Highly enantioselective synthesis of chiral secondary amines by gold(I)/ chiral bronsted acid catalyzed tandem intermodular hydroamination and transfer hydrogenation reactions

Article abstract of DOI:10.1021/ol901443b

A method for the synthesis of enantiomerically enriched secondary amines with excellent ee values through the tandem intermolecular hydroamination/ transfer hydrogenation of alkynes using a "gold(I) complex-chiral Bronsted acid" protocol is developed. The

Full text of DOI:10.1021/ol901443b

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4204-4207
Highly Enantioselective Synthesis of
Chiral Secondary Amines by Gold(I)/
Chiral Brønsted Acid Catalyzed Tandem
Intermolecular Hydroamination and
Transfer Hydrogenation Reactions
Xin-Yuan Liu and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong, P. R. China
cmche@hku.hk
Received June 25, 2009
ABSTRACT
A method for the synthesis of enantiomerically enriched secondary amines with excellent ee values through the tandem intermolecular
hydroamination/transfer hydrogenation of alkynes using a “gold(I) complex-chiral Brønsted acid” protocol is developed. The catalysis works
for a wide variety of aryl, alkenyl, and aliphatic alkynes as well as anilines with different electronic properties.
Homogeneous gold catalysis has emerged to become a
powerful tool for novel organic transformations.1 However,
compared with other transition metal catalysis, relatively few
enantioselective transformations using gold(I) catalysts have
been reported. This is possibly due to the linear coordination
geometry of gold(I), which alleviates the steric interactions
between the chiral inducer and the reactive functional group
of the substrate.2 To circumvent this problem, Toste and co-
workers proposed the development of an efficient chiral
counterion strategy and applied this strategy to accomplish
the gold(I)-catalyzed highly enantioselective intramolecular
hydroalkoxylation and hydroamination of allenes.3 Despite
this advance, the gold-catalyzed enantioselective organic
transformations are in the rudimentary stage. In recent years,
cooperative catalysis using protocols “a metal complex +
an organic molecule” has been receiving a surge of interest
in the context of developing novel organic transformations,
owing to the cooperative effect in enhancing good reactivity
and selectivity for the transformation reactions.4 Inspired by
Toste’s paper,3 we conceived that cooperative catalysis could
(2) For recent reviews, see: (a) Bongers, N.; Krause, N. Angew. Chem.,
Int. Ed. 2008, 47, 2178. (b) Widenhoefer, R. A. Chem.sEur. J. 2008, 14,
5382. For selected examples, see: (c) Paz Mun˜oz, M.; Adrio, J.; Carretero,
J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293. (d) LaLonde,
R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 2452. (e) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2007, 129, 14148. (f) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am.
Chem. Soc. 2009, 131, 2056. (g) Uemura, M.; Watson, I. D. G.; Katsukawa,
M.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464. (h) Chao, C.-M.;
Vitale, M. R.; Toullec, P. Y.; Geneˆt, J.-P.; Michelet, V. Chem.sEur. J.
2009, 15, 1319.
(1) For recent reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Gorin, D. J.; Toste, F. D. Nature 2007,
446, 395. (c) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (d) Marion,
N.; Nolan, S. P. Chem. Soc. ReV. 2008, 37, 1776. (e) Li, Z.; Brouwer, C.;
He, C. Chem. ReV. 2008, 108, 3239. (f) Arcadi, A. Chem. ReV. 2008, 108,
3266. (g) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108,
3351.
(3) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496.
10.1021/ol901443b CCC: $40.75
Published on Web 08/13/2009
 2009 American Chemical Society

also be applied to gold catalysis for new enantioselective
organic transformations, which would serve as a comple-
mentary approach to the conventional chiral gold(I)-catalyzed
asymmetric organic synthesis.2
Scheme 1
Chiral amines are ubiquitous structural motifs in a myriad
of biologically active natural products and pharmaceutically
active compounds.5 A simple and powerful tool for preparing
chiral amines is transition-metal-catalyzed hydroamination
of unsaturated carbon-carbon bonds.6 However, only a few
of these methods could be applied to the intermolecular
hydroamination for the synthesis of chiral amines with high
product yield and high enantioselectivity.7 Using alkynes as
starting materials for the synthesis of chiral amines through
intermolecular hydroamination has not been reported in
literature.1 Therefore, the development of new catalysis for
intermolecular hydroamination of alkynes to form chiral
amines would be invaluable to the synthetic organic chem-
istry community. As a continuation of our research in gold-
catalyzed hydroamination reactions and related tandem
reactions,8 we report herein a highly enantioselective one-
pot tandem intermolecular hydroamination/transfer hydro-
genation of alkynes using a cooperative catalytic system
composed of gold(I) complex and chiral Brønsted acid
(Scheme 1). The transformation shows a very broad substrate
scope toward diversely substituted chiral amines in up to
98% yields and up to 96% ee under mild conditions. After
completion of this work and during the preparation of this
manuscript, a paper by Gong and co-workers on consecutive
intramolecular hydroamination/transfer hydrogenation using
a gold complex/chiral Brønsted acid binary system for the
enantioselective synthesis of tetrahydroquinolines was pub-
lished.9
We previously reported a gold(I)-catalyzed tandem hy-
droamination/hydroarylation reaction of aryl amines and
alkynes for the synthesis of substituted 1,2-dihydro-
quinolines.8b Further studies revealed that a gold(I)-catalyzed
reaction of m-anisidine (1A) with phenylacetylene (2a) in
the presence of commercially available Hantzsch ester (3)
afforded secondary amine 4Aa (Table 1). Upon optimizing
the reaction conditions by varying gold catalyst, solvent,
temperature, and catalyst loading, we obtained 4Aa in 94%
yield from a reaction in THF at room temperature for 31 h
using 2 mol % of (tBu)2(o-biphenyl)PAuCl/AgBF4 (Table
1, entry 1). Under similar conditions, the reaction for a variety
of substituted anilines and alkynes gave secondary amines
in 76-95% yields (Table 1, entries 2-10).
Table 1. Gold(I)-Catalyzed Tandem Reactions between Aryl
Amines and Alkynesa
(4) (a) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett.
2001, 3, 3329. (b) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang,
Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12,
1567. (c) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem.
2002, 67, 7418. (d) Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y.
Angew. Chem., Int. Ed. 2003, 42, 2054. (e) Jellerichs, B. G.; Kong, J.-R.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 7758. (f) Komanduri, V.;
Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448. (g) Ibrahem, I.; Co´rdova,
A. Angew. Chem., Int. Ed. 2006, 45, 1952. (h) Chercheja, S.; Eilbracht, P.
AdV. Synth. Catal. 2007, 349, 1897. (i) Mukherjee, S.; List, B. J. Am. Chem.
Soc. 2007, 129, 11336. (j) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang,
H.; Hu, J.; Yang, L.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (k)
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452. (l) Li, C.;
Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2009, 131, 6967. For a review,
see: (m) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222.
t
yield
entry
R1
R2
Ph (2a)
product (h) (%)b
1
2
3
4
5
6
7
8
9
3-MeO (1A)
4-MeO (1B)
3,5-(MeO)2 (1F) Ph (2a)
H (1H)
4-Cl (1I)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
4Aa
4Ba
4Fa
4Ha
4Ia
4Ab
4Ac
4Ae
4Ag
4Aj
31
32
24
48
72
72
72
72
48
48
94
95
86
90
78
86
90
76
86
92
Ph (2a)
Ph (2a)
Ph (2a)
p-MeC6H4 (2b)
o-MeC6H4 (2c)
m-MeOC6H4 (2e)
p-FC6H4 (2g)
n-butyl (2j)
10
(5) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb.
Chem. 1999, 1, 55. (b) Henkel, T.; Brunne, R. M.; Mu¨ller, H.; Reichel, F.
Angew. Chem., Int. Ed. 1999, 38, 643.
a Reaction Conditions: amine (0.5 mmol), alkyne (1.0 mmol), 3 (0.75
mmol), (tBu)2(o-biphenyl)PAuCl/AgBF4 (0.01 mmol), and THF (2 mL), rt
to 60 °C. b Isolated yield based on aryl amine.
(6) For recent reviews, see: (a) Aillaud, I.; Collin, J.; Hannedouche, J.;
Schulz, E. Dalton Trans. 2007, 5015. (b) Hultzsch, K. C. Org. Biomol.
Chem. 2005, 3, 1819. (c) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347,
367. (d) Roesky, P. W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42,
2708. (e) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. ReV. 2008, 108, 3795.
To render the reaction enantioselective, we examined
various chiral diphosphine gold(I) catalysts; however, poor
ee and low yields of 4Aa were observed (Table S1 in
Supporting Information). In view of the efficiency of chiral
phosphoric acids10 in catalyzing the enantioselective transfer
(7) For examples of hydroaminations of vinylarenes and conjugated
dienes with substantial enantioselectivity, see: (a) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 2000, 122, 9546. (b) Lo¨ber, O.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. (c) Zhou, J.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 12220. (d) Zhang, Z.; Lee, S. D.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372.
(8) (a) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (b)
Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645.
(c) Liu, X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2008, 47, 3805. (d) Liu,
X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2009, 48, 2367.
(9) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc.
2009, 131, 9182.
(10) For a recent review, see: Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638.
Org. Lett., Vol. 11, No. 18, 2009
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Table 2. Gold(I)/Chiral Phosphoric Acid Catalyzed Tandem Reactions between Aryl Amines and Alkynesa
entry
R1
R2
product
t (h)
yield (%)b
ee (%)c
1
2
3-MeO (1A)
4-MeO (1B)
4-PhO(1C)
4-Me (1D)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
p-MeC6H4 (2b)
o-MeC6H4 (2c)
p-MeOC6H4 (2d)
m-MeOC6H4 (2e)
p-PhC6H4 (2f)
p-FC6H4 (2g)
4Aa
4Ba
4Ca
4Da
4Ea
4Fa
4Ga
4Ha
4Ia
4Ja
4Ab
4Ac
4Ad
4Ae
4Af
4Ag
4Ah
4Ai
4Aj
4Ak
4Al
4Am
4An
4Ao
4Ao
4Aq
4Ar
72
72
72
120
72
72
85
86
87
95
70
75
78
79
91
96
91
87
98
93
92
94
90
81
85
86
91
79
91
75
54
98
88
94
89
85
90
90
96
95
92
88
88
94
91
89
90
92
83
90
86
83
93
95
86
92
95
95
83
91
3
4d
5
4-Ph (1E)
6
7
3,5-(MeO)2 (1F)
3,5-(Me)2 (1G)
H (1H)
4-Cl (1I)
4-Br (1J)
72
8d
9d
10d
11
12
13
14
15
16
17d
18d
19
20
21
22
23
24
25d
26
27
120
144
144
96
96
96
96
96
96
120
120
72
96
72
96
72
120
120
40
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
3-MeO (1A)
p-CF3C6H4 (2h)
p-CNC6H4 (2i)
n-butyl (2j)
n-hexyl (2k)
n-octyl (2l)
i-pentyl (2m)
Ph(CH2)2 (2n)
cyclohexyl (2o)
cyclohexenyl (2p)
cyclopropyl (2q)
Me2CdCH(CH2)2 (2r)
72
a Reaction conditions: amine (0.2 mmol), alkyne (0.4 mmol), 3 (0.3 mmol), (tBu)2(o-biphenyl)PAuOTf (1 mol %), 5e (5 mol %), benzene (3 mL), and
5 Å MS (1 g), 40 °C. 5e ) (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate. b Isolated yield based on aromatic amine.
c Determined by chiral HPLC; configuration assigned by comparison with the literature (see Supporting Information for details). d Reaction conditions:
amine (0.2 mmol), phenylacetylene (0.4 mmol), 3 (0.4 mmol) added in two portions (60 h + 60 h), (tBu)2(o-biphenyl)PAuOTf (2 mol %), 5e (10 mol %),
benzene (3 mL), and 5 Å MS (1 g), 60 °C.
hydrogenation of imines11 and the possible formation of a
ketimine intermediate via gold(I)-catalyzed intermolecular
hydroamination,8b we envisioned that a binary catalytic
system composed of a gold(I) complex and a chiral Brønsted
acid could be used to prepare chiral amines. A challenge to
achieve excellent enantioselectivity in this cooperative
catalysis is to suppress the transfer hydrogenation of
ketimines catalyzed by the gold(I) complex. Using 5a (10
mol %) as a chiral Brønsted acid, reaction of 1A with 2a
and 3 catalyzed by (tBu)2(o-biphenyl)PAuBF4 (3 mol %) gave
4Aa in 84% yield and 32% ee (Table S2 in Supporting
Information). After optimization of reaction conditions, 4Aa
was obtained in 85% yield and 94% ee from a reaction in
benzene in the presence of activated, powdered molecular
sieves (MS, 5 Å) using (tBu)2(o-biphenyl)PAuOTf and 2,4,6-
triisopropylphenyl-derived chiral phosphoric acid 5e as
catalysts (see Table S2 in Supporting Information). Almost
the same product yield and ee value could still be obtained
upon lowering the gold(I) catalyst loading from 3 to 1 mol
% or the loading of 5e from 10 to 5 mol %. The reaction
was not catalyzed by 5e alone.
Under the optimal conditions, reaction of 2a with a
series of para-, meta-, or disubstituted anilines (1B-G)
bearing electron-donating substituents afforded chiral
amines 4Ba-Ga in 70-95% yields and 85-96% ee
(Table 2, entries 2-7). For para-substituted anilines 1I,J
bearing electron-withdrawing groups, their reactions gave
4Ia,Ja in 91% and 96% yields and both in 88% ee,
although a longer reaction time, a higher temperature (60
°C), and an increased catalyst loading were required for
complete substrate conversion (entries 9 and 10).
(11) For chiral phosphoric acid catalyzed reduction reactions, see: (a)
Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett.
2005, 7, 3781. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem.,
Int. Ed. 2005, 44, 7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (d) Li, G.; Liang, Y.; Antilla,
J. C. J. Am. Chem. Soc. 2007, 129, 5830.
A wide variety of alkynes (2b-r) were similarly treated
with m-anisidine (1A) to furnish diversely substituted chiral
4206
Org. Lett., Vol. 11, No. 18, 2009

amines 4Ab-Ar (Table 2). Generally, the reaction works
well for aryl alkynes possessing electron-donating/-with-
drawing ortho, meta, or para substituents (entries 11-18).
The present cooperative catalysis could be applied to aliphatic
alkynes 2j-r, although N-aryl ketimines with dialkyl sub-
stituents have rarely been reported to give the corresponding
chiral amines with both excellent product yield and high
enantioselectivity in related organocatalysis.11 Both linear
and branched aliphatic alkynes gave the corresponding chiral
amines 4Aj-Am in good to excellent yields (79-91%) and
enantioselectivities (83-95%) (entries 19-22). Cyclic ali-
phatic alkynes are also applicable without loss in reaction
efficiency and enantiocontrol (entries 23-26). 1-Ethynylcy-
clohex-1-ene (2p) underwent this tandem reaction to give
4Ao with 95% ee via a conjugate reduction step, albeit with
a moderate yield (54%) (entry 25). Notably, the catalytic
system tolerates other reactive groups, such as CN, cyclo-
propyl, and alkenyl in the alkyne substrates (entries 18, 26,
and 27).
A series of control experiments were conducted to gain
insight into the mechanism of the transformation. In the
absence of ethyl Hanzsch ester (3), ketimine 6 was afforded
in 92% yield with (tBu)2(o-biphenyl)PAuCl/ AgBF4 (eq 1);
however, no reaction was found when 5e alone was used as
the catalyst. This result reveals that the gold(I)-catalyzed
hydroamination is the first step in this tandem sequence.
Electrospray ionization mass spectroscopic analysis of a
solution of aniline, phenylacetylene, and (tBu)2(o-biphe-
nyl)PAuOTf (20 mol %) in CH2Cl2 after stirring for 15 min
at room temperature showed a peak at m/z 690, which is
consistent with the intermediacy of I depicted in Scheme 2.
Subsequent treatment of the ketimine 6 with 3 at room
temperature for 24 h in the presence of gold(I) complex alone
or chiral phosphoric acid 5e alone gave 4Aa in similar yields.
Despite the fact that gold(I) complex can efficiently catalyze
the transfer hydrogenation of ketimines, in this work,
excellent enantioselectivity (94%) has been obtained in the
presence of both gold(I) complex and 5e, revealing that the
Scheme 2
chiral phosphoric acid plays a dominant role in the reduction
process for obtaining excellent enantioselectivity (eq 2).
However, we could not exclude the possibility of an
exchange of the metal counteranion, which could lead to the
formation of a gold(I) complex cation-chiral counteranion
ion pair3 to catalyze the subsequent reaction, because the
reaction of 1A with 2a catalyzed by gold phosphate, derived
from (tBu)2(o-biphenyl)PAuCl and 5f, gave 4Aa in 80% yield
and 92% ee (eq 3). On the basis of these observations, a
reaction mechanism for the formation of chiral amines from
the cooperative gold(I)/chiral phosphoric acid catalyzed
reactions of 1 with 2 in the presence of 3 is proposed and
depicted in Scheme 2. The reaction mechanism involves
gold(I)-catalyzed intermolecular hydroamination of alkyne
to generate the ketimine intermediate,8,12 and the subsequent
chiral phosphoric acid catalyzed transfer hydrogenation of
this intermediate similar to that reported by Goodman and
co-workers.13
In summary, we have demonstrated a highly enantiose-
lective tandem intermolecular hydroamination/transfer hy-
drogenation of alkynes using a protocol composed of gold(I)
complex-chiral Brønsted acid. A wide variety of aryl,
alkenyl, and aliphatic alkynes as well as anilines with
different electronic properties can be tolerated. This approach
combines the advantages of both gold(I) and organocatalysis,
leading to an efficient synthesis of highly enantiomerically
enriched chiral secondary amine compounds.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (University
Development Fund), Hong Kong Research Grants Council
(HKU 1/CRF/08, HKU 7007/08P), and University Grants
Committee of Hong Kong (Areas of Excellence Scheme
AoE/P-10/01).
Supporting Information Available: Experimental pro-
cedures, product characterizations, Tables S1 and S2, and
Figure S1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL901443B
(12) (a) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5,
3349. (b) Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675. (c) Zhang, J.;
Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798
.
(13) For an excellent theoretical study on a related mechanism, see:
Simo´n, L.; Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741.
Org. Lett., Vol. 11, No. 18, 2009
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