A new chiral sulfinyl-NH-pyridine ligand for Ir-catalyzed asymmetric transfer hydrogenation reaction

Article abstract of DOI:10.1016/j.tetlet.2012.04.110

A new flexible C₁-symmetric tridentate ligand (S)-N-(2-(tert-butylsulfinyl)benzyl)-1-(pyridin-2-yl)methanamine sulfoxide (L1) was successfully prepared and utilized as a chiral ligand for Ir(I)-catalyzed ATH (asymmetric transfer hydrogenation) reactions. Without any cooperation of other chiral center, encouraging ee and conversion values have been achieved, which provide us a better understanding on these types of ligands and a new strategy to develop new high-efficiency chiral catalysts for asymmetric reaction.

Full text of DOI:10.1016/j.tetlet.2012.04.110

Tetrahedron Letters 53 (2012) 3839–3842
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new chiral sulfinyl–NH–pyridine ligand for Ir-catalyzed asymmetric
transfer hydrogenation reaction
Lei Tang a,c, Qiwei Wang a, Juanjuan Wang a,c, Zechao Lin a,c, Xiaobei Wang a,b, Linfeng Cun a,
Weicheng Yuan a, Jin Zhu a, Jian Liao d, Jingen Deng a,b,c,
⇑
a Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
c Graduate School of Chinese Academy of Sciences, Beijing 100049, China
d Natural Products Research Center, Chengdu Institute of Biology & Chinese Academy of Sciences, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new flexible C1-symmetric tridentate ligand (S)-N-(2-(tert-butylsulfinyl)benzyl)-1-(pyridin-2-yl)meth-
anamine sulfoxide (L1) was successfully prepared and utilized as a chiral ligand for Ir(I)-catalyzed ATH
(asymmetric transfer hydrogenation) reactions. Without any cooperation of other chiral center, encour-
aging ee and conversion values have been achieved, which provide us a better understanding on these
types of ligands and a new strategy to develop new high-efficiency chiral catalysts for asymmetric
reaction.
Received 11 February 2012
Revised 12 April 2012
Accepted 24 April 2012
Available online 28 April 2012
Keywords:
Ó 2012 Published by Elsevier Ltd.
Chiral tert-butylsulfinyl moiety
Weak coordination
Flexible tridentate ligands
ATH reaction
Chiral ligands, with fast development in recent years, are con-
sidered to be of essentially importance on asymmetric catalysis.1
Much more attentions are attracted on design and synthesis of
new chiral ligands, especially the one with new types of coordina-
tion groups. As moieties with stereogenicity at sulfur, rigid biden-
tate ligands containing chiral sulfinyl groups show excellent
stereo-control in asymmetric reactions.2–4 With the collaboration
of carbon stereogenic center, ligands containing chiral aromatic-
sulfinyl moiety exhibited good stereoselectivity in rhodium-cata-
lyzed asymmetric arylboronic acids additions.2a,4e Ligands with
tert-butylsulfinyl moiety and rigid structure made a better perfor-
mance on much more metal catalyzed reactions. They were able to
provide a good chiral environment even without any other chiral
center, and afford high ee value products.2b,3,4a–d
elimination and addition mechanism.7 Another part of ligands
was displaced with tert-butylsulfinyl moiety, which was the only
chiral source to realize stereo control. Meanwhile, the third coordi-
nation site, –PPh2 or pyridine, was kept as a strong coordination
group to keep the metal complex stable enough. Although only
the tert-butylsulfinyl group was a weak coordination site, it would
also be difficult to coordinate with the metal completely unless the
metal source was suitable. Thus, [IrCl(COE)2]2 was used.8 We ex-
pected that without any collaboration of other chiral center and ri-
gid structure, this type of catalyst would be efficient enough on
stereo selectivity.
The synthesis of these two ligands was outlined in Scheme 2.
(S)-(2-(tert-Butylsulfinyl)phenyl)methanamine (1)9 was chosen as
the starting material, which was reacted with aldehyde 2 or 310
However, bidentate ligands with chiral sulfinyl groups were not
performed so well on ATH reactions.5 Recently, Baratta and Zotto
reported a series of tridentate PNN0 ligands, which showed surpris-
ing activity and achieved encouraging ee value directed by carbon
stereogenic center on Ru-catalyzed ATH reactions.6
Therefore, a new type of tridentate ligands based on Barrata’s li-
gands were devised (Scheme 1). In our design, NH group was kept
as an initial functional moiety. It would show acidity after cooper-
ating with metal, and realize transfer hydrogenation catalysis by
N
H
N
S
O
t-Bu
L1
N
H
PPh2
N
N
H
S Ph2P
t-Bu
O
L2
⇑
Corresponding author. Fax: +86 28 85238597.
E-mail address: jgdeng@cioc.ac.cn (J. Deng).
Scheme 1. Chiral tridentate ligands design.
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.04.110

3840
L. Tang et al. / Tetrahedron Letters 53 (2012) 3839–3842
CHO
N
H
t-Bu
L1
1. Na2SO4, CH2Cl2, 30 °C
2. NaBH4, CH3OH 47 %
N
2
N
S
O
NH2
CHO
PPh
S
t-Bu
1. Na2SO4, CH2Cl2, 30 °C
O
2 3
N
H
1
S Ph2P
t-Bu L2
2. NaBH4, CH3OH
35 %
O
Scheme 2. Ligands synthesis.
Table 1
Optimizing conditions for Ir(l)/L catalyzed ATH reactiona,d
[IrCl(COE)2]2
O
OH
*
O
Ligand
S
t-Bu
L3PPh2
L/Ir = 0.9/1
S/C = 100
MeO
5a
4a
f
Entry
Ligand
Additive
Solvent, base and hydrogen source
Temp (°C)
t (h)
Convn.f (%)
ee. (%)
1
2b
3
L1
L1
L2
L2
L1
L1
L2
L2
L2
L1
L1
L1
L1
L1
—
PPh3
—
PPh3
—
PPh3
—
PPh3
—
—
PPh3
L3
—
H2O/HCOONae
H2O/HCOONa
H2O/HCOONa
H2O/HCOONa
EtOH/t-BuOK
EtOH/t-BuOK
EtOH/t-BuOK
EtOH/t-BuOK
i-PrOH/t-BuOK
i-PrOH/t-BuOK
i-PrOH/t-BuOK
i-PrOH/t-BuOK
i-PrOH/t-BuOK
i-PrOH/t-BuOK
28
28
28
28
28
28
28
28
28
28
28
28
20
0
9
9
9
9
9
9
9
9
3
3
3
3
3
3
N.D.
N.D.
N.D.
49
N.D.
7
N.D.
49
20
98
94
89
96
—
—
—
10
—
1
4b
5
c
6
7
—
2
8c
9
31
69
35
60
74
71
10
11b
12b
13
14
—
20
a
Unless otherwise noticed, activation condition was followed below: (1) [IrCl(COE)2]2 (1 mol %, 1.1 mg), ligand (0.9 mol %) in 1 ml CH2Cl2, 40 °C, 2 h. (2) Acetophenone
0.25 mmol.
b
Activation condition 2: [IrCl(COE)2]2 (1 mol%, 1.1 mg), ligand (0.9 mol%) in 1 ml CH2Cl2, 40 °C, 2 h. (2) Add PPh3 (0.9 mol %) in 1 ml CH2Cl2, 40 °C, 0.5 h. (3) AgOTf (1 mol %),
40 °C, 3 h, filtered. (3) Acetophenone 0.25 mmol.
c
Activation condition 3: [IrCl(COE)2]2 (1 mol %, 1.1 mg), ligand (0.9 mol %) in 1 ml CH2Cl2, 40 °C, 2 h. (2) Add PPh3 or L3 (0.9 mol %) in 1 ml CH2Cl2, 40 °C, 0.5 h. (3)
Acetophenone 0.25 mmol.
d
Unless otherwise noticed, reaction condition was followed by the general method for ATH reaction.
The reaction condition: Acetophenone (30 mg, 0.25 mmol), H2O (1 ml), HCOONa (85 mg, 1.25 mmol).
Determined by GC analysis.
e
f
as a condensation reaction, and reduced by NaBH4 directly to pro-
vide L1 or L2.
The substrate scope catalyzed by Ir-L1 was then performed, as
outlined in Table 2. Obviously, substrates with electron donor sub-
stituents in benzyl group had a little change on ee value, but show
lower activity than acetophenone (entries 2–4 and 7). To be con-
trast, although the reaction activity of the acetophenone deriva-
tives with electron accepter substituents was remained, the ee
value decreased, especially those of 5e and 5f (entries 5, 6, 8, and
9). Compared to electronic effects, steric hindrance had much less
effect on convention value, even though the substituents were as
large as tert-butyl and trifluoromethyl group (entries 3 and 9).
When the acetophenone derivates were substituted by n-propyl
and n-butyl groups, reaction results were just the same as template
substrate. However, when the substituents became i-propyl, only
10% product was observed (entry 12). To our surprise, when the al-
kyl group was changed into n-octyl group, the configuration was
inversed, and the conversion value declined (entry 13). What’s
more, substrates with rigid ring got the same inversion on stereo
selectivity, too (entries 15, 16 and 18). Interestingly, 20-acetonaph-
thone 5q got similar result as 5a, while 10-acetonsphthone 5r get
reversed configuration, whose ee value was 84%. Therefore, we
could speculate that affected by the chiral tert-butanesulfinyl
group of this catalyst, atoms with planar structure or flexible alkyls
which were easy to keep in a plane were favored by the catalyst. It
means that a large group with planar structure such as benzyl
23ATH reaction was performed with acetophenone as the sub-
strate, as shown in Table 1. Both of these two ligands afford poor re-
sults when the solvent was water or ethanol (entries 1–8). Most of
these conditions showed no reaction activity, and only L2 with PPh3
additive as well as ion exchanged with AgOTf7c could make this
reaction work. Nearly no stereoselectivity could be observed in
these conditions (entries 4 and 8). When the solvent was replaced
by isopropyl alcohol,7a encouraged results were obtained. Although
L2 was still of disappoint performance (entry 9), reaction catalyzed
by Ir-L1 brought us an inspired result (entry 10), which could
achieve 98% conversion and 69% ee in 3 h reaction at 28 °C. Adding
PPh3 caused a significant decline on ee value. (S) tert-Butanesulfi-
nylphosphines (L3)3c was added instead of PPh3, whose chiral
tert-butanesulfinyl moiety was considered to be an auxiliary group,
and would not coordinate with Iridium. We would like to see
whether the stereo-selectivity would be improved only by intro-
ducing another chiral tert-butanesulfinyl group. Unfortunately,
the ee value was decreased, and the reaction activity was even
much lower than that of entry 10. The effect of the reaction temper-
ature was investigated. We changed reaction temperature (entries
10, 13, and 14) and make certain that 20 °C should be most suitable,
affording 74% ee and 96% conversion.

L. Tang et al. / Tetrahedron Letters 53 (2012) 3839–3842
3841
Table 2
Table 2 (continued)
Substances scope for Ir-L1 catalyzed ketones ATH reactionsa
Entry Substance
Convnb
%
Eeb
%
Configurationc
[IrCl(COE)2]2
O
OH
O
L1
/Ir = 0.9/1, S/C = 100
R1
R2
R1
R2
4n
4o
4p
14
15
16
68
34
62
10
61
26
S
*
CF3
i-PrOH/t-BuOK, 20°C, 3h
11
10
O
R
R
Entry Substance
Convnb
%
Eeb
Configurationc
O
%
O
4a
4b
1
2
96
92
74
S
S
O
4q
4r
17
18
93
40
71
84
S
O
69
77
O
R
O
4c
3
93
S
O
O
S
4s
4t
19
20
21
22
73
56
62
—
S
O
O
80
S
4d
4e
4
5
68
70
70
S
S
O
O
4u
4v
N.D.
N.D.
—
—
O
98
98
O
—
F
O
a
Reaction conditions: [IrCl(COE)2]2 (1 mol %, 1.1 mg), ligand (0.9 mol %) in 1 ml
CH2Cl2, 40 °C, 2 h. (2) 0.25 mmol substrates 5 in 2.5 ml i-PrOH, t-BuOK (10 mol %) in
0.5 ml i-PrOH, 20 °C, 3 h.
4f
6
7
43
75
S
S
b
Determined by GC analysis.
c
Cl
O
Absolute configuration was determined by GC analysis, while the templates
were prepared by Noyori’s method.11
O
d
Determined by HPLC in chiral OD column.
4g
81
group could be tolerated by chiral tert-butylsulfinyl moiety more
easily rather than branched group even though it seemed smaller.
That might be why some of the configurations were inversed. Sub-
strates with heterocyclic group, 5s and 5t, did not get satisfied per-
formance on both activity and stereo selectivity. Besides, when the
substrates were aliphatic ketones, the reaction did not work (en-
tries 21 and 22).
In conclusion, we have designed and synthesized a new flexible
chiral tert-butylsulfinyl–NH–pyridine tridentate ligand (L1). It
realizes stereo-control only with chiral tert-butylsulfinyl moiety
and exhibits encouraged performance on ATH reaction. These
types of ligands in other metal catalyzed asymmetric reactions
are now understudy.
O
F
4h
4i
8
9
92
98
69
70
S
S
O
CF3
O
4j
10
11
12
93
91
10
79
70d
78
S
S
S
O
O
Acknowledgments
4k
4l
We gratefully acknowledge National Nature Science Foundation
of China (Grant No. 21172152), National Basic Research Program of
China (973 Program, No. 2010CB833300) and Sichuan University
for their financial supports.
4m
O
Reference and notes
13
68
75
R
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