Development of new hydrogenations of imines and benign reductive hydroaminations: Zinc triflate as a catalyst

Article abstract of DOI:10.1002/cssc.201100633

The hydrogenation of imines to amines in the presence of catalytic amounts of zinc triflate has been demonstrated for the first time. In addition, an efficient procedure for the reductive hydroamination of alkynes to amines is presented using zinc triflat

Full text of DOI:10.1002/cssc.201100633

DOI: 10.1002/cssc.201100633
Development of New Hydrogenations of Imines and
Benign Reductive Hydroaminations: Zinc Triflate as a
Catalyst
Svenja Werkmeister, Steffen Fleischer, Shaolin Zhou, Kathrin Junge, and Matthias Beller*[a]
The hydrogenation of imines to amines in the presence of cat-
alytic amounts of zinc triflate has been demonstrated for the
first time. In addition, an efficient procedure for the reductive
hydroamination of alkynes to amines is presented using zinc
triflate as a catalyst precursor. In both protocols a variety of dif-
ferent functional groups are tolerated, and the reactions pro-
ceed smoothly in high yields.
Introduction
The development of new and improved methods for the syn-
thesis of nitrogen-containing compounds such as imines, en-
amines, and amines continues to be of significant interest for
catalysis research and the chemical industry.[1,2] Amines and
their derivatives find wide applications as building blocks in or-
ganic synthesis, in biological systems, as ligands for catalysis,
and in materials science.[3] As an example of their importance,
selected compounds that were among the top 200 pharma-
ceutical products by worldwide sales in 2009 are shown in
Figure 1.[4]
less developed.[13] In this respect, our group recently published
enantioselective imine hydrogenations using Knçlker’s iron
complex.[14] During these studies, we discovered serendipitous-
ly that the hydrogenation of N-arylimines to amines also pro-
ceeds in the presence of catalytic amounts of zinc(II) triflate
(Zn(OTf)2), which we report here for the first time. To expand
this reaction, we also investigated the reductive hydroamina-
tion reaction of alkynes with amines and hydrogen (Scheme 1).
Catalytic hydroaminations constitute one of the most basic
and atom-efficient CÀN bond forming processes by the addi-
tion of an amine to an unsaturated CÀC bond.[15]
Starting from commercially available alkynes, in prin-
ciple the reaction affords the desired amines without
any formation of side products. Compared to olefins,
alkynes can undergo the reaction more easily be-
cause of steric reasons and their weaker p-bonds
(70 kJmolÀ1).[3d] Although two regioisomers, the Mar-
kovnikov and anti-Markovnivkov product, might be
formed, in general the Markovnikov product is ther-
modynamically favored in these reactions.[16]
In the past few decades, different catalysts for
inter- and intramolecular alkyne hydroaminations
Figure 1. Selection of amines that are among the top 200 pharmaceutical products by
worldwide sales in 2009.
have been developed. After the pioneering work of
Barluenga et al.[17] using Hg and Tl catalysts, the hy-
droamination of alkynes is nowadays known to be
catalyzed by a variety of early (Ti, Zr, V, Ta)[18] and late
Among the various catalytic methods available for the syn-
thesis of amines, catalytic hydrogenation of imines/enamines
and the corresponding reductive aminations of carbonyl com-
pounds represent clean and environmentally benign method-
ologies that are applied in industry for the production of chiral
and nonchiral amines.[5,6] As a reducing agent, the use of mo-
lecular hydrogen is preferred because of its price and environ-
mental friendliness.[7] To date, hydrogenations have been
mainly performed by using expensive precious metal-based
catalysts, for example, Ir, Ru, Rh, and Pd complexes.[6d,8–12] Al-
though the advantages are obvious, the reduction of imines
with H2 using nonprecious metal-complexes is considerably
transition metal (Ru, Rh, Pd, Pt, Au, Ag),[19] lanthanide (Sm, Lu,
Nd),[20] and actinide (U, Th) catalysts.[21] Furthermore, heteroge-
neous catalysts have been explored, for example, zeolites, ion-
exchanged zeolites, and transition metal-exchanged montmo-
rillonites.[22]
[a] S. Werkmeister, S. Fleischer, Dr. S. Zhou, Dr. K. Junge, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18055 Rostock (Germany)
Fax: (+49)(381)1281-51113
E-mail: matthias.beller@catalysis.de
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100633.
ChemSusChem 2012, 5, 777 – 782
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
777

M. Beller et al.
Table 1. Variation of Lewis acids and conditions for imine hydrogenation:
benchmark reaction.[a]
Entry
Lewis acid
Amount
[mol%]
T
[8C]
Conv.
[%][b]
Yield
[%][b]
1
2
3
4
5
6
7
8
9[c]
10[c]
11
12
13
14
—
–
100
0.01
5
5
5
5
5
5
5
100
25
9
41
–
87
83
13
19
20
30
57
–
–
–
<1
72
–
BF3(C2H5)2O
Fe(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OAc)2
ZnBr2
100
100
100
100
100
100
65
100
100
120
120
120
Scheme 1. Hydroamination of alkynes and reductive hydroamination of al-
kynes.
4
4
ZnCl2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
11
42
95
92
47
4
With respect to this work, the use of Zn catalysts by Mꢁller
and Blechert[23] as well as by us[15b] for alkyne hydroaminations
is of special importance.
10
5
2
95
>99
74
Finally, it should be mentioned that Che[24] and Gong[25] have
recently independently described the first examples of inter-
and intramolecular hydroamination reactions of alkynes using
a AuI catalyst and a Hanztsch ester as the reducing agent. Un-
fortunately, on applying their protocols, stoichiometric
amounts of pyridine are produced as a coproduct, and expen-
sive noble metals in combination with phosphine ligands have
to be used.
1
38
[a] Reaction conditions: 1a (0.5 mmol), Lewis acid, toluene (0.5 mL),
80 bar H2, at 1008C for 24 h. [b] Determined by performing GC analysis
using hexadecane as an internal standard. [c] 50 bar H2.
80 bar H2 in the presence of 5 mol% Zn(OTf)2 (Table 1,
entry 12).
Clearly, Zn(OTf)2 is a very unusual catalyst for the activation
of H2. Thus, we initially thought that impurities of precious
metals might be responsible for the observed activity. Howev-
er, elemental analysis and inductively coupled plasma spec-
trometry revealed no detectable amounts of Ru, Rh, Ir, and Pd.
Furthermore, various samples of Zn(OTf)2 from different suppli-
ers behave similarly. Finally, Zn(OTf)2 proved to be inactive
under the optimized conditions for the hydrogenation of ke-
tones, nitro groups, olefins, and alkynes, which proceeded in
the presence of precious metal-based catalysts. To prove the
necessity of H2, we performed one experiment without hydro-
gen gas. As expected, no amine was obtained. Furthermore,
imine 1a was reacted with D2 (Scheme 3). Here, NMR spectros-
copy clearly showed the formation of 5. Deuteration was con-
firmed by using ESI-TOF MS. D/H-exchange at the DÀN posi-
tion was observed, most likely because of the presence of
water in the reaction mixture. As expected, both experiments
showed that hydrogenation clearly originated from H2.[26]
As a preliminary mechanistic proposal, we assume the for-
mation of a Zn-coordinated iminium ion. It is likely that dimeric
or higher oligomeric Zn species are formed on which hetero-
lytic hydrogen cleavage could take place.
Results and Discussion
Based on our work with iron catalysts[14] and because of the in-
dustrial importance of 1-arylethylamines, we used 4-methoxy-
N-(1-phenylethylidene)aniline (1a) as the starting material in
our benchmark reaction (Scheme 2 and Table 1).
Firstly, we investigated the influence of different Lewis acids
as catalysts for the hydrogenation of 1a. As expected, in the
absence of a catalyst, no reduction of the imine took place
(Table 1, entry 1). The strong Lewis acid BF3·(C2H5)2O activated
the imine, but gave no hydrogenation product (Table 1,
entry 2). Similarly, a number of Zn, Cu, and Fe salts showed no
hydrogenation reactivity (Table 1, entries 3, 4, 6–8). However,
to our surprise, the desired amine was formed in 72% yield in
the presence of Zn(OTf)2 (Table 1, entry 5). The differences be-
tween conversion and product yield resulted from aldol con-
densation and decomposition of the imine. Entries 9–14 in
Table 1 represent the optimization of the Zn(OTf)2-catalyzed
hydrogenation. Reducing the H2 pressure from 80 to 50 bar
(1 bar=105 Pa) led to a decreased yield of 42% (Table 1,
entry 10). Decreasing the temperature to 658C resulted in sig-
nificantly lower conversion and produced 2a in only 11% yield
(Table 1, entry 9). Conversely, increasing the catalyst loading to
10 mol% (Table 1, entry 11) at 1008C and 80 bar H2 gave 95%
yield. A similar product yield was obtained at 1208C and
Next, we studied the scope and limitations of this remark-
able catalyst in the hydrogenation of different imines.
As shown in Scheme 4, different ortho-, meta-, and para-sub-
stituted electron-withdrawing as well as electron-donating N-
aromatic imines were hydrogenated to give the corresponding
amines in good isolated yields of 58–91%. In addition, mono-
and disubstituted N-4-methoxyphenylimines with electron-do-
nating and electron-withdrawing groups in meta- and para-po-
sitions were smoothly hydrogenated with isolated yields of
56–81% (Scheme 4, 2 f–j). To our delight, heteroaromatic and
aliphatic imines also furnished the desired products 2k and 2l
Scheme 2. Hydrogenation of 1a.
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New Hydrogenations of Imines and Benign Reductive Hydroaminations
system, the reaction of phenylacetylene with 4-me-
thoxyaniline was performed in the presence of differ-
ent Lewis acids (Scheme 5 and Table 2).
Again, Zn(OTf)2 was the only active catalyst and
gave a yield of 43% of the desired amine (Table 2,
entry 5). The other Lewis acids tested showed low
conversions (Table 2, entries 2–3, 6–10), except for
Cu(OTf)2 (Table 2, entry 4), which led mainly to aldol
condensations.
Then, we focused on the optimization of the reac-
tion conditions. By increasing the catalyst loading to
10 mol%, the yield was raised to 71% (Table 2,
entry 11). Applying the alkyne in excess gave the
amine in a high yield of 77% in one step (Table 2,
entry 12), whereas decreasing the temperature from
120 to 1008C led to a decreased yield of 42%
(Table 2, entry 13).
Finally, we used the optimized reaction parameters
for other substrates (Scheme 6). As shown in Table 3,
the reaction of seven different alkynes and six ani-
lines gave the corresponding amines in moderate to
high yields. Alkyl- and alkoxy-substituted as well as
halogenated anilines gave the secondary amines in
good yields of 79–82% (Table 3, entries 1–4).
Scheme 3. Mechanistic experiments for the reaction a) without H2 and b) with D2. c) Pro-
posed mechanism.
Scheme 5. Reductive hydroamination of phenylacetylene with p-methoxya-
niline.
Table 2. Variation of catalysts and conditions for the reductive hydroami-
nation.[a]
Entry
Lewis acid
Amount
[mol%]
T
[8C]
Conv.
[%][b]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12[c]
13[c]
–
120
25
11
18
15
57
>99
18
23
26
16
32
–
–
–
–
43
–
–
–
-
-
BF3(C2H5)2O
Fe(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OAc)2
ZnBr2
ZnCl2
ZnF2
Zn3(PO4)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
100
0.01
5
5
5
5
5
5
5
120
120
120
120
120
120
120
120
120
120
100
Scheme 4. Zn-catalyzed hydrogenation of imines: substrate scope.
10
10
10
>99
>99
>99
71
77
42
in 34 and 72% yield, respectively (Scheme 4). Unfortunately, N-
benzylic and N-aliphatic imines did not react under these con-
ditions.
[a] Reaction conditions: 3a (0.65 mmol), 4a (0.5 mmol), Lewis acid, tolu-
ene (0.5 mL), 80 bar H2, at 1208C for 24 h. [b] Determined by performing
GC analysis using hexadecane as an internal standard. [c] 3a (0.65 mmol).
After establishing a general procedure for the catalytic hy-
drogenation of imines, we attempted to use Zn(OTf)2 as a
single catalyst for the direct reductive hydroamination of al-
kynes with primary amines. Advantageously, the isolation of
sensitive imines would be avoided here. As a benchmark
Additionally, the heteroaromatic amine 1-benzothiophen-5-
amine (2o) reacted smoothly with phenylacetylene in 72%
ChemSusChem 2012, 5, 777 – 782
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779

M. Beller et al.
metals are required in this transformation. Furthermore, we
have developed an atom-efficient reductive hydroamination of
terminal alkynes with H2 also using Zn(OTf)2 as a catalyst pre-
cursor. Our environmentally friendly, inexpensive, and easy to
perform protocols represent an alternative to the more
common precious metal-based catalytic hydrogenation of
imines.
Scheme 6. Zn(OTf)2-catalyzed reductive hydroamination of arylalkynes: varia-
tion of alkynes and anilines.
Experimental Section
Table 3. Substrate scope for the zinc-catalyzed reductive hydroaminatio-
n.[a]
Unless otherwise stated, all reactions were performed under an Ar
atmosphere with exclusion of moisture from reagents and glass-
ware by using standard techniques for manipulating air-sensitive
compounds. All compounds were characterized by using 1H NMR
and 13C NMR spectroscopy, high resolution MS, and FTIR spectros-
copy. NMR spectra were recorded by using a Bruker AV 300 or AV
400 spectrometer. All chemical shifts (d) are reported in ppm and
coupling constants (J) in Hz. All chemical shifts are related to sol-
vent peaks [chloroform: d=7.26 (1H) and 77.00 ppm (13C)]. All
measurements were performed at room temperature unless other-
wise stated. MS were recorded by using a Finnigan MAT 95-XP
(Thermo Electron) or a 6210 time-of-flight LC/MS (Agilent) instru-
ment. GC was performed by using a HP 6890 chromatograph with
an HP5 column. IR spectra were recorded by using an FTIR Nicolet
6700 (Thermo Electron) instrument.
Entry
Alkyne
Amine
Yield [%][b]
1
2
3
3a
3a
3a
2a: 80
2b: 82
2d: 79
4
5
3a
2m: 80
2o: 72
3a
3a
6
7
8
9
2p: 69
2 f: 66
2g: 74
2h: 55
4a
4a
4a
Unless otherwise stated, commercial reagents were used without
purification.
General information
10
11
4a
4a
2j: 85
All catalytic hydrogenation experiments were performed by using
a Parr Instruments 4560 series autoclave (300 mL) containing an
alloy plate with wells for seven 4 mL glass vials.
2q: 69
12
13
4a
4a
2r: 60
2s: 88
Hydrogenation of imines
Under an Ar atmosphere, a glass vial was charged with Zn(OTf)2
(9.1 mg, 0.025 mmol) and 1a (112.7 mg, 0.5 mmol). Toluene
(0.5 mL) and a magnetic stirring bar were added. Afterwards, the
vial was capped with a septum equipped with a syringe and set in
the alloy plate, which was then placed into the autoclave. Once
sealed, the autoclave was purged three times with H2, then pres-
surized to 80 bar (1 bar=105 Pa) and heated to 1208C for 24 h.
The autoclave was then cooled to 258C, depressurized, and the re-
action mixture was purified by performing column chromatogra-
phy on silica gel (eluent: heptane/ethyl acetate=9:1) to give 2a
(103.4 mg, 0.46 mmol, 91% isolated yield), which was then ana-
lyzed by using NMR, FTIR, and HRMS.
[a] Reaction conditions:
(0.05 mmol), toluene (0.5 mL), H2 (80 bar), at 1208C for 24 h. [b] Isolated
yield.
3
(0.65 mmol),
4
(0.5 mmol), Lewis acid
yield. To our surprise, the secondary amine N-methylaniline
could be applied in the reductive hydroamination reaction
with a good yield of 69%, which gave access to the tertiary
amine 2p. Furthermore, mono- and disubstituted terminal aryl-
alkynes bearing electron-withdrawing and electron-donating
groups were transformed to the corresponding amines in
moderate to good yields of 55–88% (Table 3, entries 7–13).
Benzylic and aliphatic primary amines could not be converted
with phenylacetylene to the desired amines.
Reductive hydroamination
Under an Ar atmosphere, a glass vial was charged with Zn(OTf)2
(18.2 mg, 0.05 mmol), 3a (66.4 mg, 0.65 mmol), and 4a (61.6 mg,
0.5 mmol). Toluene (0.5 mL) and a magnetic stirring bar were
added. Afterwards, the vial was capped with a septum equipped
with a syringe and was set in the alloy plate, which was then
placed into the autoclave. Once sealed, the autoclave was purged
three times with H2, then pressurized to 80 bar and heated to
1208C for 24 h. The autoclave was then cooled to 258C, depressur-
ized, and the reaction mixture was purified by performing column
chromatography on silica gel (eluent: heptane/ethyl acetate=9:1)
Conclusions
We have developed the first catalytic hydrogenations using
Zn(OTf)2 as a catalyst. This rather unusual hydrogenation cata-
lyst enables the specific reduction of N-aryl imines with molec-
ular hydrogen to give the desired amines in good yields. Ad-
vantageously, no expensive phosphine ligands or precious
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New Hydrogenations of Imines and Benign Reductive Hydroaminations
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Acknowledgements
This research has been funded by the State of Mecklenburg-West-
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Dr. W. Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, A.
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Keywords: amines
hydrogenation · zinc
·
catalysis
·
hydroamination
·
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[26] We thank one of the referees for his experimental proposals.
Received: October 11, 2011
Revised: November 14, 2011
Published online on February 9, 2012
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