A novel ruthenium-catalyzed amination of primary and secondary alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.10.042

An improved method for the N-alkylation of primary amines with primary and secondary alcohols has been developed. Novel, effective catalyst systems, for example, Ru₃(CO)₁₂ combined with tri-o-tolylphosphine or n-butyl-di-1-adamantylphosphine, allow for aminations in a good yield under comparatively mild conditions.

Full text of DOI:10.1016/j.tetlet.2006.10.042

Tetrahedron Letters 47 (2006) 8881–8885
A novel ruthenium-catalyzed amination of primary and
secondary alcohols
Annegret Tillack, Dirk Hollmann, Dirk Michalik and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 11 September 2006; accepted 10 October 2006
Available online 31 October 2006
Abstract—An improved method for the N-alkylation of primary amines with primary and secondary alcohols has been developed.
Novel, effective catalyst systems, for example, Ru3(CO)12 combined with tri-o-tolylphosphine or n-butyl-di-1-adamantylphosphine,
allow for aminations in a good yield under comparatively mild conditions.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The catalytic formation of carbon–nitrogen bonds is of
a broad interest to synthetic organic chemists since a
large number of nitrogen-containing molecules are of
importance for both the bulk and fine chemical indus-
tries, for example, for the production of solvents and
emulsifiers. In addition, a variety of naturally occurring
bio-active compounds such as alkaloids, amino acids
and nucleotides contain amino groups, which are parti-
cularly useful for the development of new pharmaceuti-
cals and agrochemicals.1 Thus, the development of
improved methods for the synthesis of amines continues
to be a challenging and active area of research.2
This consecutive domino reaction consists of an initial
dehydrogenation of the alcohol, subsequent imine for-
mation followed by reduction with the initially produced
hydrogen. The advantages of this method are the ubi-
quitous availability of alcohols and high atom efficiency,
for example, no salt formation, water as the only
by-product. Moreover, compared to reductive amina-
tions, it is possible to run these reactions in the absence
of hydrogen pressure.
The general principle of alkylation of amines with alco-
hols is well known.7 The methylation of lower aliphatic
amines with methanol is even performed on an indus-
trial scale.8 Until now mainly heterogeneous catalysts
are used for N-alkylation at a high temperature and
pressure. For example, alkylations of aryl amines are
catalyzed by Raney-Ni,9 alumina,10 silica and mont-
morillonite at temperatures >200 ꢁC.11
Among the various catalytic amination methods, palla-
dium-catalyzed amination of aryl halides,3 hydroamina-
tion,4 and hydroaminomethylation5 of olefins or alkynes
has received special attention in the last decade. Less
interest has been paid to the further development of
catalytic alkylations of amines.6 Compared to the
frequently applied N-alkylations with alkyl halides and
reductive aminations, an economically and environmen-
tally attractive method is the N-alkylation of amines
using primary and secondary alcohols (Scheme 1).
The first homogeneous catalysts were introduced by
Grigg et al.12 and Watanabe et al.13 in 1981. Thereafter,
ruthenium,14 rhodium,15 platinum,16 and iridium com-
plexes15,17 have been introduced as molecular-defined
transition metal catalysts for such reactions. Similar to
heterogeneous systems the drawbacks of the known
homogeneous catalysts are the high reaction tempera-
tures (up to 215 ꢁC) and long reaction times, which are
required to obtain sufficient yields. In addition, the
scope of these reactions is limited. With regard to the
alcohol, mainly primary alcohols have been used as sub-
strates. These are more reactive compared to secondary
alcohols. With the exception of [IrCp*Cl2], which was
introduced by Fujita et al.18 no efficient catalyst is
known for the N-alkylation with secondary alcohols.
R1
R2
R1
R2
catalyst
- H2O
RNH
RNH2
OH
+
R, R1, R2 = H, alkyl, aryl
Scheme 1. Catalytic N-alkylation of amines with alcohols.
*
Corresponding author. Tel.: +49 0381 1281113; fax: +49 0381
12815000; e-mail: matthias.beller@catalysis.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.042

8882
A. Tillack et al. / Tetrahedron Letters 47 (2006) 8881–8885
Thus, a major challenge in this area is the development
of more active catalysts that work under milder condi-
tions and allow a broader substrate scope. Clearly, the
demands on improved catalysts for the N-alkylation of
amines with alcohols are: (1) High activity for the de-
hydrogenation of alcohols to ketones and the hydro-
genation of the resulting imines to amines via a
transfer hydrogenation process, and (2) low sensitivity
to water and functional groups on the substrate. From
an environmental point of view the use of additional
base for the activation of the catalyst should be avoided.
P
P
P
1
2
3
O
O
P
P
Based on our previous research in intermolecular hydro-
aminations of olefins and alkynes,19 we recently became
interested in the development of novel ruthenium com-
plexes for the amination of alcohols, especially second-
ary alcohols. Herein, we report our results from this
study and present Ru3(CO)12/ligand-systems which are
active for the N-alkylation of amines with different alco-
hols at 100–110 ꢁC.
4
5
P
P
P
P
Initial studies were performed using n-hexylamine and
1-phenylethanol as the substrates in the presence of
different ruthenium sources. As a result of these reac-
tions the ruthenium cluster Ru3(CO)12 was tested in
the presence of different phosphine ligands. Typically,
the catalytic reactions were run without a solvent using
2 mol % Ru3(CO)12 and 6 (3) mol % of monodentate
(bidentate) ligands at 110 ꢁC. The selected results and
the ligands used are shown in Table 1 and Scheme 2.
6
7
Scheme 2. Ligands for N-alkylation of amines with alcohols.
For all other tested ligands the conversion of substrate
was significantly higher than the yield of the desired
product. In these cases the corresponding imine was
observed as the major side product. Thus, the hydro-
genation of the imine appears problematic.
Notably, the reaction proceeds in a good yield (74%) in
the presence of the ruthenium carbonyl cluster (Table 1,
entry 1). With respect to the used ligands, there was no
clear trend observed. For example electron-rich bulky
Next, critical reaction parameters of the model reaction
were studied in more detail (Table 2). The Ru3(CO)12/
tri(o-tolyl)-phosphine catalyst system 4 was chosen for
its high yield, robustness and favourable price.
phosphines such as tricyclohexylphosphine
1 and
n-butyl-di-1-adamantyl-phosphine20 2 behaved quite
differently (Table 1, entries 2 and 3). Similar divergent
behaviour was observed with aryl phosphines 3 and 4
(Table 1, entries 4 and 5). The best results were obtained
with 2 and 4 (>90% of N-(1-phenyl-ethyl)hexylamine).
Reducing the catalyst loading from 2 to 1 mol %, the
conversion decreased from 100% to 79%, and the yield
of secondary amine dropped to 37%. Variation of the
alcohol/amine ratio demonstrated the importance of
the alcohol concentration for the hydrogenation step
(Table 2, entries 2–5). Although the conversion
decreased only slightly to around 80%, the product yield
decreased steadily to only 29%. Reducing the reaction
time to 7 h showed that almost 24 h are necessary for
a full conversion (Table 2, entry 8).
Table 1. N-Alkylation of n-hexylamine with 1-phenyl-ethanol in the
presence of Ru3(CO)12 and different ligandsa
2 mol % Ru3(CO)12
6 mol% Ligand, 110 °C
Ph
Ph
OH
C6H13HN
C6H13NH2
+
H3C
CH3
- H2O
The two best catalysts identified from these studies were
applied to the alkylation of various amines under the
optimized conditions (Table 3).
Entry
Ligand
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
None
100
100
100
81
100
56
74
59
90
47
97
33
30
34
1
2
3
4
5
6
7
In addition to the model reaction described above, the
N-alkylation of n-octylamine and benzylamine with
1-phenylethanol proceeded in moderate yield (64% and
49%, respectively) (Table 3, entries 4 and 8). Cyclooctyl-
amine gave 29% of the corresponding alkylated amine
(Table 3, entry 6). In all cases ligand 4 gave better prod-
uct yields than 2.
85
82
a Reaction conditions: 2 mmol n-hexylamine, 10 mmol 1-phenyletha-
nol, 0.04 mmol Ru3(CO)12 0.12 mmol monodentate ligand (or
,
Finally, different alcohols were examined in the N-alkyl-
ation of n-hexylamine (Table 4). Again, all substrates
were tested in the presence of ligands 2 and 4. Notably,
0.06 mmol bidentate ligand), 110 ꢁC, 24 h, conversion and yield
were determined by GC analysis with hexadecane as the internal
standard.

A. Tillack et al. / Tetrahedron Letters 47 (2006) 8881–8885
8883
Table 2. N-Alkylation of n-hexylamine with 1-phenylethanol in the presence of Ru3(CO)12 and tri(o-tolyl)phosphine (4)a
2 mol% Ru3(CO)12
Ligand 4, 110 °C
Ph
Ph
OH
C6H13HN
C6H13NH2
+
H3C
CH3
- H2O
Entry
Catalyst (mol %)
Amine/alcohol
Temperature (ꢁC)
Time (h)
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
1
2
2
2
2
2
2
2
1:5
1:5
1:4
1:3
1:2
1:5
1:5
1:5
110
110
110
110
110
100
90
24
24
24
24
24
24
24
7
79
100
88
80
82
90
38
58
37
97
58
38
29
52
10
22
110
a Reaction conditions: 2 mmol n-hexylamine, 10 mmol 1-phenylethanol, 0.04 mmol Ru3(CO)12, 0.12 mmol 4, conversion and yield were determined
by GC analysis with hexadecane as the internal standard.
entries 1–4). We were also pleased to find that hetero-
aromatic alcohols, for example, 1-(2-furyl)-ethanol
(Table 4, entries 5 and 6), furan-2-yl-methanol (Table
4, entries 7 and 8), and thiophen-2-yl-methanol (Table
4, entries 9 and 10) were converted to the corresponding
secondary N-hexylamines in moderate to good yields.
Ligand 4 was again superior to 2 in all cases studied.
Table 3. N-Alkylation of different amines with 1-phenyl-ethanol in the
presence of Ru3(CO)12/2 or 4a
2 mol% Ru3(CO)12
6 mol % Ligand
Ph
Ph
OH
RHN
RNH2
+
- H2O
H3C
CH3
Entry Amine
Ligand Conversion (%) Yield (%)
1
2
3
4
5
6
7
8
Hexylamine
2
4
2
4
2
4
2
4
100
100
100
100
56
44
81
72
90
97
35
64
21
29
19
49
In conclusion, we present a novel ruthenium-catalyzed
N-alkylation of amines with alcohols in the presence
of different sterically hindered phosphine ligands. The
reactions can be performed under significantly milder
conditions (110 ꢁC) compared to the known ruthenium
catalysts and proceed with good yields.
Hexylamine
Octylamine
Octylamine
Cyclooctylamine
Cyclooctylamine
Benzylamine
Benzylamine
a Reaction conditions: 1 mmol amine, 5 mmol 1-phenylethanol,
0.02 mmol Ru3(CO)12, 0.06 mmol ligand, 110 ꢁC, 24 h, conversion
and yield were determined by GC analysis with hexadecane as
Acknowledgements
This work has been supported by the State of Mecklen-
burg-Western Pommerania, the BMBF (Bundesministe-
rium fur Bildung und Forschung), the Deutsche
¨
secondary aliphatic alcohols such as 2-octanol and
cyclohexanol gave N-hexyl-2-octylamine and N-hexyl-
cyclohexylamine in excellent yields (90–94%) (Table 4,
Forschungsgemeinschaft (Leibniz-price), and the Fonds
Table 4. N-Alkylation of n-hexylamine with different alcohols in the presence of Ru3(CO)12/2 or 4a 21
2 mol% Ru3(CO)12
6 mol% Ligand
C6H13NH2
ROH
C6H13NHR
+
- H2O
Entry
Alcohol
Ligand
Temperature (ꢁC)
Conversion (ꢁC)
Yield (%)
1
2
2
4
110
110
100
100
92
90
OH
3
4
2
4
120
120
100
100
94
93
OH
OH
O
O
S
5
6
2
4
110
110
100
100
17
49
OH
OH
7
8
2
4
110
110
100
100
33
60
9
10
2
4
110
110
66
100
7
70
a Reaction conditions: 2 mol % catalyst, 24 h, conversion and yield were determined by GC analysis with hexadecane as internal standard.

8884
A. Tillack et al. / Tetrahedron Letters 47 (2006) 8881–8885
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Chem., Int. Ed. 2006, 45, 154; (b) Ko¨llhofer, A.; Plenio, H.
Adv. Synth. Catal. 2005, 347, 1295; (c) Tewari, A.; Hein,
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der Chemischen Industrie (FCI). We thank Mrs. C.
Mewes, Mrs. A. Lehmann and Mrs. S. Buchholz for
the excellent technical and analytical support as well
as Dr. D. Nielsen for the improvement of the
manuscript.
References and notes
1. (a) Lawrence, S. A. In Amines: Synthesis, Properties and
Applications; Cambridge University: Cambridge, 2004;
(b) Hartwig, J. F. In Handbook of Organo-Palladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
Wiley-Interscience: New York, 2002; Vol. 1, p 1051.
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2001, 57, 7785.
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(b) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U.
Adv. Synth. Catal. 2006, 348, 23; (c) Navarro, O.; Marion,
N.; Mei, J.; Nolan, S. P. Chem. Eur. J. 2006, 12, 5142.
4. Hydroamination reviews: (a) Hultzsch, K. C.; Gribkov, D.
V.; Hampel, F. J. Organomet. Chem. 2005, 690, 4441;
(b) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507;
(c) Doye, S. Synlett 2004, 1653; (d) Seayad, J.; Tillack, A.;
Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344,
795; (e) Beller, M.; Breindl, C.; Eichberger, M.; Hartung,
C. G.; Seayad, J.; Thiel, O.; Tillack, A.; Trauthwein, H.
Synlett 2002, 1579.
5. Hydroaminomethylation: (a) Mueller, K.-S.; Koc, F.;
Ricken, S.; Eilbracht, P. Org. Biomol. Chem. 2006, 4,
826; (b) Routaboul, L.; Buch, C.; Klein, H.; Jackstell, R.;
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A.; Seayad, A.; Jackstell, R.; Beller, M. J. Am. Chem. Soc.
2003, 125, 10311; (d) Eilbracht, P.; Ba¨rfacker, L.; Buss, C.;
Hollmann, C.; Kitsos-Rzychon, B. E.; Kranemann, C. L.;
Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev.
1999, 99, 3329.
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(b) Tararov, V. I.; Boerner, A. Synlett 2005, 203.
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21. Preparative procedure for the amination reaction: In an
Ace-pressure tube under an argon atmosphere Ru3(CO)12
(0.1 mmol) and ligand 4 (0.3 mmol) were dissolved in thio-
phen-2-yl-methanol (25 mmol) and hexylamine (5 mmol).
The pressure tube was fitted with a Teflon cap and heated
at 110 ꢁC for 48 h in an oil bath. The excess alcohol was
distilled (40 ꢁC, 0.88 mbar). The residue was extracted with
1 N HCl (3 · 5 mL). The combined HCl-phases were
spiked with 15 N NaOH solution, extracted with dichlo-
romethane (5 · 5 mL), dried over magnesium sulfate and
reduced in vacuo to yield N-(thiophen-2-ylmethyl)hexan-
1-amine hydrochloride as a brown powder. Isolated yield:
317 mg (32%). 1H NMR (500.13, CDCl3, d): 0.84 (t,
3H, 3J = 6.9 Hz, H-6); 1.21–1.35 (m, 6H, H-3,4,5); 1.84
(m, 2H, H-2); 2.81 (m, 2H, H-1); 4.26 (m, 2H, H-7); 7.03
3
3
(dd, 1H, J10,11 = 5.2 Hz, J9,10 = 3.6 Hz, H-10); 7.34 (dd,
3
4
1H, J10,11 = 5.2 Hz, J9,11 = 1.0 Hz, H-11); 7.42 (dd, 1H,
3J9,10 = 3.6 Hz, J9,11 = 1.0 Hz, H-9); 9.80 (br, 2H, NH2).
4
13C NMR (CDCl3, 125.8 MHz, d): 13.9 (C-6); 22.4 (C-5);

A. Tillack et al. / Tetrahedron Letters 47 (2006) 8881–8885
8885
25.8 (C-2); 26.4 (C-3); 31.1 (C-4); 44.3 (C-7); 45.6 (C-1);
127.9 (2) (C-10, C-11); 130.9 (C-8); 131.3 (C-9). MS (EI,
70 eV) m/z (rel. intensity): 197 (1) [M+], 126 (24) [M+–
C5H11], 112 (9) [M+–C4H3S], 97 (100) [M+–C6H14N]. FT
IR (KBr, cmÀ1): 3070 (w, C-Har), 2932 (s), 2862 (s), 2794
(s), 2740 (s), 2550 (m), 2421 (m), 1581 (m), 1472 (s), 853
(m), 717 (m), 696 (s). Anal. Calcd for C11H19NSÆHCl: C,
56.51; H, 8.62; N, 5.99; S, 13.71; Cl, 15.16. Found: C,
56.30; H, 9.08; N, 5.75; S, 13.42; Cl, 14.37. HRMS calcd for
C11H19NS: 197.12327. Found: 197.12334.