An efficient synthesis of chiral β-hydroxy sulfones via Ru-catalyzed enantioselective hydrogenation in the presence of iodine

Article abstract of DOI:10.1021/ol702565x

Ru-SUNPHOS catalyzed asymmetric hydrogenation of a variety of sulfonyl ketones (R = alkyl, aryl) in the presence of iodine gave enantioenriched hydroxyl sulfones with good catalytic efficiency. Further investigation revealed that the in situ generated anh

Full text of DOI:10.1021/ol702565x

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5613-5616
An Efficient Synthesis of Chiral
-Hydroxy Sulfones via Ru-Catalyzed
Enantioselective Hydrogenation in the
Presence of Iodine
â
Xiaobing Wan,† Qinghua Meng,‡ Hongwei Zhang,‡ Yanhui Sun,†
Weizheng Fan,‡ and Zhaoguo Zhang*,†,‡
School of Chemistry and Chemical Engineering, Shanghai Jiaotong UniVersity, 800
Dongchuan Road, Shanghai 200240, China, and Shanghai Institute of Organic
Chemistry, 354 Fenglin Road, Shanghai 200032, China
zhaoguo@sjtu.edu.cn
Received October 22, 2007
ABSTRACT
Ru-SUNPHOS catalyzed asymmetric hydrogenation of a variety of sulfonyl ketones (R
) alkyl, aryl) in the presence of iodine gave enantioenriched
hydroxyl sulfones with good catalytic efficiency. Further investigation revealed that the in situ generated anhydrous HI is the operating additive.
The increasing demand for enantiomerically pure pharma-
ceuticals, agrochemicals, flavors, and other fine chemicals
has greatly stimulated the research in the field of asymmetric
catalytic technologies.1,2 Among these, asymmetric hydro-
genation, which utilizes molecular hydrogen to reduce
prochiral olefins, ketones, and imines, has become one of
the most efficient methods for constructing chiral com-
pounds.3 It is well-known that asymmetric catalytic systems
are often very sensitive to small variations in substrate,
catalyst, and reaction conditions. Frequently, small amounts
of achiral or chiral additives have been attributed to remark-
able change in conversion rate, yield, enantioselectivity, and
even reaction pathway.4 This effect is not only significant
in academic reasearch4b but also serves a pivotal role in some
industrial applications.4c
Optically active â-hydroxy aryl sulfones are useful chiral
synthons in organic synthesis, as the R-carbon among these
compounds can be further functionalized and, moreover, the
sulfonyl groups can be easily removed from the skeleton
† Shanghai Jiaotong University.
‡ Shanghai Institute of Organic Chemistry.
(3) (a) Noyori, R.; Kitamura, M. In Mordern Synthetic Methods;
Scheffold, R., Ed.; Springer: Berlin, Germany, 1989; Vol. 5. (b) Ohkuma,
T.; Noyori, R. In Transition Metals for Organic Synthesis, Building Blocks
and Fine Chemicals; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Vol. 2. (c) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.;
Ho¨rmann, E.; McIntyre, S.; Menges, F.; Scho¨nleber, M.; Smidt, S. P.;
Wu¨stenberg, B.; Zimmermann, N. AdV. Synth. Catal. 2003, 345, 33. (d)
Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M.
AdV. Synth. Catal. 2003, 345, 103. (e) Blaser, H.-U.; Schmidt, E., Eds.
Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and
Solutions; Wiley-VCH: Weinheim, Germany, 2004.
(4) (a) Cornils, B.; Hermann, W. A., Eds. In Applied Homogeneous
Catalysis with Organometallic Compounds; VCH: Weinheim, Germany,
1996; Vol. 2, pp 74 and 351. (b) Vogl, E. M.; Gro¨ger, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1999, 38, 1570. (c) Spindler, F.; Blaser, H.-U.
Enantiomer 1999, 4, 557.
(1) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008 and references
cited therein. (b) Knowles, W. S. AdV. Synth. Catal. 2003, 345, 3. (c) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(d) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley: New York,
2000. (e) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999.
(f) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe Catalysis;
VCH: Weinheim, Germany, 1993. (g) Jannes, G.; Dubois, V., Eds. In Chiral
Reaction in Heterogeneous Catalysis; Plenum: New York, 1995. (h) Cornils,
B.; Hermann, W. A., Eds. In Applied Homogeneous Catalysis with
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and 2.
(2) (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (b) Cornils,
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10.1021/ol702565x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

without racemization5,6 They have been successfully applied
to synthesis of biologically active molecules such as
γ-butenolides,6a-c γ-butyrolactones,6d 5-disubstituted tetra-
hydrofuran and δ-valeractones,6e etc. As a result, many
methods have been developed for the enantioselective
synthesis of optically active â-hydroxy sulfones, including
kinetic resolution,7 and/or kinetically controlled oxidation of
racemic substrates by biocatalysts,8 baker’s yeast or fungus9
mediated reduction and chiral oxazaborolidine10 or polymer-
supported sulfonamide11-catalyzed borane reduction of â-keto
sulfone. Geneˆt et al. reported an enantioselective hydrogena-
tion of â-keto sulfones with chiral Ru(II) catalyst,12 and Hou
and co-workers reported Rh-catalyzed enantioselective hy-
drogenation of â-keto sulfones using a bisferrocenyl diphos-
phine ligand with planar chirality;13 however, reduction of
aromatic analogues required drastic reaction conditions to
obtain high optical purity or more expensive Rh catalyst.
Recently we have been focusing on the design and
application of new biaryl phosphine ligands. Initial work in
this area has resulted in the identification of a series of
bidentate ligands L1-L4 (Figure 1) highly effective at
enantioselective hydrogenation of ketoesters.14 We also
reported the significant improvement on catalyst stability and
enantioselectivity by Lewis acid additives in the asymmetric
hydrogenation of R-ketoesters.14c In this paper, we report a
highly enantioselective hydrogenation of â-keto sulfones in
the presence of iodine.
Figure 1. Structure of ligands.
also tested for the asymmetric hydrogenation of 1-phenyl-
2-(phenylsulfonyl)ethanone (1a) under 150 psi of H2, at
70 °C in EtOH for 20 h with 1 mol % of Ru(II) catalyst.
The â-ketosulfone 1a was successfully reduced with com-
plete conversion and good ee. We found the enantioselec-
tivities were greatly dependent on ligands, ee increasing in
the following order: (R)-BINAP (73.0%), L4 (89.7%), L2
(90.3%), (S)-SEGPhos (92.5%), L1 (94.5%), L3 (95.2%)
(Table 1).
The chiral Ru(II) catalyst was readily prepared from [Ru-
(benzene)Cl2]2 and diphosphine ligand by refluxing them in
degassed ethanol/benzene for 1 h.15 The chiral bidentate
ligands L1-L4 and two commercially available chiral
bidentate phosphines, (R)-BINAP and (S)-SEGPhos, were
(5) (a) Patai, S.; Rappoport, Z., Eds. The Chemistry of Sulfur-Containing
Functional Groups; Wiley-Interscience: New York, 1993. (b) Oae, S.
Organic Sulfur Chemistry; CRC Press: Boca Raton, FL, 1991. (c) Belenkii,
L. I. Chemistry of Organosulfur Compounds; Ellis Horwood: New York,
1990. (d) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
New York, 1993. (e) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107. (f)
Fuchs, P. L.; Breish, T. F. Chem. ReV. 1986, 86, 903.
Table 1. Catalytic Asymmetric Hydrogenation of 1a with
[RuCl(benzene)L]Cla
(6) (a) Solladie´, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem.
1986, 51, 1912. (b) Robin, S.; Huet, F.; Fauve, A.; Veschambre, H.
Tetrahedron: Asymmetry 1993, 4, 239. (c) Kozikowski, A. P.; Mugrage,
B. B.; Li, C. S.; Felder, L. Tetrahedron Lett. 1986, 27, 4817. (d) Sato, T.;
Okumura, Y.; Itai, J.; Fujisawa, T. Chem. Lett. 1988, 1537. (e) Tanikaga,
R.; Hosoya, K.; Kaji, A. J. Chem. Soc., Perkin Trans. 1 1987, 1799.
(7) Chinchilla, R.; Najera, C.; Pardo, J.; Yus, M. Tetrahedron: Asymmetry
1990, 1, 575.
(8) Ohta, H.; Kato, Y.; Tsuchihashi, G. J. Org. Chem. 1987, 52, 2735.
(9) For reviews, see: (a) Servi, S. Synthesis 1990, 1. (b) Csuk, R.;
Gla¨nzer, B. I. Chem. ReV. 1991, 91, 49. (c) Robert, S. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 1. (d) Crumbie, R. L.; Deol, B. S.; Nemorin, J. E.;
Ridley, D. D. Aust. J. Chem. 1978, 31, 1965. (e) Goto, V.; Rebolledo, F.;
Liz, R. Tetrahedron: Asymmetry 2001, 12, 513.
(10) Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043.
(11) Zhao, G.; Hu, J. B.; Qian, Z. S.; Yin, W. X. Tetrahedron:
Asymmetry 2002, 13, 2095.
(12) (a) Bertus, P.; Phansavath, V.; Ratovelomanana-Vidal, V.; Geneˆt,
J. P.; Touati, A. R.; Homri, T.; Ben Hassine, B. Tetrahedron Lett. 1999,
40, 3175. (b) Bertus, P.; Phansavath, V.; Ratovelomanana-Vidal, V.; Geneˆt,
J. P.; Touati, A. R.; Homri, T.; Ben Hassine, B. Tetrahedron: Asymmetry
1999, 10, 1369.
entry
L
ee (%)b
1
2
3
4
5
6
(R)-BINAP
(S)-SEGPhos
73.0
92.5
94.5
90.3
95.2
89.7
L1
L2
L3
L4
a All reactions were carried out under 150 psi of hydrogen with a substrate
(1 mmol) concentration of 0.25 M in EtOH at 70 °C for 20 h. Substrate/
[Ru(benzene)Cl2]2/ligand ) 100/0.5/1.1, Conversion: 100%. b Ee values
were determined by HPLC on a Chiralpak AD-H column.
It has been reported that catalytic additives play a crucial
role in improving the reactivity and enantioselectivity of
(13) Zhang, H. L.; Hou, X. L.; Dai, L. X.; Luo, Z. B. Tetrahedron:
Asymmetry 2007, 18, 224.
(14) (a) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.; Pan, Y.; Zhang,
Z. Tetrahedron: Asymmetry 2004, 15, 2185. (b) Wan, X.; Sun, Y.; Luo,
Y.; Li, D.; Zhang, Z. J. Org. Chem. 2005, 70, 1070. (c) Sun, Y.; Wan, X.;
Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7,
5425.
(15) (a) Mashima, K.; Kusano, K.; Ohta, T.; Noyori, R.; Takaya, H. J.
Chem. Soc., Chem. Commun. 1989, 1208. (b) Mashima, K.; Kusano, K.;
Sate, N.; Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori,
Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064.
5614
Org. Lett., Vol. 9, No. 26, 2007

many asymmetric reactions.4 Accordingly, we evaluated a
number of additives for asymmetric hydrogenation of 1a by
using 1 mol % of Ru(II)-L3 complex as catalyst and 3 mol
% of the additive in an attempt to promote the enantiose-
lectivity. As shown in Table 2, a series of sulfonic acids
Table 3. The Asymmetric Hydrogenation of 1 with
[RuCl(benzene)L3]Cla
entry
R
ee (%)b
Table 2. Optimization Studies of Catalytic Asymmetric
Hydrogenation of 1aa
1
2
3
4
5
6
7
8
9
10
11
12
13d
Ph (1a)
99.2
98.9
98.7c
98.8c
99.4
98.2
98.3
97.1
89.8
99.4
97.0
99.3
99.1
4-F-C6H4 (1b)
4-Cl-C6H4 (1c)
4-Br-C6H4 (1d)
4-Me-C6H4 (1e)
4-MeO-C6H4 (1f)
3-Cl-C6H4 (1g)
2-Me-C6H4 (1h)
2-Cl-C6H4 (1i)
Me (1j)
entry
additives
convn (%)
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12e
13f
CSAd
100
100
100
100
100
100
100
100
23b
15b
100
100
90b
96.6
96.2
95.6
95.7
95.9
96.1
97.0
98.9
60.1
27.6
99.2
99.1
99.0
CF3SO3H
CH3SO3H
H2SO4
TsOH‚H2O
HCl aq
HBr aq
HI aq
K2CO3
Et3N
i-Pr (1k)
Cy (1l)
Ph (1a)
I2
I2
I2
a All the reactions were carried out under 150 psi of hydrogen gas with
a substrate (1 mmol) concentration of 0.25 M in EtOH at 70 °C for 20 h.
Substrate/[Ru(benzene)Cl2]/L3/I2 ) 200/0.5/1.1/3.0. Conversion: 100%.b Ee
values were determined by HPLC on a Chiralpak AD-H column. c Ee values
were determined by HPLC on a Chiralcel OJ-H column. d S/C ) 1000/1.
Conversion: >95% (NMR).
a All reactions were carried out under 150 psi of hydrogen with a substrate
(1 mmol) concentration of 0.25 M in EtOH at 70 °C for 20 h. Substrate/
[Ru(benzene)Cl2]2/L3/additives ) 100/0.5/1.1/3.0. b Determined by 1H
NMR. c Ee values were determined by HPLC on a Chiralpak AD-H column.
d Camphor sulfonic acid. e Methanol was used as solvent. f Isopropanol was
used as solvent.
entry 8); for a coordinating ortho-substituted substrate, the
ee drops dramatically (ee 89.8%, entry 9).
Hydrogenation of an aliphatic analogue also gave excellent
enatioselectivity (R ) Me, ee 99.4%, entry 11), even for
the more hindered carbonyl groups (R ) i-Pr, ee 97.0%, entry
12 and R ) Cy, ee 99.3%, entry 13).
When the substrate/catalyst ratio increased from 200 to
1000, the hydrogenation of 1a still proceeded smoothly,
keeping the enantioselectivity (ee 99.2%, entry 1, vs ee
99.1%, entry 13).
Several groups have recently applied iodine or iodide salts
in Ir-catalyzed asymmetric hydrogenation.4c,16 To our best
knowledge, there has been no report on the effect of iodine
on Ru-catalyzed reactions. To investigate the role of iodine
in the hydrogenation reactions, we have run three experie-
ments: first, we mixed [RuCl(cymene)L3]Cl with 3 equiv
of iodine in the presence or absence of 1a in EtOH under
150 psi of hydrogen gas at room temperature for 2 h, and
we found that the purple-red color of both solutions disap-
peared; second, we dissolved substrate 1a and 1 equiv of
iodine in EtOH, and evaporated EtOH to afford an R-iodi-
nated product 2-iodo-1-phenyl-2-(phenylsulfonyl)ethanone
(4a); third, when we terminated the hydrogenation reaction
of 4a halfway, we noticed complete deiodation (1H NMR
(Table 2, entries 1-5) slightly increased the ee values of
the â-hydroxy sulfone 2a. Aqueous HX also enhanced
enantioselectivities in the following order: HCl aq (ee 96.1%,
entry 6), HBr aq (ee 97.0%, entry 7), HI aq (ee 98.9%, entry
8). In contrast to acidic additives, the addition of organic or
inorganic bases decreased both the enatioselectivities and
conversion rates (entries 9 and 10). Interestingly, when iodine
was applied to the asymmetric hydrogenation of â-ketosul-
fone 1a, an unprecedentedly high enantioselectivity was
obtained (ee 99.2%, entry 11). Similar results were obtained
when methanol or isopropanol was employed as solvent,
although a lower conversion of starting material was
observed when isopropanol was employed (Table 2, entries
12 and 13).
Under the optimized reaction conditions, a variety of
substrates were hydrogenated with use of [RuCl(benzene)-
L3]Cl/I2 as catalyst (Table 3). A series of â-keto sulfones
bearing a different substituent at the para position on the
phenyl group were studied (entries 2-6). The results show
that the electron density of the aromatic ring has little effect
on the enantioselectivities (ee 98.7-99.4%, entries 2-6),
even p-methoxy (strong electron-donating substituent) sub-
stituted aryl â-keto sulfone (ee 98.2%, entry 6). When m-Cl
was employed as the substrate, high enantioselectivity was
also obtained comparable to those of the para-substituted
substrates (98.3%, ee, entry 7). For the ortho-substituted
â-keto sulfones, the hydrogenation results are depending on
the substituents on the aromatic ring: for a noncoordinating
ortho-substituted substrate, the ee drops slightly (ee 97.1%,
(16) (a) Togni, A. Angew. Chem., Int. Ed. 1996, 35, 1475. (b) Xiao, D.;
Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (c) Wang, W.-B.; Lu,
S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003,
125, 10536. (d) Chi, Y.; Zhou, Y.; Zhang, X. J. Org. Chem. 2003, 68,
4120. (e) Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.
(f) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966. (g)
Hou, G.-H.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2006,
128, 11774. (h) Zhou, Y.-G. Acc. Chem. Res., published online Sept. 27,
http://dx.doi.org/10.1021/ar700094b.
Org. Lett., Vol. 9, No. 26, 2007
5615

detection) prior to the complete conversion to the final
compound. It is clear that the iodine or the iodated ketone
was reduced to give hydrogen iodide under the hydrogenation
conditions. So we further carried out a series of hydrogena-
tion reactions to investigate the mechanism of the iodine
effect. As shown in Table 4, asymmetric hydrogenation of
3), comparable to asymmetric hydrogenation of 1a with
addition of iodine (ee 99.2%, Table 2, entry 11). Asymmetric
hydrogenation of 1a with 4a as the additive also gave the
same result as with the addition of iodine (ee 99.2%, entry
4), but NaI was found to exert no positive effect (ee 95.2%,
entry 5). Hydrogenation of 2-bromo-1-phenyl-2-(phenylsul-
fonyl)ethanone (4b) also gave 2a as the product of excellent
enantioselectivity (ee 98.6%, entry 7). These results impli-
cated the active role of hydroiodic acid generated in situ
rather than I2 itself. The Brønsted acids HX (X ) I, Br)
generated in situ promote the enatioselectivity and serve
better than their aqueous conuterparts (X ) I, Br, Cl; Table
2, entries 6, 7, and 8). The reaction of the R,R′-dimethylated
â-ketosulfone, 2-methyl-1-phenyl-2-(phenylsulfonyl)propan-
1-one (4c), proceeded equally well with or without additives
(entry 7-9), indicating that the hydrogenation can occur in
the keto form, if not exclusively.17 Hydrogenation of
2-chloro-1-phenyl-2-(phenylsulfonyl)ethanone (4d) gave the
mixture of 5d (79%) and 2a (21%) with moderate enatiose-
lectivity (syn: 68.4% ee; anti: 89.3% ee) (entry 10).
In conclusion, we have developed a novel catalytic system
for the enantioselective hydrogenation of a variety of â-keto
sulfones using iodine as the additive; excellent enantiose-
lectivity was obtained. Work is in progress to develop a
deeper understanding into the mechanism and to apply this
methodology to asymmetric hydrogenation of other prochiral
ketones and olefins.
Table 4. Effects of the Additives under Controlled Conditionsa
entry
substrate
additives
product
ee (%)b
95.3
99.1
98.8
99.2
95.2
98.6
98.2
1c
2c
3
4
5
6
7
8
9
1a
1a
4a
1a
1a
4b
4c
4c
4c
4d
none
I2
none
4a
NaI
none
none
HI aq
I2
2a
2a
2a
2a
2a
2a
5c
5c
98.1
97.7
68.4/89.3
5c
5d, 2a
10
none
a All the reactions were carried out under 150 psi of hydrogen gas with
a substrate (1 mmol) concentration of 0.25 M in EtOH at 70 °C for 20 h.
Substrate/[Ru(benzene)Cl2]2/L3/additives ) 100/0.5/1.1/3.0. b Ee values
were determined by HPLC on a Chiralpak AD-H column. c Substrate/
[Ru(cymene)I2]2/L3/additives ) 100/0.5/1.1/3.0.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, Chinese Academy of Sciences,
and the Science and Technology Commission of Shanghai
Municipality for financial support.
Supporting Information Available: NMR and/or HPLC
data of compounds 1, 2, 3, 4, and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
1a with [RuI(cymene)L3]I as catalyst gave the same results
as with [RuCl(benzene)L3]Cl as catalyst with or without the
iodine (entries 1 and 2), revealing that the halogen atom
bound to ruthenium has no obvious effect on the enantiose-
lectivity. Asymmetric hydrogenation of 4a yielded 2a as the
sole product with excellent enantioselectivity (ee 98.8% entry
OL702565X
(17) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 2931.
5616
Org. Lett., Vol. 9, No. 26, 2007