Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with Optically Pure Difluoromethylthiolating Reagents Derived from Camphorsultam

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of Chemistry

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Accepted Article

Title: Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with Optically

Pure Difluoromethylthiolating Reagents Derived from Camphorsultam

Authors: He Zhang, Xiaolong Wan, and Qilong Shen*

This manuscript has been accepted and appears as an Accepted Article online.

This work may now be cited as: Chin. J. Chem. 2019, 37, 10.1002/cjoc.201900298.

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published online in Early View: http://dx.doi.org/10.1002/cjoc.201900298.

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Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with

Optically Pure Difluoromethylthiolating Reagents Derived from

Camphorsultam

a

He Zhang, ^aXiaolong Wan, ^aand Qilong Shen*^,

^aKey Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese

Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China

Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX

Summary of main observation and conclusion The invention of a family of optically pure electrophilic difluoromethylthiolating reagents 9a-c based on

the camphorsultam skeleton was described. These reagents reacted with a variety of soft carbon nucleophiles such as oxazolone, oxindole, benzolactone

and β-ketoester in good to excellent enantioselectivities.

Over the past few years, several difluoromethylthiolating

Background and Originality Content

reagents 1-8⁹have been developed (Fig. 1), thus allowing efficient

construction of C(sp²)-SCF₂H and C(sp³)-SCF₂H bonds under mild

Over the past several decades, the magic "fluorine effect" of

the fluorine atom and fluoroalkyl groups in new drug discovery

conditions. Nevertheless, few methods that can stereoselectively

have been well recognized,¹as evidenced by the fact that 18 out

build chiral carbon center bearing a SCF₂H group have been

reported.¹⁰To the best of our knowledge, only two such

of 42 small-molecule drugs approved by US Food and Drug

Administration (FDA) in 2018 were fluorinated.²Not surprisingly,

transformations have been described previously, both by Shibata

rational "fluorine scan" has become a routine practice in the fine

and coworkers. The first method was based on the Pd-catalyzed

tuning of the physico-chemical properties of the lead

decarboxylative asymmetric allylic alkylation of α-

compounds.³The high-demand for fluorinated molecules in these

fields has thus urged the organochemists to develop efficient

methods that are able to site-specifically incorporate the fluorine

or fluoroalkyl group into the target molecules under mild

conditions. Consequently, a large number of such elegant

fluorinating/fluoroalkylating methods have been reported in the

last decades.⁴

It is also well-known that the development of efficient

fluorinating/fluoroalkylating methods relied heavily on the

inventions of new nucleophilic or electrophilic

fluorinating/fluoroalkylating reagents.⁵For instance, the

invention of nucleophilic trifluoromethylating reagent TMSCF₃

and several electrophilic trifluoromethylation reagents such as

Umemoto's⁶and Togni's reagent⁷have revolutionized the way for

the preparation of trifluoromethylated compounds. In this

respect, the development of new broadly applicable

fluoroalkylating reagents remains an urgent and unmet task.

Figure 1 Difluoromethylthiolating reagents.

difluoromethylthiolated β-ketoesters^11aand the second method

More specifically, because the weakly acidic hydrogen of the

utilized a chiral amine auxiliary for asymmetric

difluoromethylthio group (-SCF₂H) is generally considered as a

difluoromethylthiolation of β-ketoesters with reagent 3.^11bEven

lipophilic hydrogen-bonding donor that could provide additional

though excellent enantioselectivities were achieved, the substrate

binding site when interacting with enzymes, the

scopes in both cases were limited to β-ketoesters. Thus, new

difluoromethylthio group represents a valuable yet

strategies for asymmetric difluoromethylthiolation with broad

underdeveloped fluoroalkyl group in the medicinal chemistry.⁸

substrates are urgently needed.

This article has been accepted for publication and undergone full peer review but has not been

through the copyediting, typesetting, pagination and proofreading process which may lead to

differences between this version and the Version of Record. Please cite this article as doi:

10.1002/cjoc.201900298

Chen et al.

Breaking Report

Herein, we reported an alternative strategy for the

construction of chiral carbon center bearing a SCF₂H group with

broad substrate scopes. The key of our strategy is the design and

preparation of a family of optically pure electrophilic

difluoromethylthiolating reagents 9a-c based on the

camphorsultam skeleton, a commercially available, optically pure

crystalline solid which is typically used as chiral auxiliary.¹²

Reactions of reagents 9a-c with soft carbon nucleophiles such as

oxazolone, oxindole, benzolactone and β-ketoester occurred with

good to excellent enantioselectivities.

9a

9b

9c

Figure 3. X-ray structure of

(1S)-(-)-N-difluoromethylthio-2,10-camphorsultam.

Results and Discussion

The invention of reagents 9a-c was inspired by our recent

success in the development of optically pure

With a reliable method for the preparation of compounds

9a-c in hand, the stage is now set for evaluation of their

reactivities for stereo-selectively delivering the

difluoromethylthio group into the target molecules. The reaction

of enolate derived from oxazolone was initially chosen as a model

reaction since oxazolones are a type of protected amino acids¹⁶

and fluoroalkylated amino acids are potentially useful for the

study of unnatural peptides and proteins.¹⁷Treatment of the

lithium enolate derived from oxazolone 10a with reagent 9b in

diethyl ether at -10 ^oC for 2 h afforded the desired

difluoromethylthiolated product 11a in 88% yield with 95% ee. As

shown in Scheme 1, the reaction conditions were general since a

variety of enolates derived from oxazolones with different

substituents such as n-propyl, iso-propyl, benzyl and allyl group all

reacted with reagent 9b to give the corresponding

trifluoromethylthiolating reagent

(1S)-(-)-N-trifluoromethylthio-2,10-camphorsultam,¹³we

envisaged that if a difluoromethylthio group could be attached to

the camphorsultam skeleton, an analogous optically pure

difluoromethylthiolating reagent might be developed. Yet, the

preparation of the target compounds is quite challenging. Our

initial efforts to synthesize

(1S)-(-)-N-difluoromethylthio-2,10-camphorsultam by reaction of

(1S)-(-)-N-chloro-2,10-camphorsultam with a combination of

TMSCF₂H and sulfur in the presence of various activators such as

cesium fluoride or potassium tert-butoxide were unsuccessful.

Alternatively, reaction of (1S)-(-)-N-chloro-2,10-camphorsultam

with nucleophilic difluoromethylthiolating reagent

[(SIPr)Ag(SCF₂H)] (SIPr = 1,3-bis(2,6-diisopropyl phenyl)

imidazolin-2-ylidene)¹⁴did not generate the desired product.

Finally, it was found that treatment of difluoromethanesulfenyl

chloride, which was in situ generated from

difluoromethyl-benzylthioether with a solution of chlorine in

chloroform, with the Oppolzer’s sultam sodium salt at room

temperature afforded reagent 9a after 5 h in 74% yield (Figure 2).

Likewise, reagents 9b-c were prepared in 55% and 68% yields,

respectively. White crystalline compounds 9a-c were fully

characterized by ¹H, ¹⁹F and ¹³C NMR spectroscopies¹⁵and the

structures were further unambiguously confirmed by X-ray

diffraction of their single crystals (Figure 3).

difluoromethylthiolated products in good to excellent

enantioselectivities (Scheme 1, 11a-d). Cyclic alkyl groups are

important structural motif present in many natural products and

drug scaffolds.¹⁸We therefore studied reactions of enolates

derived from oxazolones with cyclic alkyl groups. While reaction

of enolate with a cyclopropyl group occurred in moderate

enantioselectivity (Scheme 1, 11i), reactions of enolates with a

cyclobutyl, cyclopentyl or cyclohexyl group occurred in excellent

Figure 2. Preparation of

(1S)-(-)-N-difluoromethylthio-2,10-camphorsultam and its derivatives.

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

Scheme 1. Scope of asymmetric difluoromethylthiolation of oxazolone

derivatives with reagent 9b.^a

and ester group (13e) at the para-position of the phenyl

substituent of the oxindoles reacted with reagent 9c to give the

corresponding difluoromethylthiolated products in 81-93% ee,

while substrate with an electron-donating methoxy group (13d)

occurred in 88% ee. Notably, enolizable ketone or nitrile were

intact under these conditions and substrates with these two

functional groups also reacted with reagent 9c to afford the

desired products in 91% ee and 94% ee, respectively (Scheme 2,

13f-g). Likewise, oxindoles with both electron-donating and

electron-withdrawing substituents at the oxindole skeleton also

reacted to give the desired difluoromethylthiolated products in

good to excellent enantioselectivities (81-93% ee) (Scheme 2,

13j-m). Again, the

Scheme 2. Scope of asymmetric difluoromethylthiolation of oxindole,

benzolactone and β-ketoester derivatives with reagent 9c.^a

^aReaction conditions: oxazolone (0.30 mmol), reagent 9b (0.36 mmol),

LiHMDS (0.29 mmol) in 3.0 mL of diethyl ether at -10 ^oC for 2.0 h under an

argon atmosphere. Isolated yields.

enantioselectivity (Scheme 1, 11j-l).

To determine the absolute configuration of

difluoromethylthiolated compounds 11, we investigated the

reaction of 4-nitrophenyl substituted 10e with reagent 9b, which

afforded the desired product 11e as a white solid in 97% ee.

Single crystals were grown by evaporating a dichloromethane

solution of compound 11e and the absolute configuration of

compound 11e was determined to be R by X-ray diffraction of the

single crystals (Scheme 1, 11e). The configurations of the rest of

compounds 11 were assigned based on the same mechanism

assumption.

Encouraged by the excellent enantioselectivity for the

reactions of enolates derived from oxazolone, we next tried to

extend this high stereoselective reaction to other soft carbon

nucleophiles such as oxindoles, benzolactones and β-ketoesters.

Interestingly, it was found that reactions of oxindoles with

reagent 9c with two methoxy groups occurred in higher

enantioselectivities than those with reagent 9b when Cs₂CO₃was

used as the base and toluene as the solvent, as summarized in

Scheme 2. It turned out that the reaction conditions were general

toward a variety of oxindoles. For example, substrates with an

electron-withdrawing group such as chloride (13b), cyano (13c)

Chin. J. Chem. 2019, 37, XXX－XXX

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Chen et al.

Breaking Report

To probe the convertibility of difluoromethylthiolated

oxazolone derivatives, we studied the reaction of compound

11h under various conditions. While compound 11h underwent

defluorinative decomposition under both strong acidic or basic

conditions, ring-opening esterification of the oxazolone in

compound 11h was successfully achieved when compound 11h

was treated with a combination of 10 mol% Sc(OTf)₃and 10.0

equivalent of methanol in toluene at room temperature for 2.0 h.

The corresponding protected difluoromethylthiolated amino acid

16 was isolated in 55% yield without erosion of enantioselectivity

(Eq.1). These results indicate the potential application of the

current protocol in the preparation of optically pure

difluoromethylthiolated or trifluoromethylthiolated amino acids

and peptides.

Conclusions

In summary, we have successfully invented a family of easily

available, optically pure, electrophilic difluoromethylthiolating

reagents 9a-c based on the camphorsultam skeleton. Reactions of

a variety of soft carbon nucleophiles such as oxazolones,

oxindoles, benzolactones and β-ketoesters with these reagents

occurred with good to excellent enantioselectivities. Efforts to

study the enantioselective difluoromethylthiolating reaction of

reagents 9a-c with other nucleophiles such as alkenes are

undergoing currently in our lab.

Experimental

General information. All solvents were purified by standard

method. ¹H , ¹³C and ¹⁹F NMR spectra were acquired on 400 MHz,

125 MHz, 100 MHz, 375 MHz spectrometer (400 MHz for ¹H ; 100

MHz or 125 MHz for ¹³C; 375 MHz for ¹⁹F). ¹H NMR and ¹³C NMR

chemical shifts were determined relative to internal standard

TMS at δ 0.0 ppm and ¹⁹F NMR chemical shifts were determined

relative to CFCl₃as inter standard. Chemical shifts (δ) are reported

in ppm, and coupling constants (J) are in hertz (Hz). The following

abbreviations were used to explain the multiplicities: s = singlet, d

= doublet, t = triplet, q = quartet, m = multiplet, br = broad. All

reactions were monitored by TLC or ¹⁹F NMR. Flash column

chromatograph was carried out using 300-400 mesh silica gel at

medium pressure.

^aReaction conditions: oxindole, benzolactone or β-ketoester (0.30 mmol),

reagent 9c (0.36 mmol), Cs₂CO₃(0.45 mmol or 0.33 mmol) in 3.0 mL of

toluene at -40 ^oC for 12.0 h or 6.0 h under an argon atmosphere. Isolated

yields.

absolute configuration of compound 13m was determined by

X-ray diffraction of its single crystals.

On the other hand, reactions of benzolactones and

β-ketoesters with reagent 9c occurred in slightly inferior but

acceptable enantioselectivities 79-87% ee (Scheme 2, 14a-c,

15a-c). Efforts to improve the enantioselectivity of these two

types of substrates by employing reagents 9a or 9b as the

difluoromethylthio source were fruitless.

Materials. All reagents were received from commercial sources.

Solvents were freshly dried and degassed according to the

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

purification handbook Purification of Laboratory Chemicals before

using.

-101.73 (dd, J = 244.1, 51.7 Hz), -105.05 (dd, J = 266.0, 51.3 Hz)

ppm.

General Procedure for the Synthesis of

(1S)-(-)-N-difluoromethylthio-2,10-camphorsultam

Potassium hydroxide (224 g, 4.00 mol, 20.0 equiv.),

¹H NMR (400 MHz, CDCl₃, 298 K) δ 7.04 (t, J = 57.4 Hz, 1 H),

3.43 (br, 1 H), 3.25 (q, J = 13.8 Hz, 2 H), 2.15 (ddd, J = 13.2, 6.7, 3.9

Hz, 1 H), 1.95 (t, J = 3.8 Hz, 1 H), 1.93 – 1.82 (m, 2 H), 1.77 (dd, J =

13.4, 8.1 Hz, 1 H), 1.43 (dd, J = 18.7, 10.0 Hz, 1 H), 1.36 – 1.20 (m,

1 H), 0.99 (s, 3 H), 0.92 (s, 3 H); ¹³C NMR (101 MHz, CDCl₃, 298 K) δ

120.06 (t, J = 279.9 Hz), 68.42, 51.09, 48.93, 47.68, 44.17, 34.37,

32.09, 27.00, 20.07, 19.88; ¹⁹F NMR (376 MHz, CDCl₃, 298 K) δ

-92.65 (br, 1 F), -104.93 (br, 1 F) ppm.

.

acetonitrile/H₂O (1.5 L, 1:1), and benzyl mercaptan (24.8 g, 200

mmol, 1.00 equiv.) were placed into three round-bottom flask

equipped with a stirring bar. The mixture was cooled to −78 °C,

and diethyl bromodifluoromethane phosphonate (107 g, 400

mmol, 2.0 equiv.) was added. The reaction was stirred at room

temperature for 12 h. Et₂O (2.0 L) was added, and the organic

phase was separated. The aqueous phase was extracted with Et₂O

(400 mL × 3). The combined organic extracts were dried over

anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The

residue was purified by flash chromatography on silica gel to give

difluoromethyl benzyl thioether as a colorless oil (29.0 g, 83%).

¹H NMR (400 MHz, CDCl₃, 323 K) δ 7.04 (t, J = 57.2 Hz, 1 H),

3.48 – 3.40 (m, 1 H), 3.33 – 3.13 (m, 2 H), 2.29 – 2.07 (m, 1 H),

1.99 – 1.87 (m, 3 H), 1.84 – 1.74 (m, 1 H), 1.44 (dd, J = 17.1, 10.0

Hz, 1 H), 1.33 (dd, J = 16.7, 7.8 Hz, 1 H), 1.01 (s, 3 H), 0.94 (s, 3 H);

¹³C NMR (101 MHz, CDCl₃, 323 K) δ 120.19 (t, J = 279.8 Hz), 68.56,

51.13, 49.02, 47.68, 44.36, 34.44, 32.20, 27.01, 20.08, 19.87; ¹⁹F

NMR (376 MHz, CDCl₃, 323 K) δ -97.65 (br, 2 F) ppm.

To a solution of (1S)-(-)-2,10-camphorsultam (1.29 g, 6.00

mmol, 1.20 equiv.) in toluene (50.0 mL) was added NaH (240 mg,

6.00 mmol, 1.20 equiv., 60%) under an argon atmosphere at 0 ^oC.

The solution was then stirred at room temperature for 1 h to give

a suspension of sodium (1S)-(-)-2,10-camphorsultam. The mixture

can be used for the next step directly.

IR (KBr): ν_max= 3015, 3001, 2954, 2887, 1483, 1456, 1412,

1392, 1372, 1334, 1281, 1256, 1223, 1164, 1145, 1120, 1092,

1077, 1046, 1031 cm^-1. MS (DART POS): 298.0 (M+H); HRMS

(DART POS): C₁₁H₁₈O₂NF₂S₂(M+H) Calcd: 298.0742, Found:

298.0741.

Into a 2.0 L Schlenk tube was added dry CHCl₃(1.5 L) and get

weighed. Chlorine gas was bubbled slowly for 15 min. The Schlenk

tube was weighed again to get the amount of chlorine gas in

CHCl₃. The concentration of Cl₂in CHCl₃was then calculated. An

aliquot of Cl₂in CHCl₃(5.0 mL, 1.0 M) was added with 15.0 mL of

CHCl₃in a 100 mL three-neck round-bottom flask. The mixture

was cooled to −40 °C in the dark, and BnSCF₂H (871 mg, 5.00

mmol, 1.00 equiv.) was added slowly. The mixture was warmed to

23 °C, and the mixture was further stirred for 1 h. The mixture

was then cooled to −40 °C, and was added via a syringe to a

suspension of sodium (1S)-(-)-2,10-camphorsultam at -40 °C. The

temperature was then warmed to 23 °C, and the reaction was

further stirred at room temperature for 3 h. The mixture was

extracted with Et₂O (25 mL × 3). The combined organic phase was

separated and dried over anhydrous Na₂SO₄. After filtration, the

solvent was removed under vacuum. The residue was purified by

flash chromatography to give

(3aR,6S,7aS)-7,7-Dichloro-1-((difluoromethyl)thio)-8,8-dimet

hylhexahydro-3H-3a,6-methanobenzo[c]isothiazole 2,2-dioxide

9b. Yield 55%, white solid. Mp：104.5 – 105.5 ^oC. ¹H NMR (400

MHz, CDCl₃, 223 K) δ 7.57 (dd, J = 65.0, 52.2 Hz, 0.76 H), 7.18 (dd,

J = 61.3, 51.6 Hz, 0.24 H), 4.05 – 3..75 (m, 1 H), 3.51 – 3.33 (m, 2

H), 2.63 – 2.57 (m, 1 H), 2.34 – 2.21 (m, 1 H), 2.06 (t, J = 10.8 Hz, 1

H), 1.95 (t, J = 11.9 Hz, 1 H), 1.61 (t, J = 9.1 Hz, 1 H), 1.39 – 1.34

(m, 3 H), 1.03 (s, 3 H); ¹³C NMR (101 MHz, CDCl₃, 223 K) δ 123.92

(dd, J = 283.4, 271.5 Hz), 119.51 (dd, J = 289.0, 272.4 Hz), 93.07,

82.75, 81.29, 61.53, 52.67, 52.22, 49.94, 49.73, 48.89, 47.79,

32.06, 31.26, 25.68, 25.54, 23.46, 23.18; ¹⁹F NMR (376 MHz,

CDCl₃, 223 K) δ -89.69 (dd, J = 250.4, 61.3 Hz), -90.04 (dd, J =

276.9, 65.0 Hz), -100.94 (dd, J = 250.2, 51.7 Hz), -105.04 (dd, J =

276.7, 52.4 Hz) ppm.

¹H NMR (400 MHz, CDCl₃, 263 K) δ 7.46 (t, J = 58.2 Hz, 1 H),

3.96 (s, 1 H), 3.39 (s, 2 H), 2.57 (s, 1 H), 2.29 (t, J = 11.4 Hz, 1 H),

2.06 (d, J = 12.0 Hz, 1 H), 1.93 (t, J = 11.8 Hz, 1 H), 1.59 (t, J = 10.4

Hz, 1 H), 1.37 (s, 3 H), 1.04 (s, 3 H); ¹³C NMR (101 MHz, CDCl₃, 263

K) δ 92.96, 81.99, 61.83, 52.50, 49.72, 48.58, 31.42, 25.48, 23.45,

23.04; ¹⁹F NMR (376 MHz, CDCl₃, 263 K) δ -90.55 (dd, J = 267.9,

63.2 Hz, 1 F), -103.47 (br, 1 F) ppm.

(1S)-(-)-N-difluoromethylthio-2,10-camphorsultam 9a as a

white solid (1.10 g, 74% yield).

(3aR,6R,7aR)-1-((Difluoromethyl)thio)-8,8-dimethylhexahydr

o-3H-3a,6-methanobenzo[c]isothiazole 2,2-dioxide 9a. Yield

74%, white solid. Mp: 64.0 – 65.5 ^oC. ¹H NMR (400 MHz, CDCl₃,

223 K) δ 7.26 (dd, J = 63.4, 51.3 Hz, 0.5 H), 6.80 (dd, J = 60.4, 51.7

Hz, 0.5 H), 3.56 – 3.15 (m, 3 H), 2.11 (dd, J = 27.5, 13.1 Hz, 1 H),

1.96 (s, 1 H), 1.94 – 1.82 (m, 2 H), 1.76 (dt, J = 13.5, 8.2 Hz, 1 H),

1.41 – 1.38 (m, 1 H), 1.34 – 1.22 (m, 1 H), 1.01 – 0.88 (m, 6 H); ¹³C

NMR (101 MHz, CDCl₃, 223 K) δ 120.08 (dd, J = 286.4, 272.0 Hz),

119.59 (dd, J = 287.6, 273.3 Hz), 68.49, 67.98, 51.69, 50.73, 49.22,

48.44, 47.97, 43.77, 43.69, 34.55, 34.16, 32.15, 31.66, 27.19,

27.12, 20.38, 20.15, 20.05; ¹⁹F NMR (376 MHz, CDCl₃, 223 K) δ

-89.82 (dd, J = 266.0, 63.5 Hz), -92.39 (dd, J = 244.1, 60.5 Hz),

¹H NMR (600 MHz, CDCl₃, 298 K) δ 7.43 (dd, J = 62.6, 53.1 Hz,

1 H), 3.95 (s, 1 H), 3.36 (s, 2 H), 2.57 (d, J = 4.8 Hz, 1 H), 2.36 –

2.28 (m, 1 H), 2.10 – 1.99 (m, 1 H), 1.93 (td, J = 12.2, 4.2 Hz, 1 H),

1.59 (ddd, J = 13.0, 9.0, 4.2 Hz, 1 H), 1.40 (s, 3 H), 1.06 (s, 3 H); ¹³C

NMR (151 MHz, CDCl₃, 298 K) δ 120.88 (t, J = 277.6 Hz), 92.91,

82.22, 62.06, 52.47, 49.67, 48.58, 31.54, 25.39, 23.41, 22.92; ¹⁹F

NMR (376 MHz, CDCl₃, 298 K) δ -91.09 (dd, J = 266.7, 62.7 Hz, 1 F),

-103.29 (br, 1 F) ppm.

Chin. J. Chem. 2019, 37, XXX－XXX

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Chen et al.

Breaking Report

¹H NMR (400 MHz, CDCl₃, 323 K) δ 7.42 (dd, J = 62.2, 53.4 Hz,

1 H), 3.96 (s, 1 H), 3.35 (s, 2 H), 2.58 – 2.55 (d, 1H), 2.34 (ddd, J =

13.3, 9.0, 4.1 Hz, 1 H), 2.11 – 2.00 (m, 1 H), 2.00 – 1.89 (m, 1 H),

1.63 – 1.55 (m, 1 H), 1.41 (s, 3 H), 1.06 (s, 3 H); ¹³C NMR (101 MHz,

CDCl₃, 323 K) δ 120.98 (dd, J = 286.1, 273.5 Hz), 92.95, 82.43,

62.25, 52.52, 49.71, 48.64, 31.62, 25.38, 23.42, 22.88; ¹⁹F NMR

(376 MHz, CDCl₃, 323 K) δ -91.33 (dd, J = 266.0, 62.4 Hz, 1 F),

-103.04 (dd, J = 267.2, 49.6 Hz, 1 F) ppm.

the reaction was completed as monitored by ¹⁹F NMR

spectroscopy, addition of an aqueous solution of HCl (2.0 N) or

water. The mixture was extracted with Et₂O (10 mL × 3). The

combined organic phase was separated and dried over anhydrous

Na₂SO₄. After filtration, the solvent was removed under vacuum.

The residue was purified by flash chromatography to give the

difluoromethylthiolated product 11a

(R)-4-((Difluoromethyl)thio)-4-isopropyl-2-phenyloxazol-5-(4H)-on

e as a yellow oil (75 mg, 88% yield).

IR (KBr): ν_max= 3043, 3000, 2953, 2906, 1485, 1464, 1413,

1396, 1376, 1340, 1285, 1256, 1225, 1156, 1124, 1091, 1072,

1051 cm^-1. MS (DART POS): 366.0 (M+H); HRMS (DART POS):

C₁₁H₁₆O₂NCl₂F₂S₂(M+H) Calcd: 365.9962, Found: 365.9962.

(R)-4-((Difluoromethyl)thio)-4-isopropyl-2-phenyloxazol-5-(4

H)-one 11a. Yield 88%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ

8.06 (d, J = 7.4 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.7 Hz,

2 H), 6.92 (dd, J = 60.4, 54.0 Hz, 1 H), 2.53 – 2.26 (m, 1 H), 1.22 (d,

J = 6.8 Hz, 3 H), 1.04 (d, J = 6.7 Hz, 3 H); ¹⁹F NMR (376 MHz, CDCl₃)

δ -89.48 (dd, J = 258.5, 60.4 Hz, 1 F), -99.52 (dd, J = 258.4, 54.0 Hz,

1 F); ¹³C NMR (101 MHz, CDCl₃) δ 176.09, 162.47, 133.72, 129.00,

128.45, 124.75, 119.13 (dd, J = 278.6, 270.2 Hz), 78.42 (d, J = 4.2

Hz), 35.76, 16.97, 16.82 ppm. IR (KBr): ν_max= 2975, 1836, 1643,

1581, 1495, 1469, 1452, 1323, 1161, 1062, 1045, 1026 cm^-1. MS

(DART POS): 286.1 (M+H); HRMS (DART POS): C₁₃H₁₄NO₂F₂S (M+H)

Calcd: 286.0708, Found: 286.0708. HPLC: (OJH, Hexane/ⁱPrOH =

98/2, 0.7 mL/min, 214 nm), t_R(major) = 9.82 min, t_R(minor) =

10.71 min (95% ee); [α]_D²⁰= +53.20 (c = 0.200, CHCl₃, 95% ee).

(3aR,6S,7aS)-1-((Difluoromethyl)thio)-7,7-dimethoxy-8,8-dim

ethylhexahydro-3H-3a,6-methanobenzo[c]isothiazole

2,2-dioxide 9c. Yield 68%, white solid. Mp：132.5 – 133.5 ^oC. ¹H

NMR (400 MHz, CDCl₃, 223 K) δ 7.48 (dd, J = 65.3, 53.9 Hz, 0.09

H), 7.06 (dd, J = 62.1, 52.2 Hz, 0.85 H), 3.61 – 3.04 (m, 9 H), 3.30 –

3.20 (m, 1 H), 1.99 – 1.65 (m, 3 H), 1.47 (dd, J = 16.5, 8.2 Hz, 1 H),

1.28 (s, 3 H), 0.88 (s, 3 H); ¹³C NMR (101 MHz, CDCl₃, 223 K) δ

123.95 (dd, J = 284.0, 269.3 Hz), 108.97, 74.50, 51.17, 50.90,

49.86, 48.46, 47.98, 47.71, 31.99, 21.67, 20.78, 20.36; ¹⁹F NMR

(376 MHz, CDCl₃, 223 K) δ -93.10 (dd, J = 249.5, 62.1 Hz), -94.72

(dd, J = 272.3, 65.5 Hz), -103.85 (dd, J = 249.5, 52.3 Hz), -106.19

(dd, J = 272.3, 53.9 Hz) ppm.

(R)-4-((Difluoromethyl)thio)-2-phenyl-4-propyloxazol-5-(4H)-

one 11b. Yield 91%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.05

(dd, J = 8.1, 0.9 Hz, 2 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.7 Hz,

2 H), 6.93 (dd, J = 59.7, 54.2 Hz, 1 H), 2.26 – 2.13 (m, 1 H), 2.12 –

2.02 (m, 1 H), 1.54 – 1.38 (m, 1 H), 1.38 – 1.22 (m, 1 H), 0.95 (t, J =

7.3 Hz, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -89.92 (dd, J = 258.0,

59.7 Hz, 1 F), -98.56 (dd, J = 258.1, 54.3 Hz, 1 F); ¹³C NMR (101

MHz, CDCl₃) δ 176.13, 162.43, 133.77, 129.02, 128.44, 124.74,

119.00 (dd, J = 278.2, 271.3 Hz), 74.44 (d, J = 4.1 Hz), 39.49, 17.39,

13.56 ppm. IR (KBr): ν_max= 2965, 2933, 2877, 1829, 1643, 1581,

1495, 1453, 1323, 1293, 1074, 1046, 1024 cm^-1. MS (DART POS):

286.1 (M+H); HRMS (DART POS): C₁₃H₁₄NO₂F₂S (M+H) Calcd:

286.0708, Found: 286.0707. HPLC: (ODH, Hexane/ⁱPrOH = 98/2,

0.7 mL/min, 214 nm), t_R(major) = 7.45 min, t_R(minor) = 6.97 min

(91% ee); [α]_D²⁰= +6.20 (c = 0.200, CHCl₃, 91% ee).

¹H NMR (400 MHz, CDCl₃, 298 K) δ 7.13 (dd, J = 61.1, 53.6 Hz,

1 H), 3.44 – 3.20 (m, 9 H), 2.24 (d, J = 4.7 Hz, 1 H), 1.97 (ddd, J =

13.2, 9.3, 4.0 Hz, 1 H), 1.83 (td, J = 11.8, 4.0 Hz, 1 H), 1.77 – 1.65

(m, 1 H), 1.55 – 1.43 (m, 1 H), 1.31 (s, 3 H), 0.91 (s, 3 H); ¹³C NMR

(101 MHz, CDCl_3,298 K) δ 123.27 (t, J = 278.8 Hz), 109.10, 74.66

(d, J = 2.2 Hz), 51.02, 50.75, 49.40, 49.03, 47.99, 47.67, 32.22,

21.45, 20.63, 20.35; ¹⁹F NMR (376 MHz, CDCl_3,298 K) δ -94.02 (dd,

J = 252.7, 61.2 Hz), -103.20 (d, J = 243.1 Hz) ppm.

¹H NMR (400 MHz, CDCl₃, 323 K) δ 7.14 (dd, J = 60.9, 53.9 Hz,

1 H), 3.56 – 3.16 (m, 9 H), 2.43 – 2.16 (m, 1 H), 2.05 – 1.94 (m , 1

H), 1.93 – 1.66 (m, 2 H), 1.63 – 1.41 (m, 1 H), 1.33 (s, 3 H), 0.92 (s,

3 H); ¹³C NMR (101 MHz, CDCl_3,323 K) δ 123.27 (dd, J = 285.1,

273.4 Hz), 109.23, 74.80, 51.10, 50.74, 49.38, 49.25, 48.10, 47.69,

32.33, 21.46, 20.66, 20.38; ¹⁹F NMR (376 MHz, CDCl₃, 323 K) δ

-94.21 (dd, J = 253.2, 60.9 Hz), -102.99 (dd, J = 253.4, 53.5 Hz)

ppm.

(R)-4-Benzyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-(4H)-

one 11c. yield 85%, colourless oil. ¹H NMR (400 MHz, CDCl₃) δ

7.91 (d, J = 7.7 Hz, 2 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.8 Hz,

2 H), 7.21 (s, 5 H), 7.00 (dd, J = 59.6, 54.4 Hz, 1 H), 3.55 (d, J = 13.4

Hz, 1 H), 3.40 (d, J = 13.5 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-89.79 (dd, J = 257.9, 59.6 Hz, 1 F), -98.05 (dd, J = 258.0, 54.4 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 175.37, 162.36, 133.68, 132.04,

130.50, 128.93, 128.46, 128.31, 128.06, 124.58, 119.04 (dd, J =

IR (KBr): ν_max= 2994, 2960, 2839, 1478, 1461, 1419, 1397,

1378, 1327, 1273, 1263, 1230, 1195, 1161, 1136, 1114, 1065,

1039, 1023 cm^-1. HRMS (DART POS): C₁₃H₂₂O₄NF₂S₂(M+H) Calcd:

358.0953, Found: 358.0952.

278.4, 271.8 Hz), 75.02 (d, J = 3.8 Hz), 43.56 ppm. IR (KBr): ν_max

=

2927, 1824, 1644, 1580, 1496, 1452, 1323, 1292, 1093, 1061 cm^-1.

MS (DART POS): 334.1 (M+H); HRMS (DART POS): C₁₇H₁₄NO₂F₂S

(M+H) Calcd: 334.0708, Found: 334.0706. HPLC: (ADH,

Hexane/ⁱPrOH = 97/3, 0.7 mL/min, 214 nm), t_R(major) = 8.65 min,

t_R(minor) = 9.67 min (89% ee); [α]_D²⁰= +90.67 (c = 0.060, CHCl₃,

89% ee).

General procedure for asymmetric difluoromethylthiolation

of oxazolones. To a 25 mL flame-dried Schlenk tube was added

oxazolone 10a (61 mg, 0.30 mmol, 1.00 equiv). Dry Et₂O (3.0 mL)

was added under argon atmosphere. The solution was cooled to

-10 ^oC, then LiHMDS (291 µL, 0.290 mmol, 0.970 equiv.; 1.00 M in

THF) was add at -10 ^oC. The solution was stirred at -10 ^oC for 20

min, and the reagent 9b (132 mg, 0.360 mmol, 1.20 equiv.) was

added. The resulting solution was stirred at -10 ^oC for 2 h. After

www.cjc.wiley-vch.de

Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

(R)-4-Allyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-(4H)-on

278.5, 270.0 Hz), 78.80 (d, J = 4.2 Hz), 42.20, 24.04, 13.18, 11.92

ppm. IR (KBr): ν_max= 2972, 2937, 2880, 1831, 1643, 1581, 1495,

1452, 1323, 1292, 1064, 1047 cm^-1. MS (DART POS): 300.1 (M+H);

HRMS (DART POS): C₁₄H₁₆NO₂F₂S (M+H) Calcd: 300.0864, Found:

e 11d. Yield 77%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J

= 7.5 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 2 H), 6.96

(dd, J = 59.6, 54.4 Hz, 1 H), 5.88 – 5.55 (m, 1 H), 5.38 – 5.16 (m, 2

H), 2.96 (dd, J = 13.7, 6.6 Hz, 1 H), 2.82 (dd, J = 13.7, 7.9 Hz, 1 H);

¹⁹F NMR (376 MHz, CDCl₃) δ -89.98 (dd, J = 258.2, 59.6 Hz, 1 F),

-98.22 (dd, J = 258.2, 54.4 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ

175.41, 162.44, 133.78, 128.98, 128.43 (br, 2 C), 124.64, 122.57,

118.90 (dd, J = 278.3, 271.8 Hz), 74.13 (d, J = 4.1 Hz), 41.53 ppm.

IR (KBr): ν_max= 2958, 1825, 1642, 1452, 1323, 1294, 1258, 1075,

1012 cm^-1. MS (DART POS): 284.1 (M+H); HRMS (DART POS):

C₁₃H₁₂NO₂F₂S (M+H) Calcd: 284.0551, Found: 284.0551. HPLC:

(ODH, Hexane/ⁱPrOH = 99/1, 0.7 mL/min, 214 nm), t_R(major) =

8.93 min, t_R(minor) = 8.38 min (87% ee); [α]_D²⁰= +76.85 (c =

0.400, CHCl₃, 87% ee).

300.0864. HPLC: (ADH, Hexane/ⁱPrOH = 97/3, 0.7 mL/min, 214

20

nm), t_R(major) = 7.03 min, t_R(minor) = 6.51 min (95% ee); [α]_D

+43.50 (c = 0.200, CHCl₃, 95% ee).

=

(R)-4-((Difluoromethyl)thio)-4-(4-methoxybenzyl)-2-phenyl

oxazol-5-(4H)-one 11h. Yield 75%, yellow oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.92 (d, J = 7.5 Hz, 2 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.46 (t, J =

7.6 Hz, 2 H), 7.12 (d, J = 8.6 Hz, 2 H), 6.99 (dd, J = 58.6, 53.5 Hz, 1

H), 6.73 (d, J = 8.4 Hz, 2 H), 3.70 (s, 3 H), 3.48 (d, J = 13.6 Hz, 1 H),

3.34 (d, J = 13.6 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -89.75 (dd, J

= 257.9, 59.6 Hz, 1 F), -97.99 (dd, J = 257.9, 54.4 Hz, 1 F); ¹³C NMR

(101 MHz, CDCl₃) δ 175.40, 162.28, 160.76 (d, J = 305.4 Hz),

133.61, 131.57, 128.89, 128.28, 124.59, 123.93, 119.02 (dd, J =

278.4, 271.7 Hz), 113.79, 75.09 (d, J = 3.5 Hz), 55.08, 42.71 ppm.

IR (KBr): ν_max= 3008, 2980, 2956, 2935, 2839, 1825, 1643, 1611,

1510, 1466, 1452, 1324, 1302, 1248, 1179, 1117, 1032 cm^-1. MS

(DART POS): 364.1 (M+H); HRMS (DART POS): C₁₈H₁₆NO₃F₂S (M+H)

Calcd: 364.0813, Found: 364.0811. HPLC: (IG, Hexane/ⁱPrOH =

99/1, 0.7 mL/min, 214 nm), t_R(major) = 14.86 min, t_R(minor) =

15.67 min (89% ee); [α]_D²⁰= +126.00 (c = 0.260, CHCl₃, 89% ee).

(R)-4-((Difluoromethyl)thio)-4-isopropyl-2-(4-nitrophenyl)

oxazol-5-(4H)-one 11e. Yield 83%, yellow soild. ¹H NMR (400

MHz, CDCl₃) δ 8.37 (d, J = 8.7 Hz, 2 H), 8.25 (d, J = 8.6 Hz, 2 H),

6.90 (dd, J = 59.4, 54.0 Hz, 1 H), 2.41 (dt, J = 13.3, 6.6 Hz, 1 H),

1.22 (d, J = 6.7 Hz, 3 H), 1.04 (d, J = 6.7 Hz, 3 H); ¹⁹F NMR (376

MHz, CDCl₃) δ -94.38 (dd, J = 256.1, 59.4 Hz, 1 F), -103.05 (dd, J =

256.1, 53.9 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 175.08, 160.76,

150.75, 130.26, 129.48, 124.10, 118.82 (dd, J = 279.0, 271.9 Hz),

78.51 (d, J = 4.1 Hz), 35.80, 16.93, 16.79 ppm. IR (KBr): ν_max

=

(R)-4-Cyclopropyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-

(4H)-one 11i. Yield 82%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ

8.03 (dt, J = 8.5, 1.6 Hz, 2 H), 7.70 – 7.59 (m, 1 H), 7.56 – 7.47 (m,

2 H), 6.92 (dd, J = 59.4, 54.4 Hz, 1 H), 1.62 (tt, J = 8.2, 5.1 Hz, 1 H),

0.90 – 0.81 (m, 1 H), 0.81 – 0.72 (m, 1 H), 0.68 – 0.58 (m, 1 H),

0.53 (ddt, J = 10.0, 6.1, 5.0 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-90.07 (dd, J = 257.3, 59.3 Hz, 1 F), -97.65 (dd, J = 257.3, 54.4 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 175.37, 162.77, 133.84, 129.00,

128.49, 124.70, 119.03 (dd, J = 278.0, 271.9 Hz), 74.50 (d, J = 3.4

Hz), 17.21, 2.76, 2.41 ppm. IR (KBr): ν_max= 2960, 2926, 2855,

1824, 1643, 1580, 1494, 1452, 1322, 1293, 1155, 1063 cm^-1. MS

(DART POS): 284.1 (M+H); HRMS (DART POS): C₁₃H₁₂NO₂F₂S (M+H)

Calcd: 284.0551, Found: 284.0551. HPLC: (ODH, Hexane/ⁱPrOH =

99/1, 0.7 mL/min, 214 nm), t_R(major) = 9.51 min, t_R(minor) =

12.05 min (81% ee); [α]_D²⁰= +17.84 (c = 0.250, CHCl₃, 81% ee).

2985, 1840, 1642, 1599, 1527, 1491, 1465, 1351, 1325, 1307,

1294, 1157, 1087, 1063, 1035, 1020, 1013 cm^-1. MS (DART POS):

331.0 (M+H); HRMS (DART POS): C₁₃H₁₃N₂O₄F₂S (M+H) Calcd:

331.0559, Found: 331.0557. Mp: 122.0 – 123.0 ^oC. HPLC: (ADH,

Hexane/ⁱPrOH = 92/8, 0.7 mL/min, 214 nm), t_R(major) = 13.43

min, t_R(minor) = 12.79 min (97% ee); [α]_D²⁰= +39.75 (c = 0.160,

CHCl₃, 97% ee).

(R)-4-((Difluoromethyl)thio)-4-isobutyl-2-phenyloxazol-5-(4H

)-one 11f. Yield 56%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ

8.06 (dt, J = 8.5, 1.6 Hz, 2 H), 7.70 – 7.60 (m, 1 H), 7.60 – 7.48 (m,

2 H), 6.93 (dd, J = 59.6, 54.2 Hz, 1 H), 2.23 (dd, J = 14.2, 5.5 Hz, 1

H), 2.02 (dd, J = 14.2, 7.2 Hz, 1 H), 1.87 – 1.68 (m, 1 H), 0.95 (d, J =

6.7 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-90.01 (dd, J = 258.5, 59.6 Hz, 1 F), -98.46 (dd, J = 258.5, 54.2 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 176.54, 162.25, 133.77, 129.05,

128.44, 124.82, 119.03 (dd, J = 278.1, 271.3 Hz), 74.26 (d, J = 3.8

Hz), 45.92, 25.44, 23.83, 22.96 ppm. IR (KBr): ν_max= 2961, 2929,

2874, 1822, 1642, 1580, 1495, 1452, 1323, 1292, 1262, 1153,

1074, 1053, 1026 cm^-1. MS (DART POS): 300.1 (M+H); HRMS

(DART POS): C₁₄H₁₆NO₂F₂S (M+H) Calcd: 300.0864, Found:

(R)-4-Cyclobutyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-(

4H)-one 11j. Yield 86%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ

8.09 (d, J = 7.5 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.53 (t, J = 7.7 Hz,

2 H), 6.89 (dd, J = 60.2, 54.1 Hz, 1 H), 3.18 – 2.93 (m, 1 H), 2.32 –

2.03 (m, 2 H), 2.02 – 1.75 (m, 4 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-89.40 (dd, J = 257.3, 60.2 Hz, 1 F), -98.97 (dd, J = 257.3, 54.1 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 170.82, 157.75, 128.94, 124.21,

123.69, 120.03, 114.24 (dd, J = 278.9, 271.0 Hz), 71.41 (d, J = 4.2

Hz), 35.79, 18.84, 17.30, 12.34 ppm. IR (KBr): ν_max= 2960, 2856,

1833, 1641, 1580, 1495, 1452, 1322, 1292, 1260, 1149, 1080,

1045, 1025 cm^-1. MS (DART POS): 298.1 (M+H); HRMS (DART

POS): C₁₄H₁₄NO₂F₂S (M+H) Calcd: 298.0708, Found: 298.0708.

300.0864. HPLC: (OJH, Hexane/ⁱPrOH = 98/2, 0.7 mL/min, 214

nm), t_R(major) = 7.89 min, t_R(minor) = 8.77 min (88% ee); [α]_D

+95.20 (c = 0.350, CHCl₃, 88% ee).

20

=

(R)-4-((S)-sec-Butyl)-4-((difluoromethyl)thio)-2-phenyloxazol-

5-(4H)-one 11g. Yield 94%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ

8.11 – 8.03 (m, 2 H), 7.67 – 7.60 (m, 1 H), 7.56 – 7.46 (m, 2 H),

6.93 (dd, J = 60.4, 53.9 Hz, 1 H), 2.16 – 2.03 (m, 1 H), 1.53 (dqd, J =

14.9, 7.4, 2.8 Hz, 1 H), 1.33 – 1.14 (m, 4 H), 0.94 (t, J = 7.4 Hz, 3 H);

¹⁹F NMR (376 MHz, CDCl₃) δ -89.37 (dd, J = 258.6, 60.3 Hz, 1 F),

-99.48 (dd, J = 258.5, 53.9 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ

176.32, 162.35, 133.70, 129.00, 128.44, 124.79, 119.14 (dd, J =

HPLC: (OJH, Hexane/ⁱPrOH = 98/2, 0.7 mL/min, 214 nm), t_R

(major) = 4.274 min, t_R(minor) = 4.082 min (93% ee); [α]_D

+10.80 (c = 0.100, CHCl₃, 93% ee).

20

=

Chin. J. Chem. 2019, 37, XXX－XXX

www.cjc.wiley-vch.de

Chen et al.

Breaking Report

(R)-4-Cyclopentyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-

(4H)-one 11k. Yield 93%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ

8.06 (d, J = 7.4 Hz, 2 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.7 Hz,

2 H), 6.88 (dd, J = 60.4, 53.9 Hz, 1 H), 2.66 – 2.56 (m, 1 H), 2.06 –

1.89 (m, 1 H), 1.83 – 1.53 (m, 6 H), 1.40 – 1.21 (m, 1 H); ¹⁹F NMR

(376 MHz, CDCl₃) δ -89.35 (dd, J = 258.2, 60.5 Hz, 1 F), -99.70 (dd,

J = 258.2, 53.9 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 173.56,

159.78, 131.07, 126.38, 125.83, 122.21, 116.44 (dd, J = 279.1,

270.5 Hz), 74.51 (d, J = 4.5 Hz), 43.48, 25.31, 24.42, 23.10, 22.92

ppm. IR (KBr): ν_max= 2960, 2871, 1830, 1642, 1580, 1452, 1323,

1292, 1061 cm^-1. MS (DART POS): 312.1 (M+H); HRMS (DART

POS): C₁₅H₁₆NO₂F₂S (M+H) Calcd: 312.0864, Found: 312.0864.

HPLC: (PC1, Hexane/ⁱPrOH = 98/2, 0.7 mL/min, 214 nm), t_R(major)

= 4.139 min, t_R(minor) = 3.846 min (94% ee); [α]_D²⁰= +17.14 (c =

0.280, CHCl₃, 94% ee).

1446, 1421, 1368, 1349, 1302, 1257, 1227, 1156, 1129, 1091,

1063, 1038 cm^-1. MS (EI): 222 (100), 305 (5.22); HRMS (EI) for

C₁₆H₁₃NOF₂S Calcd: 305.0686, Found: 305.0676. Mp: 101.0 –

102.0 ^oC. HPLC: (IE-3, Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm),

25

t_R(major) = 9.12 min, t_R(minor) = 10.01 min (94% ee); [α]_D

-56.73 (c = 0.100, CHCl₃, 94% ee).

=

(S)-3-(4-Chlorophenyl)-3-((difluoromethyl)thio)-1-methyl

indolin -2-one 13b. Yield 92%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.61 – 7.53 (m, 2 H), 7.43 – 7.31 (m, 4 H), 7.14 (td, J = 7.6,

0.9 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.92 (dd, J = 58.5, 53.6 Hz, 1

H), 3.32 (s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.78 (dd, J = 254.5,

58.4 Hz, 1 F), -96.49 (dd, J = 254.5, 53.6 Hz, 1 F); ¹³C NMR (101

MHz, CDCl₃) δ 174.98, 142.31, 134.82, 134.59, 130.20, 129.14,

129.13, 128.04, 125.45, 123.59, 119.99 (dd, J = 275.3, 269.9 Hz),

109.13, 56.74 (d, J = 3.7 Hz), 27.01 ppm. IR (KBr): ν_max= 3068,

2968, 2937, 1707, 1611, 1591, 1492, 1473, 1419, 1400, 1371,

1351, 1304, 1261, 1159, 1132, 1112, 1096, 1071, 1042, 1013 cm^-1.

MS (EI): 256 (100), 339 (3.92); HRMS (EI) for C₁₆H₁₂NOF₂SCl Calcd:

339.0296, Found: 339.0287. HPLC: (ADH, Hexane/ⁱPrOH = 95/5,

0.7 mL/min, 214 nm), t_R(major) = 15.21 min, t_R(minor) = 20.80

min (93% ee); [α]_D²⁵= -74.35 (c = 0.100, CHCl₃, 93% ee).

(R)-4-Cyclohexyl-4-((difluoromethyl)thio)-2-phenyloxazol-5-(

4H)-one 11l. Yield 94%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ

8.05 (d, J = 7.4 Hz, 2 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz,

2 H), 6.91 (dd, J = 60.3, 54.1 Hz, 1 H), 2.19 – 1.98 (m, 2 H), 1.92 –

1.63 (m, 4 H), 1.35 – 1.02 (m, 5 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-89.38 (dd, J = 258.4, 60.4 Hz, 1 F), -99.49 (dd, J = 258.4, 54.1 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 171.31, 157.49, 128.88, 124.20,

123.63, 119.98, 114.39 (dd, J = 278.6, 270.3 Hz), 73.52 (d, J = 4.1

(S)-4-(3-((Difluoromethyl)thio)-1-methyl-2-oxoindolin-3-yl)

benzonitrile 13c. Yield 81%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.79 – 7.73 (m, 2 H), 7.70 – 7.63 (m, 2 H), 7.41 (td, J = 7.8,

1.2 Hz, 1 H), 7.31 (dd, J = 7.5, 0.7 Hz, 1 H), 7.15 (td, J = 7.6, 0.9 Hz,

1 H), 6.97 (dd, J = 58.7, 53.4 Hz, 1 H), 6.96 (d, J = 7.9 Hz, 1 H), 3.34

(s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.61 (dd, J = 255.4, 58.7 Hz,

1 F), -97.02 (dd, J = 255.2, 53.4 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃)

δ 174.35, 142.33, 141.37, 132.65, 130.57, 128.61, 127.30, 125.40,

123.82, 119.50 (dd, J = 276.8, 270.0 Hz), 118.18, 112.62, 109.39,

56.96, 27.12 ppm. IR (KBr): ν_max= 3061, 2925, 2853, 2230, 1716,

1611, 1492, 1472, 1422, 1408, 1370, 1348, 1300, 1261, 1158,

1130, 1069 cm^-1. MS (DART POS): 331.1 (M+H); HRMS (DART

POS): C₁₇H₁₃ON₂F₂S (M+H) Calcd: 331.0711, Found: 331.0709.

Hz), 40.02, 22.12, 22.00, 21.11, 20.97, 20.86 ppm. IR (KBr): ν_max

2934, 2856, 1829, 1640, 1580, 1495, 1452, 1323, 1292, 1153,

1067, 1051 cm^-1. MS (DART POS): 326.1 (M+H); HRMS (DART

POS): C₁₆H₁₈NO₂F₂S (M+H) Calcd: 326.1021, Found: 326.1020.

=

HPLC: (IG, Hexane/ⁱPrOH = 99/1, 0.7 mL/min, 214 nm), t_R(major)

= 8.79 min, t_R(minor) = 8.05 min (94% ee); [α]_D²⁰= +31.43 (c =

0.140, CHCl₃, 94% ee).

General procedure for asymmetric difluoromethylthiolation

of oxindoles. Oxindole 12a (67 mg, 0.30 mmol, 1.00 equiv.),

cesium carbonate (147 mg, 0.450 mmol, 1.50 equiv.) and

compound 9c (118 mg, 0.330 mmol, 1.10 equiv.) were added into

a flame-dried Schlenk tube. The tube was putted into liquid

nitrogen. Dry toluene (3.0 mL) was added under argon

atmosphere. The resulting solution was stirred at -40 ^oC for 12 h.

After the reaction was completed as monitored by ¹⁹F NMR

spectroscopy, the reaction was quenched by addition of an

aqueous solution of HCl (2.0 N). The mixture was extracted with

Et₂O (10 mL × 3). The combined organic phase was separated and

dried over anhydrous Na₂SO₄. After filtration, the solvent was

removed under vacuum. The residue was purified by flash

chromatography to give the difluoromethylthiolated product 13a

(S)-3-((difluoromethyl)thio)-1-methyl-3- phenylindolin-2-one as a

white solid (81 mg, 88% yield).

HPLC: (ODH, Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R

(major) = 32.39 min, t_R(minor) = 36.61 min (81% ee); [α]_D

-67.16 (c = 0.090, CHCl₃, 81% ee).

25

=

(S)-3-((Difluoromethyl)thio)-3-(4-methoxyphenyl)-1-methyl

indolin-2-one 13d. Yield 63%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.59 – 7.51 (m, 2 H), 7.37 (ddd, J = 9.0, 7.9, 0.9 Hz, 2 H),

7.13 (td, J = 7.6, 0.9 Hz, 1 H), 6.94 – 6.88 (m, 3 H), 6.87 (dd, J =

58.3, 53.8 Hz, 1 H), 3.78 (s, 3 H), 3.30 (s, 3 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ -90.90 (dd, J = 254.0, 58.3 Hz, 1 F), -96.18 (dd, J = 254.0,

53.8 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 175.53, 159.76, 142.31,

129.88, 129.01, 128.70, 127.67, 125.53, 123.41, 120.44 (dd, J =

274.4, 269.5 Hz), 114.32, 108.94, 56.90, 55.34, 26.92 ppm. IR

(KBr): ν_max= 3051, 3004, 2936, 2838, 1717, 1608, 1579, 1510,

1492, 1471, 1418, 1370, 1348, 1297, 1255, 1185, 1169, 1130,

1062, 1035 cm^-1. MS (EI): 252 (100), 335 (0.79); HRMS (EI) for

C₁₇H₁₅NO₂F₂S Calcd: 335.0792, Found: 335.0790. HPLC: (ODH,

Hexane/ⁱPrOH = 8/2, 0.7 mL/min, 214 nm), t_R(major) = 9.09 min,

t_R(minor) = 12.04 min (88% ee); [α]_D²⁵= -78.03 (c = 0.050, CHCl₃,

88% ee).

(S)-3-((Difluoromethyl)thio)-1-methyl-3-phenylindolin-2-one

13a. yield 88%, yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 –

7.60 (m, 2 H), 7.43 – 7.29 (m, 5 H), 7.13 (t, J = 8.0 Hz, 1 H), 6.94

(dd, J = 58.2, 53.8 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 3.32 (s, 3 H);

¹⁹F NMR (376 MHz, CDCl₃) δ -90.77 (dd, J = 253.7, 58.3 Hz, 1 F),

-96.01 (dd, J = 253.7, 53.7 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ

175.41, 142.35, 136.04, 130.02, 129.01, 128.67, 128.48, 127.65,

125.54, 123.49, 120.37 (dd, J = 274.5, 269.4 Hz), 109.03, 57.32,

26.97 ppm. IR (KBr): ν_max= 3063, 2941, 1710, 1608, 1489, 1470,

www.cjc.wiley-vch.de

Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

Methyl-(S)-4-(3-((difluoromethyl)thio)-1-methyl-2-oxoindolin

1 F), -97.13 (dd, J = 255.7, 53.5 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃)

δ 174.33, 142.34, 137.92, 132.37, 132.23, 131.32, 130.63, 129.90,

127.22, 125.42, 123.87, 119.52 (dd, J = 276.7, 270.2 Hz), 118.24,

113.14, 109.48, 56.52, 27.13 ppm. IR (KBr): ν_max= 3066, 2937,

2232, 1716, 1611, 1579, 1491, 1472, 1419, 1370, 1349, 1302,

1260, 1180, 1159, 1130, 1066 cm^-1. MS (DART POS): 331.1 (M+H);

HRMS (DART POS): C₁₇H₁₃ON₂F₂S (M+H) Calcd: 331.0711, Found:

331.0708. HPLC: (ID-3, Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214

nm), t_R(major) = 23.88 min, t_R(minor) = 28.17 min (92% ee);

[α]_D²⁵= -45.30 (c = 0.100, CHCl₃, 92% ee).

-3-yl)benzoate 13e. Yield 99%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.09 – 7.92 (m, 2 H), 7.77 – 7.62 (m, 2 H), 7.38 (td, J = 7.8,

1.1 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.16 – 7.10 (m, 1 H), 6.97 (dd,

J = 58.5, 53.5 Hz, 1 H), 6.94 (d, J = 7.9 Hz, 1 H), 3.91 (s, 3 H), 3.34

(s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.72 (dd, J = 254.3, 58.5 Hz,

1 F), -96.53 (dd, J = 254.2, 53.4 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃)

δ 174.86, 166.39, 142.33, 140.99, 130.34, 130.26, 130.15, 127.90,

127.78, 125.44, 123.64, 119.90 (dd, J = 275.7, 269.6 Hz), 109.16,

57.10, 52.29, 27.05 ppm. IR (KBr): ν_max= 3059, 2952, 2925, 2851,

1717, 1611, 1574, 1492, 1472, 1436, 1407, 1370, 1347, 1281,

1191, 1158, 1113, 1066, 1020 cm^-1. MS (EI): 280 (100), 363 (6.12);

HRMS (EI) for C₁₈H₁₅NO₃F₂S Calcd: 363.0741, Found: 363.0745.

(S)-3-((Difluoromethyl)thio)-1-methyl-3-(naphthalen-2-yl)

indolin-2-one 13i. Yield 96%, white solid. ¹H NMR (400 MHz,

CDCl₃) δ 8.04 (s, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.82 (m, 3 H), 7.55 –

7.47 (m, 2 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.13

(t, J = 7.6 Hz, 1 H), 7.04 (dd, J = 58.1, 53.6 Hz, 1 H), 6.95 (d, J = 7.8

Hz, 1 H), 3.38 (s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.58 (dd, J =

253.2, 58.1 Hz, 1 F), -95.74 (dd, J = 253.2, 53.7 Hz, 1 F); ¹³C NMR

(101 MHz, CDCl₃) δ 175.40, 142.37, 133.25, 133.00, 132.98,

130.06, 129.10, 128.48, 128.40, 127.60, 127.07, 126.95, 126.68,

125.55, 124.95, 123.53, 120.43 (dd, J = 274.4, 269.4 Hz), 109.07,

57.48 (d, J = 3.7 Hz), 27.04 ppm. IR (KBr): ν = 3056, 3025, 2937,

1708, 1608, 1491, 1470, 1420, 1372, 1348, 1324, 1299, 1263,

1228, 1164, 1156, 1125, 1090, 1059, 1036 cm^-1. MS (EI): 272

(100), 355 (4.27); HRMS (EI) for C₂₀H₁₅NOF₂S Calcd: 355.0842,

Found: 355.0837. Mp: 129.5 – 130.5 ^oC. HPLC: (ODH,

HPLC: (ODH, Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R

(major) = 18.99 min, t_R(minor) = 22.42 min (90% ee); [α]_D

-81.81 (c = 0.050, CHCl₃, 90% ee).

25

=

(S)-3-(4-Acetylphenyl)-3-((difluoromethyl)thio)-1-methyl

indolin-2-one 13f. Yield 90%, yellow oil. ¹H NMR (400 MHz, CDCl₃)

δ 7.95 (d, J = 8.5 Hz, 2 H), 7.75 – 7.69 (m, 2 H), 7.38 (t, J = 7.8 Hz, 1

H), 7.33 (d, J = 7.5 Hz, 1 H), 7.15 – 7.10 (t, J = 8.0 Hz 1 H), 6.97 (dd,

J = 58.5, 53.4 Hz, 1 H), 6.94 (d, J = 7.9 Hz, 1 H), 3.33 (s, 3 H), 2.57

(s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.63 (dd, J = 254.3, 58.5 Hz,

1 F), -96.52 (dd, J = 254.5, 53.5 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃)

δ 197.36, 174.81, 142.33, 141.15, 137.00, 130.32, 128.87, 127.99,

127.82, 125.42, 123.67, 119.88 (dd, J = 275.8, 269.6 Hz), 109.22,

57.13 (d, J = 3.7 Hz), 27.04, 26.68 ppm. IR (KBr): ν_max= 3059, 2937,

1716, 1685, 1610, 1568, 1491, 1472, 1423, 1405, 1366, 1347,

1291, 1268, 1191, 1158, 1129, 1064 cm^-1. MS (EI): 264 (100), 347

(5.4); HRMS (EI) for C₁₈H₁₅NO₂F₂S Calcd: 347.0792, Found:

Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R(major) = 14.19

min, t_R(minor) = 16.14 min (89% ee); [α]_D²⁵= -54.53 (c = 0.100,

CHCl₃, 89% ee).

347.0788. HPLC: (ADH, Hexane/ⁱPrOH = 9/1, 0.7 mL/min, 214 nm),

(S)-5-Acetyl-3-((difluoromethyl)thio)-1-methyl-3-phenyl

indolin-2-one 13j. Yield 94%, white solid. ¹H NMR (400 MHz,

CDCl₃) δ 8.02 (d, J = 8.3 Hz, 1 H), 7.98 (s, 1H), 7.61 (d, J = 7.2 Hz, 2

H), 7.47 – 7.30 (m, 3 H), 6.98 (d, J = 8.2 Hz, 1 H), 6.93 (dd, J = 57.7,

53.8 Hz, 1 H), 3.37 (s, 3 H), 2.57 (s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃)

δ -90.97 (dd, J = 252.8, 57.6 Hz, 1 F), -95.54 (dd, J = 252.8, 53.8 Hz,

1 F); ¹³C NMR (101 MHz, CDCl₃) δ 196.19, 175.69, 146.37, 135.24,

132.92, 131.47, 129.20, 129.09, 128.95, 127.56, 125.59, 120.03

(dd, J = 274.9, 270.7 Hz), 108.53, 56.94 (d, J = 4.2 Hz), 27.23, 26.43

ppm. IR (KBr): ν_max= 2960, 2923, 2853, 1722, 1678, 1608, 1497,

1443, 1340, 1274, 1100, 1056 cm^-1. MS (DART POS): 347.9 (M+H);

HRMS (DART POS): C₁₈H₁₆O₂NF₂S (M+H) Calcd: 348.0864, Found:

348.0864. Mp: 130.5 – 131.5 ^oC. HPLC: (ODH, Hexane/ⁱPrOH = 8/2,

0.7 mL/min, 214 nm), t_R(major) = 13.22 min, t_R(minor) = 16.93

min (81% ee); [α]_D²⁰= -7.00 (c = 0.200, CHCl₃, 81% ee).

25

t_R(major) = 25.20 min, t_R(minor) = 30.15 min (91% ee); [α]_D

-120.86 (c = 0.125, CHCl₃, 91% ee).

=

(S)-2-(4-(3-((Difluoromethyl)thio)-1-methyl-2-oxoindolin-3-yl

)phenyl)acetonitrile 13g. Yield 92%, colorless oil. ¹H NMR (400

MHz, CDCl₃) δ 7.68 – 7.64 (m, 1 H), 7.64 – 7.60 (m, 1 H), 7.37 (m, 4

H), 7.13 (td, J = 7.6, 0.9 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 1 H), 6.92 (dd,

J = 58.4, 53.6 Hz, 1 H), 3.74 (s, 2 H), 3.33 (s, 3 H); ¹⁹F NMR (376

MHz, CDCl₃) δ -90.76 (dd, J = 254.5, 58.5 Hz, 1 F), -96.49 (dd, J =

254.4, 53.6 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 175.06, 142.32,

136.24, 130.47, 130.19, 128.55, 128.52, 128.11, 125.44, 123.60,

120.01 (dd, J = 275.4, 269.5 Hz), 117.39, 109.13, 56.91 (d, J = 4.0

Hz), 27.02, 23.25 ppm. IR (KBr): ν_max= 3059, 2924, 2852, 2252,

1709, 1609, 1511, 1492, 1471, 1417, 1370, 1348, 1301, 1259,

1198, 1158, 1129, 1062 cm^-1. MS (EI): 261 (100), 344 (3.67); HRMS

(EI) for C₁₈H₁₄N₂OF₂S Calcd: 344.0795, Found: 344.0790. HPLC:

(ADH, Hexane/ⁱPrOH = 9/1, 0.7 mL/min, 214 nm), t_R(major) =

37.23 min, t_R(minor) = 45.93 min (94% ee); [α]_D²⁵= -73.29 (c =

0.150, CHCl₃, 94% ee).

(S)-3-((Difluoromethyl)thio)-1,5-dimethyl-3-phenylindolin-2-

one 13k. Yield 95%, white solid. ¹H NMR (400 MHz, cdcl₃) δ 7.62

(d, J = 7.3 Hz, 2 H), 7.36 (dt, J = 15.2, 7.2 Hz, 3 H), 7.15 (d, J = 5.2

Hz, 2 H), 6.96 (dd, J = 57.5, 52.8 Hz, 1 H), 6.81 (d, J = 8.2 Hz, 1 H),

3.31 (s, 3 H), 2.33 (s, 3 H); ¹⁹F NMR (376 MHz, cdcl₃) δ -90.85 (dd, J

= 253.6, 58.3 Hz, 1 F), -96.11 (dd, J = 253.7, 53.6 Hz, 1 F); ¹³C NMR

(101 MHz, CDCl₃) δ 175.38, 139.93, 136.26, 133.22, 130.31,

128.96, 128.55, 127.64, 126.08, 120.40 (dd, J = 274.2, 269.1 Hz),

(S)-3-(3-((Difluoromethyl)thio)-1-methyl-2-oxoindolin-3-yl)

benzonitrile 13h. Yield 86%, yellow oil. ¹H NMR (400 MHz, CDCl₃)

δ 7.94 (ddd, J = 8.1, 2.0, 1.2 Hz, 1 H), 7.86 (t, J = 1.6 Hz, 1 H), 7.61

(dt, J = 7.7, 1.3 Hz, 1 H), 7.54 – 7.48 (m, 1 H), 7.41 (td, J = 7.8, 1.2

Hz, 1 H), 7.34 (dd, J = 7.6, 0.7 Hz, 1 H), 7.16 (td, J = 7.6, 0.9 Hz, 1

H), 6.97 (d, J = 7.9 Hz, 1 H), 6.94 (dd, J = 58.8, 53.5 Hz, 1 H), 3.33

(s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.66 (dd, J = 255.7, 58.8 Hz,

108.71, 57.45 (d, J = 4.1 Hz), 26.97, 21.14 ppm. IR (KBr): ν_max

=

2952, 2923, 2855, 1698, 1618, 1602, 1500, 1352, 1322, 1272,

1147, 1059, 1039 cm^-1. MS (EI): 236 (100), 319 (7.33); HRMS (EI)

for C₁₇H₁₅NOF₂S Calcd: 319.0842, Found: 319.0847. Mp: 129.5 –

Chin. J. Chem. 2019, 37, XXX－XXX

www.cjc.wiley-vch.de

Chen et al.

Breaking Report

130.5 ^oC. nHPLC: (ADH, Hexane/ⁱPrOH = 97/3, 0.7 mL/min, 214

nm), t_R(major) = 14.61 min, t_R(minor) = 13.39 min (85% ee);

[α]_D²⁰= -32.60 (c = 0.100, CHCl₃, 85% ee).

H), 7.21 (d, J = 8.1 Hz, 1 H), 6.70 (dd, J = 58.3, 53.6 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ -90.74 (dd, J = 255.5, 58.2 Hz, 1 F), -97.18

(dd, J = 255.6, 53.5 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 174.55,

152.06, 134.46, 130.96, 129.35, 129.32, 127.33, 126.84, 125.93,

125.21, 119.73 (dd, J = 277.2, 271.7 Hz), 111.63, 56.02 (d, J = 4.0

Hz) ppm. IR (KBr): ν_max= 3063, 1807, 1617, 1598, 1495, 1477,

1464, 1448, 1318, 1298, 1230, 1126, 1061 cm^-1. MS (EI): 209

(100), 292 (0.32); HRMS (EI) for C₁₅H₁₀O₂F₂S Calcd: 292.0370,

Found: 292.0361. Mp: 72.0 – 73.0 ^oC. HPLC: (ADH, Hexane/ⁱPrOH

= 95/5, 0.7 mL/min, 214 nm), t_R(major) = 8.52 min, t_R(minor) =

9.22 min (87% ee); [α]_D²⁵= -4.96 (c = 0.120, CHCl₃, 87% ee).

Methyl-(S)-3-((difluoromethyl)thio)-1-methyl-2-oxo-3-phenyl

indoline-6-carboxylate 13l. Yield 89%, yellow oil. ¹H NMR (400

MHz, CDCl₃) δ 7.84 (d, J = 7.9 Hz, 1 H), 7.59 (d, J = 6.9 Hz, 3 H),

7.44 (d, J = 7.8 Hz, 1 H), 7.42 – 7.31 (m, 3 H), 6.91 (dd, J = 57.8,

53.9 Hz, 1 H), 3.94 (s, 3 H), 3.36 (s, 3 H); ¹⁹F NMR (376 MHz, CDCl₃)

δ -90.90 (dd, J = 253.1, 57.8 Hz, 1 F), -95.57 (dd, J = 253.2, 53.9 Hz,

1 F); ¹³C NMR (101 MHz, CDCl₃) δ 175.02, 166.20, 142.65, 135.20,

133.47, 131.88, 129.13, 128.93, 127.58, 125.52, 125.05, 119.98

(dd, J = 275.1, 271.1 Hz), 109.68, 57.17 (d, J = 3.5 Hz), 52.53, 27.18

ppm. IR (KBr): ν_max= 2998, 2953, 2925, 2853, 1720, 1621, 1452,

1333, 1300, 1273, 1249, 1158, 1111, 1062, 1040 cm^-1. MS (EI): 280

(100), 363 (4.63); HRMS (EI) for C₁₈H₁₅NO₃F₂S Calcd: 363.0741,

Found: 363.0732. HPLC: (IG, Hexane/ⁱPrOH = 9/1, 0.7 mL/min, 214

nm), t_R(major) = 14.29 min, t_R(minor) = 16.35 min (85% ee);

[α]_D²⁰= -37.00 (c = 0.140, CHCl₃, 85% ee).

(S)-3-(4-Chlorophenyl)-3-((difluoromethyl)thio)benzofuran-2

(3H)-one 14b. Yield 90%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ

7.60 – 7.54 (m, 2 H), 7.47 – 7.43 (m, 2 H), 7.41 – 7.36 (m, 2 H),

7.29 (td, J = 7.7, 0.8 Hz, 1 H), 7.24 – 7.20 (m, 1 H), 6.69 (dd, J =

58.4, 53.4 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.63 (dd, J =

255.7, 58.4 Hz, 1 F), -97.42 (dd, J = 255.9, 53.4 Hz, 1 F); ¹³C NMR

(101 MHz, CDCl₃) δ 174.17, 152.05, 135.65, 132.96, 131.21,

129.50, 128.82, 126.36, 125.83, 125.36, 119.45 (dd, J = 278.0,

272.2 Hz), 111.79, 55.45 (d, J = 4.4 Hz) ppm. IR (KBr): ν_max= 3071,

2965, 1809, 1618, 1597, 1491, 1476, 1464, 1402, 1320, 1298,

1288, 1127, 1063, 1015 cm^-1. MS (EI): 243 (100), 326.0; HRMS (EI)

for C₁₅H₉O₂F₂SCl Calcd: 325.9980, Found: 325.9978. HPLC: (ADH,

Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R(major) = 10.09

min, t_R(minor) = 11.13 min (82% ee); [α]_D²⁵= -1.87 (c = 0.225,

CHCl₃, 82% ee).

(S)-3-((Difluoromethyl)thio)-5-methoxy-1-methyl-3-phenyl

indolin-2-one 13m. Yield 95%, white solid. ¹H NMR (400 MHz,

CDCl₃) δ 7.60 (d, J = 7.4 Hz, 2 H), 7.40 – 7.31 (dt, J = 21.3, 7.1 Hz, 3

H), 6.95 (d, J = 2.5 Hz, 1 H), 6.93 (dd, J = 58.2, 53.7 Hz,1 H), 6.89

(dd, J = 8.5, 2.5 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 1 H), 3.78 (s, 3 H), 3.30

(s,3 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -95.63 (dd, J = 253.8, 58.2 Hz,

1 F), -100.85 (dd, J = 253.7, 53.7 Hz, 1 F); ¹³C NMR (101 MHz,

CDCl₃) δ 175.08, 156.50, 136.04, 135.76, 129.74, 128.99, 128.63,

127.60, 120.32 (dd, J = 274.6, 269.6 Hz), 114.46, 112.62, 109.40,

57.70 (d, J = 3.7 Hz), 55.88, 27.03 ppm. IR (KBr): ν_max= 2960, 2925,

1710, 1603, 1591, 1497, 1460, 1306, 1261, 1190, 1128, 1106,

1059, 1037 cm^-1. MS (EI): 253 (100), 335 (14.16); HRMS (EI) for

C₁₇H₁₅NO₂F₂S Calcd: 335.0792, Found: 335.0790. Mp: 94.5 – 95.5

^oC. HPLC: (ADH, Hexane/ⁱPrOH = 8/2, 0.7 mL/min, 214 nm), t_R

(major) = 9.72 min, t_R(minor) = 8.96 min (93% ee); [α]_D²⁰= -55.46

(c = 0.150, CHCl₃, 93% ee). The ee of the product after

(S)-3-(Benzo[d][1,3]dioxol-5-yl)-3-((difluoromethyl)thio)

benzofuran-2(3H)-one 14c. Yield 99%, yellow oil. ¹H NMR (400

MHz, CDCl₃) δ 7.47 – 7.39 (m, 2 H), 7.27 (td, J = 7.6, 0.8 Hz, 1 H),

7.20 (d, J = 8.2 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 7.02 (dd, J = 8.3,

2.0 Hz, 1 H), 6.79 (d, J = 8.1 Hz, 1 H), 6.66 (dd, J = 58.4, 53.7 Hz, 1

H), 5.99 (s, 2 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -90.84 (dd, J = 255.7,

58.3 Hz, 1 F), -97.31 (dd, J = 255.8, 53.6 Hz, 1 F); ¹³C NMR (101

MHz, CDCl₃) δ 174.46, 152.01, 148.58, 148.56, 130.95, 127.74,

126.85, 125.91, 125.18, 121.39, 119.68 (dd, J = 277.3, 272.0 Hz),

111.64, 108.55, 107.94, 101.78, 55.79 (d, J = 4.3 Hz) ppm. IR (KBr):

ν_max= 2904, 2782, 1808, 1617, 1598, 1505, 1489, 1464, 1440,

1350, 1320, 1290, 1252, 1232, 1132, 1063 cm^-1. MS (EI): 253

(100), 336 (2.02); HRMS (EI) for C₁₆H₁₀O₄F₂S Calcd: 336.0268,

Found: 336.0258. HPLC: (ADH, Hexane/ⁱPrOH = 95/5, 0.7 mL/min,

214 nm), t_R(major) = 14.31 min, t_R(minor) = 16.14 min (86% ee);

[α]_D²⁵= -4.24 (c = 0.150, CHCl₃, 86% ee).

recrys tallization was more than 99%.

General procedure for asymmetric difluoromethylthiolation

of benzofuran-2(3H)-one. Benzofuran-2(3H)-one (63 mg, 0.30

mmol, 1.0 equiv.), cesium carbonate (147 mg, 0.450 mmol, 1.50

equiv.) and compound 9c (129 mg, 0.360 mmol, 1.20 equiv.) were

added into a flame-dried Schlenk tube. The tube was putted into

liquid nitrogen. Dry toluene (3.0 mL) was added under argon

atmosphere. The resulting solution was stirred at -40 ^oC for 12 h.

After the reaction was completed as monitored by ¹⁹F NMR

spectroscopy, the reaction was quenched by addition of an

aqueous solution of HCl (2.0 N). The mixture was extracted with

Et₂O (10 mL × 3). The combined organic phase was separated and

dried over anhydrous Na₂SO₄. After filtration, the solvent was

removed under vacuum. The residue was purified by flash

chromatography to give the difluoromethylthiolated product 14a

(S)-3-((difluoromethyl)thio)-3-phenyl benzofuran-2(3H)-one as a

yellow solid (81 mg, 84% yield).

General procedure for enantioselective

difluoromethylthiolation of β-ketoester. β-ketoester (57 mg,

0.30 mmol, 1.0 equiv.), cesium carbonate (108 mg, 0.330 mmol,

1.10 equiv.) and the reagent 9c (129 mg, 0.360 mmol, 1.20 equiv.)

were added into a flame-dried Schlenk tube. The tube was putted

into liquid nitrogen. Anhydrous toluene (3.0 mL) was added under

argon atmosphere. The resulting solution was stirred at -40 ^oC for

6 h. After the reaction was completed as monitored by ¹⁹F NMR

spectroscopy, the reaction was quenched by addition of an

aqueous solution of HCl (2.0 N). The mixture was extracted with

Et₂O (10 mL × 3). The combined organic phase was separated and

dried over anhydrous Na₂SO₄. After filtration, the solvent was

removed under vacuum. The residue was purified by flash

(S)-3-((Difluoromethyl)thio)-3-phenylbenzofuran-2(3H)-one

14a. Yield 84%, Yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd,

J = 8.2, 1.4 Hz, 2 H), 7.50 – 7.37 (m, 5 H), 7.27 (td, J = 7.6, 0.9 Hz, 1

www.cjc.wiley-vch.de

Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

chromatography to give the difluoromethylthiolated product 15a

(R)-Methyl-1-oxo-2-((difluoromethyl)thio)

-2,3-dihydro-1H-indene-2-carboxylate as a white solid (79 mg,

96.7% yield).

atmosphere. Then Sc(OTf)₃(5.0 mg, 0.010 mmol, 0.10 equiv.) was

added under argon atmosphere. The resulting solution was

stirred for 2 h at room temperature. After the reaction was

completed as monitored by ¹⁹F NMR spectroscopy, the reaction

mixture was extracted with Et₂O (10 mL × 3). The combined

organic phase was separated and dried over anhydrous Na₂SO₄.

After filtration, the solvent was removed under vacuum. The

residue was purified by flash chromatography to give the

difluoromethylthiolated product 16 methyl-(R)-2-

Methyl-(R)-2-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-in

dene-2-carboxylate 15a. Yield 97%, white solid. ¹H NMR (400

MHz, CDCl₃) δ 7.82 (d, J = 7.7 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.50

(t, J = 55.6 Hz, 1 H), 7.48 – 7.43 (m, 2 H), 4.03 (d, J = 17.9 Hz, 1 H),

3.80 (s, 3 H), 3.26 (d, J = 17.9 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ

-91.58 (dd, J = 250.7, 55.6 Hz, 1 F), -92.90 (dd, J = 250.7, 55.6 Hz, 1

F); ¹³C NMR (101 MHz, CDCl₃) δ 196.67, 168.74, 150.52, 136.31,

132.94, 128.60, 126.26, 125.75, 120.24 (t, J = 271.1 Hz), 58.50,

53.95, 39.48 ppm. IR (KBr): ν_max= 3032, 2963, 1757, 1720, 1602,

1588, 1465, 1434, 1334, 1309, 1277, 1247, 1218, 1190, 1154,

1074, 1032 cm^-1. MS (EI): 189 (100), 272 (1.54); HRMS (EI) for

C₁₂H₁₀O₃F₂S Calcd: 272.0319, Found: 272.0322. Mp: 98.5 – 99.5

benzamido-2-((difluoromethyl)thio)-3-(4-methoxyphenyl)propano

ate as a yellow oil (22 mg, 55% yield).

Methyl-(R)-2-benzamido-2-((difluoromethyl)thio)-3-(4-meth

oxyphenyl)propanoate 16. Yield 55%, yellow oil. ¹H NMR (400

MHz, CDCl₃) δ 7.72 (d, J = 7.1 Hz, 2 H), 7.54 (t, J = 7.4 Hz, 1 H), 7.45

(t, J = 7.5 Hz, 2 H), 7.29 (s, 1 H), 7.02 (d, J = 8.7 Hz, 2 H), 6.96 (t, J =

56.0 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 2 H), 4.16 (d, J = 13.8 Hz, 1 H),

3.93 (s, 3 H), 3.74 (s, 3 H), 3.46 (d, J = 13.8 Hz, 1 H); ¹⁹F NMR (376

MHz, CDCl₃) δ -93.21 (dd, J = 254.2, 56.5 Hz, 1 F), -94.42 (dd, J =

254.3, 55.6 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 170.46, 166.52,

159.10, 134.00, 132.19, 131.13, 128.81, 126.99, 125.68, 120.25 (t,

J = 273.1 Hz), 113.93, 68.13, 55.17, 53.87, 38.88 ppm. IR (KBr):

ν_max= 2956, 2923, 2853, 1733, 1672, 1611, 1581, 1511, 1483,

1440, 1291, 1250, 1215, 1178, 1025 cm^-1. MS (DART POS): 417.9

(M+Na); HRMS (DART POS): C₁₈H₁₆NO₃F₂S (M+H) Calcd: 396.1076,

Found: 396.1074. HPLC: (IG, Hexane/ⁱPrOH = 92/8, 0.7 mL/min,

214 nm), t_R(major) = 51.96 min, t_R(minor) = 42.71 min (88% ee);

[α]_D²⁰= -51.29 (c = 0.700, CHCl₃, 88% ee).

^oC. HPLC: (ODH, Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R

25

(major) = 12.65 min, t_R(minor) = 14.21 min (83% ee); [α]_D

+1.96 (c = 0.100, CHCl₃, 83% ee).

=

Methyl-(R)-2-((difluoromethyl)thio)-6-methyl-1-oxo-2,3-dihy

dro-1H-indene-2-carboxylate 15b. Yield 99%, white oil. ¹H NMR

(400 MHz, CDCl₃) δ 7.63 (s, 1 H), 7.50 (d, J = 7.3 Hz, 1 H), 7.49 (t, J

= 55.7 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 3.97 (d, J = 17.8 Hz, 1 H),

3.80 (s, 3 H), 3.21 (d, J = 17.8 Hz, 1 H), 2.42 (s, 3 H); ¹⁹F NMR (376

MHz, CDCl₃) δ -91.62 (dd, J = 251.0, 55.7 Hz, 1 F), -92.90 (dd, J =

251.0, 55.7 Hz, 1 F); ¹³C NMR (101 MHz, CDCl₃) δ 196.80, 168.92,

147.98, 138.86, 137.65, 133.18, 125.95, 125.66, 120.29 (t, J =

271.1 Hz), 58.89, 53.96, 39.24, 21.09 ppm. IR (KBr): ν_max= 2957,

1748, 1716, 1618, 1585, 1495, 1434, 1281, 1252, 1222, 1064,

1039 cm^-1. MS (DART POS): 287.1 (M+H); HRMS (DART POS):

C₁₃H₁₃O₃F₂S (M+H) Calcd: 287.0548, Found: 287.0546. HPLC:

(ADH, Hexane/ⁱPrOH = 9/1, 0.7 mL/min, 214 nm), t_R(major) = 8.83

min, t_R(minor) = 9.44 min (80% ee); [α]_D²⁵= +4.01 (c = 0.120,

CHCl₃, 80% ee).

Supporting Information

NMR data of compounds 9a-c, 11a-l, 13a-m, 14a-c and 15a-c,

x-ray crystallograghy data of 9a-c, 11e and 13m. The supporting

information for this article is available on the WWW under

https://doi.org/10.1002/cjoc.2018xxxxx.

Acknowledgement

The authors gratefully acknowledge the financial support

from National Natural Science Foundation of China (21625206,

21632009, 21421002, 21572258).

Methyl-(R)-5-chloro-2-((difluoromethyl)thio)-1-oxo-2,3-dihy

dro-1H-indene-2-carboxylate 15c. Yield 87%, yellow solid. ¹H

NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.2 Hz, 1 H), 7.46 (t, J = 55.6

Hz, 1 H), 7.47 – 7.43 (m, 2 H), 4.02 (d, J = 18.0 Hz, 1 H), 3.81 (s, 3

H), 3.26 (d, J = 18.1 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ -91.45

(dd, J = 250.5, 55.7 Hz, 1 F), -92.91 (dd, J = 250.5, 55.6 Hz, 1 F); ¹³C

NMR (101 MHz, CDCl₃) δ 195.26, 168.40, 152.00, 143.11, 131.46,

129.53, 126.88, 126.56, 120.12 (t, J = 271.7 Hz), 58.72, 54.14,

39.20 ppm. IR (KBr): ν_max= 3068, 2958, 1751, 1717, 1600, 1581,

1435, 1321, 1265, 1209, 1181, 1071, 1041 cm^-1. MS (DART POS):

307.0 (M+H); HRMS (DART POS): C₁₂H₁₀O₃F₂SCl (M+H) Calcd:

307.0002, Found: 306.9998. Mp: 101.5 – 102.5 ^oC. HPLC: (ADH,

Hexane/ⁱPrOH = 95/5, 0.7 mL/min, 214 nm), t_R(major) = 15.35

min, t_R(minor) = 14.62 min (79% ee); [α]_D²⁵= +1.82 (c = 0.150,

CHCl₃, 79% ee).

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(The following will be filled in by the editorial staff)

Manuscript received: XXXX, 2019

Manuscript revised: XXXX, 2019

Manuscript accepted: XXXX, 2019

Accepted manuscript online: XXXX, 2019

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

Entry for the Table of Contents

Page No.

Asymmetric Difluoromethylthiolation of

Carbon Nucleophiles with Optically Pure

Difluoromethylthiolating Reagents Derived

from Camphorsultam

A family of optically pure electrophilic difluoromethylthiolating reagents based on the

camphorsultam skeleton was invented. These reagents reacted with a variety of soft carbon

nucleophiles such as oxazolone, oxindole, benzolactone and β-ketoester in good to excellent

enantioselectivities.

He Zhang, Xiaolong Wan, Qilong Shen*

Chin. J. Chem. 2019, 37, XXX－XXX

www.cjc.wiley-vch.de

Article Doi

Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with Optically Pure Difluoromethylthiolating Reagents Derived from Camphorsultam

DOI: 10.1002/cjoc.201900298

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Authors:

Article abstract of DOI:10.1002/cjoc.201900298

Full text of DOI:10.1002/cjoc.201900298

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