A highly enantioselective, Pd-TangPhos-catalyzed hydrogenation of N-tosylimines

Article abstract of DOI:10.1002/anie.200600263

(Chemical Equation Presented) A catalyst system composed of Pd-(OCOCF ₃)₂ complexed with the electron-donating, rigid chiral diphosphane Tang-Phos gives excellent enantioselectivities (up to 99% ee) and conversions (up to > 99%) in the hydrogenation of N-tosylimines 1 (see scheme). A variety of aromatic, aliphatic, and cyclic chiral amines 2 can be prepared by this methodology.

Full text of DOI:10.1002/anie.200600263

Communications
Palladium-Catalyzed Hydrogenation
DOI: 10.1002/anie.200600263
A Highly Enantioselective, Pd–TangPhos-
Catalyzed Hydrogenation of N-Tosylimines**
Qin Yang, Gao Shang, Wenzhong Gao, Jingen Deng,
and Xumu Zhang*
Although significant progress has been made in the catalytic
asymmetric reduction of ketones and olefins over the last few
decades,[1] the asymmetric reduction of imines remains a
major challenge.[2] Enantioselective reductive amination with
organocatalysts has recently been reported,[3] and a number of
transition-metal-based catalysts, such as those containing
Rh,[4] Ru,[5] Ti,[6] Zr,[6d] and Ir,[7] have been applied to the
asymmetric hydrogenation of imines. However, this method
has been less successful than the hydrogenation of other
substrates. The main obstacles in solving the problems in this
hydrogenation approach include different enantioselectivities
for E and Z isomers of acyclic imines,[6b,c,8] the instability of
some imines prepared from ketones, and the inhibitory effect
of the amine products on the metal catalysts. In order to solve
these problems, N-tosylimines were selected as the hydro-
genation substrates since they are relatively stable and can be
easily obtained from the corresponding ketones exclusively as
the E isomer.[9] In addition, the strongly electron-withdrawing
character of the tosyl group reduces the inhibitory effect of
the reduction product on the catalysts, which might lead to
higher reactivity. These advantages of N-tosylimines as
substrates prompted us to look for a good reduction catalyst
for the substrates. To the best of our knowledge, the
asymmetric hydrogenation of N-tosylimines has rarely been
explored, and the best result reported so far is the 84% ee
reported by the Charette group using a Ru–Binap catalyst.[9]
In our search for effective hydrogenation catalysts for the
reduction of N-tosylimines, we have explored this trans-
[*] Q. Yang, G. Shang, Dr. W. Gao, Prof. X. Zhang
Department of Chemistry
The Pennsylvania State University
104 Chemistry Building, University Park, PA 16802 (USA)
Fax: (+1)814-863-8403
E-mail: xumu@chem.psu.edu
Q. Yang, Prof. J. Deng
Key Laboratory of Asymmetric Synthesis & Chirotechnology of
Sichuan Province and
Union Laboratory of Asymmetric Synthesis
Chendu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu 610041 (China)
and
Graduate School of the Chinese Academy of Science
Beijing (China) Department of Chemistry
[**] This work was supported by the National Institutes of Health
(GM58832).
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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formation with many transition-metal-containing catalysts, in
particular Rh, Ru, Ir, and Pd complexes.
Palladium complexes have been extensively employed as
catalysts for a wide range of reactions, especially for carbon–
carbon and carbon–heteroatom coupling reactions.[10]
Although heterogeneous Pd/C catalysts have been used
extensively in imine reductions, there are only a few reports
of Pd-catalyzed homogeneous and asymmetric hydrogena-
tion. The first asymmetric hydrogenation of imino esters was
described by Amii with a Pd(OCOCF3)2–Binap complex that
gave up to 90% ee.[11] However, the substrate scope of this
system was limited to fluoro-substituted compounds. Raja
and Thomas have reported a heterogeneous palladium-
catalyzed asymmetric hydrogenation of a-ketoesters,[12] and,
very recently, the Zhou group disclosed their results on the
hydrogenation of functionalized ketones using Pd(OCOCF3)2
and Me-DuPhos as catalyst, with a best result of 92% ee.[13]
Our group has developed a series of diphosphane ligands,
such as TangPhos, DuanPhos, Binapine, and Cn-Tunephos
(Scheme 1), which we have successfully employed in the
asymmetric hydrogenation of a wide range of substrates.[14]
The electron-donating rigid TangPhos ligand was found to be
particularly good for highly enantioselective hydrogenation
reactions; therefore we anticipated that the combination of
Pd precursors with TangPhos could lead to outstanding results
in the asymmetric hydrogenation of imines. Here we present
our preliminary results on the Pd–TangPhos-catalyzed hydro-
genation of N-tosylimines, which occurs with up to > 99% ee
and complete conversion.
Scheme 1. Structure of ligands for asymmetric hydrogenation.
The effect of reaction temperature and hydrogen pressure
on the enantioselectivity and reactivity of the hydrogenation
was also tested. We found that both the conversion and the ee
decreased at a lower hydrogen pressure (Table 1, entry 12). A
lower temperature only resulted in a lower conversion; the
enantioselectivity remained the same (Table 1, entry 13).
Further studies indicated that changing the solvent had no
significant effect on the enantioselectivities and conversions
(Table 1, entries 15–18).
To demonstrate the efficiency of this Pd–TangPhos
catalyst, a series of substituted N-tosylimines 1 were synthe-
sized from readily available starting materials according to
Our initial study began with N-tosylimine (1a) as the
model substrate and a rhodium complex of a
chiral diphosphane as the catalyst.
A
Table 1: Enantioselective hydrogenation of N-tosylimine 1a.[a]
number of catalytic systems were tested;
the results are summarized in Table 1. First,
we investigated the asymmetric hydrogena-
tion of 1a using the Rh–TangPhos complex
A, which has been proved to be an efficient
hydrogenation catalyst for a number of
substrates. Up to 91% ee was observed Entry
Cat. precursor
Ligand
Complex
Solvent
Conv. [%][b]
ee [%][c]
(Table 1, entry 1). Other Rh complexes
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14
15
16
17
18
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OAc)2
[Pd(MeCN)]Cl2
[Pd(MeCN)4](BF4)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
(S,S,R,R)-TangPhos
(RP,SC)-DuanPhos
SP-Binapine
(R,R)-Et-DuPhos
(R,R)-Me-Duphos
(S)-C3-Tunephos
(S)-Binapine
(S)-C3-Tunephos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
(S,S,R,R)-TangPhos
A
B
C
D
E
F
G
H
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
iPrOH
toluene
EtOAc
>99
>99
>99
>99
>99
>99
15
65
n.r.
n.r.
>99
60
91
82
88
63
68
94
n.a.
n.a.
n.a.
n.a.
98
93
99
99
99
with chiral diphosphane ligands, such as B
and C, also provided good enantioselectiv-
ities (Table 1, entries 2 and 3). A systematic
study of the hydrogenation of 1a was then
performed to screen the reaction conditions.
The hydrogenation with Rh–(R,R)-Et-
DuPhos (D) or Rh–(R,R)-Met-DuPhos (E)
proceeded with high conversions; however,
the ee values of the products were relatively
low (63% and 68%, respectively; Table 1,
entries 4 and 5). To our delight, the best
result was obtained with the Pd–TangPhos
complex L (up to 99% ee and > 99%
conversion; Table 1, entry 14). In contrast,
complexes I and J did not show any reac-
tivity. These results imply that the weakly
J
K
L
L
L
L
L
L
L
75
>99
>99
>99
>99
>99
98
98
96
[a] cod=1,5-cyclooctadiene, n.r.=no reaction, n.a.= not analyzed. [b] Conversions (in %) were
determined by 1H NMR spectroscopy of the crude reaction mixture. [c] Enantiomeric excesses were
determined by chiral HPLC. [d] The reaction was carried out under 20 atm hydrogen pressure. [e] The
reaction was carried out at 248C.
À
coordinating CF3CO2 ion in complex L
might play an important role in this trans-
formation (Table 1, entries 9 and 10).
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Communications
the procedures reported in the literature.[15] The Pd–Tang-
Phos-catalyzed hydrogenation of 1 under optimized condi-
tions was then performed; the results are summarized in
Table 2. Both electron-donating and electron-withdrawing
N-tosylimine is one of their most widely used synthetic
transformations. To examine the efficiency of the Pd–
TangPhos catalysts on this transformation, compound 1o
was synthesized and hydrogenated with complex L to give the
methyl-substituted sultam 2o with good enantioselectivity
[Eq. (2)].[17] To examine the synthetic potential of this
Table 2: Pd-catalyzed asymmetric hydrogenation of N-tosylimines 1.
Entry
R’ in 1
R
Prod.
ee [%][a]
Config.[b]
1
2
3
4
5
6
7
8
9
C6H5 (1a)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
CH3
2a
2b
2c
2d
2e
2 f
2g
2h
2i
99
96
99
R (+)
(+)
(+)
(+)
(+)
4-CH3C6H4 (1b)
4-FC6H4 (1c)
4-CH3OC6H4 (1d)
3-CH3OC6H4 (1e)
2-naphthyl (1 f)
1-naphthyl (1g)
4-ClC6H4 (1h)
3-ClC6H4 (1i)
C6H5 (1j)
99
methodology, a reductive cleavage of the tosyl group in 2a
was performed according to a literature procedure.[18] (R)-a-
Methylbenzylamine was obtained in 92% yield with retention
of the previous ee.
>99
>99
99
99
>99
93
(+)
(À)
(+)
(+)
In conclusion, we have developed an efficient Pd-cata-
lyzed asymmetric hydrogenation of N-tosylimines, which are
stable and can be prepared from aromatic, aliphatic, and
cyclic ketones exclusively with the E configuration. A highly
enantioselective hydrogenation of N-tosylimines has been
achieved in the presence of Pd(OCOCF3)2–TangPhos, with
enantioselectivities of up to 99% ee and conversions of more
than 99%. However, a relatively high hydrogen pressure and
catalytic loading are important limitations of this work.
Further studies to improve the turnover number and charac-
terize the catalytic species are underway and will be reported
in due course.
10
11
12
2j
2k
2l
R (+)
R (+)
(+)
tBu (1k)
cyclopropyl (1l)
98
75
[a] Enantiomeric excesses were determined by chiral HPLC. [b] The
absolute configuration was determined by comparison of the sign of the
optical rotation with the reported data.[16]
substituents on the aryl unit of the imines gave excellent
enantioselectivities (96–99% ee; Table 2, entries 1–9). The ee
value decreased from 99% to 93% when a methyl group was
replaced by an ethyl group (Table 2, entry 10). The doubly
alkyl substituted N-tosylimines 1k and 1l were also used as
substrates. Up to 98% ee was achieved for the tert-butyl-
substituted imine 1k (Table 2, entry 11), while a lower ee was Experimental Section
General hydrogenation procedure: Pd(OCOCF3)2 (3.3 mg,
observed with 1l (75% ee; Table 2, entry 12). It is worth
noting that the Pd–TangPhos-catalyzed hydrogenation of
cyclic imines 1m and 1n also proceeded with high enantio-
selectivities (98% and 94% ee, respectively) to produce a-
aminotetralin (2m) and a-aminindanes (2n), respectively,
which are important structural motifs in biologically active
compounds [Eq. (1)]. Surprisingly, we found that N-tosyli-
0.01 mmol) and (S,S,R,R)-TangPhos (3.4 mg, 0.012 mmol) were dis-
solved in degassed acetone in a Schlenk tube under N2. After stirring
the solution at room temperature for 0.5 h, the solvent was removed
under vacuum to give the complex as a brown solid. The solid was
dissolved in degassed dichloromethane (10 mL) in a glovebox and
divided equally between 10 vials. To each vial, substrate (0.1 mmol, S/
C = 100) was then added to the catalyst solution and the resulting
mixture was transferred to an autoclave, which was charged with H2
(75 atm). The autoclave was stirred at 408C for 12–24 h, before
cooling it to room temperature and carefully releasing the H2. The
solvent was then evaporated and the residue was purified by column
chromatography to give the corresponding hydrogenation product,
which was then analyzed directly by HPLC to determine the
enantiomeric excess.
Received: January 21, 2006
Published online: May 3, 2006
mines 1l, 1m, and 1n could be prepared from the corre-
sponding ketones and readily available p-toluenesulfon-
amide in one step in up to 75% yield. The feasibility of this
method for the synthesis of other N-tosylimine substrates is
still under investigation.
Keywords: asymmetric catalysis · enantioselectivity ·
hydrogenation · imines · palladium
.
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