixtures of products.
[
2–4]
lead to poor selectivity and low atom-economy.
The
conversion of alcohols to amines by conventional methods
typically involves two or three steps, each step generally
requiring isolation and purification, making it cumbersome
[19]
[
5]
for even small-scale syntheses. Few classical methods are
known for the stepwise, one-pot conversion of alcohols into
[
6–9]
primary amines.
An attractive method for the preparation
of secondary and tertiary linear amines by hydroaminome-
[
10]
thylation of internal olefins was reported. Amines are also
prepared by the reduction of amides, generally under harsh
We have recently reported the catalytic alcohol dehydro-
[11]
[20]
conditions to result in a mixture of products. Iridium-and
rhodium-catalyzed preparation of amines from the corre-
sponding aldehydes under hydrogen pressure was also
genative coupling to form esters, hydrogenation of esters to
[21]
alcohols, and the unprecedented reaction of alcohols with
[
22]
amines to form amides with liberation of H2.
These
[
12]
reported, demonstrating homogeneous catalytic reductive
amination with ammonia. Lewis acid catalyzed reductive
amination methods for the synthesis of amines are also
reactions are catalyzed by dearomatized PNP [2,6-bis(di-
tert-butylphosphinomethyl)pyridine] and PNN [2-(di-
tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]
[
13,14]
II
known.
by palladium-catalyzed arylation of ammonia in dioxane.
Primary amines can be alkylated by alcohols to obtain
Recently, synthesis of arylamines was achieved
pincer-type Ru complexes, and involve reversible deproto-
[15]
nation of a pyridinyl methylene group as a key catalytic step.
We have now discovered that a novel pincer complex, which
lacks this pyridinylic group, is capable of efficiently catalyzing
the very desirable reaction of ammonia with alcohols to
selectively form primary amines and water. The reaction can
proceed under mild pressure and temperature, and can be
carried out under solventless conditions and on/in water.
The novel, acridine-based pincer complex [RuHCl(A-iPr-
PNP)(CO)] (1) was quantitatively prepared by reaction of the
[16]
secondary amines.
Iridium-catalyzed multialkylation of
ammonium salts with alcohols was reported for the synthesis
of secondary and tertiary amines, but selective synthesis of
[
17]
primary amines remains as a tantalizing task.
Among the methods for commercial production of
[
1,18]
amines,
by far the largest and most utilized are based on
the reaction of alcohols with ammonia. However, the
heterogeneous processes suffer from the requirement of
very high temperatures and pressures and lead to mixtures of
[
23]
new electron-rich tridentate PNP ligand 2 with [RuHCl-
(PPh ) (CO)] in toluene at 658C for 2 h (Scheme 1). Con-
3
3
[*] Dr. C. Gunanathan, Prof. D. Milstein
Department of Organic Chemistry, Weizmann Institute of Science
76100 Rehovot, (Israel)
Fax: (+972)8-934-4142
E-mail: david.milstein@weizmann.ac.il
Homepage: http://www.weizmann.ac.il/Organic_Chemistry/
milstein.shtml
[
**] This research was supported by the Israel Science Foundation and
the Kimmel CenterforMolecularDesign. C.G. is the re cipient of a
Dean of Faculties Postdoctoral Fellowship. D.M. is the Israel Matz
Professorial Chair of Organic Chemistry.
Scheme 1. Synthesis of ligand 2 and complex 1: a) 1. diisopropylphos-
phine/MeOH, 508C, 48 h; 2. triethylamine, RT, 1 h, 83%. b) [RuHCl-
(PPh ) (CO)]/toluene, 658C, 2 h, quantitative or[RuHCl(PPh ) (CO)]/
3
3
3 3
THF, RT, 9 h, 82%.
Angew. Chem. Int. Ed. 2008, 47, 8661 –8664
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8661