Base-catalyzed amination of olefins: An example of an environmentally friendly synthesis of amines

Article abstract of DOI:10.1016/S0045-6535(00)00319-2

The base-catalyzed amination of aromatic olefins is described as an environmentally friendly synthesis of various β-arylethylamines. Primary and secondary aliphatic amines as well as aromatic amines react with styrene derivatives to give the corresponding β-arylethylamines in high yield up to 99%. While aliphatic amines react with styrenes in the presence of n-BuLi as the pre-catalyst, anilines can be olefinated using KOtBu as the catalyst.

Full text of DOI:10.1016/S0045-6535(00)00319-2

Chemosphere 43 (2001) 21±26
Base-catalyzed amination of ole®ns: an example of an
environmentally friendly synthesis of amines
*
Matthias Beller , C. Breindl
Institut fur Organische Katalyseforschung an der Universitat Rostock e.V., Buchbinderstraûe 5-6, D-18055 Rostock, Germany
Abstract
The base-catalyzed amination of aromatic ole®ns is described as an environmentally friendly synthesis of various
b-arylethylamines. Primary and secondary aliphatic amines as well as aromatic amines react with styrene derivatives to
give the corresponding b-arylethylamines in high yield up to 99%. While aliphatic amines react with styrenes in the
presence of n-BuLi as the pre-catalyst, anilines can be ole®nated using KOtBu as the catalyst. Ó 2001 Published by
Elsevier Science Ltd. All rights reserved.
Keywords: Amination; Base catalysts; N-arylethylamines; Catalysis
1. Introduction
(Trost, 1991, 1998) or atom eciency (Sheldon 1994,
1997) of the reaction is low. Due to the drive towards the
so-called ``green chemistry'' (Clark, 1999; Tundo and
Anastas, 1999), the synthetic chemist in the future will
be more and more concerned about atom economy and
feedstock compared to today. Although a number of
``classic'' organic reactions developed in the ®rst half of
the 20th century, e.g., pericyclic reactions, proceed with
100% atom eciency, nowadays it is especially the cat-
alysts that o€er possibilities to achieve atom eciency
(Fig. 2) in organic synthesis.
The search for new reactions as well as the applica-
tion of known reagents towards new targets are still
important research areas in organic chemistry. In the
last two decades, stereoselective reactions have aroused
the attention of numerous academic research groups.
Hence, highly stereoselective methods with elegant ap-
plications have been developed. However, in industry,
stereoselectivity is only one among many important
criteria determining whether a given reaction is applied
or not. The challenge for synthetic chemists working in
the area of applied synthesis is more and more to de-
velop ``clean'' practical technologies for already existing
or future products. In order to achieve this, innovations
in organic synthesis are still required. The ideal chemical
synthesis of a desired product (Fig. 1) makes use of
cheap available raw materials and produces a minimum
of waste.
Industrially important catalytic reactions are often
re®nement reactions of ole®ns. Here, the catalytic for-
mation of carbon±carbon or carbon±hydrogen bonds
are particularly important in hydrogenations, telom-
erisations, hydroformylations, hydrocyanations, etc.
(Cornils and Herrmann, 1996; Beller and Bolm, 1998).
On the other hand, the atom ecient formation of car-
bon±heteroatom bonds, e.g., carbon±nitrogen bonds,
are rare. This is surprising if one considers the funda-
mental importance of amines and their derivatives as
natural products, pharmacological agents, ®ne chemi-
cals, and dyes (Gibson, 1968; Trost and Verhoeven,
1982; Collman et al., 1987; Brunet et al., 1989; March,
1992). Hence, there is a considerable interest in the de-
velopment of new ecient synthetic protocols for the
Apart from waste being produced because the reac-
tion does not give the desired product in 100% yield,
often waste is unavoidable because the atom economy
* Corresponding author.
0045-6535/01/$ - see front matter Ó 2001 Published by Elsevier Science Ltd. All rights reserved.
PII: S 0 0 4 5 - 6 5 3 5 ( 0 0 ) 0 0 3 1 9 - 2

22
M. Beller, C. Breindl / Chemosphere 43 (2001) 21±26
Recently, we became interested in the catalytic
amination of ole®ns, especially styrene derivatives. An
anti-Markovnikov amination of styrenes would allow a
direct synthesis of pharmaceutically important b-aryl-
ethylamines. Some examples of this important class of
pharmaceuticals are shown in Fig. 3.
Our approach to the amination of styrenes was
twofold. On one hand, we developed new transition
metal-catalyzed amination reactions applying cationic
rhodium catalysts (Beller et al., 1997, 1998a,c, 1999a,b)
and on the other hand, we were interested in enlarging
the synthetic utility of known base-catalyzed aminations
of styrenes (Howk et al., 1954; Stroh et al., 1957; Wol-
lensak and Closson, 1963; Pez and Galle, 1985). In this
paper, we present a short overview of our recent
achievements in this area.
Fig. 1. The ``ideal'' chemical synthesis.
2. Results
Initially, we investigated the e€ect of both base cat-
alysts and solvents on the reaction of styrene with
morpholine. As shown in Table 1, the best results are
obtained with 5 mol% n-butyl lithium in THF. In all the
cases, N-2-phenylethylmorpholine is formed, regardless
of base and solvent, due to the stabilization of the
negative charge in the a-position to the phenyl group.
In general, reactions were run for 20 h, however,
kinetic investigations in various solvents showed that
conversion was already complete after 2 h. Hence, the
actual base catalyst ± the corresponding lithium mor-
pholide ± seems to be deactivated after 2 h. Amination in
THF or DME is faster compared to the reaction in
solvents such as hexane or toluene, however, catalyst
deactivation occurs at the same time. Apart from sty-
rene, 4-vinylbiphenyl, 2-vinylnaphthalene, a-methylsty-
rene, and b-methylstyrene also react with morpholine in
good yields (69±80%). The advantage of this base-cata-
lyzed synthesis of arylethylamines compared to the tra-
ditional nucleophilic substitution reaction and the
reductive amination becomes obvious by comparing the
atom eciency of the di€erent routes to N-2-phen-
ylethylmorpholine (Scheme 2).
Fig. 2. Selected examples of atom ecient catalysis.
construction of carbon±nitrogen bonds. In this respect,
the catalytic hydroamination of ole®ns is a particularly
convenient method for the synthesis of amines
(Scheme 1) (Roundhill, 1992; Taube, 1996; Beller and

Muller, 1998).
This procedure is environmental friendly, i.e., each
atom from the starting material is present in the product
and in principle no by-products are formed. Further-
more, ole®ns and amines are both inexpensive and
readily available feedstock. Industrially important ter-
minal ole®ns provide, in principle, two regioisomeric
amines, the Markovnikov and the anti-Markovnikov
product (Markovnikov, 1875). The Markovnikov regio-
isomer is usually favored due to the higher stability of
the intermediate carbocation.
As shown in Scheme 2, the atom eciency (Mw of
P
amination product/ Mw of all products) of the base-
catalyzed amination route is 100%, while nucleophilic
substitution yields only 70%. In addition, there is an
Scheme 1. Hydroamination of ole®ns.

M. Beller, C. Breindl / Chemosphere 43 (2001) 21±26
23
Fig. 3. Important b-arylethylamines.
Table 1
Base-catalyzed amination of styrene and substituted styrenes with morpholinea
Entry
R1
R2
R3
Base (mol%)
Solvent
Yield (%)
1
2
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)
n-BuLi (5)b
KOtBu (10)
n-BuLi (5)
n-BuLi (5)
n-BuLi (10)
n-BuLi (10)
Dioxane
Toluene
DME
THF
81
37
79
89
58
7
H
3
H
4
H
5
H
Hexane
DMF
DMSO
THF
6
H
7
H
5
8
H
72
<1
80
78
81
69
9
H
4-phenyl
THF
THF
10
11
12
13
c
±
THF
THF
THF
H
H
a 4.0 mmol morpholine, 4.0 mmol ole®n in 10 ml solvent were heated to 120°C in a pressure tube for 20 h.
b 10 mol% tetramethylethylenediamine was added.
c 2-vinylnaphthaline.
economic advantage by using styrene compared to 2-
bromoethylbenzene and phenylacetaldehyde.
were obtained (Beller and Breindl, 1998). Only in the
case of b-methylstyrene, the product yield was slightly
lower (71%).
Based on investigations on the reaction of aromatic
ole®ns with morpholine, we became interested in the
amination of styrene using piperazines, since N-aryl-N0-
2-arylethylpiperazines constitute an interesting class of
pharmaceutically active agents (Glennon et al., 1991;
Kuipers et al., 1995). Again, base-catalyzed amination
proceeds smoothly in THF in the presence of 5 mol% n-
BuLi as the pre-catalyst (Table 2). Without further op-
timization, good to quantitative yields (77±99%) of
various substituted N-aryl-N0-2-arylethylpiperazines
In contrast to the amination of styrene with sec-
ondary amines, primary aliphatic amines and anilines do
not react eciently according to the literature (Wegeler
and Pieper, 1950; Asahara et al., 1969). However, re-
cently we demonstrated that N-2-phenethylanilines are
produced by the reaction of aromatic ole®ns with ani-
lines in the presence of KOtBu as a catalyst (Beller et al.,
1998b). As shown in Table 3, employing n-BuLi as the
pre-catalyst does not lead to any conversion. However,

24
M. Beller, C. Breindl / Chemosphere 43 (2001) 21±26
Scheme 2. Comparison of di€erent synthetic procedures for the synthesis of N-2-phenylethylmorpholine.
Table 2
Base-catalyzed amination of styrene and substituted styrenes with N-arylpiperazinesa
Entry
R1/ole®n
R2/R3
R4
Yieldb (%)
1
2
H
p-OCH3
H/H
H/H
p-F
p-F
99
77
3
H/H
p-F
84
4
5
p-Cl
m-CH3
H
H/H
H/H
p-F
H
98
97
99
89
95
71
86
6
H/H
H/H
m-CH3
m-CF3
o-OCH3
H
7
H
8
H
H/H
H/±CH3
±CH3/H
9c
10d
H
H
H
a Reaction conditions: 2.22 mmol N-arylpiperazine, 2.22 mmol aryl ole®n and 5 mol% n-BuLi were heated for 17 h in 4 ml THF. The
reaction was performed at 120°C in a pressure tube purchased by Aldrich.
b Determined by GC with hexadecane as internal standard.
c Determined by GC with hexadecane as internal standard.
d The reaction was performed at 90°C.
by using KOtBu as base, the more nucleophilic potas-
sium anilide seems to be produced under the reaction
conditions and various substituted N-2-arylethylanilines
are obtained in good to excellent yields (72±90%)
(Table 3).
For the ®rst time, the ole®nation of primary
aliphatic amines proceed in good yield (79%) and
selectivity. By using
2 eq of amine, only small
amounts of tertiary amines (5%) are observed. Clearly,
this is an important advantage compared to other

M. Beller, C. Breindl / Chemosphere 43 (2001) 21±26
25
Table 3
Base-catalyzed amination of styrene and substituted styrenes with primary aminesa
Entry
Amine R1
Ole®n R2/R3/R4
Base
Yield (%)
1
2
Phenyl
Phenyl
H/H/H
H/H/H
H/H/H
n-BuLi (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
KOtBu (10)
n-BuLi (10)
n-BuLi (10)
n-BuLi (10)
<1
85
3b
Phenyl
Phenyl
99
78
4
2-Cl/H/H
2-Cl/H/H
H/H/H
5
3-F-phenyl
4-F-phenyl
2-MeO-phenyl
4-F-phenyl
Phenyl
79
75
6
7
H/H/H
85
84
8
4-Cl/H/H
H/Me/H
H/H/Me
2-Cl/H/H
H/H/H
9c
10c
11
12
13e
14f
34
50
Phenyl
3-CF3-phenyl
n-C4H9
n-C4H9
82
49 (13)d
79 (5)d
77 (4)d
H/H/H
H/H/H
n-C4H9
a 11.0 mmol amine, 11.0 mmol ole®n in 10 ml THF were heated to 120°C in a pressure tube for 20 h.
b Amine/ole®n ˆ 5:1.
c 160°C.
d Amount tert. amine.
e Amine/ole®n ˆ 2:1.
f 10 mol% tetramethylethylenediamine was added.
synthetic routes for secondary amines, e.g., nucleo-
philic substitution reactions of primary amines with
alkyl halides.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft
(DFG Be 3-1) and the Bayerische Forschungsverbund
Katalyse (FORKAT II) for the ®nancial support of this
project.
3. Conclusion and outlook
The base-catalyzed amination reaction of aromatic
ole®ns o€ers the most atom economic access to 2-aryl-
ethylamines. This class of compounds is especially in-
teresting with regard to their pharmaceutical properties.
Surprisingly, this method has been scarcely investigated
in recent years. We have shown that optimization of
solvent and base catalysts lead to ecient processes for
the reaction of styrenes with secondary aliphatic amines
and anilines. First, experiments with primary amines
also show the possibility to synthesize secondary amines
highly selectively.
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