Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with enones in water

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PAPER

Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with

enones in water†

Taku Kitanosono, Masaru Sakai, Masaharu Ueno and Shū Kobayashi*

Received 11th June 2012, Accepted 6th July 2012

DOI: 10.1039/c2ob26264a

Asymmetric Michael reactions and enantioselective protonations between enones and thiols were

catalyzed by a Sc(OTf)₃–chiral 2,2′-bipyridine complex in water. The remarkable governing of the

enantioselectivity for simple introduction of protons despite their abnormally high mobility in water may

provide us with new synthetic opportunities as well as signiﬁcant chemical advances.

we initially focused on establishing a more efﬁcient catalytic

Introduction

system, especially for acyclic enones.⁶In principle, Michael

Exploring organic reactions in water is one of the hottest topics

in modern organic chemistry.¹Not only is water nontoxic, inex-

pensive and environmentally benign, but it also sometimes leads

to unexpected and unpredicted results.²Organic chemistry in

water provides us with the potential to develop innovative artiﬁ-

cial catalytic systems, which might perform selective chemical

reactions in cells. Intensive efforts have therefore been dedicated

to advances in catalytic systems in aqueous media in our labora-

tory.³However, the construction of asymmetric environments in

water poses considerable difﬁculties, such as weakness of non-

covalent interactions between substrates, chiral ligands and metal

ions under competitive polar conditions. We have focused on the

use of multidentate ligands as possible solutions to these issues.

Especially given its potential for chelating with many transition

metal ions, a chiral catalyst comprising a 2,2′-bipyridine back-

bone is one of the most attractive candidates for “privileged”

ligands, which catalyze many chemical reactions in water selec-

tively. To date, chiral 2,2′-bipyridine complexes chelating with

Sc(^III), Fe(II), Cu(II), Zn(II) and Bi(III) ions have proved to be

robust and excellent catalysts for the promotion of several cataly-

tic asymmetric reactions in water/aqueous media.⁴

addition of thiols is an ideal reaction that proceeds with perfect

atom economy under proton-transfer conditions to afford enantio-

merically enriched building blocks without employing any

auxiliary groups. This concept invoked a novel strategy for the

construction of an asymmetric carbogenic center via enantio-

selective proton transfer in proton-rich environments. Proton

transfer in water is the most fundamental phenomenon in redox

processes and therefore it plays an essential role in biological

processes such as muscle contraction and the electron transport

chain in the mitochondrial matrix. Here we describe chiral

Sc-catalyzed asymmetric Michael addition and enantioselective

protonation using thiols and enones in water.

Results and discussion

Asymmetric Michael addition of thiols with enones

The asymmetric Michael reaction of benzalacetone 2a with

benzylmercaptan 3a was initially conducted under various

conditions. We ﬁrst tested the combination of Sc³⁺and chiral

2,2′-bipyridine 1⁷because we have already revealed that this

combination creates excellent asymmetric environments in

several reactions, such as the enantioselective hydroxymethyla-

tion of silyl enol ethers,^4a,b,g,l,mring-opening reactions of meso-

epoxides,^4c–mNazarov cyclizations,^4jand allylations^4kin water

and organic solvents (Table 1). For scandium species, Sc(DS)₃

(DS = OSO₃C₁₂H₂₅) (a Lewis acid–surfactant combined cata-

lyst)⁸gave better results than Sc(OTf)₃(entries 1, 2). To avoid

the formation of undesired side products under acidic conditions

and to enhance the nucleophilicity of thiols, the addition of

bases was examined. It was found that in the presence of 10 mol

% of Sc(OTf)₃, 1, and 20 mol% of pyridine, the reaction was

signiﬁcantly accelerated and the desired Michael adduct was

obtained in 85% yield with 91% ee (entry 3).⁹In the presence of

pyridine, Sc(DS)₃also accelerated the reaction slightly, but the

Asymmetric Michael addition of thiols to α,β-unsaturated

ketones is often observed in biosynthesis as well as in the syn-

thesis of biologically active organosulfur compounds such as dil-

tiazem (a calcium antagonist).⁵Despite impressive contributions

made in recent years, reported examples with excellent enantios-

electivity have been limited mostly to cyclic enones. Therefore,

Department of Chemistry, School of Science, 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;

Tel: (+81)-03-5841-4790

†Electronic supplementary information (ESI) available. CCDC 874881

(compound 6a) and 874880 (compound 8a). For ESI and crystallo-

graphic data in CIF or other electronic format see DOI: 10.1039/

c2ob26264a

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Table 1 Effect of scandium sources and bases

Table 2 Effect of solvents and metal cations

Entry Lewis acid

Solvent

Yield (%) ee (%)

1

2

3

4

5

6

7

8

Sc(OTf)₃

Zn(OTf)₂

Cu(OTf)₂

Fe(OTf)₂

Bi(OTf)₃

Lu(OTf)₃

H₂O

H₂O–THF = 1 : 9

H₂O–EtOH = 1 : 9 90

CH₂Cl₂

THF

EtOH

Toluene

H₂O

84

54

91

64

59

28

31

63

75

0

4

7

1

66

92

90

91

Entry Lewis acid

Base (mol%)

Yield^a(%) ee (%)

93

91

88

82

45

19

46

2

73

83

87

94

91

92

1

2

3

4

5

6

7

8

Sc(OTf)₃

Sc(OSO₃C₁₂H_{25 3}

Sc(OTf)₃

Sc(OSO₃C₁₂H₂₅)₃

—

34

81

85

94

99

75

90

77

88

91

25

57

72

91

72

26

73

70

77

78

89

70

78

79

80

88

90

91

92

91

5

)

Pyridine (20)

Pyrrolidine (20)

Et₃N (20)

NMM (20)

DABCO (20)

DMAP (20)

2,6-Lutidine (20)

DTBP (20)

Methylimidazole (20) 81

Phenanthroline (20)

DBU (20)

LiOH (20)

NaOH (20)

KOH (20)

CsOH (20)

Pyridine (40)

Pyridine (30)

Pyridine (15)

Pyridine (10)

Pyridine (5)

LiOH (40)

NaOH (40)

KOH (40)

CsOH (40)

NaOH (10)

NaOH (5)

9

10

11

12

13^a

14

15

16

17^b

Sc(OTf)₃

5 mol% Sc(OTf)₃

3 mol% Sc(OTf)₃

1 mol% Sc(OTf)₃

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

0.5 mol% Sc(OTf)₃H₂O

85

86

93

91

93

Quant

89

91

85

83

84

98

89

96

93

83

73

^a20 mol% ligand 1 was used. ^bReaction time 48 h.

same results as pyridine did (entries 15–18).¹⁰The catalytic

system is not much affected by the amount of pyridine added

(entries 19–23). However, it was found that when the amount of

NaOH was decreased, the enantioselectivity decreased slightly.

In the presence of 40 mol% of alkali metal hydroxides,

the yields were high but the enantioselectivities decreased

signiﬁcantly.

4

7

87

By using an exquisite set of the catalyst and the additive, we

next investigated the effect of representative solvents and metal

cations in this reaction (Table 2). Among the representative sol-

vents, water emerged as being the most suitable (entries 1–7).

Notably, the reactions in organic solvents led to the desired

adduct in moderate selectivities (entries 4–7) even if the reac-

tions were conducted in aqueous–organic mixed solvents (entries

2, 3). For metal cations, we tested Fe(^II), Cu(II), Zn(II) and Bi(III),

which were reported to be efﬁcient Lewis acids in asymmetric

reactions in aqueous media.^4,11However, they were not very

effective here (entries 8–11). When homologous Lu(^III) was

employed as a Lewis acid instead of Sc(^III), a comparatively

sufﬁcient level of enantioselectivity was obtained (entry 12). For

the Bi(OTf)₃–chiral 2,2′-bipyridine 1 catalyzed asymmetric

hydroxymethylation in aqueous media, it has already been

reported that an excess amount of 1 enhances both reactivity and

enantioselectivity.^4lCareful examination of the ligand/Sc ratio

showed that slightly higher enantioselectivity was obtained when

10 mol% of Sc(OTf)₃and 20 mol% of 1 were used (entry 13).

Because reducing the amount of the chiral source is favorable, a

1 : 1.2 ratio of Sc(OTf)₃to ligand 1 was chosen; this was exam-

ined, as was reducing the catalyst loading (entries 14–17). The

Michael adduct was obtained in 91% yield with 91% ee using

1 mol% of Sc(OTf)₃and 1.2 mol% of 1 in the presence of

^aIsolated yield. NMM: N-methylmorpholone; DMAP: 4-dimethyl-

aminopyridine; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

enantioselectivity remained unchanged (entry 4). A number of

other bases were also examined (entries 5–18). It was interesting

to ﬁnd that in almost all cases, higher enantioselectivities were

observed when using inorganic bases or organic bases as addi-

tives compared with when no additives were used. Use of pyrro-

lidine as an additive afforded almost quantitative formation of

the Michael adduct, with poor selectivity (entry 5). This may be

ascribed to its strong basicity or high nucleophilicity. Tertiary

amines used as additives led to adducts with approximately

70–77% ee (entries 6–8). Even in the presence of a highly

nucleophilic amine such as 1,4-diazabicyclo[2,2,2]-octane

(DABCO), an undesired competitive Michael adduct of the

amine was not obtained. By contrast, unsaturated heterocycles

such as pyridine allowed the formation of the adducts in high

yields and with higher selectivities, except for 2,6-di-tert-butyl-

pyridine (DTBP), which is almost insoluble in water (entries

9–14). Alkali metal hydroxides as additives afforded almost the

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Table 3 Substrate generality of asymmetric Michael addition

Table 4 Substrate generality of asymmetric Michael addition/

protonation (1)

Substrate 2

Entry R¹

R²

Thiol 3

Yield (%) ee (%)

1

2

3

4

5

6

Ph

C₅H₁₁

Me

Me 2a BnSH 3a

Ph 2b BnSH 3a

Me 2c BnSH 3a

Et 2d BnSH 3a

Ph 2e BnSH 3a

4a 92

4b 83

4c 65

4d 84

4e 88

4f 82

4g 76

4h 80

4i 81

4j 91

93

94

85

84

90

92

85

97

86

93

90

94

44

8

Substrate 5

p-ClC₆H₄Me 2f BnSH 3a

2-Thienyl Me 2g BnSH 3a

Ph

7

Entry R¹

R²

n

Yield (%) dr (syn/anti) ee (%)

8^a

9^a,b

Ph 2b EtSH 3b

Ph 2b i-PrSH 3c

Ph 2b c-C₅H₉SH 3d

1

2

3

4

5

6

H

OMe

H

1

0

5a 6a 90

5b 6b 75

90/10

95/5

94/6

97/3

68/32

62/38

96^a

97^a

98^a

97^a

96^a

10^a,bPh

OMe

Cl

H

11

12

13

14

15

Ph

Ph 2b p-t-BuC₆H₄CH₂SH 3e 4k 87

5c

6c 56

Ph 2b p-ClC₆H₄CH₂SH 3f

Ph 2b 2-furylCH₂SH 3g

Ph 2b PhSH 3h

4l 89

5d 6d 83

4m 88

4n 92

4o 75

H

5e

5f

6e 85

6f 76

–(CH₂)₃–

2h BnSH 3a

^a5 mol% of Sc(OTf)₃, 6 mol% of 1, and 10 mol% of pyridine used.

^bReaction time 48 h.

^aee of the major isomer.

10 mol% of pyridine (entry 16). It is noteworthy that the same

level of enantioselectivity was achieved using 0.5 mol% of

Sc(OTf)₃by extending the reaction time to 48 h (entry 17).

Throughout these investigations, it was found that using a com-

bination of Sc(OTf)₃, as a Lewis acid, and water, as a solvent, is

the key to obtaining high yield and high enantioselectivity in the

asymmetric Michael addition of enone 2a to thiol 3a.

Under optimal conditions, the substrate scope of several

enones and thiols was surveyed in the presence of an exquisite

set of Sc(OTf)₃, chiral 2,2′-bipyridine 1 and pyridine (Table 3).

Enantiomerically enriched adducts were obtained with both ali-

phatic and aromatic enones (entries 1–11). Since several aliphatic

thiols are less reactive than benzylmercaptan 3a, the amount of

the catalyst and the reaction time were optimized in each case.

The conditions were further applied to a heteroaromatic enone or

thiol. The desired adducts were obtained with high enantio-

selectivities (entries 12, 13). Highly reactive thiophenol 3h

exhibited lower enantioselectivity, probably because of competi-

tive progress of a noncatalytic pathway (entry 14). The signiﬁ-

cant decrease in enantioselectivity in cyclic enone 2h provided

us with an important suggestion regarding the stereochemistry

(entry 15) (vide infra).

out in water, using our ternary catalytic system (Table 4). Very

interestingly, the corresponding product was obtained in high

yield with high diastereo- and enantioselectivities (entry 1). Both

electron-withdrawing and electron-donating substituents afforded

high selectivities, although they affected electrophilicity at the

β-position of enones (entries 2, 3). On the other hand, when

indanone-derived enone 5e or cyclohexanone-derived enone 5f

was employed as a substrate, the diastereoselectivity decreased

despite the high enantioselectivity (entries 5, 6).

These unexpected results indicated a potential application to

chiral Sc-catalyzed enantioselective protonation in water. A pio-

neering challenge for catalytic enantioselective protonation

without isolation of enolate equivalents was used in the chiral

samarium-catalyzed Michael addition of 4-tert-butylbenzylmer-

captan in dichloromethane (DCM).¹²Other catalytic enantiose-

lective protonations such as tandem 1,4-addition,¹³Rh-catalyzed

hydroarylation,¹⁴decarboxylative reaction,¹⁵coupling of ketenes

with aldehydes,¹⁶Nazarov cyclization¹⁷and umpolung¹⁸have

also been reported. Recently, a few chiral catalysts were reported

for catalytic Michael-type enantioselective protonation using

thiols.¹⁹However, most of them require strictly anhydrous and

basic conditions, and extremely high or low temperatures, to

obtain high selectivity, and the substrate scope is relatively

narrow. Furthermore, the high mobility of protons in water has

made enantioselective protonation in water impossible. To the

best of our knowledge, catalytic enantioselective protonation that

proceeds in aqueous media at room temperature under an

ambient atmosphere is currently limited to one example, namely

Enantioselective protonation with thiols and enones

In the chiral Sc-catalyzed Michael addition of thiols to α,β-unsa-

turated enones, substituents at the α-position of enones might

provide us with a new strategy for the construction of two suc-

cessive stereogenic centers. As a model, the Michael addition of

benzylmercaptan 3a to tetralone-derived enone 5a was carried

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Table 5 Optimization of reaction conditions in the asymmetric

Michael addition/protonation

Table 6 Substrate generality of asymmetric Michael addition/

protonation (2)

Entry Lewis acid

Solvent

Yield (%) ee (%)

Substrate 7

Yield

(%)

ee

(%)

Entry R¹

R²

Thiol 3

1

Sc(OTf)₃

Sc(OSO₃C₁₂H_{25 3}

ScCl₃·6H₂O

Sc(OAc)₃

Zn(OTf)₂

Fe(OTf)₂

H₂O

CH₂Cl₂

THF

EtOH

Toluene

H₂O–THF = 1 : 9

H₂O–EtOH = 1 : 9 51

H₂O

76

36

54

43

54

39

45

67

0

−5

2^a

3

1

2

3

4

5

6

7

8

9

Ph

Me 7a BnSH 3a

Bu 7b BnSH 3a

Ph 7c BnSH 3a

8a 78

8b 60

8c 75

8d 85

8e 74

8f 70

8g 51

8h 74

8i 78

67

69

74

54

70

60

63

60

53

4

5

6

7

8

9

10

11

12

13

14

−15

−19

−17

−16

−21

−3

p-OMe–C₆H₄Me 7d BnSH 3a

p-Br–C₆H₄

Ph

m-CF₃–C₆H₄Bn 7g BnSH 3a

p-OMe–C₆H₄Bn 7h BnSH 3a

Ph

Me 7e BnSH 3a

Bn 7f BnSH 3a

)

34

79

81

58

45

72

−10

4

13

Me 7a p-Cl–C₆H₄CH₂-

SH 3b

10

11

Me 7a p-OMe–C₆H₄CH₂- 8j 82

SH 3c

60

58

Lu(OTf)₃

8

Me 7a p-t-Bu–C₆H₄CH₂-

SH 3d

Me 7a 2-FurylCH₂SH 3e

7i BnSH 3a

8k74

^aWithout pyridine.

12

13

8l 92

8m 29

60

68

Nazarov cyclization in water, albeit with moderate selectivity

(75% yield, 32% ee).^4j

Initially, 2-methyl-1-phenyl-2-propen-1-one 7a was treated

with benzylmercaptan 3a using our ternary catalytic system in

water (Table 5). The reaction proceeded smoothly, to afford the

desired protonated adduct 8a in 78% yield with 67% ee,

although a fast racemic reaction proceeded competitively in the

presence of pyridine (entry 1).²⁰Recrystallization of 8a enabled

us to obtain the enantiopure compound with >99% ee. By con-

trast, no enantioselectivity of the product was observed in the

absence of pyridine (entry 2). When the protonation was carried

out in organic solvents such as DCM, the enantioselectivity was

very low (entries 3–6). In mixed aqueous solvents, H₂O–THF

and H₂O–EtOH, the enantioselectivity was slightly improved.

The conﬁguration of the product was opposite to that obtained

in water (entries 7, 8). When other scandium species were

employed instead of Sc(OTf)₃, the same tendency was observed

(entries 9–11). Poor enantioselectivity was obtained in the pres-

ence of other metal cations such as Zn(^II) and Fe(II) (entries 12,

13). In the case of Lu(OTf)₃, the enantioselectivity was also low

(entry 14). This is in contrast to the asymmetric Michael reac-

tion, when good enantioselectivity was obtained (Table 2, entry

12). This disparity implies the outstanding potential of Sc(^III) for

enantioselective protonation in water.

14

15

OMe

Me 7j BnSH 3a

7k BnSH 3a

8n 7

8o 83

21

3

16

NMe₂

Me 7l BnSH 3a

7m BnSH 3a

NR

8p 37

17^a

92

18^a

19^a

7n BnSH 3a

7o BnSH 3a

8q 26

8r 56

94

45

^aReaction time 96 h. NR: no reaction.

(entry 13). This adduct can be readily transformed to various

functional groups. The reaction of α,β-unsaturated ester 7j,

which is known to be less reactive than ketones, afforded the

poor result (entry 14). In the case of imidazole-derived ketone

7k, an almost racemic product was obtained (entry 15). An

α,β-unsaturated amide did not react under the conditions

(entry 16). When a dimethyl-substituted terminal oleﬁn was

introduced to tetralone in order to suppress the undesired

Substrate generality was examined under optimal conditions

(Table 6). Various types of ketones, including those with term-

inal oleﬁns in the structure, led to the corresponding products in

good to high yields with moderate to good enantioselectivities,

although a fast racemic reaction proceeded competitively in the

presence of pyridine (entries 1–12). When oxazolidinone 7i was

employed instead of a ketone, the reaction also proceeded to

afford the corresponding adduct with good enantioselectivity

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Fig. 2 Structure of chiral 2,2′-bipyridine derivatives.

Scheme 1 Desulfurization with RANEY® Nickel W-2.

Fig. 1 ⁴⁵Sc NMR spectrum of a Sc–1 complex in D₂O.

base-catalyzed racemic pathway, the product was obtained with

moderate to high enantioselectivity (entries 17, 18). By contrast,

an indanone derivative led to poor enantioselectivity (entry 19).

Finally, the product 8p was converted to 9p through desulfuri-

zation with RANEY® Nickel W-2. No racemization was

observed in this transformation. The absolute conﬁguration of 8p

was determined by comparison of the major enantiomer of 9p

(HPLC) (Scheme 1).^21,22

Fig. 3 Observation of the non-linear effect in chiral Sc-catalyzed reac-

tion of 2a with 3a.

Reaction mechanism

In this reaction, the Sc(OTf)₃–chiral 2,2′-bipyridine 1 complex

and pyridine (used as an additive) play crucial roles in both the

reactivity and the enantioselectivity. ⁴⁵Sc NMR spectroscopy

(Fig. 1) revealed that the catalytic system prepared by simply

mixing Sc(OTf)₃and 1.2 equiv. of 1 in water turned out to be in

dynamic equilibrium between two environmentally distinct

scandium species. One spectrum (δ = 0.0 ppm) is assigned to the

Sc(^III) ion,²³and the other (δ = 47.3 ppm) is considered to be a

1 : 1 Sc–ligand complex.

Scheme 2 Possible reaction mechanism for a catalytic pathway.

Crystallographic analysis of the chiral scandium complex

formed with 1 has been characterized as having pentagonal

bipyramidal geometry.^4aThe reaction proceeded sluggishly

when chiral 2,2′-bipyridine derivative 10 or 11 was employed,

where one or both hydroxyl groups are protected by a methyl

group.²⁴Therefore, it appears that 1 coordinates to a scandium

ion in a tetradentate fashion in water. On the other hand, ⁴⁵Sc

NMR spectroscopy indicated that the Sc(^III) ion (δ = 0.0 ppm)

disappeared in the ternary catalytic system consisting of Sc

(OTf)₃, ligand 1 and pyridine. The signiﬁcantly downﬁeld

chemical shift (δ = 79.7 ppm) suggests interaction between the

scandium ion and pyridine. Judging from a ¹⁹F NMR spectrum,

the interaction between scandium and the triﬂate anion has com-

plete ionic character.²⁵The observation of a positive nonlinear

effect in the asymmetric Michael addition of thiols with simple

enones may be ascribed to the low solubility of the hetero-

dimeric chiral 2,2′-bipyridine ligand in water (Fig. 2 and 3).

The ternary catalytic system comprising the Lewis acid and

the base exhibits two distinct reaction pathways. One is a desired

cooperative pathway depicted by precise orchestration of the

Lewis acid–base. The other is a base-catalyzed undesired

pathway with no chiral induction. In this base-catalyzed

pathway, the rate-determining step is an attack of thiolates on

enones to generate enolates.²⁶On the other hand, the desired cat-

alytic pathway may have multiple steps (Scheme 2). The initial

trigger of the reaction is catalytic generation of an activated

enone, which has been conﬁrmed by signiﬁcant changes in

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Scheme 3 Reaction in the absence of pyridine.

Scheme 5 Comparison of reaction medium.

Scheme 4 Plausible reaction mechanism via a stepwise process.

¹³C chemical shifts.²⁷The activated enone is then amenable to

nucleophilic addition of either thiol or thiolate, which is under

acid–base equilibrium.²⁸Cronin and co-workers have suggested

that the nucleophilic addition of thiols in aqueous media pro-

ceeds via a concerted mechanism.²⁹By contrast, the addition of

thiolates involves a stepwise mechanism, via the formation of

enolate intermediates.

The observation of signiﬁcant acceleration by addition of pyri-

dine strongly suggests that the major nucleophilic species are not

thiols, but thiolate anions. The nucleophilic attack of thiolate

anions leads to products via a stepwise process. On the other

hand, in the absence of pyridine, the nucleophilic attack of thiols

is possible. The experimental data using the β-substituted enone

and the α-substituted enone showed that the β-substituted enone

led to an optically active adduct, whereas the α-substituted

enone led to a racemic product (Scheme 3). Since the concerted

process should inﬂuence stereochemistry on the carbon atom, at

both the α-position and the β-position, these results indicate that

the major reaction pathway is a stepwise process, even for the

attack of thiols.

The stepwise process involves two enantiofacial differen-

tiations: nucleophilic attack and a protonation step. In the light

of the X-ray structure of the Sc–chiral-2,2′-bipyridine complex

previously reported, a nucleophile prefers to attack the Si face in

order to rationalize the observed sense of chiral induction

(Scheme 4). This tendency of the nucleophilic attack seems to be

the same even in organic solvents, although there the selectivity

is lower (Table 2, entries 2–7).

On the other hand, water and other organic solvents differ in

enantiofacial differentiation at the protonation step (Table 5,

entries 1 vs. 3–6). For example, the results obtained in H₂O and

in EtOH are compared in Scheme 5.

Scheme 6 Enantiofacial differentiation of protons.

Given signiﬁcant competition of the racemic pathway against

the desired catalytic pathway, minimization of structural ﬂuctu-

ation through the interaction between scandium and sulfur may

play an important role in governing the enantioselectivity.

According to the stereochemistry observed in the enantioselec-

tive protonation, a proton should be introduced preferentially, as

shown in Scheme 6.

In ethanol or other organic solvents, only a pyridinium cation

generated via equilibrium with thiols can behave as a proton

source, and enantiofacial differentiation must be based upon

steric hindrance. However, this explanation may also apply in the

case of aqueous media. It is considered that the key factor for

chiral induction is the abnormally high mobility of protons in

water, the value of which is >10³times greater than in organic

solvents.³⁰

To examine the deuterium kinetic isotope effect, the reaction

of 7a with 3a was carried out in D₂O. Theoretically, deuteration

should be slower than protonation. This was veriﬁed by simple

comparison of reaction rates (Fig. 4B).

As expected, there was a prominent isotope effect in the reac-

tion of 7a with 3a (B), compared with Michael addition (A),

which seems to originate from the activation energies in the pro-

tonation/deuteration step. A proton is introduced predominantly

in an initial stage of the reaction, with excellent reproducibility,

despite signiﬁcant competition of an undesired pathway cata-

lyzed by pyridine (Table 7, entry 1).

The deﬁnitive H/D ratio of the product was ﬁnally 10/90,

although a total H/D ratio in this system is <1/>99, including an

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Fig. 4 Deuterium kinetic isotope effect in the reaction rate of Michael addition and protonation/deuteration.

Table 7 Protonation/deuteration in D₂O

and 7% yield within 24 h. Employing twice the amount of thiol

did not affect the deﬁnitive H/D ratio, which excludes the invol-

vement of a free proton in the total reaction system. In that

sense, the hydroxyl groups in chiral 2,2′-bipyridine 1 seem to

function as proton sources in this catalytic system.³²Interest-

ingly, this signiﬁcantly high H/D ratio corresponds to the amount

of the hydroxyl groups in the chiral scandium catalyst formed

with Sc(OTf)₃and 1. In addition, the enantiofacial differen-

tiation shown in Scheme 6 implies the proactive involvement in

enantioselective protonation of such hydroxyl groups. As shown

in Scheme 6, this hydrogen can be affected by the reactive

π-orbital of enolate. Unfortunately, this simplest of explanation

imposes limitations on the demonstration of immediate evidence

because of the proton-rich environment. Based upon such

insight into the sense of chiral induction, a possible reaction

mechanism is postulated in Scheme 7. Because of the ionic

character that exists between the scandium cation and the triﬂate

anion, ligand exchange with the solvent molecule seems to be

very fast on the scandium atom. As the proton-transfer rate is in

the order of picoseconds, the rate-determining step must be the

Michael addition step of thiolate anions with enones.

Entry

Time (h)

Conditions

Total yield (%)

H/D ratio

1

1 h

24 h

—

14 (6)^b

71 (7)^b

72 (7)^b

43/57

10/90

2^a

3

BnSH (3 equiv.)

^aThe same level of enantioselectivity (67% ee) was observed as that

observed in H₂O. ^bYield of the protonated product 8a-H was described

in parentheses.

Conclusions

exchangeable proton in thiol (entry 2).³¹It is also noteworthy

that the proton was barely introduced after an initial stage; the

protonated product 8a-H was obtained in 6% yield within 1 h

We have developed a new catalytic system for the asymmetric

Michael addition of thiols to enones and enantioselective

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Scheme 7 Possible catalytic cycle for enantioselective protonation. Due to labile ligand exchange, the catalyst structure should be [(Ligand)Sc^III-

(H₂O)_m(py)_n(OTf)_3−m−n]

^(m+n)+(m + n) OTf⁻, py = pyridine.

protonation in water. In both processes, water plays key roles in

reactivity and selectivity. For the asymmetric Michael reactions,

the reactions proceeded in both water and organic solvents, but

higher selectivity was obtained in water. In the protonation,

lower yields and low enantioselectivities were obtained in

organic solvents. It is noted that highly enantioselective protona-

tion occurred in water. The remarkable governing of the enantio-

selectivity for the simple introduction of protons despite their

abnormally high mobility in water may provide us with not only

new synthetic opportunities but also signiﬁcant chemical

advances. Further investigations to develop new catalytic

systems or reactions in water that allow for enantioselective

proton transfer are currently underway.

High-performance liquid chromatography was carried out using

the following apparatus: SHIMADZU LC-10ATvp (liquid

chromatograph), SHIMADZU SPD-10A (UV detector) and

SHIMADZU C-R8A (Chromatopac) using Daicel chiralpak® or

chiralcel® columns. Preparative thin-layer chromatography

(PTLC) was carried out using Wakogel B-5F from Wako Pure

Chemical Industries, Ltd. High resolution mass spectra (HRMS)

were recorded using a JEOL JMS-T100TD (DART) spec-

trometer. Optical rotations were measured on a JASCO P1010

polarimeter using a 2 mL cell with 1 dm path length. Data are

reported as follows: [α]^T_D(c in g per 100 mL, solvent). Deionized

water from a MILLIPORE MilliQ machine (Gradient A 10) was

used as a solvent without further treatment. Deuterium oxide

purchased from ACROS (99.8 atom% D incorporated) was used

without further treatment. All organic solvents used were com-

mercially available dry solvents, which were distilled appropri-

ately under an argon atmosphere or were stored over molecular

sieves prior to use. Thiols 3 were commercially available and

were used without any puriﬁcation prior to use. Sc(OTf)₃,³³

Sc(OSO₃C₁₂H₂₅)₃and Bi(OTf)₃were prepared by known

methods. Other metal salts were commercially available.

Chiral 2,2′-bipyridine 1^7,35and 10^4kand 11⁷were synthesized

using protocols described in the literature. α,β-Unsaturated

ketones 2 are commercially available and were distilled or

recrystallized prior to use. α-Branched ketones 7j and 7l are

commercially available and were distilled prior to use. Other

ketones 5a,³⁶5b,³⁶5c,³⁷5d,³⁶5e,³⁷5f,³⁸7a,³⁹7b,⁴⁰7c,³⁹7d,⁴¹

7e,⁴¹7f,³⁹7i,^42,437k,⁴⁴7m,⁴⁵and 7n⁴⁵were prepared by the

following procedures.⁴⁰Similarly, 7g, 7h, and 7o were

prepared.

Experimental

General

Nuclear magnetic resonance (NMR) spectra were recorded on a

JEOL ECX-600 or ECX-500 spectrometer, operating at

8

34

1

600 MHz or 500 MHz for H and 150 MHz or 125 MHz for

¹³C NMR in CDCl₃unless otherwise noted. Tetramethylsilane

1

(TMS) served as the internal standard (δ = 0) for H NMR and

CDCl₃was used as the internal standard (δ = 77.0) for

¹³C NMR. The aqueous solution of ScCl₃[Sc(H₂O)₆³⁺] served

as the external standard (δ = 0) for ⁴⁵Sc NMR analysis. Infrared

(IR) spectra were obtained using

a JASCO FT/IR-4200

spectrometer. Data are represented as frequency of absorption

(cm⁻¹). All melting points were determined on a YAZAWA

micro-melting point BY-1 apparatus and are uncorrected.

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7g:

2-benzyl-1-(3-(triﬂuoromethyl)phenyl)prop-2-en-1-one.

4b: (R)-3-(benzylthio)-1,3-diphenylpropan-1-one.⁴⁶Colorless

solid; mp 60–62 °C; IR (KBr): ν = 3058, 3023, 2894, 1679,

Colorless oil; ¹H NMR (600 MHz): δ = 3.80 (s, 2H), 5.68

(s, 1H), 5.82 (s, 1H), 7.17–7.44 (m, 5H), 7.55 (t, 1H, J = 7.6

Hz), 7.76 (d, 1H, J = 7.6 Hz), 7.87 (d, 1H, J = 7.6 Hz), 7.95

(s, 1H). ¹³C NMR (150 MHz): δ = 38.1, 126.1, 126.5, 127.8,

128.4, 128.6, 128.8, 129.1, 132.5, 138.2, 138.3, 147.3, 196.1.

1

1595, 1448, 1341, 1224, 981, 921, 727, 693 cm⁻¹. H NMR

(600 MHz): δ = 3.37–3.50 (m, 4H), 4.38 (d, 1H, J = 5.1 Hz),

7.12–7.25 (m, 8H), 7.30–7.34 (m, 4H), 7.45 (t, 1H, J = 7.2 Hz),

7.77 (d, 2H, J = 6.9 Hz). ¹³C NMR (150 MHz): δ = 35.8, 44.1,

45.2, 127.0, 127.3, 128.0, 128.5, 128.5, 128.9, 133.1, 136.6,

137.8, 141.7, 196.7. HPLC (Daicel Chiralcel OJ-H, ⁿhexane–

i–PrOH = 4 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 22.6 min (S), t_R

= 33.1 min (R).

7h: 2-benzyl-1-(4-methoxyphenyl)prop-2-en-1-one. Colorless

1

oil; H NMR (600 MHz): δ = 3.80 (s, 2H), 3.90 (s, 3H), 5.52

(s, 1H), 5.58 (s, 1H), 6.81–6.85 (m, 2H), 7.10–7.26 (m, 5H),

7.72–7.74 (m, 2H). ¹³C NMR (150 MHz): δ = 38.7, 55.4, 113.4,

124.7, 126.3, 128.4, 129.1, 131.9, 138.6, 147.7, 163.1, 196.4.

4c: (S)-4-(benzylthio)nonan-2-one.⁴⁶Colorless oil; IR (neat):

ν = 2954, 2927, 2856, 1715, 1455, 1419, 1359, 1157, 701 cm⁻¹

.

¹H NMR (600 MHz): δ = 0.86 (t, 3H, J = 7.2 Hz), 1.16–1.37

(m, 6H), 1.46–1.50 (m, 2H), 2.08 (s, 3H), 2.63 (ddd, 2H, J =

6.7, 16.7, 20.2 Hz), 3.03 (t, 1H, J = 6.9 Hz), 3.73 (dd, 2H, J =

13.1, 8.3 Hz), 7.21–7.33 (m, 5H). ¹³C NMR (150 MHz): δ =

14.0, 22.5, 26.2, 30.5, 31.5, 35.0, 40.3, 49.6, 126.9, 128.4,

128.9, 138.5, 207.0. HPLC (Daicel Chiralcel OD-H, n-hexane–i-

PrOH = 100 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 8.0 min (S),

t_R= 8.7 min (R).

7o: 2-benzylidene-6-methoxy-3,4-dihydronaphthalen-1(2H)-

one. Colorless oil; H NMR (600 MHz): δ = 1.87 (s, 3H), 2.14

1

(s, 3H), 2.72 (t, 2H, J = 6.2 Hz), 2.84 (t, 2H, J = 6.5 Hz), 3.78

(s, 3H), 6.66 (d, 1H, J = 2.1 Hz), 6.81–6.83 (m, 1H), 8.05

(d, 1H, J = 8.9 Hz). ¹³C NMR (150 MHz): δ = 23.0, 23.3, 28.6,

30.3, 53.3, 112.0, 112.8, 128.3, 130.1, 130.3, 144.7, 145.7,

162.8, 189.9.

4d: (S)-5-(benzylthio)hexan-3-one.⁴⁶Colorless oil; IR (neat):

ν = 3061, 3028, 2973, 2934, 1712, 1494, 1454, 1410, 1361,

Typical experimental procedure for Michael reaction and

protonation in water

1

1239, 1199, 1115, 1070, 1027, 986, 769, 701 cm⁻¹. H NMR

A 0.005 M aqueous Sc(OTf)₃solution (800 μL, 0.004 mmol)

was added to chiral 2,2′-bipyridine 1 (1.6 mg, 0.0048 mmol) and

the mixture was stirred for 1 h at room temperature. After the

successive addition of pyridine (3.2 μL, 0.04 mmol), benzalace-

tone 2a (58.5 mg, 0.4 mmol) and benzylthiol 3a (56.3 μL,

0.48 mmol), the reaction mixture was vigorously stirred for 24 h

at room temperature. The resulting mixture was diluted with

water. The aqueous layer was extracted with DCM (three times),

and then the combined organic layers were washed with CuSO₄

aq., and dried over Na₂SO₄. After ﬁltration, the solvent was

removed under reduced pressure. The residue was puriﬁed by

preparative TLC (elution: chloroform–ethyl acetate = 200 : 1) to

afford the corresponding Michael adduct 4a (99.8 mg, 92%

yield). The enantiomeric excess was determined by chiral HPLC

analysis.

(600 MHz): δ = 1.02 (t, 3H, J = 7.2 Hz), 1.26 (d, 3H, J = 6.9

Hz), 2.34–2.37 (m, 2H), 2.50 (dd, 1H, J = 8.2, 16.7 Hz), 2.66

(dd, 1H, J = 7.6, 16.7 Hz), 3.15–3.21 (m, 1H), 3.75 (dd, 2H, J =

13.1, 7.9 Hz), 7.21–7.32 (m, 5H). ¹³C NMR (150 MHz): δ =

7.6, 21.5, 35.0, 35.5, 36.5, 49.5, 127.0, 128.5, 128.8, 138.3,

209.2. HPLC (Daicel Chiralcel OD-H, n-hexane–i-PrOH =

100 : 1, ﬂow rate = 0.8 mL min⁻¹); t_R= 13.2 min (R), t_R

14.1 min (S).

=

4e: (S)-3-(benzylthio)-1-phenylbutan-1-one.⁴⁷Colorless oil;

IR (neat): ν = 3584, 3060, 3027, 2964, 2921, 1683, 1597, 1580,

1493, 1449, 1353, 1221, 1180, 1071, 986, 753, 690, 641 cm⁻¹

.

¹H NMR (500 MHz): δ = 1.33 (d, 3H, J = 6.8 Hz), 3.05 (dd,

1H, J = 9.1, 17.0 Hz), 3.29 (dd, 1H, J = 5.1, 17.0 Hz),

3.34–3.41 (m, 1H), 1.53–1.58 (m, 1H), 3.80 (dd, 2H, J = 13.6,

17.6 Hz), 7.21–7.26 (m, 1H), 7.28–7.36 (m, 4H, J = 9.5),

7.40–7.48 (m, 2H), 7.53–7.56 (m, 1H), 7.83–7.92 (m, 2H).

¹³C NMR (125 MHz): δ = 21.4, 35.3, 35.6, 46.0, 126.9, 128.0,

128.5, 128.6, 128.8, 133.1, 136.8, 138.3, 198.0. HPLC (Daicel

Chiralcel OD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 7.1 min (S), t_R= 7.8 min (R).

Analytical data for Michael reactions of thiols 4a–m

Michael reactions of thiols 4a,⁴⁶4b,⁴⁶4c,⁴⁶4d,⁴⁶4e,⁴⁷4f,⁴⁶

4g,⁴⁶4h,⁴⁸4i,⁴⁸4j,⁴⁸4k,⁴⁸4l,⁴⁸and 4m⁴⁸are literature-known;

obtained analytical data for these compounds are in full agree-

ment with reported data. The absolute conﬁgurations of the opti-

cally active compounds were determined by comparison of the

measured HPLC data with the values reported in the

literature.^46–48

4f: (R)-4-(benzylthio)-4-(4-chlorophenyl)butan-2-one.⁴⁶Color-

less oil; IR (neat): ν = 3437, 2922, 1716, 1596, 1453, 1417,

1

1367, 1201, 1099, 953, 699 cm⁻¹. H NMR (600 MHz): δ =

2.02 (s, 3H), 2.89 (d, 2H, J = 7.6 Hz), 3.42 (d, 1H, J = 13.7 Hz),

3.52 (d, 1H, J = 13.7), 4.16 (t, 3H, J = 7.5 Hz), 7.18–7.29 (m,

9H). ¹³C NMR (150 MHz): δ = 30.5, 35.7, 43.0, 49.8, 127.1,

128.5, 128.7, 128.9, 129.3, 132.9, 137.5, 140.1, 204.9. HPLC

(Daicel Chiralpak AS-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate =

0.5 mL min⁻¹); t_R= 19.8 min (R), t_R= 20.9 min (S).

4a: (R)-4-(benzylthio)-4-phenylbutan-2-one.⁴⁶Colorless oil;

IR (neat): ν = 3060, 3027, 2917, 1716, 1600, 1492, 1452, 1416,

1

1358, 1329, 1240, 1154, 1074, 1024, 761, 699 cm⁻¹. H NMR

(500 MHz): δ = 1.99 (s, 3H), 2.91 (m, 2H), 3.47 (dd, 2H, J =

13.3, 19.1 Hz), 4.19 (t, 1H, J = 7.4 Hz), 7.18–7.34 (m, 10H).

¹³C NMR (125 MHz): δ = 30.4, 35.6, 43.8, 49.9, 126.9, 127.3,

127.9, 128.4, 128.5, 128.8, 137.7, 141.4, 205.2. HPLC (Daicel

Chiralcel OD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 8.3 min (R), t_R= 9.7 min (S).

4g: (R)-4-(benzylthio)-4-(thiophen-2-yl)butan-2-one.⁴⁶Color-

less oil; IR (neat): ν = 3583, 3063, 3028, 2918, 1713, 1493,

1

1450, 1417, 1360, 1242, 1154, 1043, 701, 661 cm⁻¹. H NMR

(600 MHz): δ = 2.05 (s, 3H), 2.97 (ddd, 2H, J = 7.2, 16.8,

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21.3 Hz), 3.61 (dd, 2H, J = 13.7, 18.5 Hz), 4.51 (t, 1H, J =

7.2 Hz), 6.91 (m, 2H), 7.22–7.26 (m, 4H), 7.28–7.31 (m, 2H).

¹³C NMR (150 MHz): δ = 30.5, 35.9, 39.1, 50.8, 124.8, 125.8,

126.4, 127.1, 128.5, 128.9, 137.6, 146.3, 204.9. HPLC (Daicel

Chiralpak AD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 0.5 mL

min⁻¹); t_R= 13.1 min (S), t_R= 15.0 min (R).

7.27–7.29 (m, 2H), 7.32–7.35 (m, 2H), 7.45–7.47 (m, 1H),

7.76–7.78 (m, 1H). ¹³C NMR (150 MHz): δ = 35.2, 44.1, 45.2,

127.4, 128.0, 128.5, 128.6, 130.2, 132.7, 136.4, 136.6, 141.6,

196.6. HPLC (Daicel Chiralcel OJ-H, n-hexane–i-PrOH = 7 : 3,

ﬂow rate = 0.5 mL min⁻¹); t_R= 25.2 min (S), t_R= 38.5 min (R).

HRMS calcd for C₂₂H₂₀OSCl⁺([M + H]⁺): 367.09234, found

367.09084.

4h: (R)-3-(ethylthio)-1,3-diphenylpropan-1-one.⁴⁸Colorless

solid; mp 57–60 °C; IR (KBr): ν = 2968, 2923, 1683, 1594,

4m: (R)-3-((furan-2-ylmethyl)thio)-1,3-diphenylpropan-1-

one.⁴⁸Colorless oil; IR (KBr): ν = 3061, 3029, 1686, 1597,

1448, 1409, 1365, 1338, 1222, 979, 752, 713, 695 cm⁻¹

.

¹H NMR (600 MHz, CDCl₃): δ = 1.17 (t, 3H, J = 7.2 Hz), 2.36

(q, 2H, J = 7.6 Hz), 3.54 (dd, 2H, J = 3.7, 7.2 Hz), 4.59 (t, 1H),

7.26–7.55 (m, 8H), 7.92 (d, 2H, J = 8.3 Hz). ¹³C NMR

(150 MHz, CDCl₃): d = 14.3, 25.4, 43.9, 45.3, 127.2, 127.8,

128.1, 128.5, 128.6, 133.2, 136.7, 142.2, 197.0. HPLC (Daicel

Chiralpak AS-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 0.5 mL

min⁻¹); t_R= 12.4 min (R), t_R= 15.7 min (S).

1

1449, 1227, 1150, 1011, 748 cm⁻¹. H NMR (600 MHz): δ =

3.46–3.50 (m, 2H), 3.55–3.60 (m, 2H), 4.57 (dd, 1H, J = 6.2,

8.2 Hz), 6.11 (d, 1H, J = 3.5 Hz), 6.28 (d, J = 1.3 Hz),

7.20–7.23 (m, 1H), 7.25–7.33 (m, 3H), 7.40–7.42 (m, 4H),

7.51–7.55 (m, 1H), 7.86 (d, 2H, J = 7.6 Hz). ¹³C NMR

(150 MHz): δ = 27.8, 44.0, 45.0, 107.6, 110.3, 127.3, 128.0,

128.0, 128.2, 128.5, 133.1, 136.6, 141.3, 142.0, 151.3, 196.5.

HPLC (Daicel Chiralcel OJ-H, n-hexane–i-PrOH = 7 : 3, ﬂow

rate = 0.5 mL min⁻¹); t_R= 23.3 min (S), t_R= 31.1 min (R).

4i: (R)-3-(isopropylthio)-1,3-diphenylpropan-1-one.⁴⁸Color-

less solid; mp 77–80 °C; IR (KBr): ν = 3061, 2965, 2924, 2866,

1638, 1589, 1449, 1364, 1334, 1222, 979, 750, 710, 694 cm⁻¹

.

¹H NMR (600 MHz, CDCl₃): δ = 1.06 (d, 3H, J = 6.9 Hz), 1.20

(d, 3H, J = 6.9 Hz), 2.56 (sep, 1H, J = 6.7 Hz), 3.45 (m, 2H),

4.56 (t, 1H, J = 1.7 Hz), 7.12–7.15 (m, 1H), 7.21–7.24 (m, 2H),

7.35–7.38 (m, 4H), 7.46–7.49 (m, 1H), 7.84 (d, 2H, J = 7.5 Hz).

¹³C NMR (150 MHz, CDCl₃): δ = 22.9, 23.4, 34.6, 43.3, 45.7,

127.1, 127.8, 128.1, 128.5, 128.6, 133.2, 136.8, 142.6, 197.0.

HPLC (Daicel Chiralpak AS-H, n-hexane–i-PrOH = 9 : 1, ﬂow

rate = 0.5 mL min⁻¹); t_R= 10.8 min (R), t_R= 12.2 min (S).

Analytical data for Michael additions and protonations 6a–f

Absolute conﬁguration of 6d was determined by X-ray diffrac-

tion. Conﬁgurations of 6a, 6b, 6c, 6e, 6f were determined by

analogy.

6a: (R)-2-((R)-(benzylthio)(phenyl)methyl)-3,4-dihydro-

naphthalen-1(2H)-one. Colorless oil; IR (neat) ν = 3060, 3027,

2934, 1680, 1600, 1453, 1298, 1227, 1025 cm⁻^{1 1}H NMR

.

4j: (R)-3-(cyclopentylthio)-1,3-diphenylpropan-1-one.⁴⁸Col-

orless solid; mp 67–69 °C; IR (KBr): ν = 2953, 2861, 1714,

1682, 1595, 1493, 1449, 1410, 1361, 1337, 1229, 1075, 1050,

(600 MHz, syn/anti = 90/10): δ = 1.62–1.69 (m, 1H), 2.26–2.31

(m, 1H), 2.83–2.90 (m, 3H), 3.44 (dd, 2H, J = 13.1, 51.5 Hz),

4.66 (m, 0.1 H), 4. 71 (d, 0.9 H, J = 4.8 Hz), 7.06–7.22 (m,

10H), 7.33 (dd, 1H, J = 6.2, 7.6 Hz), 7.39 (d, 2H, J = 7.6 Hz),

7.89 (d, 1H, J = 6.9 Hz). ¹³C NMR (150 MHz): δ = 25.2, 28.8,

35.9, 47.2, 53.2, 126.5, 126.9, 127.1, 127.6, 128.0, 128.3,

128.5, 128.6, 128.8, 128.8, 129.7, 132.3, 133.2, 137.8, 138.8,

143.5, 196.5. HPLC (Daicel Chiralcel OD-H, n-hexane–i-PrOH

= 100 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 13.2 min (syn, major),

980, 749, 725, 700, 687 cm⁻^{1 1}H NMR (500 MHz): δ =

.

1.31–1.38 (m, 1H), 1.41–1.54 (m, 2H), 1.57–1.81 (m, 4H),

1.93–2.00 (m, 1H), 2.80 (ddd, 1H, J = 7.4, 7.2, 14.3 Hz), 3.53

(q, 2H, J = 7.1 Hz), 4.59 (t, 1H, J = 7.1 Hz), 7.19–7.22 (m, 1H),

7.26–7.31 (m, 2H), 7.41–7.45 (m, 4H), 7.52–7.55 (m, 1H),

7.90–7.91 (m, 2H). ¹³C NMR (125 MHz): δ = 24.7, 24.9, 33.1,

34.0, 43.1, 44.4, 45.5, 127.1, 127.7, 128.1, 128.1, 128.4, 128.6,

133.1, 136.8, 197.0. HPLC (Daicel Chiralpak AS-H, n-hexane–

i-PrOH = 9 : 1, ﬂow rate = 0.5 mL min⁻¹); t_R= 12.4 min (R),

t_R= 13.6 min (S).

t_R= 15.5 min (anti, major), t_R= 16.8 min (anti, minor), t_R

=

19.4 min (syn, minor). HRMS calcd for C₂₄H₂₃OS⁺([M + H]⁺):

359.14696, found 359.14674.

6b: (R)-2-((R)-(benzylthio)(4-methoxyphenyl)methyl)-3,4-

dihydronaphthalen-1(2H)-one. White solid (mixture); IR

4k: (R)-3-((4-(tert-butyl)benzyl)thio)-1,3-diphenylpropan-

1-one.⁴⁸Colorless solid; mp 82–84 °C; IR (KBr): ν = 3429,

(KBr): ν = 2933, 2834, 1681, 1602, 1509, 1249, 1032 cm⁻¹

.

¹H NMR (600 MHz, syn/anti = 95/5): δ = 1.64–1.71 (m, 1H),

2.27–2.30 (m, 1H), 2.83–2.86 (m, 3H), 3.43 (dd, 2H, J = 13.1,

53.6 Hz), 3.70 (s, 3H), 4.58 (m, 0.05 H), 4.69 (m, 0.95 H),

6.73–6.75 (m, 2H), 7.06–7.21 (m, 7H), 7.30–7.34 (m, 3H), 7.89

(d, 1H, J = 7.6 Hz). ¹³C NMR (150 MHz): δ = 25.1, 28.6, 35.8,

46.5, 53.3, 55.1, 113.3, 126.5, 126.9, 127.6, 128.3, 128.5, 128.8,

130.8, 133.2, 137.9, 143.5, 158.6, 196.6. HPLC (Daicel

Chiralcel OJ-H, n-hexane–i-PrOH = 4 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 12.6 min (anti, major), t_R= 17.5 min (anti, minor),

t_R= 19.3 min (syn, major), t_R= 26.0 min (syn, minor). HRMS

calcd for C₂₅H₂₅O₂S⁺([M + H]⁺): 389.15752, found 389.15789.

1

2960, 1682, 1450, 1363, 1342, 1230, 754, 705, 696 cm⁻¹. H

NMR (500 MHz): δ = 1.29 (s, 9H), 3.43–3.56 (m, 4H), 4.48

(dd, 1H, J = 6.2, 7.9 Hz), 7.14 (d, 2H, J = 7.9 Hz), 7.19–7.22

(m, 1H), 7.27–7.31 (m, 4H), 7.35–7.39 (m, 4H), 7.40–7.51

(m, 1H), 7.83 (d, 2H, J = 7.9 Hz). ¹³C NMR (125 MHz): δ =

31.3, 34.4, 35.3, 44.1, 45.2, 125.3, 127.2, 128.0, 128.4, 128.5,

128.5, 133.1, 134.7, 136.6, 141.7, 149.7, 196.7. HPLC (Daicel

Chiralcel OJ-H, n-hexane–i-PrOH = 7 : 3, ﬂow rate = 0.5 mL

min⁻¹); t_R= 23.7 min (R), t_R= 30.3 min (S).

4l: (R)-3-((4-chlorobenzyl)thio)-1,3-diphenylpropan-1-one.⁴⁸

Colorless solid; mp 79–80 °C; IR (KBr): ν = 3060, 3028, 1686,

1

1596, 1489, 1449, 1334, 1226, 1092, 749, 694 cm⁻¹. H NMR

6c: (R)-2-((R)-(benzylthio)(4-chlorophenyl)methyl)-3,4-dihy-

dronaphthalen-1(2H)-one. Yellow solid (mixture); IR (KBr):

(600 MHz): δ = 3.36–3.45 (m, 4H), 4.34 (t, 1H, J = 6.9 Hz),

7.03–7.05 (m, 2H), 7.13–7.18 (m, 3H), 7.22–7.24 (m, 2H),

ν = 2932, 1682, 1599, 1489, 1228, 1092 cm⁻^{1 1}H NMR

.

Org. Biomol. Chem., 2012, 10, 7134–7147 | 7143

View Online

Analytical data for protonations 8a–r

(600 MHz, syn/anti = 94/6): δ = 1.60–1.66 (m, 1H), 2.26–2.30

(m, 1H), 2.82–2.89 (m, 3H), 3.45 (dd, 2H, J = 13.1, 66.3 Hz),

4.58 (m, 0.06 H), 4.73 (d, 0.94H, J = 4.1 Hz), 7.08–7.24

(m, 9H), 7.28–7.37 (m, 3H), 7.86–7.88 (m, 1H). ¹³C NMR

(150 MHz): δ = 25.0, 28.8, 35.9, 46.5, 53.2, 126.6, 127.0,

127.6, 128.1, 128.4, 128.5, 128.8, 131.2, 132.2, 132.9, 133.4,

137.3, 137.5, 143.5, 196.1. HPLC (Daicel Chiralpak AD-H,

Absolute conﬁguration of 8a was determined by X-ray crystallo-

graphy analysis. Conﬁgurations of 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8i,

8j, 8k, 8l, 8n, and 8o were determined by analogy. Conﬁguration

of 8m was assigned by comparison of literature data.⁴⁹The

absolute conﬁguration of 8p was assumed from the stereo-

chemistry of desulfonated compound 9p. The conﬁgurations of

8q and 8r were determined by analogy.

n-hexane–i-PrOH = 100 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R

=

26.0 min (syn, major), t_R= 33.3 min (syn, minor), t_R= 40.5 min

(anti, major), t_R= 49.1 min (anti, minor). HRMS calcd for

C₂₄H₂₂ClOS⁺([M + H]⁺): 393.10799, found 393.10827.

8a: (R)-3-(benzylthio)-2-methyl-1-phenylpropan-1-one. White

solid; mp 54–56 °C; IR (KBr): ν = 2964, 2929, 1675, 1450,

1226, 969, 677 cm⁻¹. ¹H NMR (600 MHz): δ = 1.16 (d, 3H, J =

6.9 Hz), 2.47 (dd, 1H, J = 6.9, 13.1 Hz), 2.87 (q, 1H, J = 6.2

Hz), 3.48 (dd, 1H, J = 6.9, 14.4 Hz), 3.65 (s, 2H), 7.16–7.24 (m,

5H), 7.36–7.39 (m, 2H), 7.50–7.52 (m, 1H), 7.76–7.79 (m, 1H).

¹³C NMR (150 MHz): δ = 17.7, 34.7, 37.3, 41.1, 127.0, 128.3,

128.5, 128.6, 128.8, 133.1, 136.2, 202.8. HPLC (Daicel Chiral-

pak AS-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 0.5 mL min⁻¹);

t_R= 12.8 min (R), t_R= 16.5 min (S). HRMS calcd for

6d: (R)-2-((R)-(benzylthio)(phenyl)methyl)-6-methoxy-3,4-

dihydronaphthalen-1(2H)-one. White solid; mp 99–101 °C; IR

(KBr): ν = 2949, 1668, 1602, 1258, 1058 cm⁻^{1 1}H NMR

.

(600 MHz, syn/anti = 97/3): δ = 1.65–1.71 (m, 1H), 2.29–2.33

(m, 1H), 2.83–2.90 (m, 3H), 3.49 (dd, J = 13.1, 48.1 Hz), 3.79

(s, 3H), 4.71 (m, 0.03 H), 4.79 (d, 0.97 H, J = 4.8 Hz), 6.56

(s, 1H), 6.73–6.75 (m, 1H), 7.13–7.26 (m, 9H), 7.43 (d, J = 8.2

Hz), 7.91 (d, 1H, J = 8.2 Hz). ¹³C NMR (150 MHz): δ = 25.2,

29.0, 36.0, 47.3, 52.9, 55.3, 112.2, 113.1, 126.0, 126.9, 127.1,

128.0, 128.3, 128.9, 129.7, 130.1, 137.9, 138.9, 146.0, 163.4,

195.2. HPLC (Daicel Chiralpak AD-H, n-hexane–i-PrOH =

9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 11.1 min (syn, minor), t_R=

12.3 min (syn, major), t_R= 14.2 min (anti, minor), t_R= 16.0 min

(anti, major). HRMS calcd for C₂₅H₂₅O₂S⁺([M + H]⁺):

389.15752, found 389.15437.

C₁₇H₁₉OS⁺([M + H]⁺): 271.11566, found 271.11381. [α]²_D⁰

+30.54 (c = 1.0, CHCl₃).

=

8b: (R)-2-((benzylthio)methyl)-1-phenylhexan-1-one. Color-

less oil; IR (neat): ν = 2956, 2928, 2858, 1678, 1596, 1450,

1

1229, 700 cm⁻¹. H NMR (600 MHz): δ = 0.72–0.75 (m, 3H),

1.07–1.18 (m, 4H), 1.44–1.51 (m, 1H), 1.60–1.67 (m, 1H),

2.50–2.53 (m, 1H), 2.81 (dd, 1H, J = 8.25, 13.1 Hz), 3.43–3.47

(m, 1H), 3.61 (s, 2H), 7.15–7.23 (m, 5H), 7.36–7.39 (m, 2H),

7.47–7.50 (m, 1H), 7.77–7.79 (m, 2H). ¹³C NMR (150 MHz): δ

= 13.8, 22.7, 29.3, 32.3, 33.4, 37.4, 46.3, 127.0, 128.3, 128.5,

128.6, 128.9, 133.0, 137.3, 138.4, 203.0. HPLC (Daicel Chiral-

cel OD-H, n-hexane–i-PrOH = 100 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 10.7 min (S), t_R= 11.6 min (R). HRMS calcd for

6e: (R)-2-((R)-(benzylthio)(phenyl)methyl)-2,3-dihydro-1H-

inden-1-one. Colorless oil; IR (neat): ν = 3060, 3028, 2918,

1710, 1606, 1493, 1451, 1294, 1207, 1029 cm⁻^{1 1}H NMR

.

(600 MHz, syn/anti = 68/32): δ = 3.0–3.2 (m, 3H), 3.43–3.60

(m, 3H), 4.55 (d, 0.68H, J = 2.3 Hz), 4.64 (d, 0.32H, J = 3.4

Hz), 7.11–7.46 (m, 13H), 7.56–7.59 (m, 1H), 7.77–7.78

(m, 1H). ¹³C NMR (150 MHz): δ = 28.74, 29.5, 35.8, 36.0,

48.6, 49.8, 52.4, 53.5, 123.8, 124.0, 126.2, 126.4, 126.9, 127.0,

127.1, 127.2, 127.3, 127.4, 128.0, 128.2, 128.3, 128.4, 128.6,

128.8, 128.9, 129.3, 134.6, 134.9, 136.4, 136.7, 137.2, 137.4,

137.6, 141.4, 153.6, 204.9. HPLC (Daicel Chiralpak AD-H,

C₂₀H₂₅OS⁺([M + H]⁺): 313.16261, found 313.16312. [α]²_D⁰

+14.10 (c = 1.0, CHCl₃).

=

8c: (R)-3-(benzylthio)-1,2-diphenylpropan-1-one. Yellow oil;

IR (neat): ν = 3060, 3027, 2918, 1679, 1450, 1230, 698 cm⁻¹

.

¹H NMR (600 MHz): δ = 2.73 (dd, 1H, J = 6.2, 13.1 Hz), 3.27

(dd, 1H, J = 8.3, 13.1 Hz), 3.57 (d, 2H, J = 4.1 Hz), 4.48 (dd,

1H, J = 6.2, 8.2 Hz), 7.11–7.27 (m, 12H), 7.36–7.38 (m, 1H),

7.73–7.76 (m, 2H). ¹³C NMR (150 MHz): δ = 35.3, 37.5, 54.2,

127.0, 127.5, 128.1, 128.4, 128.5, 128.7, 128.9, 129.0, 133.0,

136.4, 138.2, 138.7, 198.5. HPLC (Daicel Chiralcel OD-H, n-

hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 7.8 min

(S), t_R= 8.8 min (R). HRMS calcd for C₂₂H₂₁OS⁺([M + H]⁺):

333.13131, found 333.12972. [α]²_D⁰= −105.61 (c = 1.0, CHCl₃).

n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R

=

7.8 min (syn, minor), t_R= 8.3 min (syn, major), t_R= 9.6 min

(anti, major), t_R= 10.6 min (anti, minor). HRMS calcd for

C₂₃H₂₁OS⁺([M + H]⁺): 345.13131, found 345.13089.

6f: (R)-2-((R)-(benzylthio)(phenyl)methyl)cyclohexanone.

Colorless oil; IR (neat): ν = 3027, 2936, 2861, 1712, 1493,

1

1450, 1126, 1070 cm⁻¹. H NMR (600 MHz, syn/anti = 62/38):

δ = 1.25–1.28 (m, 1H), 1.50–1.58 (m, 1H), 1.65–1.74 (m, 2H),

1.81–1.85 (m, 1H), 1.91–1.96 (m, 0.5H), 2.16–2.19 (m, 0.5H),

2.26–2.33 (m, 2H), 2.72–2.77 (m, 1H), 3.42 (dd, 1H, J = 6.2,

13.1 Hz), 3.51 (dd, 1H, J = 13.7, 22.7 Hz), 4.12 (d, 0.5H, J =

8.9 Hz), 4.25 (d, 0.5H, J = 7.6 Hz), 7.19–7.35 (m, 9H). ¹³C

NMR (150 MHz): δ = 23.5, 24.4, 27.7, 28.0, 30.8, 31.7, 35.5,

35.7, 41.3, 42.0, 47.2, 48.4, 56.2, 56.4, 126.8, 126.9, 127.2,

128.2, 128.3, 128.5, 128.9, 129.0, 129.1, 137.9, 139.8, 141.8,

209.9, 210.7. HPLC (Daicel Chiralpak AS-H, n-hexane–i-PrOH

= 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 15.0 min (anti, major),

8d: (R)-3-(benzylthio)-1-(4-methoxyphenyl)-2-methylpropan-

1-one. White solid; mp 91–94 °C; IR (KBr): ν = 2972, 2927,

1

2839, 1667, 1602, 1454, 1235, 1174, 1024, 845, 700 cm⁻¹. H

NMR (600 MHz): δ = 1.13 (d, 3H, J = 6.9 Hz), 2.43–2.46 (m,

1H), 2.84–2.87 (m, 1H), 3.42 (q, 1H, J = 6.9 Hz), 3.79 (s, 2H),

6.84 (m, 2H), 7.16–7.22 (m, 5H), 7.77–7.77 (m, 1H). ¹³C NMR

(150 MHz): δ = 17.8, 34.9, 37.3, 40.6, 55.4, 113.8, 127.0,

128.5, 128.8, 129.1, 130.6, 138.5, 163.5, 201.3. HPLC (Daicel

Chiralcel OD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 15.7 min (S), t_R= 17.5 min (R). HRMS calcd for

t_R= 16.1 min (anti, minor), t_R= 19.1 min (syn, minor), t_R

=

25.1 min (syn, major). HRMS calcd for C₂₀H₂₃S⁺([M + H]⁺):

C₁₈H₂₁O₂S⁺([M + H]⁺): 301.12622, found 301.12631. [α]²_D⁰

+8.68 (c = 1.0, CHCl₃).

=

311.14696, found 311.14676.

7144 | Org. Biomol. Chem., 2012, 10, 7134–7147

View Online

8e: (R)-3-(benzylthio)-1-(4-bromophenyl)-2-methylpropan-

1-one. White solid; mp 70–73 °C; IR (neat): ν = 2966, 2920,

1.15 (d, 2H, J = 6.9 Hz), 2.45 (dd, 1H, J = 6.9, 13.1 Hz), 2.84

(dd, 1H, J = 6.9, 13.1 Hz), 3.43–3.49 (m, 1H, J = 6.9), 3.59 (dd,

2H, J = 14.1, 17.5 Hz), 7.14–7.18 (m, 5H), 7.36–7.39 (m, 2H),

7.48–7.50 (m, 1H), 7.77 (m, 2H). ¹³C NMR (150 MHz): δ =

17.7, 34.7, 36.6, 41.1, 128.2, 128.6, 128.7, 130.1, 132.8, 133.2,

136.1, 137.0, 202.6. HPLC (Daicel Chiralcel OD-H, n-hexane–i-

PrOH = 100 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 15.7 min (S), t_R

= 17.1 min (R). HRMS calcd for C₁₈H₁₈OSCl⁺([M + H]⁺):

305.07669, found 305.07709. [α]²_D⁰= +10.12 (c = 1.0, CHCl₃).

1

1679, 1581, 1225, 833, 701 cm⁻¹. H NMR (600 MHz): δ =

1.19 (d, 3H, J = 6.9 Hz), 2.52 (dd, 1H, J = 6.9, 13.1 Hz), 2.90

(dd, 1H, J = 6.9, 13.1 Hz), 3.43 (q, 1H, J = 6.9 Hz), 3.71 (s,

2H), 7.23–7.32 (m, 4H), 7.56–7.60 (m, 3H), 7.63–7.69 (m, 2H).

¹³C NMR (150 MHz): δ = 17.6, 34.7, 37.3, 41.2, 127.1, 128.3,

128.6, 128.8, 129.5, 129.8, 131.8, 131.9, 134.9, 201.8. HPLC

(Daicel Chiralcel OD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate =

1.0 mL min⁻¹); t_R= 4.8 min (S), t_R= 7.6 min (R). HRMS calcd

for C₁₇H₁₈OSBr⁺([M + H]⁺): 349.02617, found 349.02532.

[α]²_D⁰= +10.53 (c = 1.0, CHCl₃).

8j: (R)-3-((4-methoxybenzyl)thio)-2-methyl-1-phenylpropan-

1-one. Colorless oil; IR (neat): ν = 2966, 2930, 1680, 1608,

1510, 1451, 1247, 1177, 1033, 971, 701 cm⁻^{1 1}H NMR

.

8f: (R)-2-benzyl-3-(benzylthio)-1-phenylpropan-1-one. Color-

less oil; IR (neat): ν = 3060, 3026, 2919, 1678, 1597, 1493,

(600 MHz): δ = 1.5 (d, 3H, J = 6.9 Hz), 2.45 (dd, 1H, J = 7.8,

13.1 Hz), 2.84 (dd, 1H, J = 6.2, 13.1 Hz), 3.46 (q, 1H, J = 6.8),

3.60 (d, 2H, J = 2.8 Hz), 3.71 (s, 3H), 6.74 (d, 2H, J = 9 Hz),

7.12–7.14 (m, 2H), 7.35–7.38 (m, 2H), 7.46–7.49 (m, 1H),

7.76–7.78 (m, 2H). ¹³C NMR (150 MHz): δ = 17.6, 34.6, 36.6,

41.1, 55.2, 113.9, 128.1, 128.3, 129.9, 130.3, 133.0, 136.2,

158.6, 202.8. HPLC (Daicel Chiralcel OD-H, n-hexane–i-PrOH

= 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R= 8.2 min (S), t_R= 9.3 min

(R). HRMS calcd for C₁₈H₂₁O₂S⁺([M + H]⁺): 301.12622, found

301.12691. [α]_D²⁰= +16.39 (c = 1.0, CHCl₃).

1

1449, 1230, 698 cm⁻¹. H NMR (600 MHz): δ = 2.50 (dd, 1H,

J = 5.5, 13.1 Hz), 2.74 (q, 1H, J = 6.9 Hz), 2.83 (dd, 1H, J =

8.2, 13.1 Hz), 2.94 (q, 1H, J = 6.9 Hz), 3.54 (dd, 2H, J = 13.7,

17.2 Hz), 3.71–3.73 (m, 1H), 6.99–7.01 (m, 2H), 7.07–7.09 (m,

3H), 7.12–7.18 (m, 5H), 7.30–7.33 (m, 2H), 7.42–7.45 (m, 1H),

7.65–7.68 (m, 2H). ¹³C NMR (150 MHz): δ = 32.9, 37.2, 38.3,

48.5, 126.40, 127.0, 128.3, 128.4, 128.5, 128.5, 128.5, 128.8,

129.0, 133.0, 137.0, 138.4, 138.8, 202.3. HPLC (Daicel Chiral-

pak AS-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹);

t_R= 11.9 min (R), t_R= 12.8 min (S). HRMS calcd for

8k: (R)-3-((4-(tert-butyl)benzyl)thio)-2-methyl-1-phenyl-

propan-1-one. Colorless oil; IR (neat): ν = 2963, 2869, 1681,

C₂₃H₂₃OS⁺([M + H]⁺): 347.14696, found 347.14757. [α]²_D⁰

−3.53 (c = 1.0, CHCl₃).

=

1

1596, 1451, 1364, 1230, 971, 701 cm⁻¹. H NMR (600 MHz):

δ = 1.15 (d, 3H, J = 6.9 Hz), 1.23 (s, 9H), 2.47 (dd, 1H, J = 6.9,

13.1 Hz), 2.88 (dd, 1H, J = 6.2, 13.1 Hz), 3.46 (q, 1H, J =

6.9 Hz), 3.62 (s, 2H), 7.14–7.17 (m, 2H), 7.23–7.24 (m, 2H),

7.35–7.37 (m, 2H), 7.46–7.48 (m, 1H), 7.77–7.78 (m, 2H).

¹³C NMR (150 MHz): δ = 17.7, 31.3, 34.5, 34.8, 36.9, 41.1,

125.4, 128.3, 128.5, 128.6, 133.1, 135.4, 136.2, 149.9, 202.8.

HPLC (Daicel Chiralcel OD-H, n-hexane–i-PrOH = 100 : 1, ﬂow

rate = 1.0 mL min⁻¹); t_R= 9.4 min (S), t_R= 11.7 min (R).

HRMS calcd for C₂₁H₂₈OS⁺([M + H]⁺): 327.17826, found

327.17792. [α]_D²⁰= +19.23 (c = 1.0, CHCl₃).

8g: (R)-2-benzyl-3-(benzylthio)-1-(3-(triﬂuoromethyl)phenyl)

propan-1-one. Colorless oil; IR (neat): ν = 3063, 3029, 1688,

1

1609, 1495, 1453, 1331, 1170, 1127, 1072, 804, 751 cm⁻¹. H

NMR (600 MHz): δ = 2.54 (dd, 1H, J = 5.5, 13.1 Hz), 2.76 (q,

1H, J = 6.9 Hz), 2.83–2.86 (m, 1H), 3.53–3.59 (m, 3H),

6.91–6.94 (m, 2H), 7.02–7.20 (m, 8H), 7.40–7.42 (m, 1H),

7.63–7.66 (m, 1H), 7.72–7.79 (m, 2H). ¹³C NMR (150 MHz): δ

= 33.2, 37.4, 38.7, 49.1, 122.7, 124.5, 125.0, 15.1, 126.6, 127.1,

128.5, 128.6, 128.8, 128.9, 129.1, 129.3, 130.9, 131.1, 131.3,

137.7, 138.2, 138.4, 201.5. HPLC (Daicel Chiralcel OD-H, n-

hexane–i-PrOH = 19 : 1, ﬂow rate = 0.5 mL min⁻¹); t_R

=

8l: (R)-3-((furan-2-ylmethyl)thio)-2-methyl-1-phenylpropan-

1-one. Colorless oil; IR (neat): ν = 2971, 2928, 1680, 1594,

1451, 1230, 972, 790, 701 cm⁻¹. ¹H NMR (600 MHz): δ = 1.17

(d, 3H, J = 6.9 Hz), 2.51–2.54 (m, 1H), 2.94 (dd, 1H, J = 6.9,

13.1 Hz), 3.52 (q, 1H, J = 6.9 Hz), 3.64 (dd, 2H, J = 9.6,

14.4 Hz), 6.09 (d, 1H, J = 3.4Hz), 6.22–6.22 (m, 1H), 7.26 (m,

1H), 7.37–7.40 (m, 2H), 7.47–7.50 (m, 1H), 7.83–7.84 (m, 2H).

¹³C NMR (150 MHz): δ = 17.7, 29.1, 34.9, 41.1, 107.5, 110.4,

128.3, 128.3, 128.6, 128.6, 133.1, 136.1, 142.1, 151.6, 202.7.

HPLC (Daicel Chiralcel OJ-H, n-hexane–i-PrOH = 100 : 1, ﬂow

rate = 1.0 mL min⁻¹); t_R= 15.3 min (R), t_R= 16.5 min (S).

HRMS calcd for C₁₅H₁₇O₂S⁺([M + H]⁺): 261.09492, found

261.09377. [α]_D²⁰= +15.76 (c = 1.0, CHCl₃).

20.6 min (S), t_R= 22.3 min (R). HRMS calcd for C₂₄H₂₂F₃OS⁺

([M + H]⁺): 415.13434, found 415.13134.

8h: (R)-2-benzyl-3-(benzylthio)-1-(4-methoxyphenyl)propan-

1-one. White solid; mp 97–100 °C; IR (KBr): ν = 3014, 2928,

1670, 1596, 1455, 1367, 1235, 1166, 1024, 931, 854, 763, 701,

605 cm⁻¹. ¹H NMR (600 MHz): δ = 2.50 (dd, 1H, J = 5.5, 13.1

Hz), 2.80 (q, 1H, J = 6.9 Hz), 2.88 (dd, 1H, J = 8.2, 13.1 Hz),

2.98–3.01 (m, 1H), 3.54 (d, 2H, J = 3.4 Hz), 3.70–3.75 (m, 1H),

3.85 (s, 3H), 6.78 (d, 2H, J = 8.9 Hz), 7.00 (d, 2H, J = 8.2 Hz),

7.06–7.19 (m, 8H), 7.67 (d, 2H, J = 8.3 Hz). ¹³C NMR

(150 MHz): δ = 33.1, 37.2, 38.4, 48.0, 56.4, 113.6, 126.3,

126.9, 128.4, 128.5, 128.8, 129.0, 130.6, 163.4, 200.6. HPLC

(Daicel Chiralcel OD-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate =

1.0 mL min⁻¹); t_R= 12.1 min (S), t_R= 14.5 min (R). HRMS

calcd for C₂₄H₂₅OS⁺([M + H]⁺): 377.15752, found 377.15695.

[α]²_D⁰= −8.47 (c = 1.0, CHCl₃).

8m: (R)-3-(3-(benzylthio)-2-methylpropanoyl)oxazolidin-

2-one.⁴⁹Colorless oil; IR (neat): ν = 2977, 2921, 1777, 1696,

1

1387, 1266, 1225, 1044, 757, 704 cm⁻¹. H NMR (600 MHz,

CDCl₃): δ = 1.20 (d, 3H, J = 6.9 Hz), 2.42–2.45 (m, 1H),

2.80–2.83 (m, 1H), 3.74 (d, 2H, J = 3.4 Hz), 3.99–4.13 (m, 3H),

4.41–4.44 (m, 2H), 7.22–7.33 (m, 5H). ¹³C NMR (150 MHz,

CDCl₃): δ = 17.4, 34.6, 36.4, 37.6, 42.7, 61.9, 126.9, 128.5,

128.9, 138.1, 153.2, 175.8. HPLC (Daicel Chiralcel OD-H,

8i: (R)-3-((4-chlorobenzyl)thio)-2-methyl-1-phenylpropan-1-

one. Colorless oil; IR (neat): ν = 2971, 2927, 1680, 1489,

1

1451, 1230, 1092, 972, 700 cm⁻¹. H NMR (600 MHz): δ =

Org. Biomol. Chem., 2012, 10, 7134–7147 | 7145

View Online

n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R

=

(m, 1H), 3.29 (dd, 1H, J = 4.1, 17.9 Hz), 3.69 (q, 2H, J =

11.7 Hz), 7.11–7.14 (m, 1H), 7.18–7.21 (m, 4H), 7.25–7.28

(m, 1H), 7.36–7.38 (m, 1H), 7.48–7.51 (m, 1H), 7.62 (d, 1H,

J = 7.6 Hz). ¹³C NMR (150 MHz): δ = 24.1, 28.8, 31.2, 33.2,

48.9, 55.6, 123.6, 126.2, 126.9, 127.2, 128.4, 128.9, 134.7,

13.6, 137.9, 153.4, 206.0. HPLC (Daicel Chiralcel OD-H,

32.8 min (S), t_R= 44.6 min (R). HRMS calcd for C₁₄H₁₈NO₃S⁺

([M + H]⁺): 280.10074, found 280.09974. [α]²_D⁰= +58.8 (c =

1.09, CHCl₃).

8n: (R)-methyl 3-(benzylthio)-2-methylpropanoate. Colorless

oil; IR (neat): ν = 2924, 1735, 1455, 1212, 1160, 1096,

n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R

=

1

701 cm⁻¹. H NMR (600 MHz): δ = 1.13 (d, 3H, J = 6.9 Hz),

7.2 min (S), t_R= 7.7 min (R). HRMS calcd for C₁₉H₂₁OS⁺

2.40 (dd, 1H, J = 6.9, 13.1 Hz), 2.57 (q, 1H, J = 6.9 Hz), 2.68

(dd, 1H, J = 6.9, 13.1 Hz), 3.61 (s, 3H), 3.64 (s, 2H), 7.16–7.25

(m, 5H). ¹³C NMR (150 MHz): δ = 16.8, 34.5, 36.6, 39.8, 51.8,

127.0, 128.5, 128.8, 175.5. HPLC: Daicel Chiralcel OD-H, n-

hexane–i-PrOH = 9 : 1, ﬂow rate = 0.5 mL min⁻¹: t_R= 12.8 min

(S), t_R= 13.4 min (R). HRMS calcd for C₁₂H₁₇O₂S⁺([M + H]⁺):

225.09492, found 225.09485.

([M + H]⁺): 297.13131, found 297.13191.

Desulfurization of protonated products and determination of

absolute conﬁgurations

RANEY® Ni W-2 (suspension in EtOH, 2 mL) was added to a

solution of protonated product 8p (0.1 mmol) in acetate buffer

(pH 5.2, 1 mL) and a 1 : 1 mixture of EtOH (2 mL), followed by

the addition of NaPH₂O₂·H₂O (1.0 mmol) immediately. The

resultant suspension was stirred for 1 h at room temperature, and

the reaction mixture was ﬁltered. Water was added to the ﬁltrate,

and the aqueous layer was then extracted with ether. The com-

bined organic layers were successively washed with satd

NaHCO₃aq. and brine, and then dried over Na₂SO₄. After ﬁl-

tration, the solvent was removed under reduced pressure. The

residue was puriﬁed by silica gel column chromatography

(elution: n-hexane–AcOEt = 10 : 1) to afford the desulfurized

product 9p as a colorless oil.

8o: 3-(benzylthio)-2-methyl-1-(1-methyl-1H-imidazol-2-yl)-

propan-1-one. Colorless oil; IR (neat): ν = 2968, 2927, 1672,

1

1407, 1290, 1155, 972, 773, 702 cm⁻¹. H NMR (600 MHz):

δ = 1.26 (d, 3H, J = 6.9 Hz), 2.51 (dd, 1H, J = 6.2, 13.1 Hz),

2.84–2.88 (m, 1H), 3.74 (d, 2H, J = 2.1 Hz), 4.00 (s, 3H), 4.20

(dd, 1H, J = 6.9, 14.4 Hz), 7.04 (s, 1H), 7.16 (s, 1H), 7.20–7.31

(m, 5H). ¹³C NMR (150 MHz): δ = 17.3, 34.1, 36.2, 40.9,

126.8, 127.2, 128.3, 128.4, 128.9, 129.1, 138.2, 138.2, 142.5,

195.1. HPLC (Daicel Chiralpak AS-H, n-hexane–i-PrOH = 9 : 1,

ﬂow rate = 0.5 mL min⁻¹, racemic); t_R= 19.6 min (S), t_R

=

20.5 min (R). HRMS calcd for C₁₅H₁₉N₂OS⁺([M + H]⁺):

275.12181, found 275.12209.

9p: (S)-2-isopropyl-3,4-dihydronaphthalen-1(2H)-one.²²Col-

orless oil; H NMR (600 MHz): δ = 0.84 (d, 3H, J = 6.9 Hz),

8p: (R)-2-(2-(benzylthio)propan-2-yl)-3,4-dihydronaphthalen-

1(2H)-one. Colorless oil; IR (neat): ν = 2965, 2929, 1684, 1453,

1

1216, 913, 748, 711 cm⁻^{1 1}H NMR (600 MHz): δ = 1.36

.

0.94 (d, 3H, J = 7.6 Hz), 1.85–1.91 (m, 1H), 2.05–2.10 (m, 1H),

2.23–2.27 (m, 1H), 2.43–2.47 (m, 1H), 2.84–2.97 (m, 2H),

7.14–7.23 (m, 2H), 7.36–7.38 (m, 1H), 7.95 (d, 1H, J = 8.2 Hz).

¹³C NMR (150 MHz): δ = 18.4, 20.6, 23.4, 26.1, 28.5, 53.7,

126.5, 127.4, 128.5, 132.9, 133.0, 143.9, 199.8. HPLC (Daicel

Chiralpak AS, n-hexane–i-PrOH = 100 : 1, ﬂow rate = 1.0 mL

min⁻¹); t_R= 8.8 min (R), t_R= 9.7 min (S).

(s, 3H), 1.73 (s, 3H), 1.91–1.99 (m, 1H), 2.49 (dd, 1H, J = 4.1,

13.1 Hz), 2.62–2.70 (m, 2H), 2.87–2.92 (m, 1H), 3.69 (s, 2H),

7.10–7.15 (m, 2H), 7.20–7.26 (m, 5H), 7.34–7.36 (m, 1H), 7.86

(d, 1H, J = 7.6 Hz). ¹³C NMR (150 MHz): δ = 24.2, 26.5, 29.2,

29.6, 33.3, 49.2, 55.5, 126.4, 126.9, 127.7, 128.4, 128.5, 129.0,

132.9, 134.3, 138.3, 143.5, 198.7. HPLC (Daicel Chiralcel

OJ-H, n-hexane–i-PrOH = 9 : 1, ﬂow rate = 1.0 mL min⁻¹); t_R=

12.9 min (S), t_R= 14.4 min (R). HRMS calcd for C₂₀H₂₃OS⁺

([M + H]⁺): 311.14696, found 311.14716. [α]²_D⁰= −5.39 (c =

1.0, CHCl₃).

Deuterium kinetic isotope effect experiments

The reaction of 7a with 3a in D₂O was carried out as described

in the typical procedure for Michael reactions. The resulting

mixture was diluted with water. The aqueous layer was extracted

with dichloromethane (three times), and the combined organic

layers were washed with CuSO₄aq., and dried over Na₂SO₄.

After ﬁltration, the solvent was removed under reduced pressure.

The residue was puriﬁed by preparative TLC (elution:

chloroform–ethyl acetate = 200 : 1) to afford the protonated

adduct 8a-H and deuterated adduct 8a-D as a mixture. The H/D

8q: (R)-2-(2-(benzylthio)propan-2-yl)-6-methoxy-3,4-dihydro-

naphthalen-1(2H)-one. Colorless oil; IR (neat): ν = 2964, 1674,

1

1600, 1249, 1106, 1028, 1094, 711 cm⁻¹. H NMR (600 MHz):

δ = 1.42 (s, 3H), 1.81 (s, 3H), 1.98–2.04 (m, 1H), 2.48–2.51 (m,

1H), 2.64–2.73 (m, 2H), 2.91–2.95 (m, 1H), 3.76 (s, 2H), 3.84

(s, 3H), 6.62 (d, 1H, J = 2.1 Hz), 6.78–6.80 (m, 1H), 7.20–7.33

(m, 5H), 7.92 (d, 1H, J = 8.9 Hz). ¹³C NMR (150 MHz): δ =

24.4, 26.5, 29.5, 29.9, 33.3, 49.4, 55.2, 55.3, 112.1, 113.0,

126.8, 127.8, 128.5, 129.0, 129.6, 138.4, 146.0, 163.2, 197.4.

HPLC (Daicel Chiralpak AD-H, n-hexane–i-PrOH = 100 : 1,

ﬂow rate = 1.0 mL min⁻¹); t_R= 29.9 min (S), t_R= 35.0 min (R).

HRMS calcd for C₂₁H₂₅O₂S⁺([M + H]⁺): 341.13977, found

341.14070.

1

ratio of the product mixture was determined by H NMR analy-

sis. The enantiomeric excess was determined by chiral HPLC

analysis.

Acknowledgements

8r: (R)-2-(2-(benzylthio)propan-2-yl)-2,3-dihydro-1H-inden-

1-one. Colorless oil; IR (neat): ν = 2965, 2926, 1704, 1606,

This work was partially supported by a Grant-in-Aid for Science

Research from the Japan Society for the Promotion of Science

(JSPS).

1

1460, 1275, 1096, 752 cm⁻¹. H NMR (600 MHz): δ = 1.22

(s, 3H), 1.67 (s, 3H), 2.71 (q, 1H, J = 4.1 Hz), 3.08–3.12

7146 | Org. Biomol. Chem., 2012, 10, 7134–7147

View Online

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Org. Biomol. Chem., 2012, 10, 7134–7147 | 7147

Article Doi

Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with enones in water

DOI: 10.1039/c2ob26264a

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