Synthesis of chiral cyclohexane-backbone P,N-ligands derived from pyridine and their applications in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2007.01.123

P,N-ligands trans-4 and cis-5 with a cyclohexane backbone were easily synthesized. The key step was chiral resolution of (±)-trans-2-pyridylcyclohexanols with DBTA. Enantiopure trans isomer was subjected to Mitsunobu reaction and deprotection to give the

Full text of DOI:10.1016/j.tetlet.2007.01.123

Tetrahedron Letters 48 (2007) 2101–2104
Synthesis of chiral cyclohexane-backbone P,N-ligands derived
from pyridine and their applications in asymmetric catalysis
Qi-Bin Liu and Yong-Gui Zhou*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, PR China
Received 14 November 2006; revised 23 January 2007; accepted 24 January 2007
Available online 27 January 2007
Abstract—P,N-ligands trans-4 and cis-5 with a cyclohexane backbone were easily synthesized. The key step was chiral resolution of
( )-trans-2-pyridylcyclohexanols with DBTA. Enantiopure trans isomer was subjected to Mitsunobu reaction and deprotection to
give the corresponding cis isomer. These ligands have been successfully used in asymmetric hydrogenation of arylalkenes with up to
93% ee using 5 and 90% ee using 4 and asymmetric allylic alkylations with up to 95% ee using 5 and 93% ee using 4. Trans and cis
P,N-ligands 4 and 5 all gave the product with the same configuration. It was suggested that the absolute configuration of the product
was controlled by the configuration of the stereogenic pyridyl-bearing carbon of the ligands.
Ó 2007 Elsevier Ltd. All rights reserved.
R1
1. Introduction
R1
PPh2
O
Transition-metal-catalyzed asymmetric transformations
in the presence of chiral ligands have proved to be one
of the most efficient methods for the construction of
enantioenriched chiral compounds.1 Design and synthe-
sis of novel chiral ligands have therefore been a topic of
great interest in organic and organometallic chemistry in
the past few decades. In late-transition-metal catalysis,
the development of phosphorus- and nitrogen-based
chiral ligands has been most extensively investigated.2
Pfaltz and others have developed chiral mimics of Crab-
tree’s catalyst,3 and successfully used iridium complexes
of P,N-ligands for the asymmetric hydrogenation of
unfunctionalized olefins.4 However, P,N-ligands derived
from pyridine have been reported in only a few exam-
ples. The representative examples were ligands 1 and 2
(Fig. 1). Very recently, we5 and Pfaltz6 have also devel-
oped a class of bicycle P,N-ligands 3 and successfully
applied in iridium-catalyzed asymmetric hydrogenation.
As our work extends, herein, we wish to report the
synthesis of a new class of trans and cis chiral cyclo-
hexane-backbone P,N-ligands 4 and 5, which form
seven-member ring in their metal-complex, and their
applications in Ir-catalyzed hydrogenations of arylalk-
enes and Pd-catalyzed allylic alkylations.
N
R
( )
n
R2
N
PR2
N
R1
OPAr2
3 R1 = H (Pfaltz)
R1 = Me (Our)
1
2
O
PAr2
O
PAr2
N
R
N
R
trans-4
cis-5
Figure 1.
The synthesis of chiral cyclohexane-backbone P,N-
ligands 4 and 5 starts from the known racemic com-
pounds 67,8 (Scheme 1), which can be obtained by
NaBH4 reduction (mixture of trans and cis isomer,
trans/cis: ꢀ2/1) of the corresponding ketones. The prep-
aration of the optical pure of trans and cis isomers was
the key step. Kita reported a simple method of separa-
tion by extraction.8,9a The ( )-trans-2-pyridylcyclohexa-
nols reacted with chiral 3b-acetoxyetienic acid chloride
to give the corresponding diastereomeric esters, which
were separated by extraction using achiral-organic
solvent and acid solution based on a difference in pKa
values of the diastereomers. Reduction of the corre-
sponding diastereomeric esters gave optically active pyr-
idyl alcohols. Subsequently, Kita also reported kinetic
resolution of ( )-trans-2-pyridylcyclohexanols using
chiral 3b-acetoxyetienic acid, DCC and DMAP.9b Due
*
Corresponding author. Tel./fax: +86 411 84379220; e-mail:
ygzhou@dicp.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.123

2102
Q.-B. Liu, Y.-G. Zhou / Tetrahedron Letters 48 (2007) 2101–2104
OH
Ph2
P
OPPh2
OH
d
O
a
Ir(COD)
R
b or c
N
R
N
R
N
R
N
BARF
trans-6 (racemic)
R = H, Me, Et, i-Pr
(1R,2S)-trans-6
(1R,2S)-trans-4
4a: R = H; 4b: R = Me
4c: R = Et; 4d: R = i-Pr
trans-8a: R = H
trans-8b: R = Me
trans-8c: R = i-Pr
Ar2
OPAr2
d
OH
OH
P
O
Ir(COD)
R
c
e
N
R
N
R
N
R
N
BARF
(1R,2S)-trans-6
(1S,2S)-cis-7
(1S,2S)-cis-5
5a: R = H; 5b: R = Me
5c: R = Et; 5d: R = i-Pr
cis-9a: R = H, Ar = Ph
cis-9b: R = Me, Ar = Ph
cis-9c: R = i-Pr, Ar = Ph
cis-9d: R = H, Ar = o-Tol
Scheme 1. Reagents and conditions: (a) (L)-DBTA, MeOH (trans-6a), EtOH (trans-6b), acetone/EtOH (trans-6c and cis-7c), petroleum/EtOH (trans-
6d and cis-7d); then KOH, CH2Cl2, 40% (6a), 56% (6b), 7% (6c), 12% (6d) (two steps); (b) n-BuLi, THF, Ph2PCl; (c) Ar2PNEt2, Et3N, 4,5-
dichloroimidazole, DCM or ClCH2CH2Cl, reflux; (d) for trans series: [Ir(COD)Cl]2 (0.5 equiv), CH2Cl2, reflux, then NaBARF (1.0 equiv), H2O, rt,
10 min; for cis series: [Ir(COD)Cl]2 (0.5 equiv), CH2Cl2, reflux, 1.5 h, then NaBARF (1.5 equiv), H2O, 50 °C, 30 min. BARF = (tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate); (e) p-NO2C6H4COOH, PPh3, DIAD, benzene, rt, then K2CO3/MeOH, reflux, 67–91% (two steps).
to the difficulty in obtaining the enantiopure pyridylhex-
anols for the above methods, therefore, developing a
convenient method to enantiopure trans- and cis-pyridyl
cyclohexanols was still required. Encouraged by the suc-
cessful use of crystallization procedures of diastereo-
meric salts of tartaric acid with secondary alcohols
containing the pyridyl group,10 we focused on the devel-
opment of a resolution protocol of pyridyl alcohols 6
with inexpensive tartaric acid derivatives.
substance trans-6b–d were slightly low due to the
increasing bulk of the R group. Hydrolysis of the corre-
sponding esters with K2CO3/methanol at reflux afforded
the corresponding enantiopure cis-7a–d in high yields.
Trans-6a–d were deprotonated with n-BuLi at 0 °C, then
treated with chlorodiphenylphosphine to afford the
desired trans-4a–d in 34–82% yields. Cis isomer 7a–d
cannot afford the desirable products under the above
condition, the reason might be the strong intramolecular
hydrogen bonding of cis-7a–d. Using Pfaltz’s condition,
Ar2PNEt2/Et3N/4,5-dichloroimidazole/reflux, the de-
sired phosphinites cis-5a–d can be obtained in 56–77%
yields.4l,6b Although the resulting ligands are acid-labile,
they can be purified by rapid flash chromatography on
silica gel.
In our attempts for ( )-trans-2-pyridylcyclohexanols
resolution, we found the di-benzyl tartaric acid (DBTA)
be an efficient resolving agent. When ( )-trans-pyridyl-
cyclohexanols 6a was reacted with 1.0 equiv (L)-DBTAÆ
H2O in methanol, the collected diastereomeric salts of
(L)-DBTAÆH2O by filtration can be upgraded to
>99% ee via three recrystallization in MeOH. The abso-
lute stereochemistry of trans-6a was determined by com-
parison of the sign of the optical rotation with reported
data.8 The cis isomer could not form the diastereomeric
salt with (L)-DBTAÆH2O due to the intramolecular
hydrogen bonding between pyridine nitrogen and
hydroxyl group. So, we can resolve directly the trans
and cis mixtures to give only chiral trans isomer 6a.
trans-6b was also resolved with (L)-DBTA in ethanol.
For the mixture of trans-6c–d and cis-7c–d, no single
solvent was suitable, but when the mixture solvents were
used, the enantiopure trans-6c or 6d could be easily
obtained (see Supplementary data).
2. Pd-catalyzed asymmetric allylic alkylation
Ligands trans-4 and cis-5 were evaluated in the palla-
dium-catalyzed asymmetric allylic alkylation of 1,3-di-
phenyl-2-propenyl acetate (10) with dimethyl malonate
as shown in Table 1. The reaction was carried out in
the presence of 2.5 mol% [Pd(C3H5)Cl]2, 5 mol% of
ligand 4 or 5 and a mixture of N,O-bis(trimethylsilyl)
acetamide (BSA) and 5 mol% of KOAc. All reactions
were complete in 2 h at 20 °C. For ligands trans-4 series,
the enantioselectivity increased from 53% to 93% when
R group of the ligand increased from hydrogen to iso-
propyl group (entries 1–4). Ligand trans-4d afforded
the highest enantiomeric excess of up to 93% (entry 4).
A key transformation in our synthetic approach toward
the enantiopure cis isomer 7 was configuration inversion
of the secondary alcohol moiety of trans-6. After survey-
ing a variety of modifications of the Mitsunobu reaction
for more sterically congested substrates, we found that
using p-nitrobenzoic acid in benzene resulted in almost
quantitative yield with perfect inversion of stereochemis-
try with secondary alcohols by SN2 replacement (by
HPLC, (1S,2S)-cis-7a: >99% ee).11 The yields for other
Very interestingly, cis-5a–d ligands gave slightly higher
activity and enantioselectivity than the corresponding
trans isomer except for ligand 5d. The enantioselectivity
increased from 79% to 95% when the bulk of R group in
the ligand increased from hydrogen to methyl group
(entries 5–6). However, when R group was isopropyl

Q.-B. Liu, Y.-G. Zhou / Tetrahedron Letters 48 (2007) 2101–2104
2103
Table 1. Palladium-catalyzed asymmetric allylic substitution reac-
tionsa
Table 2. Iridium-catalyzed asymmetric hydrogenations of arylalkenesa
Ph
Ph
Catalyst (0.5 mol%)
H2 (50 bar), DCM
OAc
Ph
[Pd(C3H5)Cl]2 / L*
CH(CO2Me)2
Ph
CH2(CO2Me)2
BSA / KOAc / DCM
R
Ph
Ph
R
10
11
12a: R = H
12b: R = OMe
13a: R = H
13b: R = OMe
Entry
Ligand
Yieldb (%)
ee (%)/Conf.
Entry
Sub.
Catalyst
Convn.b (%)
eec (%)
1
2
3
4
5
6
7
8
trans-4a
trans-4b
trans-4c
trans-4d
cis-5a
cis-5b
cis-5c
cis-5d
98
94
98
92
95
92
91
92
53 (R)
84 (R)
89 (R)
93 (R)
79 (R)
95 (R)
94 (R)
92 (R)
1
2
3
4
5
6
7
8
9
12a
12a
12a
12b
12a
12a
12a
12a
12b
12b
trans-8a
trans-8b
trans-8c
trans-8a
cis-9a
>99
<5
<5
>99
98
88 (S)
—
—
90 (S)
90 (S)
—
cis-9b
<5
cis-9c
<5
—
cis-9d
cis-9a
cis-9d
>99
>99
>99
90 (S)
91 (S)
93 (S)
a Reaction conditions: 2.5 mol% [Pd(C3H5)Cl]2 and 5 mol% ligand
was stirred for 1 h and subsequently 5 mol% KOAc and 10 was
added, after 1 h, dimethylmalonate and BSA was added to the
reaction solution.
10
a Reaction conditions: all reactions were performed using 0.5 mmol of
substrate and 2 mL of dichloromethane in the pressure of 50 bar
hydrogen.
b Conversion was determined by 1H NMR.
c Determination by HPLC with a chiral column.
b Isolated yield.
group, slightly lower enantioselectivity (92%) was ob-
served (entry 8). Among all cis-5 series, ligand cis-5b
afforded the highest enantiomeric excess of up to 95%
(entry 6). In the above experiments, P,N ligands trans-
4 and cis-5 gave the products with the same absolute
configuration, so, the absolute configuration of the
product was controlled by the configuration of the stereo-
genic pyridyl-bearing carbon of the ligands.
cis-9a with Ph2P group (entry 8 vs entry 5, entry 10 vs
entry 9).
In comparison to the configuration of the product ob-
served in palladium-catalyzed asymmetric allylic alkyl-
ation, catalyst 8 and 9 also afforded a similar result
giving product with the same configuration in asymmet-
ric hydrogenations of aryl alkenes. This fact, again
strongly suggests that the absolute configuration of the
product was controlled by the configuration of the stereo-
genic pyridyl-bearing carbon of the ligands.
3. Ir-catalyzed asymmetric hydrogenations
Chiral P,N-ligands have showed high activity and excel-
lent enantioselectivity in Ir-catalyzed asymmetric hydro-
genation of unfunctionalized olefins. To evaluate the
catalytic properties of ligands 4 and 5 in asymmetric
hydrogenation, their Ir-complexes were prepared
according to the known literature procedure,4d,l,5,6 in
which a weakly coordinating group BARF (tetra-
kis[3,5-bis(trifluoromethyl)phenyl]borate) was used as
the counter ion (Scheme 1).
In summary, a new type of P,N-ligands, trans-4 and
cis-5 containing a cyclohexane backbone, was easily
synthesized. The key steps were chiral resolution of
( )-trans-2-pyridylcyclohexanols
and
Mitsunobu
inversion. These ligands have been successfully used in
asymmetric hydrogenation of arylalkenes with up to
93% ee using 5 and 90% ee using 4 and asymmetric
allylic alkylations with up to 95% ee using 5 and
93% ee using 4. Trans and cis P,N-ligands 4 and 5 all
gave the product with the same configuration. Further
studies on application to other asymmetric reactions
are underway.
Methylstilbene 12a, a typical substrate for Ir-catalyzed
asymmetric hydrogenation of unfunctionalized olefins,
was initially tested with complexes trans-8a-c under
50 bar of H2 pressure at room temperature in CH2Cl2.
As shown in Table 2, catalyst trans-8a gave complete
conversions and 88% ee, however, catalysts trans-8b–c
exhibited no reactivity (entries 2–3). Substitution of pyr-
idine ring in ligands remarkably lowered the catalyst
activities. The product of 90% ee can be obtained for
substrate 12b in the presence of catalyst trans-8a (entry
4). For the catalyst cis-9a, the conversion of 98% and
90% ee were obtained under the standard conditions.
Consistently, for cis-9 series, substitution of pyridine
ring in ligands remarkably lowered the catalyst activities
(entries 6–7). The product of 91% ee and full conversion
were obtained for substrate 12b in the presence of cata-
lyst cis-9a (entry 9). The enantioselecitivities and activi-
ties of catalyst cis-9d with steric (o-Tol)2P group were
slightly superior to that of the corresponding catalyst
Acknowledgment
We are grateful for the financial support from National
Science Foundation of China (20672112).
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