A novel salt-free ruthenium-catalyzed alkylation of aryl amines

Article abstract of DOI:10.1016/j.tetlet.2008.07.107

The alkylation of aryl amines using cyclic amines such as pyrrolidine proceeds via borrowing hydrogen methodology in the presence of 1 mol % Shvo catalyst. During the reaction multiple carbon-nitrogen cleavage and formation occurred. This novel reaction sequence leads to N-aryl-pyrrolidines and -piperidines.

Full text of DOI:10.1016/j.tetlet.2008.07.107

Tetrahedron Letters 49 (2008) 5742–5745
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Tetrahedron Letters
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A novel salt-free ruthenium-catalyzed alkylation of aryl amines
Dirk Hollmann a, Sebastian Bähn a, Annegret Tillack a, Rudy Parton b, Rinke Altink b, Matthias Beller a,
*
a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b DSM Research, Technology and Analysis Geleen, PO Box 18, 6160 MD Geleen, Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The alkylation of aryl amines using cyclic amines such as pyrrolidine proceeds via borrowing hydrogen
methodology in the presence of 1 mol % Shvo catalyst. During the reaction multiple carbon–nitrogen
cleavage and formation occurred. This novel reaction sequence leads to N-aryl-pyrrolidines and
-piperidines.
Received 3 July 2008
Accepted 18 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Shvo catalyst
Amination
Amines
N-Alkylation
Ruthenium
Aromatic amines are important intermediates in the bulk and
fine chemical industry.1 In addition, the presence of carbon–nitro-
gen bonds is essential for the function of most biologically active
molecules.2 Apart from amino acids, DNA and RNA bases, espe-
cially alkaloids constitute privileged naturally occurring amines.
One of the simplest alkaloid structures represents the pyrrolidine
skeleton. Based on this structure many important natural products,
for example, proline, as well as pharmaceuticals like retronecine
and opiod receptor agonists (CJ-15,161) are known (Fig. 1).3
Clearly, a number of practical methods have been developed for
the synthesis of amines in the past decades. Besides the well-
known non-catalytic N-alkylations of amines with alkyl halides
and reductive alkylations, various catalytic reactions, like reductive
amination,4 palladium-5 and copper-catalyzed6 aminations of aryl
halides,7 hydroaminations,8 and hydroaminomethylations9 of ole-
fins or alkynes have been developed within the last decade. Never-
theless, the diversity of amines as well as their biological and
pharmaceutical relevance is still motivating academic and indus-
trial researchers to look for new and improved syntheses for all
kinds of amine derivatives. In this respect, the N-alkylation of
amines using primary10 and secondary alcohols11,12 is an environ-
mentally attractive method, which is not fully exploited yet.
Based on our interest in new synthetic methods for salt-free
alkylation of amines via borrowing hydrogen methodology,13 we
recently discovered that aryl amines react with alkyl amines to
furnish the corresponding N-alkyl-aryl amines in high yields
(Scheme 1).14 Although this transformation—alkylation of amines
Me
HN
OH
HO
HO
H
N
O
O
N
N
H
OH
N
Me
CJ-15,161 (Pfizer)
Proline
Retronecine
Figure 1. Selected examples of alkaloids and pharmaceuticals with pyrrolidine
motif.
with amines—seems to be unusual at first sight, there is significant
industrial interest in analogous transalkylations.15 Clearly, this
atom efficient alkyl transfer proceeds with primary as well as sec-
ondary and tertiary aliphatic amines leaving ammonia as the only
side product.16
Here, we report for the first time the selective N-alkylation of
aryl amines using cyclic alkyl amines such as pyrrolidine (Scheme
1; right arrow). Remarkably, in this novel catalytic transformation
three C–N bond cleaving and forming steps take place.
As a starting point of our investigations we examined the reac-
tion of aniline with pyrrolidine in the presence of catalytic
amounts of the so-called Shvo catalyst I17 (Table 1). After the reac-
tion N-phenylpyrrolidine 1, 1,4-diphenyl-aminobutane 2 and N-(4-
phenylaminobutyl)-pyrrolidine 3 were isolated and identified.
Upon variation of the concentrations of aniline and pyrrolidine
the ring opening products were observed in diverse amounts.
Applying an excess of pyrrolidine, mainly 1 and self-condensation
products of pyrrolidine as by-products were obtained (Table 1,
entry 1). In the presence of excess or stoichiometric amounts of
* Corresponding author. Tel.: +49 (0)381 1281113; fax: +49 (0)381 12815000.
E-mail address: matthias.beller@catalysis.de (M. Beller).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.107

D. Hollmann et al. / Tetrahedron Letters 49 (2008) 5742–5745
5743
N
R-NH2
H
H
H
O
O
Ph
Ph
R
NH2
N
NH
Ph
Ph
Ph
Ph
1 mol% I
1 mol% I
Ru Ru
Ph
Ph
OC
OC
CO
CO
-NH3
-NH3
I
Scheme 1. Amination of aniline using non-cyclic and cyclic alkylamines.
Table 1
N-Alkylation of aniline with pyrrolidine in the presence of the Shvo catalyst I under different conditionsa
NH2
H
N
H
Ph
N
N
Ph
N
Ph
N
N
H
H
Ph
1
2
3
Entry
Solvent
T (°C)
Ratio py:an
1 (%)
2 (%)
3 (%)
1
2
3
4
5
6
7
—
—
—
—
—
—
150
150
150
140
130
110
130
2:1
1:1
1:2
1:2
1:2
1:2
1:2
22 (21)
47 (32)
53 (32)
22
3
4 (2)
<1
5
—
—
8 (7)
3
2
—
—
—
—
—
—
—
—
Toluene
a
Reaction conditions: 1 mol % Shvo catalyst, 24 h. Yields were determined by GC analysis with hexadecane as internal standard. Isolated yields in brackets.
aniline, N-phenylpyrrolidine 1 was observed as the major product
in up to 53% yield (Table 1, entries 2 and 3). Here, no self-conden-
sation products of pyrrolidine have been detected. The arylated
1,4-diamine derivates 2 and 3 were determined as minor products.
Lowering of the reaction temperature provided a higher selectivity
towards 1 but decreased the reactivity. Interestingly, in the pres-
ence of a solvent, for example, toluene, no reaction with aniline
was observed (Table 1, entry 7).
In analogy to the monoalkylation of aryl amines,16 the supposed
reaction mechanism is illustrated in Scheme 2. Initially, ruthe-
nium-catalyzed dehydrogenation of pyrrolidine should occur via
coordination and b-hydride elimination. Then, nucleophilic attack
of the aryl amine on the resulting imine to give the aminal, ring
opening and hydrogenation yields the corresponding 1,4-diamine.
Here, dehydrogenation of the primary amino group is fast
compared to that of the secondary amine. Subsequent nucleophilic
Ph
N
H
H
N
N
NH2
Ph
Ph
HN
- H2 [Ru]
- NH3
- H2 [Ru]
N
Ph
N
H
N
H2N
4
NH2
+ H2 [Ru]
+ H2 [Ru]
H
H
Ph
N
H
N
N
N
Ph
H2N
Ph
~ H
1
Scheme 2. Proposed mechanism for the reaction of pyrrolidine with aniline.

5744
D. Hollmann et al. / Tetrahedron Letters 49 (2008) 5742–5745
attack on the imine, elimination of ammonia and catalytic hydro-
Ph
N
[Ru],
H
N
genation lead to the arylated pyrrolidine. Notably, N-phenyl-
butan-1,4-diamine 4 might react intermolecular with a second
molecule of aniline to give 2. Moreover, the primary amine group
of 4 reacts with dehydrogenated pyrrolidine to yield 3 after a
similar sequence of reaction steps (Scheme 3).
In order to demonstrate the general applicability of the Shvo
catalyst and the scope of the process, the reaction of various aryl
amines and three cyclic alkyl amines were investigated. These
results are summarized in Table 2.
Aniline
[Ru]
PhHN
NH2
-/+H2
-/+H2
- NH3
4
1
[Ru],
Pyrrolidine
[Ru],
Aniline
-/+H2
-NH3
-NH3
In general, catalytic experiments were run with 1 mol % of Shvo
I in the presence of 2 equiv of aryl amine (Table 2). Noteworthy, the
product yield depends on the electron density of the aromatic ring
and thus the nucleophilicity of the amino group. Apparently, the
nucleophilic attack of the aryl amine is involved in the rate-deter-
mined step. We were pleased to find that electron-rich aryl amines
PhHN
N
PhHN
NHPh
3
2
Scheme 3. Synthesis of the side products 2 and 3.
Table 2
N-Alkylation of aryl amines with cyclic secondary alkylamines in the presence of Shvo Ia,18
R
1 mol% Shvo
-NH3
R
R
R
N
NH
H2N
n = 1,2
n
n
Entry
1
Arylamine
Product
Yieldb (%)
67
H2N
OMe
N
OMe
OMe
OMe
2
48
H2N
H2N
N
N
3
4
31
51
Me
Me
Me
Me
H2N
H2N
N
N
O
O
5
6
7
8
9
58
31
25
28
58
68
O
O
H2N
H2N
H2N
H2N
H2N
F
N
N
N
F
Cl
Cl
Br
Br
OMe
OMe
N
OMe
10
N
OMe
a
Reaction conditions: 1 mol % Shvo catalyst, 24 h, 150 °C.
Isolated yields, Yields in brackets were determined by GC analysis with hexadecane as internal standard.
b

D. Hollmann et al. / Tetrahedron Letters 49 (2008) 5742–5745
5745
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Acknowledgments
This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF (Bundesministerium für Bildung
und Forschung), and the Deutsche Forschungsgemeinschaft (DFG
BE 1931/16-1, Leibniz-price). We thank Mrs. K. Mevius, and Mrs.
S. Buchholz for excellent technical and analytical support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.107.
16. Hollmann, D.; Bähn, S.; Tillack, A.; Beller, M. Chem. Commun. doi:10.1039/
b803114b.
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18. General procedure for the amination reaction: In an ACE-pressure tube under
an argon atmosphere the Shvo catalyst (0.02 mmol) and pyrrolidine (2 mmol)
were dissolved in tert-amylalcohol (0.5 ml) and 4-methoxyaniline (4 mmol).
The pressure tube was fitted with a Teflon cap and heated at 150 °C for 24 h.
The solvent was removed in vacuo, and the crude alkyl aryl amine product is
easily purified by column chromatography with pentane/ethyl acetate (20:1)
to give N-(4-methoxyphenyl)pyrrolidine in 67% yield (238 mg) as red pale
crystals. 1H NMR (300 MHz, CDCl3): d (ppm) = 1.98–2.03 (m, 4H), 3.22–3.28 (m,
4H), 3.76 (s, 3H), 6.55–6.62 (m, 2H), 6.83–6.88 (m, 2H). 13C NMR (75 MHz,
CDCl3): d (ppm) = 25.4 (CH2), 48.6 (CH2), 56.0 (CH3), 113.0 (CH), 115.1 (CH),
ˇ
ˇ
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142.9 (Cq), 151.1 (Cq). IR (ATR):
m
(cmÀ1) = 3045w, 2977m, 2958m, 2947m,
2905w, 2863m, 2825m, 1616m, 1510m, 1487m, 1465m, 1439m, 1369m,
1337m, 1282m, 1234m, 1178m, 1155m, 1043m, 1034m, 964m, 869m, 812s,
799m, 743m. MS (EI): m/z (rel. int.) 177 (69), 176 (30), 162 (100), 134 (11), 121
(13), 120 (16). HRMS (EI): calcd for
177.114495. For characterization of the other products see Supplementary
data.
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Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096–3099; Monnier, F.; Taillefer,
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Chem., Int. Ed. 2008, 47, 3096–3099; (c) Taillefer, M.; Xia, N.; Ouali, N. Angew.
Chem., Int. Ed. 2007, 46, 934–936; (d) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org.
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C
11H15O1N1 (M+) 177.11482, found