Consecutive intermolecular reductive hydroamination: Cooperative transition-metal and chiral Br?nsted acid catalysis

Article abstract of DOI:10.1002/chem.201200109

Enantiomerically pure chiral amines are of increasing importance and commercial value in the fine chemical, pharmaceutical, and agrochemical industries. Here, we describe the straightforward synthesis of chiral amines by combining the atom-economic and environmentally friendly hydroamination of alkynes with an enantioselective hydrogenation of in situ generated imines by using inexpensive hydrogen. By following this novel approach, a wide range of terminal alkynes can be reductively hydroaminated with primary amines including alkyl-, and arylalkynes as well as aryl and heteroaryl amines. Excellent yields and selectivities up to 94 % ee and 96 % isolated yield were obtained.

Full text of DOI:10.1002/chem.201200109

FULL PAPER
DOI: 10.1002/chem.201200109
Consecutive Intermolecular Reductive Hydroamination: Cooperative
Transition-Metal and Chiral Brønsted Acid Catalysis
Steffen Fleischer, Svenja Werkmeister, Shaolin Zhou, Kathrin Junge, and
Matthias Beller*[a]
Abstract: Enantiomerically pure chiral
amines are of increasing importance
and commercial value in the fine chem-
ical, pharmaceutical, and agrochemical
industries. Here, we describe the
straightforward synthesis of chiral
amines by combining the atom-eco-
nomic and environmentally friendly hy-
droamination of alkynes with an enan-
tioselective hydrogenation of in situ
generated imines by using inexpensive
hydrogen. By following this novel ap-
proach, a wide range of terminal al-
kynes can be reductively hydroaminat-
ed with primary amines including
alkyl-, and arylalkynes as well as aryl
and heteroaryl amines. Excellent yields
and selectivities up to 94% ee and
96% isolated yield were obtained.
Keywords: amines
· enantioselec-
tivity · hydroamination · hydrogena-
tion · iron
Introduction
developed.[2] Unfortunately, in these procedures the corre-
sponding imine has to be synthesized and isolated in an ad-
ditional reaction step. A more efficient and direct synthesis
constitutes the enantioselective reductive amination of ke-
tones (Scheme 1). Although various methods have been de-
veloped[3] since the first report by Blaser et al. in 1999,[4]
a highly selective and general method is still lacking.
The enantioselective synthesis of chiral amines continues to
attract considerable academic and industrial interest due to
the importance of the resulting enantiomers as resolving
agents, chiral auxiliaries, agrochemicals, and pharmaceuti-
cals. To illustrate their significance in chiral drugs, a selection
of top 100 brand-name drugs with chiral amine building
blocks is shown below. In addition, the herbicide S-Metola-
chlor[1] is produced on a multi-thousand ton-scale per year.
In the last two decades highly selective catalytic reduc-
tions of prochiral ketimines to a-chiral amines have been
Recently, significant progress has been achieved in the hy-
droamination of alkynes as this method constitutes an at-
tractive alternative for the synthesis of imines.[5] A variety of
catalysts based on early transition metals,[6] lanthanides,[7] ac-
tinides,[8] late transition metals,[9] strong bases,[10] even
heteroACHTUNGTRNEUNG
geneous systems[11] have
been developed for the hydro-
À
G
bonds with primary amines.
Notably in 2009, Che[12] and
Gong[13] developed indepen-
AHCTUNGTERGdNNUN ently from each other inter-
and intramolecular reductive
hydroaminations of alkynes.
The enantioselective reduction
was achieved by using stoichio-
metric amounts of a Hanztsch
ester in the presence of a chiral
organocatalyst, whereas stoi-
chiometric amounts of pyridine
were produced as co-products.
[a] S. Fleischer,+ S. Werkmeister,+ Dr. S. Zhou, Dr. K. Junge,
Prof. Dr. M. Beller
Obviously, more convenient reducing agents would repre-
sent an important advancement in this methodology. How-
ever, to the best of our knowledge no catalytic reactions
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
À
combining the atom economic hydroamination of C C
triple bonds with an enantioselective reduction using envi-
ronmental friendly, inexpensive, and readily available hydro-
gen has been reported so far.
E-mail: matthias.beller@catalysis.de
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200109.
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AHCTUNGRTEGNUN(N OTf)2 or AuCl yielded the amine 6a with moderate enan-
tioselectivities of 67 and 65% ee, respectively (Table 1, en-
tries 3 and 4). Different PtII and PtIV salts showed only mod-
erate activity giving 6a in yields between 24–28% with 20–
40% ee (Table 1, entries 9–11). It should be noted that the
differences between conversion and product yield resulted
from hydrolysis of the imine and from aldol condensation
reactions, which are observed as side reactions.
As AuI precursors proved to be both active and selective
in hydroamination reactions different AuI complexes were
applied to our reaction. Complex 1a did not show any activ-
ity in the reductive hydroamination of 4a with p-anisidine
5a. Next, we exchanged the counteranion of 1a to the less
coordinating tetrafluoroborate anion to access complex 1b.
To our delight, 1 mol% of 1b in combination with 2 mol%
(R)-TRIP 3e and 5 mol% iron complex 2 yielded 6a in
80% yield and with an excellent enantiomeric excess of
94% ee (Table 1, entry 7). This phenomenon can be referred
to the fact that the presence of a weakly coordinated anion
Scheme 1. Reductive hydroamination as alternative approach for the syn-
thesis of amines compared to classical reductive amination.
À
Results and Discussion
like BF4 supports the formation of a cationic species.
For comparison we hydrogenated the isolated correspond-
ing imine applying the same hydrogenation conditions by
using 2 mol% (R)-TRIP and 5 mol% iron complex 2 and
yielded 6a in 90% yield and with 92% ee.[15b] These results
clearly indicate that 1b has no significant influence on the
yield and enantioselectivity of this transformation.
Based on our experience in both the catalytic hydroamina-
tion of alkynes[14] and the iron-catalyzed enantioselective re-
duction of imines,[15] we set up a project to combine these
two methodologies for a more efficient synthesis of chiral
amines.
Herein, we present for the first time a suitable catalyst
system consisting of an active gold(I) complex 1,
Knçlkerꢃs[16] iron complex 2, and a chiral Brønsted acid 3 to
yield chiral amines directly from alkynes.
Next, well-known homogeneous hydrogenation catalysts
(7–11) were tested instead of the iron complex 2 to promote
the desired catalytic hydrogenation of the in situ formed
imine. First experiments revealed that the desired N-(1-phe-
nylethyl)aniline 6a was formed in the presence of various
Ru, Rh, and Ir catalysts. However, none of these established
precious-metal hydrogenation catalysts in combination with
chiral Brønsted acids, for example (R)-TRIP 3e, induced
any significant enantioselectivity.
Owing to the industrial importance of 1-arylethyl amines,
our initial catalytic investigations were carried out on the re-
action of phenylacetylene 4a with p-anisidine 5a as the
benchmark reaction (Table 1). According to our concept, we
used well-known commercially available hydroamination
catalysts in the presence of molecular hydrogen. The consec-
utive catalytic hydrogenation was catalyzed by a combination
of (R)-TRIP 3e (3,3’-bis(2,4,6-triisopropyl-phenyl)-1,1’-bi-
naphthyl-2,2’-diyl hydrogen phosphate) with the iron com-
plex 2. Surprisingly, the hydroamination catalyst has a signifi-
cant influence on both the yield and the enantiomeric excess
(ee) of amine 6a. First experiments revealed that the desired
chiral amine 6a was formed in the presence of various com-
mercially available ZnII, CuII, AuI, Ru0, PtII, and PtIV com-
As chiral 1,1’-binaphthalene-2,2’-diol (binol) phosphoric
acids showed high selectivity in the enantioselective reduc-
tion of C=X bonds when using Hanztsch Ester as the reduc-
ing agent[17] we draw our attention towards the combination
of 2 with different chiral phosphoric acids 3. As expected,
1,1’-binaphthyl-2,2’-diyl hydrogen phosphate 3a showed only
plexes (Table 1, entries 1–11). However, with Zn
ACHTUNGRTENN(UNG OTf)2 only
the racemic amine was produced, whereas the use of Cu-
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Consecutive Intermolecular Reductive Hydroamination
FULL PAPER
Table 1. Consecutive reductive hydroamination of phenylacetylene with p-anisidine: Variation of the hydro-
The H8-1,1’-binaphthyl-2,2’-
diyl hydrogen phosphates 3 f
and 3g yielded 6a in moderate
yield and enantioselectivity
whereas VAPOL 3h showed
only a low enantioselectivity of
21% ee in the enantioselective
reductive hydroamination reac-
tion.
Encouraged by these results,
we wanted to expand the reac-
tion protocol towards a direct
enantioselective reductive hy-
ACHTUNGTRENNUNG
amination catalyst.[a]
Entry
Metal catalyst [mol%]
Zn(OTf)2 [5]
Zn(OTf)2 [5] in situ
Cu(OTf)2 [4]
AuCl [4]
1a [2]
T [8C]
Conv. [%][d]
Yield [%][d]
ee [%][e]
1
2
3
4
G
120
100
100
100
RT
65
74
87
80
17
20
42
33
<1
78
80
40
4
rac
67
65
–
92
94
58
ACHTUNGTRENNUNG
E
91
5
<1
>99
>99
77
6[b]
7[c]
8
1b [1]
1b [1]
droamination.
Hence,
we
RT
100
stirred 4a and 5a for 16 h at
room temperature with the hy-
droamination catalyst 1b and
(R)-TRIP 3e and added consec-
utively the hydrogenation cata-
lyst 2. Under these conditions,
6a was obtained in good yield
and with a high enantioselectiv-
ity of 87% ee. (Scheme 2; con-
ditions A). A comparable yield
Ru3(CO)12 [1]
NH4PF6 [3]
PtCl2 [4]
PtCl4 [4]
PtBr2 [4]
9
10
11
100
100
100
76
63
70
29
24
28
40
32
20
[a] Unless otherwise noted, the reaction was carried out with phenylacetylene 4a (0.5 mmol), p-anisidine 5a
(0.5 mmol), hydroamination catalyst, toluene (0.5 mL) at various temperatures for 24 h, then (R)-TRIP 3e
(2 mol%), 2 (5 mol%), H2 (50 bar) at 658C for 24 h. [b] t=5 h. [c] t=16 h. [d] Determined by GC analysis
using hexadecane as an internal standard. [e] Determined by chiral HPLC analysis.
a low enantioselectivity of 23% ee in the reductive hydro-
amination reaction (Table 2, entry 1). The selectivity was im-
proved when sterically demanding 1,1’-binaphthyl-2,2’-diyl
hydrogen phosphates were used (Table 2, entries 2 and 5),
whereby 3e achieved a high yield of 80% and excellent
enantioselectivity of 94% ee (Table 2, entry 5).
and a lower ee of 66% are observed when (R)-TRIP 3e was
added consecutively after the hydroamination reaction by
using the Knçlker complex 2 in cooperation with the AuI
complex 1 (Scheme 2; conditions B). The direct reductive
hydroamination with 1b (1 mol%), 2 (5 mol%), and (R)-
TRIP 3e (2 mol%) gave 6a after 24 h at 50 bar H2 in a mod-
erate yield of 42% and 49% ee (Scheme 2; conditions C). It
is shown that the one step reaction is basically possi-
ble, whereas the two step one-pot synthesis is more re-
liable. Next, a series of control experiments were con-
ducted to gain insight into the mechanism of the reac-
tion sequence.
ACHTUNGTRENNUNG
Table 2. Influence of different Brønsted acids on the enantioselective re-
ductive hydroamination of phenylacetylene with p-anisidine.[a]
In the absence of iron complex 2, phenylacetylene
4a and p-anisidine 5a afforded ketimine 12a in 99%
yield with the gold catalyst 1b. However, by using
Knçlker complex 2 in the absence of 1b, no product
was obtained at all. Clearly, the AuI-catalyzed hydro-
AHCTUNGTRENNUNG
gave 6l in 90% yield and with 92% ee, whereas in the
absence of (R)-TRIP 3e only minor amounts of the
product were obtained.[15b] These results show that 2 in
cooperation with (R)-TRIP 3e is performing the enan-
tioselective hydrogenation as a second step of this re-
action (Scheme 3).
On the basis of these observations, a reaction mech-
anism for the formation of chiral amines from 4a with
5a in the presence of hydrogen gas is proposed in
Scheme 4. Initially, alkyne 4 and the cationic gold(I)
species 1b form a cationic AuI–alkyne complex. Next,
Entry
Brønsted acid [mol%]
Conv. [%][b]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a [5]
3b [5]
3c [5]
3d [5]
3e [5]
3 f [5]
3g [5]
3h [5]
99
99
98
97
>99
98
16
9
23
41
11
7
94
32
40
21
65
40
80
19
38
13
98
97
[a] Unless otherwise noted, the reaction was carried out with phenylace-
tylene 4a (0.5 mmol), p-anisidine 5a (0.5 mmol), 1b (1 mol%), toluene
(0.5 mL) at RT for 16 h, then 3 (2 mol%), 2 (5 mol%), H2 (50 bar) at
658C for 24 h. [b] Determined by GC analysis using hexadecane as an in-
ternal standard. [c] Determined by chiral HPLC analysis.
p-anisidine is coordinated to the Au center prior to the
[12,18]
À
C N bond formation.
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M. Beller et al.
and para-substituted 2-aryl alkynes with p-anisidine (91–
94% ee; Table 3, entries 1, 2, 4, and 5).
Gratifyingly, disubstituted alkynes and 4-ethynalbiphenyl
were also transformed with high yield and enantioselectivity
(81–93% ee; Table 3, entries 6 and 7). While acetophenone-
AHCTUNGTREGiNNUN mines are typical substrates for asymmetric hydrogenation
reactions, we were also interested in using more challenging
chiral dialkyl amines. Indeed, the reductive hydroamination
of aliphatic alkynes occurred with high yields and good
enantioselectivities (75–86% yield; 67–70% ee, Table 3, en-
tries 9 and 10).
Finally, the reductive hydroamination of phenylacetylene
4a with different anilines was investigated. Meta- and para-
substituted anilines with both electron-donating and -with-
drawing groups reacted with phenylacetylene 4a smoothly
with excellent yields up to 96% and enantioselectivities up
to 93% to the corresponding amines (Table 3, entries 11, 12,
and 14–16). Also heterocyclic primary amines like benzo-
thiophene-6-amine can be used in the reported reductive hy-
droamination procedure to give 94% ee (Table 3, entry 17).
Unfortunately, aliphatic amines and anilines with elec-
tron-withdrawing groups in the ortho-position did not react
under the optimized conditions. The secondary amine N-
methylaniline gave a lower yield of 25% but only the race-
mic amine was formed.
Scheme 2. Direct reductive hydroamination of phenylacetylene with p-
anisidine.
Scheme 3. Hydrogenation of the N-phenylimine 12l.
After the gold(I)-catalyzed intermolecular hydroamina-
tion cooperative enantioselective phosphoric acid catalyzed
hydrogenation of the ketimine intermediate 12 takes place
through the formation of a chiral ion pair and hydrogen
bonding.[19] Finally, the iminium ion is reduced by Knçlkerꢃs
iron complex 2 similar to that reported by Goodman[20] to
form the chiral amine 6a. To explore the scope and limita-
tions of the presented catalytic system in more detail, reduc-
tive hydroamination reactions of different terminal alkynes
4 with p-anisidine 5a were carried out. As shown in Table 3,
various aromatic alkynes were reductively hydroaminated
smoothly in high yields with excellent enantioselectivities.
Both electron-donating and -withdrawing substituents on
the aromatic ring at meta- or para-positions had little impact
on the reductive hydroamination activity and high enantio-
selectivities were observed for unsubstituted as well as meta-
Conclusion
We have demonstrated the enantioselective reductive hydro-
amination of alkynes with primary amines in the presence of
molecular hydrogen as the reducing agent. Key to success is
the use of a three-component catalyst system consisting of
a hydroamination, an imine activation, and a hydrogen acti-
vation catalyst. Notably, AuI complexes do not interfere sig-
nificantly with the iron-catalyzed stereoselective hydroami-
nation. In general, this reaction sequence constitutes an in-
teresting alternative to the classic reductive amination pro-
tocols. Excellent enantioselectivities and high yields were
observed for a variety of alkynes and amines.
Scheme 4. Proposed mechanism for the sequential reductive hydroamination of alkynes with amines.
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Consecutive Intermolecular Reductive Hydroamination
FULL PAPER
Table 3. Reductive hydroamination of different alkynes and amines.[a]
Entry
Alkyne
Amine
Yield ee
Entry
Alkyne
Amine
Yield ee
[%][b] [%][c]
[%][b] [%][c]
1
2
3
4a
4b
4c
5a 6a 76 94
5a 6b 71 93
5a 6c 72 79
10
11
12
4j
4k
4a
5a
5k
5k
6j 86
6k 84 87
6l 91 87
67
4
5
4d
4e
5a 6d 74 94
5a 6e 73 91
13
14
4a
4a
5m 6m 76 90
5n
6n 96 93
6
4 f
5a 6 f 76 93
15
16
4a
4a
5o
5p
6o 82 86
6p 83 90
7
8
9
4g
4h
4i
5a 6g 76 81
5a 6h 75 75
5a 6i 75 70
17
4a
5q
6q 93 94
[a] General reaction conditions: alkyne 4 (0.5 mmol), amine 5 (0.5 mmol), 1b (1 mol%), toluene (0.5 mL), RT, 16 h, then (R)-TRIP 3e (2 mol%), 2
(5 mol%), H2 (50 bar) at 658C for 24 h. [b] Isolated yield of the pure product. [c] Determined by chiral HPLC analysis.
Fischer, S. Buchholz, S. Schareina, A. Koch, and S. Smyczek (all at the
LIKAT) for their excellent technical and analytical support.
Experimental Section
All experiments have been performed in 4 mL glass vials. The hydrogen
experiments were carried out in a Parr Instruments 4560 series autoclave
(300 mL) containing an alloy plate with wells for seven 4 mL glass vials.
[1] a) H.-U. Blaser, Adv. Synth. Catal. 2002, 344, 17–31; b) H.-U.
Representative experimental procedure: A vial was charged under an
Blaser, B. Pugin, F. Splinder, M. Thommen, Acc. Chem. Res. 2007,
argon atmosphere inside a glove box with alkyne 4 (0.5 mmol), amine 5
40, 1240–1250.
(0.5 mmol), (tBu)2(o-diphenyl)PAuBF4 (1b) (0.005 mmol), dry toluene
[2] For reviews on this topic, see: a) F. Spindler, H.-U. Blaser, in: Tran-
(0.2 mL), and a magnetic stirring bar and capped with a septum. The
mixture was stirred for 16 h at room temperature. (R)-TRIP 3e
sition Metals for Organic Synthesis 2nd ed., Vol. 2 (Eds.: Beller, M.;
Bolm, C.), WILEY-VCH, Weinheim, 2004, p. 113; b) H.-U. Blaser,
(0.01 mmol in 0.2 mL toluene) and iron complex 2 (0.025 mmol) were
F. Spindler, in Handbook of Homogeneous Hydrogenation, Vol. 3
added and the septum was equipped with a needle. The vial was placed
(Eds.: de Vires, J. G.; Elsevier, C. J.), WILEY-VCH, Weinheim,
in the alloy plate, which was then placed into the predried autoclave.
2007, pp. 1193; c) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry
1999, 10, 2045–2061; d) H.-U. Blaser, C. Malan, B. Pugin, F. Spinder,
H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103–151; e) W.
Tang, X. Zhang, Chem. Rev. 2003, 103, 3029–3069; f) T. C. Nugent,
Once sealed, the autoclave was purged 3 times with hydrogen, then pres-
surized to 50 bar and heated at 658C for 24 h. The autoclave was cooled
to RT, depressurized, and the reaction mixture was transferred to a flask,
evaporated under reduced pressure, and the residue was purified by
M. EI-Shazly, Adv. Synth. Catal. 2010, 352, 753–819; g) M. Rꢀping,
column chromatography on silica gel (eluent: heptane/ethyl acetate=
E. Sugiono, F. R. Schoepke, Synlett 2010, 852–865; h) N. Fleury-Brꢄ-
10:1) to give the corresponding amine 6, which was then analyzed by
geot, V. de La Fuente, S. Castillꢅn, C. Claver, ChemCatChem 2010,
2, 1346–1371; i) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011,
HPLC to determine the ee value.
111, 1713–1760; j) C. Wang, B. Villa-Marcos, J. Xiao, Chem.
Commun. 2011, 47, 9773–9785.
[3] a) Y. Chi, Y.-G. Zhou, X. Zhang, J. Org. Chem. 2003, 68, 4120–
4122; b) R. Kadyrov, T. H. Riermeier, Angew. Chem. 2003, 115,
Acknowledgements
5630–5632; Angew. Chem. Int. Ed. 2003, 42, 5472–5474; c) C. Li, C.
Wang, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2008, 130, 14450–
This research has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF, and the DFG (Leibniz Prize). S.F. thanks the
Evonik Foundation for a grant. We thank Dr. W. Baumann, Dr. C.
14451; d) C. Li, C. Wang, B. Villa-Marcos, J. Xiao, J. Am. Chem.
Soc. 2009, 131, 6967–6969; e) B. Villa-Marcos, C. Li, K. Mulholland,
P. J. Hogan, J. Xiao, Molecules 2010, 15, 2453–2472.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
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M. Beller et al.
[4] H.-U. Blaser, H. P. Buser, H. P. Jalett, B. Pugin, F. Spindler, Synlett
1999, 867–868.
[11] For selected recent articles, see: a) G. V. Shanbhag, S. B. Halligudi,
J. Mol. Catal. A 2004, 222, 223–228; b) J. Penzien, A. Abraham, J.
van Bokhoven, A. Jentys, T. E. Mꢀller, C. Sievers, J. A. Lercher, J.
Phys. Chem. B 2004, 108, 4116–4126; c) T. Joseph, G. V. Shanbhag,
[5] For recent reviews, see: a) J. Seayad, A. Tillack, C. G. Hartung, M.
Beller, Adv. Synth Catal. 2002, 344, 795–813; b) F. Pohlki, S. Doye,
Chem. Soc. Rev. 2003, 32, 104–114; c) M. Beller, J. Seayad, A.
Tillack, H. Jiao, Angew. Chem. 2004, 116, 3448–3479; Angew.
Chem. Int. Ed. 2004, 43, 3368–3398; d) F. Alonso, I. P. Beletskaya,
M. Yus, Chem. Rev. 2004, 104, 3079–3159; e) I. Aillaud, J. Collin, J.
Hannedouche, E. Schulz, Dalton Trans. 2007, 5105–5118; f) P. A.
Hunt, Dalton Trans. 2007, 1743–1754; g) T. E. Mꢀller, C. Kai, K. C.
Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008, 108, 3795–
3892; h) N. T. Patil, V. Singh, J. Organomet. Chem. 2011, 696, 419–
432.
S. B. Halligudi, J. Mol. Catal.
A 2005, 236, 139–144; d) G. V.
Shanbhag, S. M. Kumbar, T. Joseph, S. B. Halligudi, Tetrahedron
Lett. 2006, 47, 141–143.
[12] X.-Y. Liu, C.-M. Che, Org. Lett. 2009, 11, 4204–4207.
[13] Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc.
2009, 131, 9182–9183.
[14] a) M. Beller, C. Breindl, T. H. Riermeier, M. Eichberger, H.
Trauthwein, Angew. Chem. 1998, 110, 3571–3573; Angew. Chem.
Int. Ed. 1998, 37, 3389–3391; b) M. Beller, C. Breindl, T. H.
Riermeier, A. Tillack, J. Org. Chem. 2001, 66, 1403–1412.
[15] a) S. Zhou, S. Fleischer, K. Junge, S. Das, D. Addis, M. Beller,
Angew. Chem. 2010, 122, 8298–8302; Angew. Chem. Int. Ed. 2010,
49, 8121–8125; b) S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew.
Chem. 2011, 123, 5226–5230; Angew. Chem. Int. Ed. 2011, 50, 5120–
5124.
[16] a) H.-J. Knçlker, E. Baum, J. Heber, Tetrahedron Lett. 1995, 36,
7647–7650; b) H.-J. Knçlker, E. Baum, H. Goesmann, R. Klauss,
Angew. Chem. 1999, 111, 2196–2199; Angew. Chem. Int. Ed. 1999,
38, 2064–2066.
[17] For selected examples see: a) M. Rueping, E. Sugiono, C. Azap, T.
Theissmann, M. Bolte, Org. Lett. 2005, 7, 3781–3783; b) S.
Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005, 117, 7590–
7593; Angew. Chem. Int. Ed. 2005, 44, 7424–7427; c) M. Rueping,
A. P. Antonchik, T. Theissmann, Angew. Chem. 2006, 118, 3765–
3768; Angew. Chem. Int. Ed. 2006, 45, 3683–3686; d) M. Rueping,
S. P. Antonchik, T. Theissmann, Angew. Chem. 2006, 118, 6903–
6907; Angew. Chem. Int. Ed. 2006, 45, 6751–6755; e) S. Hoffmann,
M. Nicoletti, B. List, J. Am. Chem. Soc. 2006, 128, 13074–13075;
f) R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am.
Chem. Soc. 2006, 128, 84–86; g) G. Li, Y. Liang, J. C. Antilla, J. Am.
Chem. Soc. 2007, 129, 5830–5831; h) V. N. Wakchaure, J. Zhou, S.
Hoffmann, B. List, Angew. Chem. 2010, 122, 4716–4718; Angew.
Chem. Int. Ed. 2010, 49, 4612–4614; i) V. N. Wakchaure, M.
Nicoletti, L. Batjen, B. List, Synlett 2010, 2708–2710.
[6] For selected recent articles, see: a) J. S. Johnson, R. G. Bergman, J.
Am. Chem. Soc. 2001, 123, 2923–2924; b) P. D. Knight, I. Munslow,
P. N. OꢃShaughnessy, P. Scott, Chem. Commun. 2004, 894–895;
c) D. V. Gribkov, K. C. Hultzsch, Angew. Chem. 2004, 116, 5659–
5663; Angew. Chem. Int. Ed. 2004, 43, 5542–5546; d) J. A. Bexrud,
J. D. Beard, D. C. Leitch, L. L. Schafer, Org. Lett. 2005, 7, 1959–
1962; e) C. Mꢀller, C. Loos, N. Schulenberg, S. Doye, Eur. J. Org.
Chem. 2006, 2499–2503; f) K. Marcsekovaꢃ, C. Loos, F. Rominger,
S. Doye, Synlett 2007, 2564–2568; g) H. Kim, P. H. Lee, T.
Livinghouse, Chem. Commun. 2005, 5205–5207; h) R. K. Thomson,
J. A. Bexrud, L. L. Schafer, Organometallics 2006, 25, 4069–4071;
i) D. A. Watson, M. Chiu, R. G. Bergman, Organometallics 2006, 25,
4731–4733; j) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak,
L. L. Schafer, Angew. Chem. 2006, 119, 358–362; Angew. Chem. Int.
Ed. 2006, 46, 354–358; k) A. L. Gott, A. J. Clarke, G. J. Clarkson, P.
Scott, Organometallics 2007, 26, 1729–1737; l) A. L. Gott, A. J.
Clarke, G. L. Clarkson, P. Scott, Chem. Commun. 2008, 1422–1424;
m) S. Majumder, A. L. Odom, Organometallics 2008, 27, 1174–1177.
[7] For selected articles, see: a) M. R. Gagne, T. J. Marks, J. Am. Chem.
Soc. 1989, 111, 4108–4110; b) M. R. Gagne, C. L. Stern, T. J. Marks,
J. Am. Chem. Soc. 1992, 114, 275–294; c) M. A. Giardello, V. P.
Conticello, L. Brard, M. R. Gagnꢄ, T. J. Marks, J. Am. Chem. Soc.
1994, 116, 10241–10254; d) M. R. Douglass, M. Ogasawara, S. Hong,
M. V. Metz, T. J. Marks, Organometallics 2002, 21, 283–292.
[8] For selected recent articles, see: a) B. D. Stubbert, C. L. Stern, T. J.
Marks, Organometallics 2003, 22, 4836–4838; b) B. D. Stubbert, T. J.
Marks, J. Am. Chem. Soc. 2007, 129, 4253–4271; c) B. D. Stubbert,
T. J. Marks, J. Am. Chem. Soc. 2007, 129, 6149–6167.
[18] E. Mizushima, T. Hayashi, M. Tanaka, Org. Lett. 2003, 5, 3349–
3352.
[19] For a study on the mode of activation, see: M. Fleischmann, D.
Drettwan, E. Sugiono, M. Rueping, R. M. Gschwind, Angew. Chem.
2011, 123, 6488; Angew. Chem. Int. Ed. 2011, 50, 6364.
[9] a) E. Mizushima, N. Chatani, F. Kakiuchi, J. Organomet. Chem.
2006, 691, 5739–5745; b) L. Ackermann, A. Althammer, Synlett
2006, 3125–3129; c) S. Chang, M. Lee, D. Y. Jung, E. J. Yoo, S. H.
Cho, S. K. Han, J. Am. Chem. Soc. 2006, 128, 12366–12367; d) Y.
Kuninobu, Y. Nishina, K. Takai, Org. Lett. 2006, 8, 2891–2893.
[10] P. Horrillo-Martꢆnez, K. C. Hultzsch, A. Gil, V. Branchadell, Eur. J.
Org. Chem. 2007, 3311–3325.
[20] For a theoretical study on a related mechanism, see: L. Simꢅn, J. M.
Goodman, J. Am. Chem. Soc. 2008, 130, 8741.
Received: January 11, 2012
Revised: April 5, 2012
Published online: && &&, 2012
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Consecutive Intermolecular Reductive Hydroamination
FULL PAPER
Enantioselectivity
S. Fleischer, S. Werkmeister, S. Zhou,
K. Junge, M. Beller* ......... &&&& — &&&&
Consecutive Intermolecular Reductive
Hydroamination: Cooperative Transi-
tion-Metal and Chiral Brønsted Acid
Catalysis
The three musketeers! The enantiose-
lective reductive hydroamination of
alkynes with primary amines in the
presence of molecular hydrogen as the
reducing agent is demonstrated (see
scheme). Key to success is the use of
a three-component catalyst system
consisting of a hydroamination, an
imine activation, and a hydrogen acti-
vation catalyst.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!