Ru-catalyzed highly chemo- and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-β-keto esters under neutral conditions

Article abstract of DOI:10.1039/c2cc30925d

Finely-tuned ruthenium-catalyzed highly chemoselective and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-β-keto esters at the carbonyl group was achieved under neutral reaction conditions (ee up to 97%). Both olefin and alkenyl halogen moieties, which are labile under hydrogenation conditions, remained untouched during the reaction.

Full text of DOI:10.1039/c2cc30925d

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COMMUNICATION
Ru-catalyzed highly chemo- and enantioselective hydrogenation of
c-halo-c,d-unsaturated-b-keto esters under neutral conditionsw
Xin Ma,a Wanfang Li,a Xiaoming Li,a Xiaoming Tao,a Weizheng Fan,a Xiaomin Xie,a
Tahar Ayad,b Virginie Ratovelomanana-Vidalb and Zhaoguo Zhang*ac
Received 9th February 2012, Accepted 27th March 2012
DOI: 10.1039/c2cc30925d
Finely-tuned ruthenium-catalyzed highly chemoselective and
enantioselective hydrogenation of c-halo-c,d-unsaturated-b-keto
esters at the carbonyl group was achieved under neutral reaction
conditions (ee up to 97%). Both olefin and alkenyl halogen
moieties, which are labile under hydrogenation conditions,
remained untouched during the reaction.
by metal hydride reagents,7 for which stoichiometric reductants
are required.
Asymmetric hydrogenation has become one of the most
efficient and practical strategies for building up chiral centers.8
Noyori and co-workers accomplished the carbonyl-selective
asymmetric hydrogenation of many a,b-unsaturated carbonyls
with a Ru/diphosphine/diamine system under basic conditions.9
However, this efficient catalytic system was totally ineffective
for b-keto esters,10 which served as common touchstones for
many newly-designed ligands for asymmetric hydrogenations,8e,11
in addition, some substrates were not stable in the presence of a
base. As a result, carbonyl-selective asymmetric hydrogenation of
conjugated unsaturated b-keto esters under neutral conditions
was less developed,12 as the olefin moiety inclined to undergo
hydrogenation as well. Only one example was reported up to now
by asymmetric transfer hydrogenation.12b Consequently, selective
hydrogenation of the CQO group of those polyfunctionalized
conjugated keto esters is still challenging.
The importance of chiral secondary allyl alcohols is not only
due to their occurrence as vital building blocks in many
natural, pharmaceutical and agrochemical products (Fig. 1),
but also lies in that they serve as versatile intermediates for
many useful synthetic elaborations, for example the Claisen
rearrangement1 or SN20 displacement reactions,2 which enable
transfer of chirality by cleavage of C–O bonds and formation
of C–C bonds to new chiral centers. Hence various synthetic
methods have been developed over the past decades. For
instance, kinetic resolution of racemic allyl alcohols by
enantioselective acylation,3 Sharpless epoxidation,4 asym-
metric transfer hydrogenation,5 enantioselective aldehyde
vinylation6 or asymmetric reduction of a,b-unsaturated ketones
Our group previously designed a family of chiral biaryl
diphosphine ligands, SunPhos, and explored their applications
in asymmetric hydrogenation of functionalized ketones.13
Herein we report our recent progress in highly carbonyl-
selective asymmetric hydrogenation of g-halo-g,d-unsaturated
b-keto esters, giving the corresponding chiral allyl alcohols.
Previous studies showed that achieving highly carbonyl-
selective hydrogenation of unsaturated keto esters was rather
difficult, especially for those conjugated ones.12,13d,14 There-
fore, we designed a g-halogen substituted g,d-unsaturated
b-keto ester, of which the di-substituted olefin was switched
to a tri-substituted one, which may reduce the possibility of
the olefin reduction thus improving the chemoselectivity.
Moreover, the vinyl halide moiety could undergo further
transformations by organometallic methods.15 Considering
the probability of debromination during hydrogenation,13b
the g-chlorine substituted substrate 1a was employed for initial
trials. The reaction was carried out with 0.5 mol% of
[RuCl(benzene)(S)-SunPhos]Cl with a substrate concentration
of 0.5 M in EtOH at 50 1C under 10 bar of H2. To our delight,
the ketone was fully converted to the reduced alcoholic
product in 90.6% ee under this neutral condition, with trace
of ketal impurities. Neither CQC bond-saturated nor dechlori-
nated byproduct was detected by 1H NMR and TLC.16
Encouraged by this exciting result, we screened a series of
Fig. 1 Examples of chiral allyl alcohols in pharmaceuticals.
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai 200240, China
b ENSCP Chimie ParisTech, Laboratoire Charles Friedel (LCF),
CNRS, UMR 7223, 75005 Paris, France
c Shanghai Institute of Organic Chemistry, 345 Lingling Road,
Shanghai 200032, China. E-mail: zhaoguo@sjtu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details of substrate synthesis, NMR and HPLC data. See DOI:
10.1039/c2cc30925d
c
5352 Chem. Commun., 2012, 48, 5352–5354
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but was accompanied by ca. 3% of fully saturated byproduct,
as determined by 1H NMR analysis of the crude reaction
mixture. Therefore, the optimized temperature was set at 70 1C
as a compromise between chemo- and enantioselectivity.
When MeOH and n-PrOH were used as solvents, the ee’s of
2a were promoted to 93.4% and 95.5% (entries 3–4, Table 1).
Partial ethyl ester was converted to methyl and n-propyl ester
in each case. To avoid transesterification, n-propyl (1b) and
methyl (1c) esters were hydrogenated in corresponding
alcohols at 70 1C, giving 2b and 2c in 95.1% and 94.9% ee,
respectively (entries 5–6, Table 1). Obviously, the latter two
were superior to ethyl ester (1a). Although the n-propyl ester
(1b) presented a better enantioselectivity, methyl ester (1c)
was chosen for the following investigation, allowing for its
convenience of synthesis and purification (see experimental
section, ESIw). Furthermore, 1c could be completely converted
to the corresponding chloro-substituted allyl alcohol 2c within
30 min with slightly higher ee under the standard conditions:
0.5 mol% of [RuCl(benzene)(S)-SunPhos]Cl as a catalyst,
0.5 molar concentration of substrate in MeOH, and at 70 1C
under 10 bar of H2 (entry 7 vs. 6, Table 1).
Scheme 1 Screening of ligands.
atropisomeric biaryl diphosphine ligands (Scheme 1). All the
tested ligands demonstrated similar CQO/CQC selectivity,
giving the sole chlorine substituted allyl alcohol 2a. The ee’s of
2a were considerably dependent on the ligands employed.
Substituents on the phenyl appendages of the ligands were
adverse to achieving higher ee’s, which might have resulted
from the steric effect. (R)-BINAP, (S)-SEGPhos, (S)-MeO-
BIPHEP and (R)-SYNPhos were inferior to (S)-SunPhos.
(S)-p-CF3-SYNPhos, an electron-deficient ligand, resulted in
only a 15.5% ee of 2a. Based on the above results, (S)-SunPhos
was the ligand of choice.
A variety of (Z)-methyl 4-chloro-3-oxo-5-arylpent-4-enoates
(1) were submitted to assess the substrate scope, as shown in
Table 2. In all cases, the reaction proceeded very well, giving
exclusively the carbonyl reduction product with good enantio-
selectivity and a wide tolerance of functional groups. The
electronic nature of the substitution pattern showed insigni-
ficant influence on enantio-discrimination. The ee’s of 2
fluctuated slightly, from 94.9% (2m) to 96.0% (2d), when
electron neutral (entries 1–2, Table 2), electron rich (entry 3,
Table 2) and electron deficient (entries 9, 11, Table 2) substrates
were investigated. Substitution at the meta position on the phenyl
ring led to relatively lower ee, while ortho substituted substrates
gave the best results, for example, ee’s of MeO-substituted
2e–g were 95.6% (para), 94.7% (meta) and 97.0% (ortho).
Next we investigated the influence of solvent, pressure and
temperature on this reaction. Alcoholic solvents were superior
to DCM. The pressure exerted little impact on the enantio-
selectivity, whilst temperature showed significant influence on
the results of enantio-discrimination. When 1a was hydro-
genated at 70 1C in EtOH, the ee of 2a raised to 92.8%, which
further upgraded to 93.5% at 90 1C (entries 1–2, Table 1),
Table 2 Asymmetric hydrogenation of 1 by [RuCl(benzene)(S)-
SunPhos]Cla
Table 1 Optimization of the reaction conditionsa
Substrate
Yield (%)b
ee (%)c
1
R
Entry
1
2
3
4
5
6
7
8
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
C6H5
96
98
98
95
98
95
95
98
97
96d
95
97
95.7
96.0
95.6
94.7
97.0
95.3
94.2
95.5
95.4
95.1
94.9
94.1
Entry
R
Solvent
Temp. (1C)
ee (%)b
4-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
4-Cl-C6H4
3-Cl-C6H4
2-Cl-C6H4
4-F-C6H4
1
Et (1a)
Et (1a)
Et (1a)
Et (1a)
n-Pr (1b)
Me (1c)
Me (1c)
EtOH
EtOH
70
90
70
70
70
70
70
92.8
93.5
2c
3d
4d
5
MeOH
n-PrOH
n-PrOH
MeOH
MeOH
93.4 (93.2)e
95.5 (95.6)e
95.1
6
94.9
95.7
9
7f
10
11
12
4-Br-C6H4
4-CF3-C6H4
E-PhCHQCH
a
1m
1n
Unless otherwise specified, all reactions were carried out with a
substrate (1.0 mmol) concentration 0.5 M for 15 h under 10 bar of H2,
b
S/C = 200/1. ee’s were determined by HPLC on a Chiralpak IC-3
a
All reactions were carried out with a substrate (1.0 mmol) concentration
of 0.5 M in MeOH at 70 1C for 0.5 h under 10 bar of H2, S/C = 200/1.
Isolated yield. ee’s were determined by HPLC on a Chiralpak IC-3
c
d
column. CQC bond-saturated byproduct formed. Transesterification
occurred. ee’s of the corresponding transesterificated products were
f
stated in parentheses. 0.5 h.
e
b
c
d
column. Trace of debrominated product (2c) formed.
c
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K. Murata, E. Katayama, T. Yokozawa, T. Ikariya and
R. Noyori, J. Am. Chem. Soc., 1998, 120, 13529; (c) N. Arai,
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J. Am. Chem. Soc., 1995, 117, 2675.
11 D. J. Ager and S. A. Laneman, Tetrahedron: Asymmetry, 1997,
8, 3327.
12 For an example of carbonyl-selective asymmetric hydrogenation of
tri-substituted g,d-unsaturated b-keto ester with partial conversion
see: E. A. Reiff, S. K. Nair, B. S. N. Reddy, J. Inagaki, J. T. Henri,
J. F. Greiner and G. I. Georg, Tetrahedron Lett., 2004, 45, 5845.
For an example of the asymmetric transfer hydrogenation of a
di-substituted g,d-unsaturated b-keto ester see: D. Cartigny,
K. Puntener, T. Ayad, M. Scalone and V. Ratovelomanana-Vidal,
Org. Lett., 2010, 12, 3788.
13 For recent results see: (a) W. Li, X. Ma, W. Fan, X. Tao, X. Li,
X. Xie and Z. Zhang, Org. Lett., 2011, 13, 3876; (b) W. Fan, W. Li,
X. Ma, X. Tao, X. Li, Y. Yao, X. Xie and Z. Zhang, J. Org. Chem.,
2011, 76, 9444; (c) X. Tao, W. Li, X. Ma, X. Li, W. Fan, X. Xie
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and Z. Zhang, J. Org. Chem., 2008, 73, 7209.
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V. Ratovelomanana-Vidal, S. Mallart, M. X. Pfister, L. Bischoff,
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Metals, John Wiley & Sons, Hoboken, NJ, 4th edn, 2005.
16 For an example of asymmetric hydrogantion of vinyl chloride see:
I. G. Smilovic, E. Casas-Arce, S. J. Roseblade, U. Nettekoven,
A. Zanotti-Gerosa, M. Kovacevic and Z. Casar, Angew. Chem.,
Int. Ed., 2012, 51, 1014.
Scheme 2 Asymmetric hydrogenation of the bromo analogues and
their debromination.
The same trend was found when Cl was the substituent
(entries 3–5 vs. 6–8, Table 2). When 1l was hydrogenated
under these reaction conditions, only trace of debrominated
product 2c was detected by HPLC. (4Z,6E)-Methyl 4-chloro-
3-oxo-7-phenylhepta-4,6-dienoate (1n), a more functionalized
olefinic ketone, was tolerant under these conditions as well,
both CQC bonds remained untouched (entry 12, Table 2).
On the basis of the success in asymmetric hydrogenation of 1l, an
aryl bromide, we wondered whether a vinyl bromide moiety would
be tolerant under this specified condition. Bromo analogues 3a–c
were synthesized and submitted to hydrogenation. Gratifyingly,
they were fully transformed to bromo-substituted allyl alcohols
4a–c in high yields and enantioselectivities (Scheme 2), ee’s were
even higher than their chloro analogues. Phenyl ring substituted
substrates 3b and 3c need longer reaction times to achieve full
conversion. No debromination occurred, only trace of fully
saturated byproduct was detected by 1H NMR. Compared with
vinyl chloride, the remaining vinyl bromide ending could be
more easily converted to other structures by transition metal-
catalyzed reactions. For example, the C–Br bond could be
reduced to a C–H bond by HCO2Na in high yield without
racemisation under the catalysis of PdCl2(dppf) (Scheme 2).
In conclusion, we have successfully achieved a highly chemo-
selective and enantioselective asymmetric hydrogenation of a
series of g-halo-g,d-unsaturated b-keto esters at the carbonyl
group by a Ru/diphosphine catalytic system under neutral
conditions. Both the conjugated CQC double bonds and
adjacent vinyl halogens remained untouched even at the risk
of over-reduction and dehalogenation.17 This method showed
high enantioselectivity (up to 97% ee) with a wide substrate
scope. The halogen substituted chiral allyl alcohol may undergo
further derivation to access more complex building blocks,
especially in the case of the vinyl bromide.
We thank the National Natural Science Foundation of
China for financial support and Johnson Matthey (Shanghai)
Chemicals Limited for the generous loan of precious metal
catalysts.
Notes and references
1 (a) The Claisen Rearrangement: Methods and Applications,
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2007; (b) P. Wipf, in Comprehensive Organic Synthesis, ed. B. M. Trost,
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vol. 5, pp. 827–873; (c) S. Rhoads and N. Raulins, Org. React., 1975,
22, 1.
2 For an example see: G. Stork and A. R. Schoofs, J. Am. Chem.
Soc., 1979, 101, 5081.
3 (a) For an example see: J. A. MacKay and E. Vedejs, J. Org.
Chem., 2004, 69, 6934. For recent reviews of kinetic resolution
see(b) H. Pellissier, Adv. Synth. Catal., 2011, 353, 1613;
(c) E. Vedejs and M. Jure, Angew. Chem., Int. Ed., 2005, 44, 3974.
17 The introduction of halogen was crucial for the selectivity of the
CQO/CQC bond. When (E)-methyl 3-oxo-5-phenylpent-4-enoate
was hydrogenated under standard conditions for 1 h, ca. 15% fully
saturated byproduct was detected by 1H NMR at ca. 85%
conversion.
c
5354 Chem. Commun., 2012, 48, 5352–5354
This journal is The Royal Society of Chemistry 2012