Synthesis of tunable phosphinite-pyridine ligands and their applications in asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2006.04.111

A new class of modular conformationally rigid N,P ligands is conveniently synthesized from readily available starting material. Iridium complexes with these ligands have demonstrated excellent enantioselectivity (up to 99% ee) in the asymmetric hydrogenation of aryl alkenes.

Full text of DOI:10.1016/j.tetlet.2006.04.111

Tetrahedron Letters 47 (2006) 4733–4736
Synthesis of tunable phosphinite–pyridine ligands and
their applications in asymmetric hydrogenation
Qi-Bin Liu, Chang-Bin Yu and Yong-Gui Zhou*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, PR China
Received 5 April 2006; revised 20 April 2006; accepted 21 April 2006
Abstract—A new class of modular conformationally rigid N,P ligands is conveniently synthesized from readily available starting
material. Iridium complexes with these ligands have demonstrated excellent enantioselectivity (up to 99% ee) in the asymmetric
hydrogenation of aryl alkenes.
Ó 2006 Elsevier Ltd. All rights reserved.
Transition-metal catalyzed asymmetric hydrogenation is
one of the most powerful methods for preparing chiral
compounds. While ruthenium- and rhodium-catalyzed
asymmetric hydrogenations of chelating olefins have a
long history,1 unfunctionalized olefins still represent a
challenging class of substrates. During the past few
years, Pfaltz and others2a–m have developed chiral mim-
ics of Crabtree’s catalyst,3 which have been used success-
fully for asymmetric hydrogenation of arylalkenes.
However, since iridium-catalyzed asymmetric hydroge-
nation is still highly substrate dependent, subtle changes
of ligand structure either electronically or sterically
often bring in dramatic impacts on enantioselectivities.
Therefore, the development of new efficient and tunable
chiral ligands for iridium-catalyzed hydrogenation is a
continuing challenge.
to the aromatic heterocycle to reduce conformational
flexibility. With these criteria in mind, the success of
the above ligands 1 and 2 motivated us to develop a
new class of modular conformationally rigid and struc-
ture tunable pyridine-derived chiral N,P ligands 3.4 This
ligand contains the following three sites, which can be
finely tuned: substituent Ar of phosphorus, substituent
R of pyridine ring and size n of the fused ring. Herein,
we report a procedure suitable for convenient ligand
synthesis and in application of aryl alkenes as a means
of hydrogenation with up to 99% ee.
The synthesis of pyridyl phosphinites ligands 3 was sum-
marized in Scheme 1. The acetate 6 was synthesized on a
multigram scale in three steps from cheap starting mate-
rials such as simple cyclic ketones 4 and ethyl acetoace-
tate 5 according to the known procedure.5a–d Hydrolysis
of the acetate 6 with K2CO3/methanol afforded the cor-
responding racemic chloro alcohol 7 in high yields.
Chemical resolution of 7 or 6 is the most convenient
method to obtain the chiral intermediate 7. Unfortu-
nately, all attempts for selective crystallization of a dia-
stereomeric salt with chiral acids were unsuccessful,
presumably due to the weak basicity of pyridine nitro-
gen and intramolecular hydrogen bonding.6 Then, we
turned our attention to the enantioselective preparation
of 7 by an asymmetric reduction of corresponding ke-
tone.7 Therefore, the racemic chloro alcohol 7 was trans-
formed to the corresponding chloroketone 8 in 90–91%
yields by Swern oxidation according to the literature
procedure.5b The commercially available reagent CBS
was used for the enantioselective reduction. Under opti-
mized conditions,8 catalytic asymmetric reduction of
Among many chiral N,P ligands successfully applied in
the asymmetric hydrogenation, the N,P ligands derived
from pyridine was reported in only a few cases.2d,i
The representative examples were ligands 1 and 2
(Fig. 1), but both synthetic routes are long and they
made it difficult to finely tune the electronic and steric
effect. For designing of a new class of N,P ligands,
Andersson2k recently summarized the following criteria:
(1) contain a nitrogen atom and a phosphorus to get a
significant trans effect and reaction site discrimination,
(2) be able to form a six-member chelate ring upon com-
plex formation, and (3) contain a rigid backbone fused
*
Corresponding author. Tel./fax: +86 411 84379220; e-mail:
ygzhou@dicp.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.111

4734
Q.-B. Liu et al. / Tetrahedron Letters 47 (2006) 4733–4736
+
Me
N
R1
PPh2
N
_
PF6
Cy3P Ir
N
R
O
( )
n
PR2
N
R
R1
O
PAr2
2
1
3
Crabtree's catalyst
Figure 1.
Me
Me
O
O
O
a
b
+
n
( )
( )
n
n
OEt
Cl
N
Cl
N
OAc
OH
7 ( n = 0, 1)
Me
4
5
6 (n = 0, 1)
Me
Me
c
+
e, f
d
( )
( )
n
n
Cl
N
Ir
Cl
N
Cl
N
O
O
OH
_
8 ( n = 0, 1)
PPh2
7 ( n = 0, 1)
BARF
11a: 54%
Me
Me
+
g
e, f
7
N
Ir
N
O
11b: 28%
OH
_
9
PPh2
BARF
+
11c-11h: n = 0; 11i-11j: n = 1
11c: R = Ph, Ar = Ph, 48%
Me
Me
11d: R = Ph, Ar = o-Tol, 34%
11e: R = p-MeC6H4, Ar = Ph, 61%
11f: R =p-MeC6H4, Ar = o-Tol, 32%
11g: R = p-CF3C6H4, Ar = Ph, 65%
e, f
h
7
( )
R
N
Ir
n
R
N
O
11h: R = p-CF3C6H4, Ar = o-Tol, 46%
11i : R = Ph, Ar = Ph, 81%
OH
10 (n = 0,1)
PAr2
_
11j: R = Ph, Ar = o-Tol, 36%
BARF
Scheme 1. Synthesis of pyridyl phosphinite complexes 11a–j. Reagents and conditions: (a) see Ref. 5; (b) K2CO3, methanol, rt, 2–6 h; (c) DMSO,
(COCl)2, CH2Cl2, Et3N, À78 °C to rt; (d) (S)-Me–CBS (0.1 equiv), BH3ÆTHF, 30 °C, 1.5–2 h, 87% ee (n = 1, 99% ee after crystallization) and 68% ee
(n = 2, >99% ee after crystallization); (e) for Ar = Ph: Ph2PNEt2/imidazole/Et3N, CH2Cl2, 10–24 h; for Ar = o-Tol: (o-Tol)2PNEt2/4,5-
dichloroimidazole/Et3N, ClCH2CH2Cl, reflux, 36 h; (f) [Ir(COD)Cl]2, CH2Cl2, reflux, 1.5 h, then NaBArF, reflux, 30 min, H2O, 10 min,
BArF = (tetrakis[3,5-bis(trifluoromethyl)phenyl]borate); (g) Pd/C, 95% EtOH, H2, rt, 4 h, 75%; (h) Pd(PPh3)4, ArB(OH)2, Na2CO3/H2O, EtOH,
MeOCH2CH2OMe, reflux, 16 h.
chloroketone with (S)-Me–CBS–borane9 provided (R)-
chloro alcohol 710 in quantitative yields and 87% ee
(n = 0) or 68% ee (n = 1). For 7 (n = 0), the mother
liquor of one recrystallization from the petroleum
ether/Et2O/EtOH was subsequently crystallized three
times in i-PrOH/hexane to give the optically pure
compound with 6% recovery. For 7 (n = 1), the mother
liquor of three recrystallization from Et2O was then
crystallized once in hexane to give the optically pure
compound with 55% recovery.
chloro alcohol 7 was also subjected to a Suzuki coupling
reaction with the corresponding arylboronic acid. The
reactions proceeded smoothly in the presence of
3 mol % Pd(PPh3)4 and afforded the desired products
10 in high yields.
Deprotonation of the alcohol 7 with n-BuLi and subse-
quent reaction with the chlorodiphenylphosphine did
not afford the desirable phosphinites 3.2d However, reac-
tion with N,N-diethyl aminodiphenylphosphanes in the
presence of imidazole, the desired phosphinites were
obtained at room temperature or reflux condition.2d
For the steric hindered diethylaminodiarylphosphanes
(Ar = o-Tol), no product was obtained under the above
conditions even when 4,5-dichloroimidazole was used.
To study the influence of three modular centers of the
ligands, a series of ligands were synthesized from the
intermediate 7. The chloro alcohol 7 was dechlorinated
to afford 9 using Pd/C in 95% EtOH. Likewise, the

Q.-B. Liu et al. / Tetrahedron Letters 47 (2006) 4733–4736
4735
Nevertheless, the corresponding product was success-
fully obtained at reflux when a higher boiling point sol-
vent 1,2-dichloroethane was used in the presence of 4,5-
dichloroimidazole. The products namely, phosphinites 3
can be isolated by column chromatography under nitro-
gen in over 50% yields. However, these compounds are
not stable, therefore, the reaction mixtures were sub-
jected to a flash chromatography through a degassed sil-
ica gel in order to remove some impurities and directly
used for the next step. The corresponding iridium com-
plexes were made by a slightly modified standard litera-
ture procedure, and the resulting complexes are air
stable foaming orange to red solid, which can be conve-
niently purified by chromatography.
ligands with (o-Tol)2P group was slightly superior to that
of the corresponding ligands with Ph2P group. Among
the iridium complexes, the highest ee value (99%) was
obtained with catalyst 11f, which has a p-methylphenyl
group on pyridine ring. It is noteworthy that the enantio-
selectivity with ligands 3 was comparable to that
achieved with other chiral N,P ligands.2 We have tested
other two substrates ethyl 2-methylcinnamate 14 and
allylic alcohol 15 with catalyst 11, good enantioselectiv-
ities (88% ee and 86% ee) were also obtained,
respectively.
In conclusion, we have developed a new class of modu-
lar conformationally rigid N,P-ligands for iridium-cata-
lyzed asymmetric hydrogenation. Excellent reactivities
and enantioselectivities were obtained in the hydrogena-
tion of aryl alkenes. Further studies on optimized syn-
thesis of the ligand and application to other
asymmetric reactions are underway.
Hydrogenation of (E)-1,2-diphenylpropene 12 was cho-
sen as a model reaction to test potential catalysts. The
hydrogenations were carried out at room temperature
under 50 bar of hydrogen pressure using CH2Cl2 as
the solvent. In this system, the selectivity and reaction
reactivity were dependent on catalyst structure (Table
1). Firstly, for cyclopentanone derived catalysts (11a–
h), excellent reactivity was observed except for 11b.
The enantioselectivity increased from 86% ee (R = H)
to 98% ee (R = Ph) when the bulk of R group increased.
The similar enantioselectivity was obtained when aryl
group changed from electron-withdrawing group p-
CF3C6H4 to electron-donating p-CH3C6H4. Secondly,
upon the changing from five-member-ring to a six-mem-
ber-ring derivative, the selectivity and reactivity of cata-
lyst lowered significantly (entry 9 vs entry 3 and entry 10
vs entry 4). Thirdly, the enantioselectivities of the
Acknowledgments
We are grateful to the financial support from National
Science Foundation of China (20532050) and Talent
Scientist Program, Chinese Academy of Sciences.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.04.111.
Table 1. Iridium-catalyzed asymmetric hydrogenation of (E)-1,2-
diphenylpropene 12
References and notes
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12
Entry
13
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Catalyst
Conv (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
11g
11h
11i
>99
83
86 (R)
95 (R)
98 (R)
98 (R)
98 (R)
99 (R)
98 (R)
97 (R)
86 (R)
89 (R)
>99
>99
>99
>99
>99
>99
32
10
11j
85
a
The conversion was calculated based on the ratio of methyl group by
1H NMR.
b Ee was measured by HPLC and absolute configuration of the
product was determined by comparison of the sign of the optical
rotation to reported data.
CO2Et
OH
15
14
11f: 88% ee, >99%
11g: 86% ee, >99%
3. Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331–338.

4736
Q.-B. Liu et al. / Tetrahedron Letters 47 (2006) 4733–4736
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Me–CBS asymmetric reduction.
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