Consecutive intramolecular hydroamination/asymmetric transfer hydrogenation under relay catalysis of an achiral gold complex/chiral Bronsted acid binary system

Article abstract of DOI:10.1021/ja903547q

(Chemical Equation Presented) Consecutive hydroamination/asymmetric transfer hydrogenation under relay catalysis of an achiral gold complex/chiral Bronsted acid binary system has been described for the direct transformation of 2-(2-propynyl)aniline deriva

Full text of DOI:10.1021/ja903547q

Published on Web 06/11/2009
Consecutive Intramolecular Hydroamination/Asymmetric Transfer
Hydrogenation under Relay Catalysis of an Achiral Gold Complex/Chiral
Brønsted Acid Binary System
Zhi-Yong Han, Han Xiao, Xiao-Hua Chen, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, UniVersity of
Science and Technology of China, Hefei, 230026, China
Received May 1, 2009; E-mail: gonglz@ustc.edu.cn
Either metal-based catalysts or organocatalysts are generally used
alone to promote fundamentally different reactions in asymmetric
catalytic processes.1 The combination of metal complexes and organic
molecules in cooperative and relay catalysis may enable new trans-
formations through the simultaneous or sequential activation and
reorganization of multiple chemical bonds by the metal catalysts and
Gratifyingly, the reaction proceeded cleanly and afforded 2-phenyltet-
organocatalysts. This concept holds great potential for application to
rahydroquinoline 3a in 98% yield with 92% ee (Table 1, entry 1). A
a broad scope of organic synthetic reactions, as previously demonstrated
control experiment in the presence of 5 mol % of Ph3PAuOTf led to
by transformations accelerated by metal/organic binary catalyst
an incomplete reaction, giving racemic 3a in low yield (entry 2). The
systems.2,3 However, relatively few asymmetric protocols gave
use of HAuCl4 as the collaborator with 5 provided poor enantiose-
synthetically useful enantioiselectivity,2d,f,h-k and thus the potential
lectivity (18% ee, entry 3), presumably due to a nonenantioselective
of the concept in asymmetric catalysis is poorly understood.
transfer hydrogenation accelerated by the proton of HAuCl4 competing
Given their widespread applications as intermediates, building
with that of 5, which significantly eroded the stereoselectivity.
blocks, or reagents in organic synthesis, chiral amines are of increasing
Significantly, Ph3PAuCH3 was found to be the best partner of 5 and
commercial importance in fine chemical and pharmaceutical processes.
provided 97% yield and 97% ee for 3a (entry 4). Tuning the ratio of
Among numerous synthetic approaches, the enantioselective hydroami-
the phosphoric acid 5 to Ph3PAuCH3 had little effect on the stereo-
nation of an unsaturated C-C bond is unarguably the most atom-
selectivity (entries 4-6), although the reaction slowed when the ratio
economic pathway and, hence, is of fundamental significance.4 Alkynes
was varied from 3/1 to 1/1 (entry 4 vs 6). This finding demonstrated
are more reactive in hydroamination reactions than alkenes.5 However,
that the phosphoric acid participated in the second catalysis by
hydroamination reactions of alkynes basically generate enamines or
activating the imines formed from the hydroamination catalyzed by
imines.4 An asymmetric catalytic method for the direct transformation
Au. In the previous work, Ph3PAuCH3 reacted with some strong
of alkynes into amines with high enantiomeric purity is therefore
Brønsted acid to form a chiral cationic Au(I) complex,7c which might
important from a synthetic point of view but has not yet been readily
afford the enantioselective sequential reactions by use of its chiral
available. Recent reports of elegant sequential processes involving
counterion to control the stereochemistry.10 Thus, we conducted a
hydroamination of alkynes and a subsequent reduction have trans-
control reaction exploiting pure chiral gold phosphorate, derived from
formed alkynes into amines.6 In these one pot reactions, the reductive
6 and Ph3PAuCl, as the catalyst.10a However, the reaction with gold
reagent was added separately after the hydroamination step, but a low
phosphorate was incomplete, with a lower enantioselectivity in
ee was obtained. Herein, we report a novel protocol that directly
comparison with the binary system (entry 7 vs 4). These outcomes
converted 2-(2-propynyl)aniline derivatives (1) into tetrahydroquino-
indicated that the gold phosphorate, even if it was formed, had little
lines (3) with high ee in one operation through consecutive hydroami-
influence on the enantioselective transfer hydrogenation. Instead, the
nation of alkynes/asymmetric transfer hydrogenation reactions under
phosphoric acid really controlled the stereochemistry. An examination
the relay catalysis of an achiral Au complex/chiral Brønsted acid binary
of other reaction parameters, including solvent and different Hantzsch
system.
esters, revealed that toluene was a suitable medium and that 2a was
Our proposed relay catalysis for the conversion of 2-(2-propyny-
the best hydride source (entries 8-13). Notably, reducing the catalyst
l)anilines 1 into tetrahydroquinolines 3 involves a sequence of reactions
loading still provided high yield and enantioselectivity in a prolonged
initiated by an intramolecular hydroamination catalyzed by an ap-
reaction time (entries 14-15).
propriate Au complex,7 furnishing a 1,4-dihydroquinoline 4, followed
Under the optimized reaction conditions, we investigated the
by isomerization of 4 into 3,4-dihydroquinolinium II with a chiral
generality of the protocol for 2-(2-propynyl)aniline derivatives
Brønsted acid,8,9 and, ultimately, the asymmetric transfer hydrogenation
Scheme 1. Relay Catalysis by a Gold Complex/Chiral Brønsted
of the chiral II9 with a Hantzsch ester 2 producing optically active
Acid Binary System in Consecutive Intramolecular Hydroamination/
Asymmetric Transfer Hydrogenation
tetrahydroquinoline 3 (Scheme 1). Central to the realization of this
strategy would be the identification of a Au complex that would afford
an efficient hydroamination but would not affect the Brønsted acid-
catalyzed enantioselective transfer hydrogenation. Moreover, appropri-
ate conditions that tolerate either of the two different catalytic reactions
are also very important for the proposed relay catalysis.
An initial validation of our hypothesis included a reaction of 2-(3-
phenyl-2-propynyl) aniline (1a) with Hantzsch ester 2a using a binary
catalyst system consisting of Ph3PAuOTf (5 mol %), generated in situ
from Ph3PAuCl and AgOTf, and Brønsted acid 5 (15 mol %).
9
9182 J. AM. CHEM. SOC. 2009, 131, 9182–9183
10.1021/ja903547q CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Evaluation of Gold Complexes and Optimization of
Reaction Conditions
neutral, or electron-donating substituents were well tolerated,
providing excellent conversions (94->99% yields) and stereo-
chemical outcomes (90-98% ee). The stereoselectivity is sensitive
to the position of the substituent when comparing the reactions
producing 3o and 3p (entries 14 and 15).
In summary, we have developed an unprecedented protocol which
directly transformed 2-(2-propynyl)aniline derivatives into tetrahyd-
roquinolines in one operation with excellent enantioselectivity under
the relay catalysis of an achiral Au complex and a chiral phosphoric
acid. This reaction was considered a consecutive catalytic process
consisting of a Au-catalyzed intramolecular hydroamination of a C-C
triple bond and a Brønsted acid catalyzed enantioselective transfer
hydrogenation. This work not only provides a new entry to tetrahy-
droquinolines complementary to the known asymmetric hydrogenation
reactions of quinolines9,11 but also suggests a powerful strategy
applicable to the design of transformations beyond the scope of those
afforded by either Au complexes12 or Brønsted acids13 alone.
Au
(x mol %)
5 or 6
(y mol %)
time
(h)
yieldb
(%)
eec
(%)
entry
92d
0d
1
2
3
4
5
6
7
8
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgOTf (5)
HAuCl4 ·4H2O (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuCl (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (5)
Ph3PAuMe (2)
Ph3PAuMe (1)
5 (15)
0
5 (15)
5 (15)
5 (20)
5 (5)
16
16
16
11
12
80
80
14
14
14
14
14
14
32
32
98
<40
78
97
98
90
35
91
85
88
78
99
99
98
96
18d, g
97
97
97
90
6 (5)
95e
96f
75g
91h
94i
95j
96d
97d
5 (15)
5 (15)
5 (15)
5 (15)
5 (15)
5 (15)
5 (6)
9
10
11
12
13
14
15
Acknowledgment. We are grateful for financial support from
NSFC (20732006), CAS, 973 program (2009CB825300), and
Ministry of Education.
5 (3)
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Unless indicated otherwise, the reaction of 1a (0.1 mmol) and
Hantzsch ester 2a was carried out in toluene at room temperature.
b Isolated yield. c The ee was determined by HPLC. d 0.2 mmol 1a used.
e In CH2Cl2. f In CHCl3. g In CH3CN. h In THF. i Using 2b as hydride
source. j Using 2c as hydride source.
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a Unless indicated otherwise, the reaction of 1 (0.1 mmol) and
Hantzsch ester 2a was carried out in toluene at room temperature.
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