A general and selective copper-catalyzed reduction of secondary amides

Article abstract of DOI:10.1039/c2cc17209g

In situ-generated cationic copper/pybox catalyst systems allow for the selective reduction of secondary amides into the corresponding amines under mild conditions. This novel protocol has a wide substrate scope and shows good functional group tolerance. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17209g

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COMMUNICATION
A general and selective copper-catalyzed reduction of secondary amidesw
ˆ
Shoubhik Das, Benoıt Join, Kathrin Junge and Matthias Beller*
Received 19th November 2011, Accepted 19th January 2012
DOI: 10.1039/c2cc17209g
In situ-generated cationic copper/pybox catalyst systems allow
for the selective reduction of secondary amides into the corre-
sponding amines under mild conditions. This novel protocol has a
wide substrate scope and shows good functional group tolerance.
Reduction of amides constitutes an important synthetic
method for the preparation of functionalized amines both on
the laboratory as well as on the industrial scale. Until today,
often traditional boron and aluminium hydride-mediated
reductions prevail for such processes.1 Tedious product
Fig. 1 Selected examples of therapeutically important secondary amines.
purification and concomitant formation of salt by-products
are disadvantages of these stoichiometric procedures. In
contrast, catalytic methods offer more versatile strategies for
selective reductions and might allow for improved chemo- and
regioselectivities.2 Obviously, catalytic hydrogenation represents
the ideal method for the reduction of amides but unfortunately
a general methodology is still missing.3 Complementary to
hydrogenations, catalytic hydrosilylations are operationally
simple to perform and often allow for improved chemo-
selectivity and regioselectivity under mild conditions.4 Hence,
during the last decade metal-catalyzed hydrosilylations of
amides have received considerable interest. Until to date
various catalyst systems including Rh,5 Ru,6 Mo,7 In,8 Pt,9
Zn,10 and Fe11 have proven to be effective for this reduction.
Notably, the vast majority of these catalysts can be only
used for the reduction of tertiary amides. On the other hand
based on their diverse biological activities, secondary amines
in particular are important pharmacophores found in various
drugs (Fig. 1).12 Hence, the development of novel selective
catalysts for the hydrosilylation of secondary amides is still
desirable.13
parameters (Table 1). As expected no reaction occurred in
the absence of any catalyst (Table 1, entry 1). In contrast, in
the presence of 10 mol% of Cu(OTf)2 moderate activity was
observed at 65 1C (Table 1, entry 2). Next, several nitrogen
and phosphorus ligands (Fig. 2) were tested together with
Cu(OTf)2 as the catalyst precursor in the presence of TMDS.
Surprisingly, in the presence of phosphorus ligands no
appreciable activity is observed (Table 1, entries 10, 11, 17,
19–20). However, applying nitrogen ligands especially substi-
tuted pyridinebisoxazolines L5 and L8 gave excellent yields up
to 97% within 24 hours (Table 1, entries 14 and 3). While
lowering the amount of the metal precursor decreased the
product yield, astonishingly reduction of the ligand loading to
1.25 mol% is possible and increased even the yield of the
desired product (Table 1, entries 21–25).
Applying commercially available 1,1,3,3-tetramethyldisiloxane,
we investigated the effect of various metal triflates and copper
sources on the reduction of N-benzyl benzamide. Other metal
triflates such as scandium triflate, iron(II) triflate, iron(III)
triflate, ytterbium triflate, and zirconium triflate did not show
any activity even in the presence of 10 mol% ligand (Table 1,
entries 26–30). Among the different copper precursors tested,
poor catalytic performance was detected only for CuF2,
Cu(OAc)2ÁH2O and Cu(OAc)2 (Table 1, entries 4, 8, and 9).
In all of these cases we observed only the starting material
after the reaction. To exclude the influence of potential precious
metal contaminants on the catalyst precursor we also used
Cu(OTf)2 from different suppliers (ABCR, Sigma Aldrich,
Acros). In all cases similar yields of the product were obtained
in the model reaction.
The abundant availability and biomimetic nature of copper
makes it an attractive candidate for catalysis.14 Based on our
recent studies on biomimetic metal-catalyzed reductions of
secondary and tertiary amides,10,11a herein we report the first
general copper-catalyzed hydrosilylation of secondary amides
to generate the corresponding amines in high yields.
Initially, the reaction of N-benzylbenzamide 1a with 1,1,3,3-
tetramethyldisiloxane (TMDS) in toluene was investigated as
a model system to identify and optimize critical reaction
Leibniz-Institut fur Katalyse e. V., A.-Einstein-Str. 29a, Rostock,
18059, Germany. E-mail: Matthias.Beller@catalysis.de;
Fax: +49 (381)1281 51113; Tel: +49 (381)1281 113
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17209g
Next, we started to investigate the influence of different
silanes on the reaction. In addition to TMDS, several mono-
silanes such as PhSiH3, Ph2SiH2, PMHS, (EtO)2MeSiH,
and (EtO)3SiH were also run under the optimized reaction
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2683–2685 2683

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Table 1 Reduction of N-benzyl benzamide with TMDS in the
presence of various catalystsa
Table 2 Copper-catalyzed reduction of N-benzyl benzamide with
different silanes and in different solventsa
Yieldb [%]
Entry
Copper source/mol%
Ligand/mol%
Yieldb [%]
Entry
Hydrosilanes (equiv.)
Solvent
1
2
3
4
5
6
7
8
—
—
—
—
54
97
10
—
—
—
10
5
1
2
3
4
5
6
7
8
TMDS
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
99
—
10
20
—
5
Cu(OTf)2 (10)
Cu(OTf)2 (10)
CuF2 (10)
CuCl2 (10)
CuBr2 (10)
CuI (10)
PMHS (3)
PhSiH3 (3)
Ph2SiH2 (3)
Et3SiH (3)
(EtO)2MeSiH (3)
(EtO)3SiH
TMDS
L8 (10)
L8 (10)
L8 (10)
L8 (10)
L8 (10)
L8 (10)
L8 (10)
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L6 (10)
L7 (10)
L9 (10)
L10 (10)
L11 (10)
L12 (10)
L8 (5)
L8 (2.5)
L8 (1.25)
L8 (5)
L8 (2.5)
L8 (10)
L8 (10)
L8 (10)
L8 (10)
L8 (10)
10
5
Cu(OAc)2ÁH2O (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Fe(OTf)2 (10)
Fe(OTf)3 (10)
Sc(OTf)2 (10)
Yb(OTf)2 (10)
Zr(OTf)4 (10)
9
a
Reaction condtions: 1a (1.0 mmol), catalyst, ligand, solvent (3 mL),
b
silane (3 equiv.), argon atmosphere. Determined by GC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2
4
5
60
95
6
70
5
58
5
4
98
99
99
75
78
—
—
—
—
—
and produced 90% of dibenzylamine (1b) after concomitant
hydrolysis of the resulting silylether.
Once optimized reaction conditions were identified, the
scope and limitations of the copper-catalyzed reduction of
amides using TMDS were explored. Different secondary
amides, including aromatic, aliphatic, and heterocyclic amides,
were reduced smoothly to the corresponding amines (Table 3).
Noteworthily, N-methylbenzamide was completely unreactive
at 65 1C, but increasing the reaction temperature to 100 1C
produced the corresponding amines in excellent yields
(Table 3, entry 3). Substitution with more bulky groups on
both the aromatic and the amine sides of the amide did not
Table 3 Copper-catalyzed reduction of secondary amides to aminesa
a
Reaction conditions: 1a (1.0 mmol), catalyst, ligand, TMDS (3.0 equiv),
b
toluene (3 mL), argon atmosphere. Determined by GC using hexa-
c
decane as a standard. TMDS = 1,1,3,3-tetramethyldisiloxane.
Entry Amides
Ligand/mol% Temp./1C Yieldb [%]
1
1.25
1.25
3
65
65
90
85
90
2
3
100
4
5
6
3
3
3
65
65
65
83
81
82
Fig. 2 Structures of different ligands for hydrosilylation of secondary
amides.
conditions (Table 2, entries 1–7). However, TMDS (1,1,3,3-
tetramethyldisiloxane) showed best activity while monosilanes
were only slightly active. It should be noted that the scale up of
the model reaction to 10 mmol-scale resulted in no problem
c
This journal is The Royal Society of Chemistry 2012
2684 Chem. Commun., 2012, 48, 2683–2685

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Table 3 (continued )
been developed. The general applicability of the methodology
and functional group tolerance of the presented catalyst
system are shown by reduction of 16 different aromatic,
heteroaromatic and aliphatic amides.
Entry Amides
Ligand/mol% Temp./1C Yieldb [%]
In general, the presented transformation can be viewed as
an alternative for more classical reductive aminations. The
safe and simple operational procedures, the mild conditions
and easy purification make this new protocol attractive for
organic synthesis.
7
8
9
3
3
3
65
65
65
75
80
85
The authors thank Dr W. Baumann, Dr C. Fischer,
S. Buchholz, S. Schareina, A. Koch, and S. Rossmeisl (all at
the Leibniz-Institut fur Katalyse e.V.) for excellent analytical
¨
and technical support.
Notes and references
10
11
3
3
65
65
72
73
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Organic Synthesis, 2nd edn, Wiley, New York, 1997.
2 G. Rothenberg, Catalysis: Concepts and Green Applications, Wiley,
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3 (a) J. G. de Vries and C. J. Elsevier, Handbook of Homogeneous
Hydrogenation, Wiley-VCH, Weinheim, 2007; (b) A. A. Nu´ nez
Magro, G. R. Eastham and D. J. Cole-Hamilton, Chem. Commun.,
2007, 3154.
12
13
14
3
3
3
65
65
65
70
80
75
4 (a) B. Marciniec, Coord. Chem. Rev., 2005, 249, 2374;
(b) M. A. Brook, Silicon in Organic, Organometallic and Polymer
Chemistry, Wiley, New York, 2000; (c) B. Marciniec, J. Gulinsky,
W. Urbaniak and Z. W. Kornetka, Comprehensive Handbook on
Hydrosilylation, ed. B. Marciniec, Pergamon Press, Oxford, 1992;
(d) V. B. Pukhnarevich, E. Lukevics, L. T. Kopylova and M. G.
Voronkov, Perspectives of Hydrosilylation, ed. E. Lukevics, Riga,
Latvia, 1992; (e) I. Ojima, The Chemistry of Organic Silicon
Compounds, ed. S. Patai and Z. Rapport, Wiley, Chichester,
1989, vol. 1.
5 (a) T. Ohta, M. Kamiya, M. Nobumoto, K. Kusui and I. Furukawa,
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H. Nagashima, J. Am. Chem. Soc., 2005, 127, 13150; (c) M. Igarashi
and T. Fuchikami, Tetrahedron Lett., 2001, 42, 1945.
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272, 60.
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49, 6873.
9 S. Hanada, E. Tsutsumi, Y. Motoyama and H. Nagashima, J. Am.
Chem. Soc., 2009, 131, 15032.
15
3
3
100
100
78
76
16
a
Reaction conditions: amides (1.0 mmol), Cu(OTf)2 (10 mol%),
ligand L8 (1.25–3 mol%), TMDS (3.0 mmol), toluene (3 mL), argon
b
atmosphere. Isolated yield except entries 3, 10 and 11.
10 (a) S. Das, D. Addis, K. Junge and M. Beller, Chem.–Eur. J., 2011,
17, 12186; (b) S. Das, D. Addis, S. Zhou, K. Junge and M. Beller,
J. Am. Chem. Soc., 2010, 132, 1770.
11 (a) S. Zhou, K. Junge, D. Addis, S. Das and M. Beller, Angew.
Chem., Int. Ed., 2009, 48, 9507; (b) Y. Sunada, H. Kawakami,
T. Imaoka, Y. Motoyama and H. Nagashima, Angew. Chem., Int.
Ed., 2009, 48, 9511.
12 (a) B. R. Brown, The organic chemistry of aliphatic nitrogen com-
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Pergamon, Oxford, 1991, vol. 6; (c) R. C. Larock, Comprehensive
Organic Transformations, VCH, New York, 1989, p. 819.
13 For catalytic hydrosilylations of secondary amides see: (a) ref. 6a
for the Ru catalyst; (b) ref. 10a for the Zn catalyst; (c) S. Hanada,
E. Tsutsumi, Y. Motoyama and H. Nagashima, J. Am. Chem. Soc.,
2009, 131, 15032; (d) M. Igarashi and T. Fuchikami, Tetrahedron
Lett., 2001, 42, 1945.
14 For recent reviews using copper in catalysis see: (a) S. Cacchi,
G. Fabrizi and A. Goggiamani, Org. Biomol. Chem., 2011, 9, 641;
(b) G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008,
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decrease the product yield. In addition, electron-withdrawing
and electron-donating substituents on the aryl part behaved
similarly (Table 3, entries 6–8). Notably, aliphatic and hetero-
cyclic compounds did not interfere with the amide reduction,
giving the corresponding amines in good to very good yields
(Table 3, entries 9–12). Also to our delight different aliphatic
and alicyclic moieties in the amine part render a good yield of
the corresponding amines (Table 3, entries 13–16). Under
optimized reaction conditions functional groups such as ester,
halides, and ether were tolerated and provided smoothly the
corresponding amines in good to excellent yield (Table 3, entries
4–7, 9). It should be noted that in no case additional reduction
of the functional group was observed. However, in the case of
aldehyde- and acetyl-substituted benzamides reduction of the
aldehyde or keto group took place preferentially.
In summary, the first copper-catalyzed reduction of secondary
amides to give amines with commercially available TMDS has
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2683–2685 2685