Download PDF
Synthesis 2022; 54(21): 4703-4710
DOI: 10.1055/a-1588-0072
special topic
Asymmetric C–H Functionalization

Ruthenium(II)/Chiral Carboxylic Acid Catalyzed Enantioselective C–H Functionalization of Sulfoximines

Long-Tao Huang
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
,
Yuki Hirata
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
,
Yoshimi Kato
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
,
Luqing Lin 
b   Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
c   Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian 116024, P. R. of China   linluqing@dlut.edu.cn
,
Masahiro Kojima 
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
,
Tatsuhiko Yoshino  ∗
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
,
Shigeki Matsunaga  ∗
a   Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
b   Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812, Japan
› Author Affiliations

This work was supported in part by the Japan Society for the Promotion of Science (JSPS; KAKENHI grant number JP20H02730 and JP20H04794 in Hybrid Catalysis).
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Ruthenium(II)-catalyzed enantioselective C–H functionalization reactions of sulfoximines with sulfoxonium ylides are described. The combination of [RuCl2(p-cymene)]2 and a pseudo-C 2-symmetric binaphthyl monocarboxylic acid furnished the S-chiral products in 76:24 to 92:8 er.


#

Key words

ruthenium catalysis - C–H activation - asymmetric catalysis - chiral carboxylic acid - sulfoximine

The catalytic C–H functionalization of organic molecules using transition metal catalysts is a powerful strategy that streamlines the synthesis of valuable molecules, such as organic materials, natural products, and biologically active compounds.[1] In this context, Ru(II) catalysts appended with arene ligands have been widely employed in directing-group-assisted C–H activation/functionalization processes.[2] [3] After a seminal study by Oi, Inoue, and co-workers, published in 2001,[2] various transformations have been reported by many researchers including Ackermann as well as Bruneau and Dixneuf.[3] Compared to other 4d and 5d transition metals often used for C–H functionalization reactions, for example, Pd, Rh, and Ir, Ru is relatively inexpensive and is therefore an attractive metal for use in synthetic applications. However, catalytic control of the enantioselectivity of Ru(II)-catalyzed C–H functionalization reactions is still a highly challenging problem and only a few successful examples­ have been reported to date (Scheme [1]).[4] [5] [6] [7] [8] Cui[5] and Wang[6] independently reported an enantioselective intramolecular hydroarylation based on methodology that utilizes a chiral transient directing group[9] (Scheme [1a]). Ackermann and co-workers demonstrated that a chiral carboxylic acid can assist an enantioselective intramolecular hydroarylation via a reversible insertion/selective protonation mechanism (Scheme [1b]).[7] The [Ru(II)–arene] fragment has similar features to those of group 9 [Cp*M(III)] fragments (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl; M = Co, Rh, Ir). Both fragments possess a dicationic d6 metal center and a half-sandwich structure with three available cis coordination sites. Thus, asymmetric catalytic systems efficiently employed with the group 9 catalysts[10] can also be used with Ru(II) catalysts, except for the introduction of chiral Cpx ligands.[10`] [b] [c] It is worth noting that both the strategies mentioned above (Scheme [1a] and 1b) have been successfully employed in Rh(III)-[11] and Co(III)-catalyzed[12] reactions to control the enantio-determining step that takes place after the cleavage of a C–H bond.

Zoom Image
Scheme 1 Enantioselective C–H functionalization reactions with Ru(II)–arene catalysts that utilize (a) a chiral transient directing group, (b) a chiral carboxylic acid for enantioselective protonation, and (c) and (d) chiral carboxylic acids for enantioselective C–H activation

When C–H bonds are cleaved by an electrophilic high-valent metal catalyst, carboxylates and other basic anionic ligands participate via ambiphilic metal–ligand activation (AMLA), a concerted metalation–deprotonation (CMD), or a base-assisted internal electrophilic substitution (BIES) mechanism. Therefore enantio-induction can be achieved by using a chiral carboxylic acid (CCA) or a related ligand.[13] This strategy was first introduced to the field of Pd(II) catalysis by the Yu group[14] and was recently expanded to be used with group 9 metal catalysts.[15] Our group has been engaged in the development of enantioselective C–H functionalization of prochiral substrates using Co(III)/CCA[15c] [f] and Rh(III)/CCA[15b,d,i,j] systems. The similarity between Ru(II) catalysis and Cp*M(III) catalysis as well as our own research background prompted us to investigate the possibility of enantioselective C–H bond cleavage using a Ru(II) catalyst and a CCA. During the preparation of this manuscript, Shi and co-workers reported enantioselective C–H alkylation/cyclization reactions between sulfoximines and sulfoxonium ylides using [RuCl2(p-cymene)]2 and a C 1-symmetric binaphthyl CCA (Scheme [1c]).[16] Here we report on our own study demonstrating that a pseudo-C 2-symmetric binaphthyl CCA that we recently developed for Rh(III) catalysis[15j] is a suitable CCA for enantioselective C–H bond cleavage of prochiral sulfoximines (Scheme [1d]).

We commenced our investigation using sulfoximine 1a and sulfoxonium ylide 2a as the model substrates (Table [1]). Sulfoximines and their derivatives bearing a sulfur chiral center are important molecules in medicinal chemistry.[17] As such, directed C–H functionalization reactions of sulfoximines, including enantioselective variants, have recently been reported.[18] [19] [20] We selected the standard commercially available [RuCl2(p-cymene)]2/AgSbF6 as the metal catalyst. We chose pseudo-C 2-symmetric binaphthyl monocarboxylic acid 4a (Figure [1]), the best performing CCA in our previous report on Rh(III) catalysis,[15j] as the initial CCA. To our delight, the reaction proceeded at 20 °C in DCE in good enantioselectivity (86:14 er), albeit with low reactivity (entry 1). A high yield was achieved without a decrease in selectivity when the reaction temperature was increased to 40 °C (entry 2), while lower selectivity was observed at 80 °C (entry 3). We next screened various solvents (entries 4–11), finding that halogenated solvents are suitable in terms of both reactivity and selectivity (entries 2, 10, 11). Slightly higher enantioselectivity was observed with CHCl3 (90:10 er, entry 11) than with DCE. Finally, other related chiral carboxylic acids 4b–d were examined (entries 12–14), but none of them exhibited higher enantioselectivity. Thus, we concluded that the conditions in entry 11 were optimal.

Zoom Image
Figure 1 Chiral carboxylic acids 4

With the best conditions in hand, we next explored various other sulfoximines 1 and sulfoxonium ylides 2 (Scheme [2]). Sulfoximines with p-, m-, and o-substituents generally provided the corresponding products in good yields and similar enantioselectivities (3aa–ga, 85:15 to 92:8 er). Particularly, sulfoximines bearing electron-withdrawing groups afforded higher enantioselectivities (3ba and 3ca) than others, albeit with slightly decreased reactivity. A sterically demanding substrate with o-Me groups (1g) was also compatible with the optimal catalytic system (3ga). We then investigated several sulfoxonium ylides 2 using 1a and 1b as substrates (3ab–af, 3bb, 3be, 3bf). Aromatic-, heteroaromatic-, and aliphatic-substituted sulfoxonium ylides were all tolerated under the reaction conditions, providing the products in high yields and 76:24 to 90:10 er. The absolute configuration of 3 was determined to be S by comparing the optical rotation of 3aa ([α]D 24 +10.2 in CHCl3) with the previously reported value for the R-enantiomer ([α]D 20 –11.3 in CHCl3).[20b]

Table 1 Optimization of the Reaction Conditionsa

Entry

Temp ( °C)

Solvent

CCA 4

Yield (%)b

erc

 1

20

DCE

4a

 38

86:14

 2

40

DCE

4a

>95

86:14

 3

80

DCE

4a

>95

83:17

 4

40

MeOH

4a

 88

87:13

 5

40

HFIP

4a

 74

76:24

 6

40

1,4-dioxane

4a

 36

83:17

 7

40

DMF

4a

 30

64:36

 8

40

toluene

4a

 50

87:13

 9

40

PhCl

4a

 56

89:11

10

40

CH2Cl2

4a

 90

88:12

11

40

CHCl3

4a

>95

90:10

12

40

CHCl3

4b

 93

90:10

13

40

CHCl3

4c

 80

89:11

14

40

CHCl3

4d

 67

85:15

a Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), [RuCl2(p-cymene)]2 (0.00125 mmol, 2.5 mol%), AgSbF6 (0.01 mmol, 20 mol%), CCA 4 (0.005 mmol, 10 mol%), solvent (1 mL).

b Determined by 1H NMR analysis of the crude mixture using 1,1,2,2-tetrachloroethane as the internal standard.

c Determined by chiral HPLC analysis.

Zoom Image
Scheme 2 Substrate scope for enantioselective C–H alkylation/cyclization of sulfoximines 1 with sulfoxonium ylides 2. Reagents and conditions: 1 (0.2 mmol), 2 (0.3 mmol), [RuCl2(p-cymene)]2 (0.005 mmol, 2.5 mol%), AgSbF6 (0.04 mmol, 20 mol%), CCA 4a (0.02 mmol, 10 mol%), CHCl3 (4 mL), 40 °C, 24 h.
Zoom Image
Scheme 3 Plausible catalytic cycle

A plausible catalytic cycle is shown in Scheme [3]. An active Ru–carboxylate catalyst (A) is generated from [RuCl2(p-cymene)]2, AgSbF6, and CCA 4a, which would be coordinated with 1 (B). A key C–H activation step proceeds via a carboxylate-assisted mechanism, in which the chiral carboxylate base derived from CCA 4a selectively deprotonates one of the enantiotopic protons of 1. Thus-generated chiral metallacycle C reacts with sulfoxonium ylide 2 to afford intermediate D with the release of DMSO. The subsequent protonation furnishes E and regenerates the active catalyst. Finally, intramolecular condensation between the sulfoximine moiety and introduced ketone provides 3. While unprotected NH-sulfoximines are proposed to undergo deprotonation before C–H activation in the previous study,[18i] a metallacycle intermediate isolated by Bolm and co-workers clearly has a remaining NH proton.[18a] In addition, our catalytic system does not involve any efficient bases, such as metal carbonates, to facilitate the deprotonation. Therefore, we speculate that the unprotected sulfoximine moiety may work as the directing group without deprotonation, although the catalytic cycle involving the deprotonation of the NH moiety cannot be excluded at this point.

In summary, we have found that the combination of a Ru(II) catalyst and a pseudo-C 2-symmetric binaphthyl CCA (4a) is an effective catalytic system for enantioselective C–H functionalization of sulfoximines 1 with sulfoxonium ylides 2. Although the observed enantioselectivities were lower than those reported in the recent work by Shi and co-workers (Scheme [1c]),[16] we demonstrated that our CCA 4a is also a suitable chiral source for Ru(II)-catalyzed C–H functionalization, for which chiral catalytic systems remain underdeveloped. Further investigation on the combination of CCAs that we developed and Ru(II) catalysts are ongoing in our group.

Reactions were carried out under argon atmosphere unless otherwise noted. Enantioselectivities were determined by HPLC, using 4.6 mm × 25 cm Daicel Chiralpak columns. NMR spectra were recorded on JEOL JNM-ECS400 spectrometers operating at 391.78 MHz for 1H NMR and 98.52 MHz for 13C NMR, JOEL JNM-ECX400 spectrometers operating at 395.88 MHz for 1H NMR and 99.55 MHz for 13C NMR, and JNM-ECA500 spectrometers operating at 500.16 MHz for 1H NMR and 125.77 MHz for 13C NMR. 1H and 13C NMR chemical shifts are given in ppm relative to SiMe4, with the solvent resonance used as an internal reference: CHCl3 (δ = 7.26 for 1H NMR), CDCl3 (δ = 77.16 for 13C NMR). ESI mass spectra were measured on a Thermo Scientific Exactive spectrometer. Optical rotations were measured on a JASCO P-1010 polarimeter. Column chromatography was performed on silica gel (Kanto Silica gel 60 N, 40–50 mesh) or on a Yamazen YFLC AI-580 using Universal Column SiOH. CH2Cl2, THF, Et2O, and toluene were purified on a Glass Contour solvent purification system before use. DCE, NMP, EtOH, DMF, CHCl3, and MeCN were purchased from Kanto Chemicals (dehydrated grade) and used as received. Chlorobenzene and MeOH were purchased from Aldrich (dehydrated grade) and used as received. Sulfoximines 1a–g,[21a] sulfoxonium ylides 2a–f,[21b] and chiral carboxylic acids 4a–d [15j] were prepared according to literature procedures. All other reagents were commercially available and used as received unless otherwise noted.


#

Benzo[e][1,2]thiazine 1-Oxides 3; General Procedure

In an argon-filled glovebox, a screw-capped test tube was charged with sulfoximine 1 (0.20 mmol, 1.0 equiv), sulfoxonium ylide 2 (0.3 mmol, 1.5 equiv), chiral carboxylic acid 4a (0.02 mmol, 8.4 mg), AgSbF6 (13.6 mg, 20 mol%), [RuCl2(p-cymene)]2 (3.0 mg, 2.5 mol%), and CHCl3 (4.0 mL). Then the reaction mixture was stirred at 40 °C for 24 h. The resulting mixture was directly purified by column chromatography (silica gel, hexane/EtOAc) to afford 3.


#

(S)-1,3-Diphenylbenzo[e][1,2]thiazine 1-Oxide (3aa)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3aa as a yellow foam (51.0 mg, 80%) after chromatographic purification by Yamazen­ YFLC AI-580 with Universal Column SiOH (hexane/EtOAc, gradient to 6:1).

[α]D 24 +10.2 (c = 1.0, CHCl3).

TLC (silica gel): Rf = 0.4 (hexane/EtOAc, 6:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.2 mL/min; tR (minor) = 10.4 min, tR (major) = 11.9 min; 12:88 er.

1H NMR (400 MHz, CDCl3): δ = 8.03–7.97 (m, 4 H), 7.66–7.53 (m, 3 H), 7.51–7.30 (m, 6 H), 7.25–7.19 (m, 1 H), 6.81 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 147.2, 140.5, 138.7, 136.5, 133.3, 132.1, 129.3, 129.0, 128.8, 128.3, 126.9, 126.6, 126.2, 124.9, 119.6, 98.1.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-6-Chloro-1-(4-chlorophenyl)-3-phenylbenzo[e][1,2]thiazine 1-Oxide (3ba)

According to the general procedure, sulfoximine 1b (0.20 mmol, 56.8 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3ba as a yellow foam (55.0 mg, 72%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

TLC (silica gel): Rf = 0.4 (hexane/EtOAc, 3:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 0.7 mL/min; tR (major) = 21.8 min, tR (minor) = 26.9 min; 92:8 er.

1H NMR (500 MHz, CDCl3): δ = 7.99–7.95 (m, 2 H), 7.92–7.87 (m, 2 H), 7.58–7.53 (m, 2 H), 7.46–7.36 (m, 4 H), 7.26 (t, J = 4.3 Hz, 1 H), 7.18 (dd, J = 8.6, 1.7 Hz, 1 H), 6.74 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 148.6, 140.6, 138.8, 138.6, 138.1, 138.1, 130.6, 129.4, 129.3, 128.4, 126.7, 126.7, 126.5, 126.1, 117.3, 97.4

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-1-[4-(6-Acetyl-1-oxido-3-phenylbenzo[e][1,2]thiazin-1-yl)phenyl]ethan-1-one (3ca)

According to the general procedure, sulfoximine 1c (0.20 mmol, 60.2 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3ca as a yellow foam (58.0 mg, 72%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 2:1).

TLC (silica gel): Rf = 0.3 (hexane/EtOAc, 1:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (2:1), 1.0 mL/min; tR (major) = 21.4 min, tR (minor) = 35.2 min; 91:9 er.

1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 9.0 Hz, 2 H), 8.09 (d, J = 8.5 Hz, 3 H), 8.04–7.97 (m, 3 H), 7.75 (dd, J = 8.5, 1.8 Hz, 1 H), 7.47–7.37 (m, 4 H), 6.95 (s, 1 H), 2.67 (s, 3 H), 2.66 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 197.0, 196.6, 148.2, 143.6, 140.8, 139.7, 138.0, 136.8, 129.7, 129.3, 128.8, 128.5, 127.9, 126.7, 125.4, 124.9, 121.1, 98.6, 27.0, 26.8

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-6-Methyl-3-phenyl-1-(p-tolyl)benzo[e][1,2]thiazine 1-Oxide (3da)

According to the general procedure, sulfoximine 1d (0.20 mmol, 49.0 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3da as a yellow foam (70.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, gradient to 4:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 4:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.0 mL/min; tR (major) = 20.5 min, tR (minor) = 25.7 min; 89:11 er.

1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.2 Hz, 2 H), 7.84 (d, J = 8.6 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.37–7.31 (m, 3 H), 7.26–7.18 (m, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 6.73 (s, 1 H), 2.43 (s, 3 H), 2.38 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.1, 144.2, 142.5, 138.9, 137.9, 136.6, 129.6, 129.2, 128.6, 128.3, 127.6, 126.6, 126.5, 124.8, 117.5, 97.9, 21.7, 21.5

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-6-Methoxy-1-(4-methoxyphenyl)-3-phenylbenzo[e][1,2]thiazine 1-Oxide (3ea)

According to the general procedure, sulfoximine 1e (0.20 mmol, 55.4 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3ea as a yellow solid (75.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, gradient to 4:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 4:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.2 mL/min; tR (major) = 26.7 min, tR (minor) = 30.1 min; 85:15 er.

1H NMR (500 MHz, CDCl3): δ = 8.03- 7.96(m, 2 H), 7.91–7.84 (m, 2 H), 7.44–7.32 (m, 3 H), 7.29–7.23 (m, 1 H), 7.04–6.97 (m, 2 H), 6.82–6.77 (m, 2 H), 6.71 (s, 1 H), 3.87 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 163.4, 162.0, 147.8, 138.9, 138.7, 132.6, 131.1, 128.7, 128.3, 126.9, 126.6, 115.8, 114.1, 113.3, 107.4, 98.0, 55.7, 55.5.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-7-Methyl-3-phenyl-1-(m-tolyl)benzo[e][1,2]thiazine 1-Oxide (3fa)

According to the general procedure, sulfoximine 1f (0.20 mmol, 49.0 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3fa as a yellow solid (69.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, gradient to 4:1).

TLC (silica gel): Rf = 0.4 (hexane/EtOAc, 4:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (19:1), 1.0 mL/min; tR (major) = 26.1 min, tR (minor) = 28.1 min; 88:12 er.

1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 7.2, 1.6 Hz, 2 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.77 (s, 1 H), 7.49–7.28 (m, 7 H), 7.11 (s, 1 H), 6.78 (s, 1 H), 2.43 (s, 3 H), 2.30 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.1, 140.4, 139.2, 138.9, 136.5, 134.1, 134.1, 133.6, 129.6, 128.8, 128.5, 128.3, 126.8, 126.5, 124.2, 119.6, 98.0, 21.3, 21.3. One aromatic signal was missing, probably due to overlapping.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-8-Methyl-3-phenyl-1-(o-tolyl)benzo[e][1,2]thiazine 1-Oxide (3ga)

According to the general procedure, sulfoximine 1g (0.20 mmol, 49.0 mg) and sulfoxonium ylide 2a (0.30 mmol, 59.1 mg) afforded 3ga as a yellow foam (70.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, gradient to 4:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 4:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.0 mL/min; tR (minor) = 7.3 min, tR (major) = 9.0 min; 11:89 er.

1H NMR (400 MHz, CDCl3): δ = 8.44–8.38 (m, 1 H), 7.97–7.91 (m, 2 H), 7.52–7.47 (m, 2 H), 7.45–7.28 (m, 5 H), 7.24–7.18 (m, 1 H), 7.02 (d, J = 7.6 Hz, 1 H), 6.76 (s, 1 H), 2.08 (s, 3 H), 1.73 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.2, 140.5, 140.0, 138.5, 135.4, 133.4, 132.8, 132.3, 129.2, 128.7, 128.6, 128.3, 126.4, 126.2, 125.5, 117.0, 97.8, 20.1, 19.1. One aromatic signal was missing, probably due to overlapping.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-1-Phenyl-3-(p-tolyl)benzo[e][1,2]thiazine 1-Oxide (3ab)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2b (0.30 mmol, 63.3 mg) afforded 3ab as a yellow foam (66.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 5:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.2 mL/min; tR (minor) = 12.1 min, tR (major) = 13.0 min; 12:88 er.

1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.2 Hz, 2 H), 7.90 (d, J = 8.5 Hz, 2 H), 7.63 (t, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.2 Hz, 2 H), 7.47 (t, J = 7.4 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.26–7.17 (m, 3 H), 6.78 (s, 1 H), 2.38 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.2, 140.4, 138.8, 136.6, 135.9, 133.3, 132.0, 129.3, 129.0, 128.9, 126.7, 126.5, 126.0, 124.9, 119.4, 97.5, 21.3.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-3-(4-Fluorophenyl)-1-phenylbenzo[e][1,2]thiazine 1-Oxide (3ac)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2c (0.30 mmol, 64.2 mg) afforded 3ac as a yellow foam (60.0 mg, 90%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

TLC (silica gel): Rf = 0.3 (hexane/EtOAc, 5:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.2 mL/min; tR (minor) = 10.6 min, tR (major) = 12.2 min; 13:87 er.

1H NMR (500 MHz, CDCl3): δ = 8.02–7.95 (m, 4 H), 7.67–7.62 (m, 1 H), 7.61–7.55 (m, 2 H), 7.51–7.47 (m, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.25–7.20 (m, 1 H), 7.12–7.06 (m, 2 H), 6.75 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 163.3 (d, 1 J C-F = 248.0 Hz), 146.1, 140.1, 136.3, 134.9 (d, 4 J C-F = 2.8 Hz), 133.4, 132.1, 129.3, 129.0, 128.4 (d, 3 J C-F = 8.5 Hz), 126.8, 126.3, 124.9, 119.4, 115.2 (d, 2 J C-F= 21.6 Hz), 97.9.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-3-(Naphthalen-2-yl)-1-phenylbenzo[e][1,2]thiazine 1-Oxide (3ad)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2d (0.30 mmol, 73.8 mg) afforded 3ad as a yellow foam (68.0 mg, 92%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

TLC (silica gel): Rf = 0.6 (hexane/EtOAc, 3:1, UV).

HPLC: Chiralpak AD-H column, hexane–iPrOH (4:1), 1.2 mL/min; tR (minor) = 14.1 min, tR (major) = 17.1 min; 14:86 er.

1H NMR (400 MHz, CDCl3): δ = 8.55 (s, 1 H), 8.10–8.01 (m, 3 H), 7.91–7.80 (m, 3 H), 7.67–7.55 (m, 3 H), 7.51–7.44 (m, 4 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.26–7.19 (m, 1 H), 6.96 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 146.9, 140.4, 136.4, 135.9, 133.6, 133.4, 133.4, 132.1, 129.4, 129.0, 128.8, 127.8, 127.5, 127.0, 126.4, 126.4, 126.3, 126.1, 125.0, 124.0, 119.8, 98.7.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-3-(Furan-2-yl)-1-phenylbenzo[e][1,2]thiazine 1-Oxide (3ae)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2e (0.30 mmol, 54.9 mg) afforded 3ae a brown foam (62.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 4:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 1:1, UV).

HPLC: Chiralpak IB column, hexane–iPrOH (4:1), 1.0 mL/min; tR (major) = 8.5 min, tR (minor) = 19.1 min; 84:16 er.

1H NMR (400 MHz, CDCl3): δ = 7.94–7.88 (m, 2 H), 7.59–7.54 (m, 1 H), 7.53–7.47 (m, 2 H), 7.42–7.32 (m, 3 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.14–7.10 (m, 1 H), 6.83 (d, J = 3.6 Hz, 1 H), 6.73 (s, 1 H), 6.40 (dd, J = 3.6, 1.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 153.3, 143.0, 140.0, 138.5, 136.1, 133.4, 132.1, 129.4, 129.0, 126.8, 126.1, 125.0, 120.1, 111.8, 109.4, 96.4.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-3-(tert-Butyl)-1-phenylbenzo[e][1,2]thiazine 1-Oxide (3af)

According to the general procedure, sulfoximine 1a (0.20 mmol, 43.4 mg) and sulfoxonium ylide 2f (0.30 mmol, 52.8 mg) afforded 3af as a white solid (60.0 mg, >99%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 10:1).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 6:1, UV).

HPLC: Chiralpak IF column, hexane–iPrOH (19:1), 1.0 mL/min; tR (minor) = 7.8 min, tR (major) = 8.5 min; 18:82 er.

1H NMR (400 MHz, CDCl3): δ = 7.89–7.81 (m, 2 H), 7.56–7.45 (m, 3 H), 7.36–7.31 (m, 1 H), 7.25–7.17 (m, 2 H), 7.11–7.06 (m, 1 H), 6.12 (s, 1 H), 1.27 (s, 9 H).

13C NMR (100 MHz, CDCl3): δ = 159.7, 141.0, 136.6, 133.0, 131.7, 129.1, 128.8, 126.5, 125.6, 124.7, 118.6, 95.0, 37.5, 28.9.

The NMR spectra of the obtained product were consistent with the reported data.[16]


#

(S)-6-Chloro-1-(4-chlorophenyl)-3-(p-tolyl)benzo[e][1,2]thiazine 1-Oxide (3bb)

According to the general procedure, sulfoximine 1b (0.20 mmol, 56.8 mg) and sulfoxonium ylide 2b (0.30 mmol, 63.3 mg) afforded 3bb as a yellow solid (54.0 mg, 68%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

Mp 146–147 °C.

[α]D 24 +160.4 (c = 0.5, CHCl3).

TLC (silica gel): Rf = 0.5 (hexane/EtOAc, 6:1, UV).

HPLC: Chiralpak IA column, hexane–iPrOH (2:1), 1.0 mL/min; tR (major) = 10.8 min, tR (minor) = 14.4 min; 89:11 er.

1H NMR (400 MHz, CDCl3): δ = 7.83–7.78 (m, 4 H), 7.50–7.46 (m, 2 H), 7.34 (d, J = 1.8 Hz, 1 H), 7.17 (t, J = 8.0 Hz, 3 H ), 7.09 (dd, J = 8.0, 1.8 Hz, 1 H ), 6.63 (s, 1 H), 2.32 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 148.6, 140.5, 139.4, 138.9, 138.5, 138.2, 135.3, 130.5, 129.4, 129.2, 126.6, 126.5, 126.4, 125.9, 117.1, 96.8, 21.3.

HRMS (ESI): m/z [M + Na]+ calcd for C21H15Cl2NOSNa+: 422.0144; found: 422.0137.


#

(S)-6-Chloro-1-(4-chlorophenyl)-3-(furan-2-yl)benzo[e][1,2]thiazine 1-Oxide (3be)

According to the general procedure, sulfoximine 1b (0.20 mmol, 56.8 mg) and sulfoxonium ylide 2e (0.30 mmol, 54.9 mg) afforded 3be as a yellow solid (74.0 mg, >99%) after chromatographic purification by Yamazen YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

Mp 141–142 °C.

[α]D 24 +203.2 (c = 0.5, CHCl3).

TLC (silica gel): Rf = 0.4 (hexane/EtOAc, 3:1, UV).

HPLC: Chiralpak IC column, hexane–iPrOH (4:1), 1.0 mL/min; tR (minor) = 8.5 min, tR (major) = 9.7 min; 10:90 er.

1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.5 Hz, 2 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.43 (s, 1 H), 7.32 (s, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 9.0 Hz, 1 H), 6.83 (d, J = 3.1 Hz, 1 H), 6.65 (s, 1 H), 6.42 (dd, J = 2.9, 1.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 152.7, 143.5, 140.7, 139.7, 138.7, 138.6, 137.8, 130.6, 129.4, 126.6, 126.5, 125.9, 117.8, 112.0, 110.3, 95.6.

HRMS (ESI): m/z [M + Na]+ calcd for C18H11Cl2NO2SNa+: 397.9780; found: 397.9775.


#

(S)-3-(tert-Butyl)-6-chloro-1-(4-chlorophenyl)benzo[e][1,2]thiazine 1-Oxide (3bf)

According to the general procedure, sulfoximine 1b (0.20 mmol, 56.8 mg) and sulfoxonium ylide 2f (0.30 mmol, 52.8 mg) afforded 3bf as a yellow oil (70.0 mg, 95%) after chromatographic purification by Yamazen­ YFLC AI-580 using Universal Column SiOH (hexane/EtOAc, 8:1).

[α]D 24 +54.6 (c = 0.5, CHCl3).

TLC (silica gel): Rf = 0.6 (hexane/EtOAc, 6:1, UV).

HPLC: Chiralpak IC column, hexane–iPrOH (19:1), 1.0 mL/min; tR (major) = 6.3 min, tR (minor) = 7.2 min; 76:24 er.

1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 9.0 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 2.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.05 (dd, J = 8.5, 2.2 Hz, 1 H), 6.05 (s, 1 H), 1.24 (s, 9 H).

13C NMR (100 MHz, CDCl3): δ = 161.4, 140.2, 139.4, 138.2, 138.2, 130.3, 129.3, 126.3, 126.2, 125.8, 116.3, 94.6, 37.7, 28.8.

HRMS (ESI): m/z [M + Na]+ calcd for C18H17Cl2NOSNa+: 388.0301; found: 388.0294.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1588-0072.
  • Supporting Information

Corresponding Authors

Tatsuhiko Yoshino
Faculty of Pharmaceutical Sciences, Hokkaido University
Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812
Japan   

Shigeki Matsunaga
Faculty of Pharmaceutical Sciences, Hokkaido University
Kita-12 Nishi-6, Sapporo, Hokkaido 060-0812
Japan   

Publication History

Received: 13 July 2021

Accepted after revision: 16 August 2021

Accepted Manuscript online:
16 August 2021

Article published online:
11 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Enantioselective C–H functionalization reactions with Ru(II)–arene catalysts that utilize (a) a chiral transient directing group, (b) a chiral carboxylic acid for enantioselective protonation, and (c) and (d) chiral carboxylic acids for enantioselective C–H activation
Zoom Image
Figure 1 Chiral carboxylic acids 4
Zoom Image
Scheme 2 Substrate scope for enantioselective C–H alkylation/cyclization of sulfoximines 1 with sulfoxonium ylides 2. Reagents and conditions: 1 (0.2 mmol), 2 (0.3 mmol), [RuCl2(p-cymene)]2 (0.005 mmol, 2.5 mol%), AgSbF6 (0.04 mmol, 20 mol%), CCA 4a (0.02 mmol, 10 mol%), CHCl3 (4 mL), 40 °C, 24 h.
Zoom Image
Scheme 3 Plausible catalytic cycle