Chiral Sc-catalyzed asymmetric Michael reactions of thiols with enones in water

Article abstract of DOI:10.1039/c1ob05424d

Asymmetric Michael reactions of thiols with enones were catalyzed by a Sc(OTf)₃-chiral bipyridine complex at room temperature in water without using any organic solvents, to afford the desired sulfides in high yields with high enantioselectivities.

Full text of DOI:10.1039/c1ob05424d

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Chiral Sc-catalyzed asymmetric Michael reactions of thiols with enones in
water†‡
Masaharu Ueno, Taku Kitanosono, Masaru Sakai and Shu¯ Kobayashi*
Received 22nd February 2011, Accepted 18th March 2011
DOI: 10.1039/c1ob05424d
Table 1 Optimization of reaction conditions in the asymmetric Michael
reactions of 1a with 2a
Asymmetric Michael reactions of thiols with enones were
catalyzed by a Sc(OTf)3–chiral bipyridine complex at room
temperature in water without using any organic solvents, to
afford the desired sulfides in high yields with high enantiose-
lectivities.
Organic reactions in water are now of great interest because
remarkable reactivity and selectivity that are unobtainable in
organic solvents are often observed in water.1 In addition, from an
environmental point of view, it is desirable to use water rather than
organic compounds as a solvent. In this context, several types of
reactions in aqueous media have been developed; however, organic
solvents are required in many cases as cosolvents to dissolve
organic materials. Another issue of organic reactions in water is
that most reactive species are not stable in the presence of water.
This is also the case for chiral catalysts, which are often unstable
in the presence of water and thus it is difficult to conduct catalytic
asymmetric reactions in the presence of water.2
Asymmetric Michael reactions of thiols with enones mediated
by chiral catalysts are among the most efficient methods for the
preparation of optically active sulfides. Although several chiral
catalysts have been developed, most asymmetric reactions have
been carried out in organic solvents.3–5 In addition, Michael
acceptors are rather limited to cyclic enones, and few successful
examples using acyclic enones have been reported.4a,4e,4f,4g
Entry
Lewis acid
Additive
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Sc(OTf)3
Pyridine (20)
Pyridine (20)
Pyridine (20)
Pyridine (20)
Pyridine (20)
Et3N (20)
Lutidine (20)
DBU (20)
LiOH (20)
NaOH (20)
KOH (20)
CsOH (20)
NaOH (10)
NaOH (40)
—
85
94
19
45
2
75
91
86
93
91
93
Quant.
83
98
34
81
91
72
4
0
1
73
89
80
88
90
90
90
87
5
Sc(OSO3C12H25)3
Cu(OTf)2
Zn(OTf)2
Bi(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
57
72
Sc(OSO3C12H25)3
—
In previous papers, we have disclosed that Sc(OTf)3–chiral
bipyridine 1 is an effective catalyst for enantioselective hydroxy-
methylation of silyl enol ethers with formaldehyde in aqueous
media.6 When Sc(OSO3C12H25)3–chiral bipyridine 1 was used
as a chiral Lewis acid catalyst, the same reactions proceeded
in water without using any organic solvents.7 The catalyst has
also been applied to enantioselective ring-opening reactions of
meso-epoxides8–10 and Nazarov-type reactions11 in water. In these
reactions, the chiral Sc Lewis acids are stable, and efficiently
catalyzed the enantioselective reactions in the presence of water.
We then decided to use these chiral Lewis acids for asymmetric
Michael reactions of thiols with enones.
First, we set the reaction of benzalacetone (2a) with ben-
zylthiol (3a) as a model, and several reaction conditions were
examined (Table 1). Interestingly, the reaction proceeded in
water without using any organic solvents. High yields and high
enantioselectivities were obtained even at room temperature. The
use of Sc(OTf)3–chiral bipyridine 1 with a base (entry 1) gave
better results than that of Sc(OSO3C12H25)3–1 (entry 2), which
is contrary to our previous results.7 Other metal triflates such
as Cu(OTf)2, Zn(OTf)2, and Bi(OTf)3, which worked well in
asymmetric ring-opening reactions of meso-epoxides, were not
effective (entries 3–5).9,10 For bases, organic bases (pyridine, Et3N,
lutidine, and DBU) as well as inorganic bases (LiOH, NaOH,
KOH, and CsOH) worked well to afford the desired adducts in
high yields with high enantioselectivities (entries 6–12). In the
presence of an excess amount of base (40 mol% (entry 14) vs.
Department of Chemistry, School of Science and Graduate School of
Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo, 113-0033, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp;
Fax: (+81)-3-5684-0634
† This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science (JSPS).
‡ Electronic supplementary information (ESI) available: Experimental
details and physical data of the products. See DOI: 10.1039/c1ob05424d
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Table 2 Effect of solvents
Table 3 Chiral Sc-catalyzed catalytic asymmetric Michael reactions of
thiols with enones
Entry
Solvent
Yield (%)
Ee (%)
Entry Substrate 2
Thiol 3
Product 4
Yield (%) Ee (%)
92 (92)a 93 (91)a
1
2
3
4
5
6
7
H2O
84
54
90
93
91
82
88
91
64
59
28
31
75
63
H2O/THF = 1/9
H2O/EtOH = 1/9
CH2Cl2
THF
Toluene
1
BnSH 3a
2
3
BnSH 3a
BnSH 3a
83
65
94
85
EtOH
10 mol% (entry 13) catalyst), the reaction proceeded smoothly,
but low enantioselectivity was observed, probably because a base-
catalyzed racemic reaction was predominant over the chiral Sc-
catalyzed enantioselective reaction. The reaction also proceeded
without base; however, lower yields and selectivities were obtained
(entries 15 and 16). We then investigated the effect of solvents in
this catalytic asymmetric reaction (Table 2). Although the reaction
proceeded smoothly to afford the desired product in high yield with
high enantioselectivity in water (entry 1), selectivities decreased
in aqueous organic solvents (entries 2 and 3). In other organic
solvents (without water), the adduct was obtained in high yields,
but a significant decrease in the enantioselectivity was observed
(entries 4–7).
4
5
6
BnSH 3a
BnSH 3a
BnSH 3a
84
88
82
84
90
92
7
BnSH 3a
76
85
Several examples of asymmetric Michael reactions of thiols with
enones are shown in Table 3. In most cases, the reactions proceeded
smoothly at room temperature in the presence of 1 mol% of
Sc(OTf)3, 1.2 mol% of chiral ligand 1, and pyridine (10 mol%) in
water to afford the desired sulfides in high yields with high levels of
enantioselectivities. It is noted that water on its own without using
any organic solvents worked well as a solvent in these reactions.
Various acyclic enones were successfully employed under the
conditions to attain high yields and high enantioselectivities
(entries 1–12), although the enantioselectivity was significantly
decreased using a cyclic enone (entry 13). For sulfides, while alkyl
sulfides gave high yields and high enantioselectivities in most
cases, benzenethiol showed lower enantioselectivity (entry 8). It
is noteworthy that even 0.5 mol% of the catalyst worked well to
afford the desired sulfide 4a in 92% yield with 91% ee (entry 1).
As a preliminary kinetic study, we have shown the profile of the
reaction of 2a with 3a in the presence of Sc(OTf)3 (1 mol%), 1
(1.2 mol%), and pyridine (10 mol%) in water at room temperature
(Fig. 1). For the Sc3+–chiral bipyridine 1 complex, we have already
obtained solid-state information (X-ray crystallography).6a We
next conducted experiments on the nonlinear effect to obtain
information on the structure in water. As shown in Fig. 2, a
positive nonlinear effect between the enantiomeric excess of the
product and the enantiomeric excess of 1 was observed, which
suggested formation of a dimer (or a similar aggregation form)
of the Sc3+–chiral bipyridine 1 complex in water. This result is in
contrast to a similar catalyst that was used in asymmetric ring-
opening reactions of meso-epoxides in water.12 We also observed
a remarkable ligand acceleration by 1 (The reaction of 2a with 3a
gave 4a in 17% yield in the presence of Sc(OTf)3 (10 mol%) and
8
PhSH 3b
EtSH 3c
iPrSH 3d
92
80
81
91
44
97
86
93
9b,c
10b,d
11b,d
12
13
87
78
90
8
BnSH 3a
a 0.5 mol% Sc(OTf)3, 0.6 mol% ligand 1, and 10 mol% pyridine were used
for the values in parentheses. b 5 mol% Sc(OTf)3, 6 mol% ligand 1, 10 mol%
pyridine were used. c 1.5 equiv. of thiol 3c was used. d 48 h.
pyridine (20 mol%) at room temperature in water). It is noted
that the reaction also proceeded sluggishly by using Sc(OTf)3
(10 mol%), ligand 5 (12 mol%), and pyridine (20 mol%) at room
temperature in water (2% yield, 19% ee). Further investigations on
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room temperature in water without using any organic solvents,
and high yields and high enantioselectivities were obtained.
Notes and references
1 (a) Aqueous-Phase Organometallic Catalysis, ed. B. Cornils and W. A.
Herrmann, Wiley-VCH, Weinheim, 2nd ed., 2004; (b) Organic Reac-
tions in Water, ed. U. M. Lindstro¨m, Blackwell, Oxford, 2007; (c) S.
Kobayashi, Pure Appl. Chem., 2007, 79, 235.
2 C. Ogawa and S. Kobayashi, in Catalytic Asymmetric Synthesis, ed.
I. Ojima, Wiley-VCH, Weinheim, 3rd edn, 2010, pp. 1–35.
3 Review: D. Enders, K. Lu¨ttgen and A. Narine, Synthesis, 2007, 959.
4 Recent studies on catalytic asymmetric Michael reactions of thiols,
see: (a) P. Ricci, A. Carlone, G. Bartoli, M. Bosco, L. Sambri and
P. Melchiorre, Adv. Synth. Catal., 2008, 350, 49; (b) S. Shirakawa,
A. Moriyama and S. Shimizu, Eur. J. Org. Chem., 2008, 5957; (c) S.
Shirakawa and S. Shimizu, Eur. J. Org. Chem., 2009, 1916; (d) A.
Ba˜doiu, G. Bernardinelli, C. Besnard and E. P. Ku¨ndig, Org. Biomol.
Chem., 2010, 8, 193; (e) L. Dai, S.-X. Wang and F.-E. Chen, Adv. Synth.
Catal., 2010, 352, 2137; (f) J. Skarzewski, M. Zielinska-Blajet and I.
Turowska-Tyrk, Tetrahedron: Asymmetry, 2001, 12, 1923; (g) H. Li, L.
Zu, Z. Wang and W. Wang, Tetrahedron Lett., 2006, 47, 3145.
5 A stoichiometric amount of cyclodextrin derivative-catalyzed asym-
metric Michael addition of thiols to chalcones in water has been
reported. P. Suresh and K. Pitchumani, Tetrahedron: Asymmetry, 2008,
19, 2037.
Fig. 1 Profile of the reaction of 2a with 3a.
6 (a) S. Ishikawa, T. Hamada, K. Manabe and S. Kobayashi, J. Am. Chem.
Soc., 2004, 126, 12236; Chiral bipyridine 1 was originally developed by
Bolm, et al.: (b) C. Bolm, M. Zehnder and D. Bur, Angew. Chem., Int.
Ed. Engl., 1990, 29, 205; (c) C. Bolm, M. Ewald, M. Felder and G.
Schlingloff, Chem. Ber., 1992, 125, 1169; See also: (d) S. Ishikawa, T.
Hamada, K. Manabe and S. Kobayashi, Synthesis, 2005, 13, 2176.
7 (a) M. Kokubo, C. Ogawa and S. Kobayashi, Angew. Chem., Int. Ed.,
2008, 47, 6909; (b) S. Kobayashi, M. Kokubo, K. Kawasumi and T.
Nagano, Chem.–Asian J., 2010, 5, 490.
Fig. 2 Nonlinear effect experiments between the ee of the product and ee
of 1.
8 Sc3+-catalyzed reactions: (a) S. Azoulay, K. Manabe and S. Kobayashi,
Org. Lett., 2005, 7, 4593; (b) M. Boudou, C. Ogawa and S. Kobayashi,
Adv. Synth. Catal., 2006, 348, 2585; (c) C. Ogawa, N. Wang, M. Boudou,
S. Azoulay, K. Manabe and S. Kobayashi, Heterocycles, 2007, 72, 589;
(d) M. Kokubo, T. Naito and S. Kobayashi, Chem. Lett., 2009, 38, 904;
cf. (e) C. Ogawa, N. Wang and S. Kobayashi, Chem. Lett., 2007, 36,
34.
detailed kinetic studies, structure of catalysts, effects of ligands, etc.
are now in progress.
9 Zn2+- and Cu2+-catalyzed reactions: M. Kokubo, T. Naito and S.
Kobayashi, Tetrahedron, 2010, 66, 1111.
10 Bi3+-catalyzed reactions: (a) C. Ogawa, S. Azoulay and S. Kobayashi,
Heterocycles, 2005, 66, 201. See also: (b) S. Kobayashi, T. Ogino, H.
Shimizu, S. Ishikawa, T. Hamada and K. Manabe, Org. Lett., 2005, 7,
4729.
In conclusion, we have developed chiral Sc-catalyzed asymmet-
ric Michael reactions of thiols with enones in water. Sc(OTf)3–
chiral bipyridine 1 was found to be an excellent catalyst. The
reactions proceeded smoothly with a small amount of base at
11 M. Kokubo and S. Kobayashi, Chem.–Asian J., 2009, 4, 526.
12 A nonlinear effect was not observed in water, but a positive effect was
observed in DCM: see also ref. 11.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3619–3621 | 3621
©