α-functionalization of non-activated aliphatic amines: Ruthenium-catalyzed alkynylations and alkylations

Article abstract of DOI:10.1039/b924674f

Novel catalytic α-functionalizations of non-activated aliphatic amines with silylated alkynes are reported. In the presence of the Shvo catalyst alkylations and alkynylations proceed highly selectively to the branched amines. The Royal Society of Chemistr

Full text of DOI:10.1039/b924674f

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a-Functionalization of non-activated aliphatic amines:
ruthenium-catalyzed alkynylations and alkylationsw
Irina Jovel,a Saisuree Prateeptongkum,a Ralf Jackstell,a Nadine Vogl,b
Christoph Weckbeckerb and Matthias Beller*a
Received (in Cambridge, UK) 24th November 2009, Accepted 22nd December 2009
First published as an Advance Article on the web 14th January 2010
DOI: 10.1039/b924674f
Novel catalytic a-functionalizations of non-activated aliphatic
amines with silylated alkynes are reported. In the presence of the
Shvo catalyst alkylations and alkynylations proceed highly
selectively to the branched amines.
The development of novel methods for the synthesis of
aliphatic amines constitutes an ongoing active field in organic
Scheme 2 Ru-catalyzed alkynylation of amines.
synthesis and catalysis.1 In the past most efforts focussed on
the catalytic formation of the crucial C–N bond.2 For some
years we have been interested in this area and reported
advancements in catalytic hydroaminations,3 and hydroamino-
methylations.4 While these typical amination methods are
based on the nucleophilic reactivity of the N–H bond, more
recently methods are developed, which make use of the
inherent reactivity of the existing C–N bond to activate
the a-C atom of the amine. An early example of this strategy
is the so-called hydroaminoalkylation reaction. Based on the
work of Clerici and Maspero and Nugent et al.,5 Herzon and
Hartwig improved this tantalum-catalyzed procedure using
N-aryl alkylamines.6 Here, branched alkylamines are synthesized
via metal-catalyzed addition of the a-C bond of an amine across
olefins (Scheme 1).7
initial idea of the possible reaction sequence is shown in
Scheme 2.
Obviously, the desired transformation should proceed via a
dehydrogenation–alkynylation sequence in the presence of the
ruthenium catalyst.
For our first experiments, the reaction of tri-n-butylamine
with trimethylsilylacetylene was chosen as a model system.
This benchmark reaction was performed in different solvents
and neat amine at temperatures in between 120–150 1C.
Among the various metal complexes studied, only the Shvo
complex catalyzed the reaction to a significant extent. Other
metal complexes such as Ru3(CO)12, [RuCl2(p-cymene)]2,
RuCl2(COD), Ru(acac)3, CpRu(PPh3)2Cl, RuCl2(PPh3)3,
Fe3(CO)12, [CpFe(CO)2]2, [Ir(COD)Cl]2, Ir(COD)(acac),
Ir(CO)2(acac), and RhH(CO)(PPh3)3 were not active at all.
Selected results of the optimization of reaction conditions in
the presence of the Shvo catalyst are summarized in Table 1.
Without any solvent in neat amine product yields are much
better compared to reactions in DME, DMF, DMSO or
toluene. Hence, 69% of the resulting propargyl amine are
obtained at 150 1C in the presence of 2 mol% of the catalyst
(Table 1, entry 2). In addition to the desired product the
bissilylated 1,3-butadiyne, which resulted from dimerization of
the alkyne, is detected by GC. Similar types of condensations
are known in the presence of Pd(0), Rh(I), Ru(I), Ru(II)
catalysts, too.10
Notably, Doye and co-workers demonstrated that intra-
molecular hydroaminoalkylations proceed also in the presence
of easily available [Ti(NMe2)4].8 Based on our work on the
ruthenium-catalyzed N-alkylation of anilines and tert-alkyl
amines applying aliphatic amines,9 herein we wish to report
the first catalytic alkynylations of aliphatic amines by employing
the so-called Shvo catalyst I.z To the best of our knowledge
catalytic reactions of tertiary aliphatic or cyclic amines
with terminal unstrained alkynes are not known. Our
In order to improve the efficiency of the process and to
minimize the amount of catalyst, we considered the addition of
a hydrogen acceptor to be useful. At this point it should be
Scheme 1 Catalytic hydroaminoalkylation reactions.
noted that Backvall and co-workers demonstrated the
¨
synthesis of imines from amines applying I in the presence of
quinones as oxidants.11 In our system we have chosen cyclo-
hexanone as the hydrogen acceptor. Indeed, the addition of
1 equiv. of cyclohexanone increased the yield of branched
propargyl amine to 71% at 1 mol% of catalyst (Table 1, entry
10). In addition, after 24 h cyclohexanol was determined in the
reaction mixtures by GC. With respect to the mechanism, we
a Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock,
¨
¨
Albert-Einstein-Str. 29a, 18059 Rostock, Germany.
E-mail: matthias.beller@catalysis.de; Fax: +49-381-1281-51113
b Evonik Degussa GmbH, Health and Nutrition,
Rodenbacher Chaussee 4, 63457 Hanau, Germany
w Electronic supplementary information (ESI) available: General
procedure, characterization data for compounds. See DOI: 10.1039/
b924674f
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Table 1 Catalytic alkynylation of tributylamine: variation of reaction conditionsa
Solvent,
additive
Entry
Amine
Catalyst/mol%
T/1C
t/h
Conv. (%)
Yieldb (%)
150
150
150
150
150
150
150
150
170
20
20
24
24
24
24
24
24
24
67
92
64
80
55
73
58
71
88
55
69
23
21
13
4
1
2
3
4
5
6
7
8
9
2 mL
2 mL
1
2
1
1
1
1
1
1
1
—
—
2 mmol
2 mmol
2 mmol
2 mmol
2 mmol
1 mL
—
DMEc
DMFc
DMSOc
Toluenec
—
18
48
39
1 mL
—
d
e
10
11
12
1 mL
1 mL
2 mL
1
1
1
150
150
150
24
24
24
87
100
93
71
20
67
d
d
13
1 mL
1
120
30
89
54
a
b
c
d
e
Reaction conditions: 1 mmol trimethylsilylacetylene. GC yields. 2 mL of solvent. 1 mmol. 2 mmol.
propose that dehydrogenation of the amine by the ruthenium
hydrogen acceptor complex initially gives the corresponding
iminium ion and the hydrogenated ruthenium complex
(Scheme 2). Attack of the alkyne on the iminium ion
leads to the product. Finally, the hydrogenated ruthenium
complex is recycled by hydrogenation of cyclohexanone
(Scheme 3). Remarkably, the reaction proceeds also without
the oxidant in only slightly lower yields demonstrating the
possibility to release free hydrogen from the hydrogenated
ruthenium complex. It is assumed that the rate determining
step in the mechanism is the initial formation of the iminium
ion. In Scheme 3 the proposed mechanism of process is
illustrated.
Next, the scope and limitations of the new protocol were
investigated by employing various olefins and silylated alkynes
(Table 2). For convenience the reactions were performed in
standard pressure tubes in neat amine with 1 mol% of the
Shvo catalyst at 100–150 1C.
Different non-functionalized aliphatic and cyclic amines
gave the desired products in mediocre to good yields with
excellent chemoselectivity. For example n-Hex3N and n-Octyl3N
react with trimethylsilylacetylene to give the desired products
in 75 and 68% yield, respectively. Apart from trimethylsilyl-
acetylene, dimethylphenylsilylacetylene and triethylsilylacetylene
have been successfully used as silylated alkynes. N-Alkylated
pyrrolidine, piperidine, and piperazine also reacted selectively,
but gave somewhat lower yields. However, when these cyclic
amines were applied in the presence of cyclohexanone to our
surprise the corresponding alkylated products were obtained
(Table 2, entries 9, 10, 12 and 14). Apparently, the initially
formed cyclohexanol reacts further on with the alkyne to give
the saturated products. On the other hand with non-cyclic
amines only traces (o5%) of the reduced products were
formed.
In summary, we have developed the first catalytic alkynylation
and alkylations of aliphatic and cyclic amines applying different
silylacetylenes. In the presence of the Shvo catalyst activation of
the a-carbon of inert linear aliphatic and cyclic amines takes
place highly selectively. The present reactions constitute valuable
examples of direct salt-free C–H functionalizations of amines.
Scheme 3 Proposed mechanism for alkynylation of amines.
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Table 2 Shvo-catalyzed alkynylation of aminesa
10 and 13 were isolated by fractional vacuum distillation. GC yields
were determined after the calibration; decane was the internal
standard.
1 For some reviews see: (a) J. J. Brunet, N. C. Chu and
M. Rodriguez-Zubiri, Eur. J. Inorg. Chem., 2007, 4711;
(b) A. V. Lee and L. L. Schafer, Eur. J. Inorg. Chem., 2007,
2243; (c) R. Severin and S. Doye, Chem. Soc. Rev., 2007, 36,
1407; (d) K. C. Hultzsch, D. V. Gribkov and F. Hampel,
J. Organomet. Chem., 2005, 690, 4441; (e) A. L. Odom, Dalton
Trans., 2005, 225; (f) J. F. Hartwig, Pure Appl. Chem., 2004, 76,
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C. G. Hartung and M. Beller, Adv. Synth. Catal., 2002, 344,
795; (i) M. Beller, C. Breindl, M. Eichberger, C. G. Hartung,
J. Seayad, O. Thiel, A. Tillack and H. Trauthwein, Synlett, 2002,
1579.
Conv.
T/1C t/h (%)
Yieldb
(%)
Entry Amine
Product
1
2
Et3N
Et3N
100
100
40 93
57
59
2 (a) A. Borner, M. Beller and B. Wunsch, Sci. Synth., 2008, 40a,
46 83d
¨
111; (b) C. Muller, W. Saak and S. Doye, Eur. J. Org. Chem., 2008,
¨
¨
2731; (c) C. Muller, Ch. Loos, N. Schulenberg and S. Doye, Eur. J.
¨
Org. Chem., 2006, 2499; (d) J. F. Hartwig, Synlett, 2006, 1283;
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Chem., Int. Ed., 2005, 44, 1371; (f) K. Fujita, Y. Enoki and
R. Yamaguchi, Tetrahedron, 2008, 64, 1943.
3
n-Bu3N
150
20 97d
35
4
5
n-Bu3N
n-Bu3N
150
150
24 80d
24 48d
25
28
3 Some recent examples from our group: (a) K. Alex, A. Tillack,
N. Schwarz and M. Beller, ChemSusChem, 2008, 1, 333;
(b) A. Tillack, V. Khedkar, J. Jiao and M. Beller, Eur. J. Org.
Chem., 2005, 5001; (c) V. Khedkar, A. Tillack, C. Benisch,
J.-P. Melder and M. Beller, J. Mol. Catal. A: Chem., 2005, 241,
175; (d) V. Khedkar, A. Tillack, M. Michalik and M. Beller,
Tetrahedron Lett., 2004, 45, 3123; (e) A. Tillack, H. Jiao, I. Garcia
Castro, C. G. Hartung and M. Beller, Chem.–Eur. J., 2004, 10, 2409;
(f) M. Beller, J. Seayad, A. Tillack and H. Jiao, Angew. Chem., 2004,
116, 3448 (Angew. Chem., Int. Ed., 2004, 43, 3368); (g) V. Khedkar,
A. Tillack and M. Beller, Org. Lett., 2003, 5, 4767.
6c
7c
n-Hex3N
150
24 79
24 81
75
68
n-Octyl3N 150
4 (a) A. Moballigh, C. Buch, L. Routaboul, R. Jackstell, H. Klein,
A. Spannenberg and M. Beller, Chem.–Eur. J., 2007, 13, 1594;
(b) K.-S. Mueller, F. Koc, S. Ricken and P. Eilbracht, Org. Biomol.
Chem., 2006, 4, 826; (c) L. Routaboul, C. Buch, H. Klein,
R. Jackstell and M. Beller, Tetrahedron Lett., 2005, 46, 7401;
(d) A. Moballigh, A. Seayad, R. Jackstell and M. Beller, J. Am.
8c,e
120
150
120
30 87
19 99
30 94
20 87
39
32
38
9c,f
10c,g
¨
Chem.Soc., 2003, 125, 10311; (e) P. Eilbracht, L. Barfacker,
C. Buss, C. Hollmann, B. E. Kitsos-Rzychon, C. L. Kranemann,
T. Rische, R. Roggenbuck and A. Schmidt, Chem. Rev., 1999, 99,
3329.
5 (a) W. A. Nugent, D. W. Ovenall and S. J. Holmes, Organo-
metallics, 1983, 2, 161; (b) M. G. Clerici and F. Maspero, Synthesis,
1980, 305.
6 (a) S. B. Herzon and J. F. Hartwig, J. Am. Chem. Soc., 2007, 129,
6690; (b) S. B. Herzon and J. F. Hartwig, J. Am. Chem. Soc., 2008,
130, 14940.
11
150
150
65
30
12c
7
96
24
13
150
150
40 90
22 99
28
41
7 (a) K. Kruger, A. Tillack and M. Beller, ChemSusChem, 2009, 2,
715; (b) P. W. Roesky, Angew. Chem., Int. Ed., 2009, 48,
4892.
8 R. Kubiak, I. Prochnow and S. Doye, Angew. Chem., 2009, 121,
1173 (Angew. Chem., Int. Ed., 2009, 48, 1153).
¨
14c
9 (a) D. Hollmann, H. Jiao, A. Spannenberg, S. Bahn, A. Tillack,
a
¨
R. Parton, R. Altink and M. Beller, Organometallics, 2009, 28, 473;
Reaction conditions: 1 mmol silylated acetylene, 1–3 mL amine, 1 mol%
b
of the Shvo catalyst. GC yields. 1 mmol of cyclohexanone was added.
d
c
(b) D. Hollmann, S. Bahn, A. Tillack and M. Beller, Chem.
¨
¨
Commun., 2008, 3199; (c) D. Hollmann, S. Bahn, A. Tillack and
e
Dimeric alkynes were observed by GC after the reaction. 4% of
the corresponding alkylated pyrrolidine were also obtained. f 4% of the
corresponding alkynylated product were also obtained. g 11% of the
corresponding alkylated product were obtained.
M. Beller, Angew. Chem., 2007, 119, 8440 (Angew. Chem., Int. Ed.,
2007, 46, 8291); (d) see also: T. D. Nixon, M. K. Whittlesey and J.
M. J. Williams, Dalton Trans., 2009, 753.
10 (a) J. Ohshita, K. Furumori, A. Matsuguchi and M. Ishikawa,
J. Org. Chem., 1990, 55, 3277; (b) W. Baratta, W. A. Herrmann,
P. Rigo and J. Schwarz, J. Organomet. Chem., 2000, 593, 489;
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Notes and references
z General procedure for amine alkynylation: in an ACE-pressure tube
under an argon atmosphere the Shvo catalyst (0.01 mmol) and
silylacetylene (1 mmol) were dissolved in the corresponding amine
(1 mL). The tube was fitted with a Teflon cap and heated at 150 1C for
24 h. The reaction mixture was concentrated in vacuum, and the
products were isolated by column chromatography. The compounds
11 (a) A. Ell, J. S. Samec, C. Brasse and J.-E. Ba
Commun., 2002, 1144; (b) A. Ell, J. B. Johnson and
J.-E. Backvall, Chem. Commun., 2003, 1652; (c) J. B. Johnson
and J.-E. Backvall, J. Org. Chem., 2003, 68, 7681.
ckvall, Chem.
¨
¨
¨
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1958 | Chem. Commun., 2010, 46, 1956–1958