Palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic ketones for the synthesis oftranscycloalkanols through dynamic kinetic resolution under acidic conditions

Article abstract of DOI:10.1039/d0cc00480d

The first efficient palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic ketones has been described through dynamic kinetic resolution under acidic conditions, providing a facile access to chiraltranscycloalkanol derivatives with excellent enantioselectivities.

Full text of DOI:10.1039/d0cc00480d

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S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC00480D
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Palladium-Catalyzed Asymmetric Hydrogenation of 2-Aryl Cyclic
Ketones for the Synthesis of trans Cycloalkanols through Dynamic
Kinetic Resolution under Acidic Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Xiang Li,a,b Zi-Biao Zhao,b Mu-Wang Chen,b Bo Wu,b Han Wang,a Chang-Bin Yub,* and Yong-Gui
DOI: 10.1039/x0xx00000x
Zhoua,b,
*
www.rsc.org/
The first efficient palladium-catalyzed asymmetric hydrogenation
of 2-aryl cyclic ketones has been described through dynamic
kinetic resolution under acidic conditions, providing a facile access
to chiral trans cycloalkanol derivatives with excellent enantiose-
lectivities.
a) Previous Work:
Cis Product under Basic Condition (Ru, Ir and Cu)
O
O
OH
R
M H
R
M = Ru, Ir, Cu
Cis Product
O
R
Base
The significance of chiral cycloalkanols with two contiguous
stereocenters has been widely recognized in natural products,
pharmaceuticals and other bioactive molecules.1 Transition
metal-catalyzed asymmetric hydrogenation of corresponding
cyclic ketones is one of the most efficient and facile methods
because of their high atom economy and environmental
friendliness.2 In the past decades, asymmetric hydrogenation
of 2-substituted cyclic ketones was usually carried out under
basic conditions using chiral metal complexes such as
ruthenium3-5 or iridium6 or copper7 via dynamic kinetic
resolution (DKR)8,9, and cis selective products were obtained
due to the steric hindrance effect of the substituents (Scheme
1a). To the best of our knowledge, although the asymmetric
hydrogenation of linear ketones to construct anti alkanols has
obtained success,10 there are rare examples for the synthesis
of trans selective products through asymmetric hydrogenation
of 2-substituted cyclic ketones except a directing ester group11
in the 2-position. Therefore, the development of transition
metal-catalyzed asymmetric hydrogenation to construct the
chiral trans cycloalkanols through DKR is highly desired.
R
Dynamic Kinetic Resolution
b) This Work:
Trans Product under Acidic Condition (Pd)
O
OH
Ar
Ar
Pd
H
Ar
Trans Product
OH
Ar
Acid
O
Dynamic Kinetic Resolution
Scheme 1. Metal-Catalyzed Asymmetric Hydrogenation of 2-
Substituted Cyclic Ketones.
the hydrogenation transition state.13 Thus, we envisioned
whether the palladium/acid co-catalysis system could be used
for the asymmetric hydrogenation of simple 2-aryl substituted
cyclic ketones14 to construct trans cycloalkanols through the
interaction between the palladium and the aromatic ring
(Scheme 1b). However, there are some challenges in this topic:
1) the interaction is very weak between metal palladium and
aryl ring; 2) the racemization of 2-aryl cyclic ketones under
acidic conditions is more difficult than that in basic conditions;
3) secondary alcohols are unstable in the presence of strong
acid, which would be leading to dehydration. In order to verify
the hypothesis, we firstly performed the racemization
experiments of chiral ketone (S)-3. When benzoic acid was
used, the ee value of ketone (S)-3 was maintained. Almost
racemic product was obtained in the presence of strong acidic
TsOH•H2O. The results of experiments showed that the
ketones were able to fast racemize via an enol intermediate
In recent years, our group has been working on palladium-
catalyzed asymmetric hydrogenation.2f,12 Lately, we disclosed a
palladium-catalyzed asymmetric hydrogenative desymmetriza-
tion of 2-aryl-1,3-cyclopentanediones, giving the trans 2-aryl
substituted -hydroxy ketones, the possible reason ascribes to
the interaction between palladium and aromatic ring during
a Zhang DayuSchool of Chemistry, Dalian University of Technology, 2 Linggong
Road, Dalian 116024, P. R. China. E-mail: ygzhou@dicp.ac.cn.
b State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China. E-mail: cbyu@dicp.ac.cn.,
ygzhou@dicp.ac.cn.
Electronic Supplementary Information (ESI) available: [details of any supplemen-
tary information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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under strong acidic conditions (Scheme 2), which provide a slightly lower diastereoselectivity were observVeiedw A(r2tichle-iO).nlinAe
DOI: 10.1039/D0CC00480D
prerequisite for the asymmetric hydrogenation of ketones methyl group at the ortho-, meta- or para-position of phenyl
through DKR. Herein, we report
a palladium-catalyzed ring had a marginal effect on the reactivities and
asymmetric hydrogenation of 2-aryl cyclic ketones to construct enantioselectivities (2j-l). Both electron-donating and electron-
trans cycloalkanols through DKR under acidic conditions.
withdrawing groups at para-position were compatible, giving
the desirable products in high yields and stereoselectivities
(2m-p). In addition, it was also suitable to have two
substituents on the phenyl ring (2q). When benzyl group was
introduced, low conversion was observed, the stereoselectivity
was also low, which indicated that the aryl on 2-position was
very crucial to activity and enantioselectivity (2r). This catalytic
system is not well compatible for the hydrogenation of 5-
membered and 7-membered ketones. Although the desirable
products could be successfully obtained under modified
conditions, the yields were low due to incomplete conversion
(2s-t).
O
PhCO2H, TFE, 30 oC, 2 h
Ar
O
Ar
93% ee (S)
O
93% ee
Ar = 1-Naphthyl
TsOH•H2O, TFE, 30 oC, 2 h
Ar
3
(S)-
1.1% ee
Scheme 2. Racemization Experiments of Chiral Ketone (S)-3.
Table 1. Optimization of the Reaction Conditions.a
At the outset, 2-(naphthalen-1-yl)cyclohexan-1-one 1a was
chosen as a model substrate for condition optimization. We
found that 81% yield of 2a with 13% ee and 6:1 trans/cis ratio
could be obtained when acid was not added (Table 1, entry 1).
Considering the importance of acid for racemization, we
turned our attention to the evaluation of acids. To our delight,
the anticipated product 2a was obtained with 83% ee and >
20:1 trans/cis ratio in the presence of TsOH•H2O (entry 2).
However, other acids including Zn(OTf)2, PhCO2H and CF3CO2H,
exhibited the lower stereoselectivities (entries 3-5). We
further investigated the effect of the amount of acid (entries 6-
7). Gratifyingly, increasing the amount of acid to 50 mol%, the
ee value of the product was increased to 91% (entry 6).
Subsequently, some commercially available chiral diphosphine
ligands were screened. Among them, (R)-SegPhos L1 proved to
be a suitable ligand in view of yield and enantioselectivity
(entries 8-10). To further improve enantioselectivity and yield,
the effect of temperature was examined (entries 11-13). When
O
OH
L
Pd(OCOCF3)2,
Ar
Ar
Acid, TFE, H2 (100 psi), 60 oC, 24 h
Ar = 1-Naphthyl
1a
2a
O
O
O
O
O
O
PPh2
PPh2
PAr2
PAr2
PPh2
PPh2
PPh2
PPh2
O
O
Ar = 3,5-DiMeC6H3
L2: (R)-DM-SegPhos
L4: (R)-H8-BINAP
L1: (R)-SegPhos
L3: (R)-BINAP
Entry
Acid
L
Trans:cisb 2a (%)b Ee (%)c
1
2
none
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
6:1
81
82
13
83
12
21
33
91
89
89
87
83
94
95
97
TsOH•H2O
Zn(OTf)2
> 20:1
6:1
3
77
4
PhCO2H
4:1
80
o
the reaction was conducted at 30 C, the desired product was
5
6d
7e
8d
CF3CO2H
2:1
63
obtained in 92% yield with 97% ee and > 20:1 trans/cis ratio
(entry 13). Therefore, the optimal conditions were established
as Pd(OCOCF3)2 (5 mol%)/(R)-SegPhos (6 mol%)/TsOH•H2O (50
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
TsOH•H2O
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
76
63
o
mol%)/TFE/H2 (100 psi)/30 C. The absolute configuration of
81
hydrogenation product 2a was determined to be (1R,2S)-2a by
comparison with the value of optical rotations reported in the
literature.15
9d
71
10d
11d,f
12d,g
13d,h
73
With the optimized reaction conditions established, we
investigated the substrate scope of the reaction. The results
were summarized in Scheme 3. Substrates 1b and 1c bearing
polycyclic aryls exhibited comparable trans selectivities and
yields with 1a albeit with the lower enantioselectivities.
Subsequently, we explored the effect of substituents on the
naphthyl ring. Various groups at para-position including MeO-,
Me-, and F- were compatible under the standard reaction
conditions, furnishing the products with excellent yields and
stereoselectivities (2d-f). Furthermore, phenyl substrate 1g
was favorable reaction partners, and the reaction proceeded
smoothly in high yield and stereoselectivity (91% yield, 88%
ee, > 20:1 trans/cis ratio). The presence of a MeO- or a CF3- at
ortho-position of phenyl ring, incomplete conversion and
86
90
92 (91)i
a Reaction conditions: 1a (0.2 mmol), Pd(OCOCF3)2 (5 mol%), L (6 mol%),
acid (20 mol%), TFE (2.0 mL), 60 oC, H2 (100 psi), 24 h. All the
b
conversions > 95%.
Determined by 1H NMR analysis using the
dibromomethane as the internal standard. c Determined by chiral HPLC
analysis. TsOH•H2O (50 mol%). TsOH•H2O (100 mol%). 50 oC. 40
d
e
f
g
oC. h 30 oC. i Isolated yield.
To further illustrate the reaction process, asymmetric
hydrogenation of chiral ketone (S)-3 was performed by using
ligands (R)- or (S)-SegPhos under the optimal conditions. The
products with opposite configuration could be obtained with
2 | J. Name., 2012, 00, 1-3
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the same ee values (Scheme 4), respectively, indicating that
the chiral ketone (S)-3 was initially racemized via keto-enol
tautomerism, and then further hydrogenated. The above
experimental results showed that the asymmetric hydrogena-
tion of 2-aryl substituted cyclic ketones undergoes dynamic
kinetic resolution process under palladium/acid conditions.
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DOI: 10.1039/D0CC00480D
This reaction could be also scaled up smoothly, when
substrate 1a and 1d were conducted at 1.5 mmol scale, both
activity and enantioselectivity maintained. Considering that
hydroxyl group is versatile functional group, further
transformations of chiral product 2a was conducted (Scheme
5). Firstly, chlorination of cyclic alcohol 2a using PPh3-NCS
afforded chloroalkane 4 with 84% yield and 95% ee. In addition,
esterification of 2a with methanesulfonyl chloride followed by
a nucleophilic substitution with NaN3 furnished the chiral azide
product 5 (81% yield, 97% ee) without loss of optical purity,
which can be further converted into amine or triazole
derivatives.16
O
OH
Pd(OCOCF3)2, (R)-SegPhos
R
R
TsOH•H2O, TFE, H2 (100 psi), 30 oC, 24 h
(
)
(
)
n
n
n = 0, 1, 2
1
2
OMe
HO
HO
HO
HO
OH
O
Pd(OCOCF3)2 (5 mol%)
(R)-SegPhos (6 mol%)
Ar
Ar
H2
(100 psi)
+
TsOH H O (50 mol%)
•
b
b
b
b
2
2a
2b
2c
2d
83% , 97% ee
91% , 97% ee
94% , 82% ee
83% , 91% ee
TFE, 42 h, 30 o
C
1a, 1d
(1.5 mmol)
2a, 2d
Yield (%) Ee (%)
93 (315 mg) 97
97
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
Ar
Me
F
2a
2d
1-Naphthyl
4-Methoxy-1-naphthyl 85 (324 mg)
HO
HO
HO
HO
OMe
Cl
Ar
OH
N3
Ar
Ar
1) MsCl, Et3N, DCM
NCS
b
b
b
b
2e
2f
2g
2h
77% , 93% ee
89% , 98% ee
88% , 97% ee
91% , 88% ee
2) NaN3, DMF, 90 o
81% yield
C
PPh3, THF
84% yield
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
trans:cis = 13:1
2a
5
97% ee
4
(97% ee)
Ar = 1-Naphthyl
95% ee
Me
Me
HO
HO
HO
HO
Scheme 5. Scale-up Experiment and Transformations of 2a.
CF3
Me
b
b
b
b
2i
2j
2k
2l
40% , 86% ee
86% , 94% ee
79% , 89% ee
86% , 92% ee
Conclusions
trans:cis = 11:1
OMe
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
CF3
F
Cl
In summary, we have successfully developed the first
palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic
ketones via dynamic kinetic resolution under acidic conditions.
A series of cyclic ketones were hydrogenated to construct
chiral trans cycloalkanols with two contiguous stereocenters in
high yields with excellent enantioselectivities and trans
selectivities.17 Notably, the Brønsted acids had a significant
influence in the reaction and accelerated the racemization of
the substrates. Further investigations on the asymmetric
synthesis of trans cycloalkanol derivatives with multiple chiral
sterocenters under acidic conditions are being performed.
HO
HO
HO
HO
b
b
b
b
2m
2n
2o
2p
82% , 88% ee
84% , 82% ee
72% , 81% ee
92% , 83% ee
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
trans:cis > 20:1
Me
HO
HO
HO
HO
Me
b
2q
2rc
2sd
92% , 95% ee
28%b, 9% ee
trans:cis = 8:1
63%b, 77% ee
trans:cis = 11:1
trans-2te
39%b, 72% ee
14%b, 73% ee
cis-
2t'e
trans:cis > 20:1
trans:cis = 3:1
a Reaction Conditions: 1 (0.3 mmol), Pd(OCOCF3)2 (5 mol%), (R)-SegPhos (6
Acknowledgements
Financial support from National Natural Science Foundation of
China (21532006, 21690074) and Chinese Academy of Sciences
b
mol%), TsOH•H2O (50 mol%), TFE (3.0 mL), 30 oC, H2 (100 psi), 24 h.
Isolated yield. c 48 h. d The pentafluorobenzoic acid (200 mol%) was used
e
instead of TsOH•H2O and the reaction was run at 80 oC for 24 h. The
bis(4-nitrophenyl)phosphate (200 mol%) was used instead of TsOH•H2O
(XDB17020300, QYZDJ-SSW-SLH035) is acknowledged
.
and the reaction was runned at 60 oC for 48 h.
Scheme 3. Substrate Scope of 2-Substituted Cyclic Ketones.a
Notes and references
‡Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
OH
Ar
(R)-SegPhos
Pd(OCOCF3)2/
TsOH•H2O, TFE, H2, 30 o
C
O
2a
2a
97% ee (1R,2S)-
Ar
1
For selected reviews, see: (a) B. Heasley, Eur. J. Org. Chem.,
2009, 1477; (b) B. Heasley, Curr. Org. Chem., 2014, 18, 641;
(c) S. P. Simeonov, J. P. M. Nunes, K. Guerra, V. B. Kurteva
and C. A. M. Afonso, Chem. Rev., 2016, 116, 5744.
OH
Ar
(S)-SegPhos
Pd(OCOCF3)2/
93% ee
Ar = 1-Naphthyl
TsOH•H2O, TFE, H2, 30 o
C
3
(S)-
97% ee (1S,2R)-
Scheme 4. The Control Experiments.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC00480D
Table of Contents:
O
OH
Pd(OCOCF3)2, (R)-SegPhos
TsOH H2O, TFE, H2 (100 psi)
Ar
Ar
Ar
OH
Trans Product
20 examples
up to 98% ee
Ar
TsOH H O
•
2
O
Dynamic Kinetic Resolution in Acidic Condition
The first efficient palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic ketones has been
described through dynamic kinetic resolution under acidic conditions, providing a facile access to chiral
trans cycloalkanoles with excellent enantioselectivities. Notably, the Brnsted acids had a significant
influence and accelerated the racemization of the substrates.