Copper-Catalyzed Selective Defluorinative Sulfuration of Trifluoropropanamides Leading to α-Fluorothioacrylamides

Tri ﬂ uoropropanamides Leading to α ‑Fluorothioacrylamides

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Copper-Catalyzed Selective Deﬂuorinative Sulfuration of

Xiao-Qin Shen, Sui-Qian Wang, Dongfeng Fan, Xing-Guo Zhang,* and Hai-Yong Tu*

Cite This: J. Org. Chem. 2021, 86, 1591 −1600

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sı Supporting Information

ABSTRACT: A practical and eﬃcient method for the synthesis of α-

ﬂuorothioacrylamide was developed from selective deﬂuorinative sulfu-

ration of triﬂuoropropanamides with disulﬁdes. The N-chelation-assisted

copper-catalyzed deﬂuorination and sulfurization reactions feature excellent

functional group tolerance and incorporation of both sulfur atoms of

disulﬁdes into acrylamides.

INTRODUCTION

Scheme 1. Synthesis of α-Fluorvinylthioethers

■

The carbon−sulfur (C−S) bond is prevalently existed in

natural products, potential pharmaceuticals, and materials

science, and a large number of methods have been

successfully developed to construct carbon−sulfur bonds

including transition metal-catalyzed cross-coupling reactions,

sulfur-Michael addition reactions, thiocarbonylations, and

insertion reactions. Acrylamide, as a kind of water-soluble

vinyl monomer, is widely used in cosmetic and dye

manufacturing, permanent press fabrics, water management,

as well as building blocks for the synthesis of oxindoles.

However, the eﬃcient preparation of α-thioacrylamides is

rare, albeit they exhibit antifungal and insect-toxic properties.

Given the increasing importance of ﬂuorinated compounds

in the areas of medicinal chemistry, agrochemicals and material

sciences, monoﬂuoralkenes are particular important amide

bond mimics due to their stable conformation and enhanced

peptidase stability. Traditionally, the hydroﬂuorination of

alkynyl sulﬁde (Scheme 1, eq 1) and deﬂuorinative

sulfurization of gem-diﬂuoroalkenes with malodorous thiols

(

eq 2)

are commonly used for the preparation of

monoﬂuoralkenes. Inspired by some transition-metal-catalyzed

selective activation of C−F bond, we envision that nitrogen

atom of triﬂuoropropanamide could chelate the copper(III)

complex to stabilize the intermediate and promote the

following β-H elimination. Then, gem-diﬂuoroacrylamide is

generated in situ and could participate in some deﬂuorinative

cross-coupling reactions. Herein, we report a deﬂuorinative

sulfuration reaction of triﬂuoropropanamides with disulﬁdes

through N-chelation-assisted and copper-catalyzed carbon−

sulfur bonds formation, delivering valuable α-ﬂuorothioacryla-

mides which could not be obtained from previous methods (eq

2a, and the results are summarized in Table 1. Initially,

treatment of 1a with 0.5 equiv of 2a, 10 mol % CuCl and 3

equiv of K CO in THF at 80 °C aﬀorded the target product

3a in 33% yield (Table 1, entry 1). The structure of Z-isomer

of product 3a was conﬁrmed by X-ray single-crystal diﬀraction

analysis. Subsequently, a variety of copper catalysts were

screened, CuBr, CuI, CuCl , and Cu(OAc) could provide

products in 37−66% yields (entries 2−5). When CuI was used

Received: October 14, 2020

Published: December 29, 2020

RESULTS AND DISCUSSION

■

We began our investigations by testing the model reaction of

,3,3-triﬂuoro-N-phenylpropanamide 1a with p-tolyldisulﬁde

2020 American Chemical Society

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Table 1. Optimization of the Reaction Conditions

investigated. The results disclosed that both electron-donating

and withdrawing groups could be tolerated well to deliver the

corresponding products 3p−3w in moderate to good yields.

For example, Me, MeO, Cl and Br at diﬀerent substituted

positions on the aryl ring gave the products 3p−3w in 66%−

78% yields. The benzothiazole heterocyclic compound also

entry

[Cu]

CuCl

CuBr

CuI

CuCl₂

Cu(OAc)₂

CuI

base

solvent

yield (%)

could be applied to this strategy, aﬀording product 3x in 51%

yield. The aliphatic substituted compounds also performed

well under the standard conditions to give the corresponding

products 3y and 3z in 56% and 48% yields. In addition, the

naphthalene group could be successfully incorporated into the

corresponding product 3aa in 75% yield. Moreover, the

blocked N-ethyl-N-phenylpropanamide also underwent this

protocol smoothly to aﬀord the product 3ab, albeit in relatively

low yield (24% yield).

K CO

THF

MeCN

DMSO

Toluene

THF

trace

K CO

Na CO

Cs CO

DBU

K CO

To demonstrate the synthetic utility of this reaction, further

transformation of products was performed as outlined in

Scheme 2. Treatment of product 3a with 30% H O in AcOH

K CO

CuI

K CO

at room temperature aﬀorded ﬂuorovinyl sulfone 4 in 74%

yield (Scheme 2, eq 1). The intramolecular cross-coupling of

product 3w was conducted by treated with 5 mol % CuI, 10

mol % 1,10-phen and 1.5 equiv of Cs CO in DME under

K CO

CuI

K CO

THF

Reaction conditions: 1a (0.1 mmol), 2a (0.05 mmol), [Cu] (10 mol

), PPh (0.6 equiv), base (3.0 equiv), H O (5.0 equiv), solvent (2.0

mL), at 80 °C under air until the starting material 1a was consumed

completely by TLC, isolated yield. Base (4.0 equiv). No PPh .

reﬂux for 24 h aﬀorded ﬂuorovinylbenzo[d]oxazole 5 in 63%

yield (eq 2).

To probe the mechanism of deﬂuorinative sulfurization

process, a preliminary mechanism experiment was also carried

out (Scheme 3). When the reaction of substrate 1a was

conducted in the absence of sulfur nucleophile under standard

conditions for 1 h, the 3,3-diﬂuoro-N-phenylacrylamide was

as catalyst, the desired product 3a was isolated in 66% yield

entry 3). Considering that the base could facilitate

deﬂuorination process, we tested some bases including

Na CO , Cs CO and DBU (entries 6−8). However, only

trace amount of the target product was obtained when Na CO

(

not detected by F NMR and acetanilide was detected by

GCMS (eq 1). These results indicated that disulﬁdes played

a key role to inhibit the cleavage of C−CF bond and to

promote the selective deﬂuorination. Moreover, when the

reaction was carried out at room temperature for 1 h in the

absence of disulﬁdes, and the possible copper(III) intermediate

was detected by HRMS (eq 2). To further demonstrate the

importance of the N-Cu chelation eﬀect in this deﬂuorinative

sulfurization, 4,4,4-triﬂuorobutan-2-one without a N-chelation

group was performed under standard condition. As expected,

the deﬂuorinative sulfurization product could not be observed

was used as the base (entry 6). Other bases were not beneﬁcial

to deﬂuorination process, and low yields were observed

(entries 7 and 8). During the examination of solvents,

MeCN, DMSO and toluene were found to be less eﬀective

than THF (entries 9−11). In order to further increase the

reaction yield, we tried to increase the amount of K CO

(

entry 12). Pleasingly, the yield was increased to 83% in the

presence of 4 equiv of K CO . Control experiment results

(

eq 3).

conﬁrmed that copper catalyst, base and PPh were required

Based on previous literature reports and above experimental

for this deﬂuorinative sulfurization (entries 13−15).

0,13

results,

a plausible mechanism was depicted in Scheme 4.

With the optimal reaction conditions in hand, we further

investigated the scope of the reaction. As shown in Table 2, a

variety of disulﬁdes bearing electron-withdrawing and electron-

donating groups underwent the deﬂuorinative sulfurization

successfully, delivering the corresponding α-ﬂuorovinyl thio-

ethers 3a-3o in 36−83% yields. All ortho- and para-substituted

disulﬁdes were suitable substrates. For instance, para-

methoxyphenyl disulﬁde provided product 3c in 65% yield,

para-ﬂuorine and para-chlorine disulﬁde gave products 3e and

−

Initially, the RS anion is produced from the reaction of

disulﬁde with PPh and water under basic condition. The

oxidative addition of triﬂuoroacrylamide to Cu(I) and the

chelation of nitrogen atom with copper aﬀord the crucial N-

chelated 5-membered intermediate A, which undergoes ligand

−

exchange with RS anion to generate intermediate B. Then, β-

H elimination of intermediate B generates gem-diﬂuoroacryla-

mide in situ, and the following migratory insertion of RSCu to

carbon−carbon double bond forms the intermediate D.

Finally, the trans-elimination of intermediate D gives the

desired product 3, in which Z-isomers are major products due

3f in 77% and 75% yield, respectively. It should be mentioned

that 4-aminophenyl and 4-nitrophenyl disulﬁde provided

products 3d and 3g in 68% and 56% yield, respectively.

ortho-Fluorine and chlorine substituted disulﬁdes provided

products 3h and 3i in 70% and 80% yields. meta-Fluorine

disulﬁde provided product Z-3j in 40% yield. Pleasingly,

heteroaryl and alkyl disulﬁdes also underwent deﬂuorinative

sulfurization successfully to produce the Z-isomers of 3k−3o

as the exclusive products in moderate yields. For example,

dimethyl disulﬁde and diethyl disulﬁde aﬀorded products Z-3n

and Z-3o in 54% and 55% yield, respectively. Subsequently, the

substitution of the aromatic ring of the N-aryl moiety was

^t^o^t^h^e^e^l^e^c^t^r^o^p^hⁱ^lⁱ^cⁱ^t^y^o^f^t^h^e^d^o^u^b^l^e^b^oⁿ^d^t^o^w^a^r^d^P^P^h3^.

CONCLUSIONS

■

In summary, we have developed a practical deﬂuorinative

sulfurization for the eﬃcient synthesis of α-ﬂuorothioacryla-

mide. In the presence of CuI, PPh , H O, and K CO , a variety

of triﬂuoropropanamides underwent the deﬂuorinative sulfu-

rization successfully with various less foul disulﬁdes to aﬀord α-

ﬂuorothioacrylamides in moderate to good yields. The present

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Table 2. Copper-Catalyzed Deﬂuorinative Sulfurization of Triﬂuoropropanamides with Disulﬁdes

Reaction conditions: 1 (0.1 mmol), 2 (0.05 mmol), CuI (10 mol %), PPh (0.6 equiv), K CO (4.0 equiv), H O (5.0 equiv), THF (2.0 mL) at 80

°C for 12 h, isolated yield. At 5 mmol scales. The Z/E ratio was determined by F NMR analysis of the crude reaction mixture.

Scheme 2. Further Transformation of Products 3a and 3w

ﬂuorothioacrylamides which could not be obtained from the

previously reported methods.

EXPERIMENTAL SECTION

■

General Information. All commercially available materials were

used without further puriﬁcation unless otherwise mentioned.

Triﬂuoropropanamides 1e, 1g, and 1i are commercially available.

Triﬂuoropropanamides 1a−1c, 1k, and 1n are known compounds and

synthesized according to previously reported methods. The disulﬁdes

are commercially available. The reaction setup was under air

atmosphere and performed in a pressure tube (capacity: 10.0 mL)

reaction demonstrates excellent functional group tolerance and

substrate scope to give potentially pharmaceutically active α-

with an oil bath. H NMR and C{ H} NMR spectra were measured

on a 500 MHz spectrometer (500 MHz for H and 125 MHz for C)

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the eluent to aﬀord the desired products 3a (976 mg, 68% yield, Z/E

Scheme 3. Control Experiments

70:30).

General Procedure for the Synthesis of Fluorovinyl Sulfone

To a solution containing 3a (0.2 mmol) in 2 mL of glacial acetic

acid was added 30% hydrogen peroxide (0.08 mL) dropwise at room

temperature. After the addition was complete, the reaction mixture

was allowed to stir at room temperature for 16 h. The reaction

mixture was concentrated under reduced pressure. The residue was

puriﬁed by ﬂash column chromatography on silica gel to give the

ﬂuorovinyl sulfone.

General Procedure for the Preparation of Fluorovinyl-

benzo[d]oxazole 5.

To a mixture of the N-(2-bromophenyl)-3-

ﬂuoro-3-(p-tolylthio)acrylamide 3w (73.0 mg, 0.2 mmol), CuI (1.9

mg, 0.01 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol), and

Cs CO (97.7 mg, 0.3 mmol) was added DCE (2 mL) at room

temperature under a nitrogen atmosphere. The reaction was reﬂuxed

for 24 h and then allowed to cool to room temperature. The residue

was puriﬁed by ﬂash column chromatography on silica gel to give the

product 5.

Scheme 4. Possible Mechanism

,3,3-Triﬂuoro-N-phenylpropanamide (1a). White solid ob-

tained by column chromatography (petroleum ether/ethyl acetate =

:1), 0.934 g, yield: 92%; m.p.: 118.2−120.4 °C. H NMR (400 MHz,

CDCl ): δ 7.69 (brs, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0

Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 3.23 (q, J = 10.4 Hz, 2H).

,3,3-Triﬂuoro-N-(p-tolyl)propanamide (1b).

White solid ob-

tained by column chromatography (petroleum ether/ethyl acetate =

:1), 0.966 g, yield: 89%; m.p.: 143.4−143.7 °C. H NMR (500 MHz,

DMSO-d ): δ 10.20 (brs, 1H), 7.46−7.44 (m, 2H), 7.13 (d, J = 8.5

Hz, 2H), 3.47 (q, J = 11.0 Hz, 2H), 2.25 (s, 3H).

16d

,3,3-Triﬂuoro-N-(4-methoxyphenyl)propanamide (1c). White

solid obtained by column chromatography (petroleum ether/ethyl

acetate = 4:1), 0.990 g, yield: 85%; m.p.: 132.0−132.1 °C. H NMR

(

500 MHz, DMSO-d ): δ 10.16 (brs, 1H), 7.50−7.47 (m, 2H), 6.92−

or a 400 MHz spectrometer (400 MHz for ¹H), using CDCl₃,

.89 (m, 2H), 3.72 (s, 3H), 3.45 (q, J = 11.0 Hz, 2H).

,3,3-Triﬂuoro-N-(m-tolyl)propanamide (1d). White solid ob-

tained by column chromatography (petroleum ether/ethyl acetate =

DMSO-d , or acetone-d as the solvent with tetramethylsilane (TMS)

as an internal standard at room temperature. Chemical shifts are given

in δ relative to TMS, and the coupling constants J are given in Hz.

High resolution mass spectra were recorded on an ESI-Q-TOF mass

spectrometry. Melting points were measured on a X4 melting point

apparatus and uncorrected. Column chromatography was performed

using EM silica gel 60 (300−400 mesh).

:1), 0.944 g, yield: 87%; m.p.: 92.6−92.8 °C. H NMR (500 MHz,

DMSO-d ): δ 10.22 (brs, 1H), 7.42 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H),

.21 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.49 (q, J = 11.0 Hz,

H), 2.28 (s, 3H). C{ H} NMR (125 MHz, CDCl ): δ 161.8 (C−F,

J_C₋_F= 3.4 Hz), 139.0, 136.7, 128.8, 126.2, 124.0 (C−F, J

= 274.9

C−F

General Procedure for the Synthesis of Triﬂuoropropana-

Hz), 121.5, 117.9, 41.9 (C−F, J

= 29.3 Hz), 21.2. F NMR (470

mides 1. To a stirred suspension of 3,3,3-triﬂuoropropionic acid

C−F

MHz, CDCl ): δ −137.11. GC-MS (EI, 70 eV) m/z (%): 217 (73),

(

0.58 mL, 6.5 mmol) in dichloromethane (20 mL) was added oxalyl

07 (100), 106 (51), 77 (18), 111 (14). HRMS (ESI) m/z: [M +

chloride (0.52 mL, 6 mmol) followed by three drops of DMF at 0 °C.

The reaction mixture was stirred at room temperature for 3 h. To this

solution was added a solution of anilines (5 mmol) in dichloro-

methane (10 mL) followed by triethylamine (1.74 mL, 12.5 mmol) at

Na] Calcd for C H F NONa 240.0607; found 240.0605.

10 10

N-(4-Chlorophenyl)-3,3,3-triﬂuoropropanamide (1f). White solid

obtained by column chromatography (petroleum ether/ethyl acetate

MHz, DMSO-d ): δ 10.44 (brs, 1H), 7.61−7.59 (m, 2H), 7.39−7.37

(

4:1), 0.948 g, yield: 80%; m.p.: 146.0−146.5 °C. H NMR (500

°C. The reaction mixture was stirred for 12−24 h and then washed

with water (15 mL) and 1 N HCl (15 mL). The organic layer was

m, 2H), 3.51 (q, J = 11.0 Hz, 2H). C{ H} NMR (125 MHz,

dried over Na SO and evaporated to aﬀord a residue, which was

CDCl ): δ 160.7 (C−F, J = 2.9 Hz), 135.3, 130.5, 129.2, 123.8

puriﬁed by ﬂash column chromatography (petroleum ether/ethyl

acetate) to aﬀord triﬂuoropropanamides.

General Procedure for the Synthesis of α-Fluorothioacry-

lamides 3. A Schlenk tube with a magnetic stirring bar was charged

with 1 (0.1 mmol, 1.0 equiv), 2 (0.05 mmol, 0.5 equiv), CuI (1.9 mg,

C−F

(

C−F, J

= 270.4 Hz), 121.6, 42.6 (C−F, J

= 29.5 Hz).

C−F

NMR (470 MHz, CDCl ): δ −137.22. GC-MS (EI, 70 eV) m/z (%):

37 (43), 129 (32), 128 (13), 127 (100), 111 (22); HRMS (ESI) m/

z: [M + H] Calcd for C H ClF NO 238.0241; found 238.0237.

N-(3-Chlorophenyl)-3,3,3-triﬂuoropropanamide (1h). White solid

.01 mmol, 10 mol %), K CO (55.3 mg, 0.4 mmol, 4.0 equiv), PPh

obtained by column chromatography (petroleum ether/ethyl acetate

(

15.7 mg, 0.06 mmol, 0.6 equiv), and H O (9.0 mg, 0.5 mmol, 5.0

equiv) in THF (2 mL). The mixture was stirred under air atmosphere

and heated at 80 °C. After 12 h, the reaction mixture was

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash column chromatography using petroleum ether/ethyl acetate as

the eluent to aﬀord the desired products 3.

= 4:1), 0.924 g, yield: 78%; m.p.: 102.2−104.1 °C. H NMR (500

MHz, DMSO-d ): δ 10.47 (brs, 1H), 7.84−7.83 (m, 1H), 7.45−7.43

(m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.07−7.05 (m, 1H), 3.49 (q, J =

11.0 Hz, 2H). C{ H} NMR (125 MHz, DMSO-d ): δ 161.9 (C−F,

C−F = 3.5 Hz), 139.7, 133.2, 130.6, 124.6 (C−F, JC−F = 274.8 Hz),

2 19

A Schlenk tube with a magnetic stirring bar was charged with 1a

1.015 g, 5.0 mmol, 1.0 equiv), 2a (615 mg, 2.5 mmol, 0.5 equiv), CuI

123.6, 118.8, 117.7, 40.5 (C−F, JC−F = 27.8 Hz). F NMR (470

(

MHz, CDCl ): δ −137.20. GC-MS (EI, 70 eV) m/z (%): 237 (46),

95.3 mg, 0.5 mmol, 10 mol %), K CO (2.76 g, 20.0 mmol, 4.0

129 (33), 128 (12), 127 (100), 111 (23). HRMS (ESI) m/z: [M +

equiv), PPh (786 mg, 3.0 mmol, 0.6 equiv), and H O (450 mg, 25.0

H] Calcd for C H ClF NO 238.0241; found 238.0237.

9 8 3

mmol, 5.0 equiv) in THF (100 mL). The mixture was stirred under

air atmosphere and heated at 80 °C. After 12 h, the reaction mixture

was concentrated under reduced pressure. The residue was puriﬁed by

ﬂash column chromatography using petroleum ether/ethyl acetate as

N-(Benzo[d]thiazol-2-yl)-3,3,3-triﬂuoropropanamide (1j). Light-

yellow solid obtained by column chromatography (petroleum ether/

ethyl acetate = 4:1), 0.819 g, yield: 63%; m.p.: 214.0−214.9 °C. H

NMR (500 MHz, DMSO-d ): δ 12.75 (brs, 1H), 8.01 (d, J = 8.0 Hz,

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H), 7.78 (d, J = 8.0 Hz, 1H), 7.48−7.44 (m, 1H), 7.35−7.32 (m,

3-Fluoro-3-((4-methoxyphenyl)thio)-N-phenylacrylamide (3c).

Both isomers: yellow solid obtained by column chromatography

(petroleum ether/ethyl acetate = 8:1), 19.7 mg, yield: 65%; m.p.:

H), 3.76 (q, J = 11.0 Hz, 2H). C{ H} NMR (125 MHz, Acetone-

d ): δ 163.2 (C−F, J

= 3.9 Hz), 158.0, 149.6, 133.0, 127.0, 125.2

C−F

(

C−F, J

= 274.3 Hz), 124.8, 122.3, 121.9, 40.8 (C−F, J

117.9−120.3 °C. H NMR (400 MHz, CDCl

): δ 7.80 (d, J = 9.6 Hz,

C−F

9.4 Hz). ¹⁹F NMR (470 MHz, DMSO-d ): δ −138.41. GC-MS (EI,

0.61H), 7.57 (m, 1.37H), 7.50−7.48 (m, 3H), 7.33−7.28 (m, 2H),

0 eV) m/z (%): 260 (42), 150 (100), 123 (16), 111 (10), 96 (8).

7.12−7.08 (m, 1H), 6.95−6.89 (m, 2H), 5.86 (d, J = 16.4 Hz, 0.61H),

HRMS (ESI) m/z: [M + H] Calcd for C H F N OS 261.0304,

found: 261.0300.

5.31 (d, J = 34.8 Hz, 0.43H), 3.83−3.82 (m, 3H). C{ H} NMR

(125 MHz, CDCl

): δ 164.5 (C−F, JC−F = 311.0 Hz), 161.5, 161.0,

N-Benzyl-3,3,3-triﬂuoropropanamide (1k).

White solid ob-

160.3, 137.9, 137.6, 136.8, 136.5, 129.0, 124.5, 124.4, 120.2, 119.9,

tained by column chromatography (petroleum ether/ethyl acetate =

117.2, 116.9 (C−F, JC−F = 9.0 Hz), 115.6, 114.8, 105.0 (C−F, JC−F

2 19

:1), 0.651 g, yield: 60%; m.p.: 125.8−125.9 °C. H NMR (500 MHz,

= 11.1 Hz), 101.3 (C−F, JC−F = 15.8 Hz), 55.5, 55.4. F NMR (470

MHz, CDCl ): δ −74.36 (s, 0.59F), −78.88 (s, 0.41F). GC-MS (EI

0 eV) m/z (%): 303 (13), 195 (34), 93 (100), 71 (32). HRMS

CDCl ): δ 7.34−7.26 (m, 3H), 7.24−7.22 (m, 2H), 6.51 (brs, 1H),

(

.40 (d, J = 5.5 Hz, 2H), 3.04 (q, J = 10.5 Hz, 2H).

,3,3-Triﬂuoro-N-hexylpropanamide (1l). White solid obtained by

column chromatography (petroleum ether/ethyl acetate = 20:1),

ESI) m/z: [M + H] Calcd for C H FNO S 304.0802, found:

16 15 2

04.0802.

Z)-3-((4-Aminophenyl)thio)-3-ﬂuoro-N-phenylacrylamide (Z-

d). Yellow solid obtained by column chromatography (petroleum

(

.560 g, yield: 53%; m.p.: 47.4−47.8 °C. H NMR (500 MHz,

DMSO-d ): δ 8.20 (brs, 1H), 3.19 (q, J = 11.5 Hz, 2H), 3.08 (q, J =

Hz), 124.2 (C−F, J

ether/ethyl acetate = 2:1), 13.5 mg, yield: 47%; m.p.: 157.0−160.0

.5 Hz, 2H), 1.42−1.38 (m, 2H), 1.31−1.26 (m, 6H), 0.88−0.85 (m,

_H₎_.1 C{ H} NMR (125 MHz, CDCl ): δ 163.4 (C−F, J

°C. H NMR (400 MHz, DMSO-d ): δ 10.03 (s, 1H), 7.60−7.58 (m,

= 2.9

C−F

2H), 7.33−7.31 (m, 2H), 7.20−7.18 (m, 2H), 7.06−7.03 (m, 1H),

= 275.0 Hz), 40.9 (C−F, J

= 28.9 Hz),

C−F

6.59−6.57 (m, 2H), 6.04 (d, J = 17.6 Hz, 1H), 5.58 (s, 2H). C{ H}

9.9, 31.3, 29.0, 26.4, 22.4, 13.7. F NMR (470 MHz, CDCl ): δ

NMR (125 MHz, DMSO-d ): δ 167.9 (C−F, J

= 300.4 Hz),

C−F

−

136.66. GC-MS (EI, 70 eV) m/z (%): 211 (6), 141 (100), 128

162.8 (C−F, JC−F = 20.5 Hz), 150.6, 139.1, 136.5, 128.7, 123.2,

(

43), 140 (41), 111 (39). HRMS (ESI) m/z: [M + H] Calcd for

118.9, 114.3, 108.8 (C−F, JC−F = 8.8 Hz), 100.8 (C−F, JC−F = 23.4

C H F NONa 234.1076, found: 234.1074.

Hz). F NMR (470 MHz, DMSO-d ): δ −78.71. GC-MS (EI 70 eV)

,3,3-Triﬂuoro-N-(naphthalen-2-yl)propanamide (1m). Brown

m/z (%): 288 (35), 207 (29), 195 (100), 152 (20). HRMS (ESI) m/

solid obtained by column chromatography (petroleum ether/ethyl

z: [M + Na] Calcd for C15H13FN OSNa 311.0625, found:

acetate = 4:1), 0.924 g, yield: 73%; m.p.: 167.2−167.7 °C. H NMR

11.0626.

E)-3-((4-Aminophenyl)thio)-3-ﬂuoro-N-phenylacrylamide (E-

d). Yellow solid obtained by column chromatography (petroleum

(500 MHz, DMSO-d ): δ 10.53 (brs, 1H), 8.29 (s, 1H), 7.89 (d, J =

(

.0 Hz 1H), 7.86−7.84 (m, 2H), 7.57−7.55 (m, 1H), 7.50−7.47(m,

13 1

H), 7.44−7.41(m, 1H), 3.58 (q, J = 11.0 Hz, 2H). C{ H} NMR

ether/ethyl acetate = 2:1), 6.1 mg, yield: 21%; m.p.: 131.0−134.0 °C.

(

125 MHz, DMSO-d ): δ 161.9 (C−F, J

= 3.4 Hz), 136.1, 133.5,

C−F

H NMR (400 MHz, CDCl ): δ 7.72 (brs, 1H), 7.50−7.48 (m, 2H),

30.2, 128.6, 127.54, 127.48, 126.6, 124.94, 124.93 (C−F, J

C−F

.36−7.28 (m, 4H), 7.11−7.08 (m, 1H), 6.70−6.68 (m, 2H), 5.26 (d,

74.6 Hz), 119.9, 115.9, 40.8 (C−F, J

= 27.6 Hz). F NMR (470

13 1

C−F

J = 35.2 Hz, 1H), 3.95 (brs, 2H). C{ H} NMR (125 MHz, CDCl ):

MHz, DMSO-d ): δ −138.48. GC-MS (EI, 70 eV) m/z (%): 253

δ 159.5 (C−F, J

= 309.4 Hz), 148.8, 137.7, 136.7, 135.8, 134.7,

C−F

(

[

79), 144 (25), 143 (100), 116 (13), 115 (58). HRMS (ESI) m/z:

M + H] Calcd for C H F NO 254.0787, found: 254.0782.

(

29.0, 124.4, 120.1, 115.9, 103.9 (C−F, J

= 26.1 Hz). F NMR

C−F

11 3

470 MHz, CDCl ): δ −80.09. GC-MS (EI 70 eV) m/z (%): 288

N-Ethyl-3,3,3-triﬂuoro-N-phenylpropanamide (1n). Light-yel-

28), 207 (42), 195 (100), 152 (23). HRMS (ESI) m/z: [M + Na]

low oil obtained by column chromatography (petroleum ether/ethyl

acetate = 10:1), 0.462 g, yield: 40%; H NMR (500 MHz, DMSO-

d ): δ 7.51−7.41 (m, 3H), 7.33−7.32 (m, 2H), 3.69−3.65 (m, 2H),

Calcd for C H FN OSNa 311.0625, found: 311.0631.

15 13

-Fluoro-3-((4-ﬂuorophenyl)thio)-N-phenylacrylamide (3e). Both

isomers: yellow solid obtained by column chromatography (petro-

leum ether/ethyl acetate = 8:1), 22.4 mg, yield: 77%; m.p.: 129.5−

.12 (q, J = 11.0 Hz, 2H), 1.00 (t, J = 7.0 Hz, 3H).

-Fluoro-N-phenyl-3-(p-tolylthio)acrylamide (3a). Both isomers:

32.1 °C. H NMR (400 MHz, CDCl ): δ 7.93−7.74 (m, 1H), 7.57−

yellow solid obtained by column chromatography (petroleum ether/

ethyl acetate = 8:1), 23.8 mg, yield: 83%; m.p.: 119.4−121.4 °C. H

NMR (400 MHz, CDCl ): δ 7.85 (d, J = 8.8 Hz, 0.63H), 7.62−7.60

.55 (m, 2H), 7.47−7.31 (m, 5H), 7.19−7.16 (m, 2H), 6.01 (d, J =

6.4 Hz, 0.35H), 5.72 (d, J = 32.8 Hz, 0.62H). C{ H} NMR (125

MHz, CDCl ): δ 163.2 (C−F, J

= 307.8 Hz), 162.9 (C−F, J

C−F

(

m, 1.41H), 7.55−7.48 (m, 3H), 7.38−7.33 (m, 2H), 7.29−7.23 (m,

249.6 Hz), 159.7 (C−F, J

= 19.6 Hz), 137.3, 131.1 (C−F, J

C−F

H), 7.17−7.13 (m, 1H), 5.93 (d, J = 16.8 Hz, 0.70H), 5.46 (d, J = 34

8.3 Hz), 130.5, 130.4, 130.3, 129.7 (C−F, J

= 8.5 Hz), 129.1,

C−F

Hz, 0.30H), 2.43−2.42 (m, 3H). C{ H} NMR (125 MHz, CDCl ):

128.7, 124.8, 121.6 (C−F, J

= 22.5 Hz), 120.3, 120.2, 120.1 (C−

C−F

δ 166.6 (C−F, J

= 302.3 Hz), 162.1 (C−F, J

= 19.5 Hz),

C−F

F, J

= 23.1 Hz), 117.0, 116.8, 116.7, 109.2 (C−F, J

= 13.1

C−F

51.3, 144.2, 140.7, 140.0, 137.8, 137.5, 134.9, 134.3, 130.7, 130.0,

29.0, 124.6, 123.0 (C−F, J

Hz). F NMR (470 MHz, CDCl ): δ −74.90 (s, 0.28 F), −76.84 (s,

= 8.4 Hz), 120.2, 102.0 (C−F, J

C−F

0.72F), −110.15 (s, 0.72F), −111.33 (s, 0.28F). GC-MS (EI 70 eV)

m/z (%): 291 (8), 199 (22), 127 (33), 93 (100). HRMS (ESI) m/z:

18.7 Hz), 21.26, 21.25. F NMR (470 MHz, CDCl ): δ −74.35 (s,

0.70F), −77.84 (s, 0.30F). GC-MS (EI, 70 eV) m/z (%): 287 (12),

195 (47), 152 (17), 93 (100), 65 (20). HRMS (ESI) m/z: [M + Na]

[

M + Na] Calcd for C H F NOSNa 314.0422, found: 314.0424.

15 11 2

-((4-Chlorophenyl)thio)-3-ﬂuoro-N-phenylacrylamide (3f). Both

Calcd for C H FNOSNa 310.0672, found: 310.0664.

isomers: yellow solid obtained by column chromatography (petro-

-Fluoro-N-phenyl-3-(phenylthio)acrylamide (3b). Both isomers:

leum ether/ethyl acetate = 8:1), 23.0 mg, yield: 75%; m.p.: 125.8−

yellow solid obtained by column chromatography (petroleum ether/

ethyl acetate = 8:1), 20.7 mg, yield: 76%; m.p.: 85.9−88.3 °C. H

NMR (400 MHz, CDCl ): δ 7.83 (d, J = 9.6 Hz, 0.46H), 7.62 (s,

27.6 °C. H NMR (400 MHz, CDCl ): δ 7.89 (d, J = 8.4 Hz,

.13H), 7.68 (s, 0.84H), 7.61−7.51 (m, 4H), 7.44−7.34 (m, 4H),

7.17−7.14 (m, 1H), 5.99 (d, J = 16.4 Hz, 0.88H), 5.63 (d, J = 33.2

.37H), 7.57−7.56 (m, 3H), 7.51−7.49 (m, 1H), 7.44−7.38 (m, 3H),

Hz, 0.12H). C{ H} NMR (125 MHz, CDCl ): δ 167.7 (C−F, J

C−F

.33−7.29 (m, 2H), 7.13−7.09 (m, 1H), 5.92 (d, J = 16.8 Hz, 0.57H),

= 305.4 Hz), 163.5, 163.2, 137.7, 137.6, 137.3, 136.10, 136.07, 134.9,

.52 (d, J = 33.6 Hz, 0.44H). C{ H} NMR (125 MHz, CDCl ): δ

130.1, 129.4, 129.0, 125.1, 124.5, 120.3, 119.9, 102.2 (C−F, J

C−F

66.4 (C−F, J

= 300.4 Hz), 161.2 (C−F, J

37.5, 134.8, 133.8, 130.0, 129.9, 129.6, 129.2, 129.0, 127.5, 126.7

= 19.7 Hz), 137.8,

8.5 Hz), 102.1 (C−F,

= 14.6 Hz). F NMR (470 MHz,

C−F

CDCl ): δ −75.12 (s, 0.85F), −77.10 (s, 0.15F). GC-MS (EI 70 eV)

(C−F, J

= 8.3 Hz), 124.7, 124.4, 120.3, 107.3 (C−F, J

= 20.3

m/z (%): 307 (28), 162 (47), 124 (100), 93 (34), 77 (23). HRMS

C−F

Hz). F NMR (470 MHz, CDCl ): δ −74.10 (s, 0.55F), −77.26 (s,

(ESI) m/z: [M + H] Calcd for C H FClNOS 308.0307, found:

15 12

.45F). GC-MS (EI 70 eV) m/z (%): 273 (10), 181 (34), 109 (32),

308.0302.

3 (100), 77 (20). HRMS (ESI) m/z: [M + Na] Calcd for

(Z)-3-Fluoro-3-((4-nitrophenyl)thio)-N-phenylacrylamide (Z-3g).

Yellow solid obtained by column chromatography (petroleum ether/

C H FNOSNa 296.0516, found: 296.0539.

595

J. Org. Chem. 2021, 86, 1591−1600

The Journal of Organic Chemistry

Article

ethyl acetate = 2:1), 11.1 mg, yield: 35%; m.p.: 158.0−160.0 °C. H

7.61−7.59 (m, 2H), 7.46−7.45 (m, 1H), 7.34−7.31 (m, 2H), 7.19−

7.17 (m, 1H), 7.09−7.05 (m, 1H), 6.20 (d, J = 16.8 Hz, 1H).

NMR (400 MHz, DMSO-d ): δ 10.26 (s, 1H), 8.28−8.25 (m, 2H),

.85−7.83 (m, 2H), 7.62−7.60 (m, 2H), 7.35−7.31 (m, 2H), 7.10−

C{ H} NMR (125 MHz, DMSO-d ): δ 170.6 (C−F, J

= 302.8

C−F

.06 (m, 1H), 6.39 (d, J = 17.6 Hz, 1H). C{ H} NMR (125 MHz,

Hz), 167.8 (C−F, J

= 20.1 Hz), 144.0, 143.4, 139.2, 134.1, 133.6,

C−F

DMSO-d ): δ 163.0 (C−F, J

= 303.3 Hz), 162.0 (C−F, J

128.7, 127.8 (C−F, J

= 11.4 Hz), 120.3, 107.6 (C−F, J

= 23.4

C−F

9.9 Hz), 147.6, 138.7, 136.3 (C−F, J

= 7.3 Hz), 133.8, 128.8,

= 23.6 Hz). F NMR (470

MHz, DMSO-d ): δ −80.06. GC-MS (EI 70 eV) m/z (%): 318 (13),

95 (100), 127 (44), 93 (85), 77 (32). HRMS (ESI) m/z: [M + Na]

Hz). F NMR (470 MHz, DMSO-d ): δ −76.83. GC-MS (EI 70 eV)

C−F

24.1, 123.6, 119.1, 105.8 (C−F, J

m/z (%): 279 (15), 187 (22), 115 (78), 93 (100). HRMS (ESI) m/z:

C−F

[M + H] Calcd for C H FNOS 280.0261, found: 280.0247.

13 11 2

(Z)-3-Fluoro-N-phenyl-3-(pyridin-2-ylthio)acrylamide (3l). Yellow

Calcd for C H FN O SNa 341.0367, found: 341.0378.

oil obtained by column chromatography (petroleum ether/ethyl

(

E)-3-Fluoro-3-((4-nitrophenyl)thio)-N-phenylacrylamide (E-3g).

acetate = 4:1), 12.1 mg, yield: 44%. H NMR (400 MHz, DMSO-d ):

Yellow solid obtained by column chromatography (petroleum ether/

δ 10.23 (s, 1H), 8.57−8.56 (m, 1H), 7.87−7.83 (m, 1H), 7.65−7.60

ethyl acetate = 2:1), 6.7 mg, yield: 21%; m.p.: 166.4−167.8 °C. H

(m, 3H), 7.41−7.38 (m, 1H), 7.34−7.30 (m, 2H), 7.09−7.05 (m,

NMR (400 MHz, CDCl ): δ 8.31 (d, J = 8.8 Hz, 2H), 7.82−7.80 (m,

1H), 6.40 (d, J = 17.2 Hz, 1H). C{ H} NMR (125 MHz, DMSO-

H), 7.70−7.68 (m, 2H), 7.59−7.57 (m, 2H), 7.40 (t, J = 7.6 Hz,

d ): δ 168.3 (C−F, J

= 302.8 Hz), 167.0 (C−F, J

= 19.5 Hz),

C−F

H), 7.20 (t, J = 7.6 Hz, 1H), 5.99 (d, J = 32.0 Hz, 1H).

156.8, 155.6, 144.1, 143.1, 134.0, 132.3, 128.8, 128.5, 124.4, 112.6

= 24.0 Hz). F NMR (470 MHz, DMSO-d ): δ −72.82.

GC-MS (EI 70 eV) m/z (%): 274 (8), 195 (100), 134 (14), 105 (21),

C{ H}NMR (125 MHz, CDCl ): δ 161.2 (C−F, J

= 306.8 Hz),

= 23.1 Hz), 137.5, 137.1, 131.3, 129.1, 127.1,

= 11.1 Hz). F NMR (470

MHz, CDCl ): δ −76.06. GC-MS (EI 70 eV) m/z (%):318 (15), 195

100), 127 (49), 93 (83), 77 (24). HRMS (ESI) m/z: [M + Na]

(C−F, J

C−F

151.8 (C−F, J

C−F

25.0, 124.6, 120.2, 112.8 (C−F, J

77 (32). HRMS (ESI) m/z: [M + H] Calcd for C H FN OS

C−F

14 12 2

275.0649, found: 275.0659.

(Z)-3-(Benzylthio)-3-ﬂuoro-N-phenylacrylamide (3m). Yellow

(

Calcd for C H FN O SNa 341.0367, found: 341.0357.

solid obtained by column chromatography (petroleum ether/ethyl

-Fluoro-3-((2-ﬂuorophenyl)thio)-N-phenylacrylamide (3h).

Both isomers: white solid obtained by column chromatography

petroleum ether/ethyl acetate = 8:1), 20.4 mg, yield: 70%; m.p.:

acetate = 4:1), 14.6 mg, yield: 51%; m.p.: 100.0−102.0 °C. H NMR

(400 MHz, DMSO-d ): δ 9.99 (s, 1H), 7.57−7.55 (m, 2H), 7.39−

(

7.32 (m, 4H), 7.30−7.27 (m, 3H), 7.05−7.01 (m, 1H), 6.10(d, J =

38.9−141.4 °C. H NMR (400 MHz, CDCl ): δ 7.99−7.88 (m,

19.2, 1H), 4.18 (s, 2H). C{ H} NMR (125 MHz, DMSO-d ): δ

H), 7.61−7.55 (m, 2H), 7.46−7.30 (m, 5H), 7.19−7.14 (m, 2H),

168.3 (C−F, JC−F = 302.9 Hz), 162.8 (C−F, JC−F = 21.4 Hz), 139.0,

.03 (d, J = 16.4 Hz, 0.59H), 5.72 (d, J = 32.8 Hz, 0.39H). C{ H}

137.4, 128.8, 128.7, 128.6, 127.3, 123.2, 118.9, 102.1 (C−F, JC−F =

3 19

NMR (125 MHz, CDCl ): δ 167.3 (C−F, J

= 304.1 Hz), 162.5

= 249.5 Hz), 161.1,

= 8.3 Hz), 130.44, 130.37,

23.9 Hz), 32.8 (C−F, JC−F = 14.4 Hz). F NMR (470 MHz, DMSO-

d ): δ −76.39. GC-MS (EI 70 eV) m/z (%): 287 (12), 195 (47), 152

C−F

(

C−F, J

= 248.5 Hz), 162.8 (C−F, J

C−F

59.9, 137.8, 137.3, 131.1 (C−F, J

(24), 93 (100). HRMS (ESI) m/z: [M + Na] Calcd for

C−F

29.1, 129.0, 128.8, 128.7, 124.9, 124.5, 121.6 (C−F, J

= 22.4

14FNOSNa 310.0672, found: 310.0682.

C−F

Hz), 120.4, 120.0 (C−F, J

= 22.9 Hz), 117.0, 116.8, 116.7, 108.8

(Z)-3-Fluoro-3-(methylthio)-N-phenylacrylamide (3n). White

C−F

(C−F, J

= 9.0 Hz), 102.7 (C−F, J

= 24.0 Hz). F NMR (470

solid obtained by column chromatography (petroleum ether/ethyl

C−F

MHz, CDCl ): δ −75.19 (s, 0.60F), −76.34 (s, 0.40F), −110.13 (s,

acetate = 8:1), 11.4 mg, yield: 54%; m.p.: 101.2−102.3 °C. H NMR

.40F), −111.35 (s, 0.60F). GC-MS (EI 70 eV) m/z (%): 291 (13),

(400 MHz, CDCl ): δ 7.66 (s, 1H), 7.54−7.53 (m, 2H), 7.29 (t, J =

99 (37), 127 (44), 93 (100). HRMS (ESI) m/z: [M + Na] Calcd

7.8 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 5.94 (d, J = 18.0 Hz, 1H), 2.39

for C H F NOSNa 314.0422, found: 314.0427.

(s, 3H). C{ H} NMR (125 MHz, Acetone-d

): δ 170.6 (C−F, JC−F

11 2

-((2-Chlorophenyl)thio)-3-ﬂuoro-N-phenylacrylamide (3i). Both

isomers: white solid obtained by column chromatography (petroleum

= 302.5 Hz), 163.8 (C−F, JC−F = 22.5 Hz), 139.7, 129.1, 123.7,

119.5, 101.5 (C−F, JC−F = 25.0 Hz), 11.3 (C−F, JC−F = 18.8 Hz).

ether/ethyl acetate = 8:1), 24.6 mg, yield: 80%; m.p.: 159.2−162.9

F NMR (470 MHz, Acetone-d

): δ −117.45. GC-MS (EI, 70 eV)

(

C. H NMR (400 MHz, CDCl ): δ 8.02−7.95 (m, 1H), 7.69−7.52

m/z (%): 211 (27), 119 (66), 93 (100), 91 (16), 65 (12). HRMS

(ESI) m/z: [M + Na] Calcd for C H FNOSNa 234.0359; found

10 10

m, 4H), 7.43−7.29 (m, 4H), 7.18−7.12 (m, 1H), 6.05 (d, J = 16.4

Hz, 0.59H), 5.69 (d, J = 32.8 Hz, 0.39H). C{ H} NMR (125 MHz,

234.0353.

CDCl ): δ 167.1 (C−F, J

= 309.3 Hz), 162.9, 160.5, 139.2, 137.8,

37.3, 136.8, 134.8, 131.2, 131.0, 130.7, 130.2, 129.03, 128.98, 127.9,

(Z)-3-(Ethylthio)-3-ﬂuoro-N-phenylacrylamide (3o). White solid

C−F

obtained by column chromatography (petroleum ether/ethyl acetate

27.3, 126.5 (C−F, J

= 8.3 Hz), 124.8, 124.1, 120.4, 120.0, 108.8

= 8:1), 12.4 mg, yield: 55%; m.p.: H NMR (400 MHz, Acetone-d ):

C−F

(

C−F, J

= 8.8 Hz), 102.6 (C−F, J

= 21.0 Hz). F NMR (470

δ 9.18 (s, 1H), 7.66−7.64 (m, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.03 (t, J

C−F

MHz, CDCl ): δ −75.31 (s, 0.57F), −77.22 (s, 0.43F). GC-MS (EI

= 7.6 Hz, 1H), 6.09 (d, J = 19.2 Hz, 1H), 2.91 (q, J = 7.6 Hz, 2H),

(

0 eV) m/z (%): 307 (28), 124 (100), 93 (34), 77 (23). HRMS

1.31 (t, J = 7.6 Hz, 3H). C{ H} NMR (125 MHz, Acetone-d ): δ

ESI) m/z: [M + Na]⁺Calcd for C H FClNOSNa 330.0126,

170.5 (C−F, J

= 302.1 Hz), 163.7 (C−F, J

= 21.5 Hz), 140.1,

= 24.5 Hz), 23.9 (C−F, J

C−F C−F

C−F

found: 330.0119.

(

129.3, 123.9, 119.7, 102.5 (C−F, J

Z)-3-Fluoro-3-((3-ﬂuorophenyl)thio)-N-phenylacrylamide (3j).

= 15.4 Hz), 15.6. F NMR (470 MHz, Acetone-d ): δ −116.77. GC-

White solid obtained by column chromatography (petroleum ether/

MS (EI, 70 eV) m/z (%): 225 (11), 133 (41), 105 (42), 93 (100), 77

ethyl acetate = 8:1), 11.6 mg, yield: 40%; m.p.: 94.9−96.1 °C. H

(14). HRMS (ESI) m/z: [M + H] Calcd for C H FNOS

11 13

NMR (400 MHz, Acetone-d ): δ 9.35 (s, 1H), 7.69 (d, J = 7.8 Hz,

226.0696; found 226.0692.

H), 7.53−7.48 (m, 1H), 7.44−7.39 (m, 2H), 7.32 (t, J = 7.2 Hz,

3-Fluoro-N-(p-tolyl)-3-(p-tolylthio)acrylamide (3p). Both isomers:

H), 7.28−7.23 (m, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.21 (d, J = 17.2

white solid obtained by column chromatography (petroleum ether/

Hz, 1H). C{ H} NMR (125 MHz, Acetone-d ): δ 166.7 (C−F,

ethyl acetate = 8:1), 20.8 mg, yield: 69%; m.p.: 125.1−127.7 °C. H

J_C₋_F= 303.0 Hz), 163.3 (C−F, J

= 19.8 Hz), 163.1 (C−F, J

= 8.4 Hz), 131.1, 129.4, 124.2,

= 22.5 Hz), 119.8, 117.1 (C−F, J

= 23.8 Hz). F NMR (470 MHz, Acetone-d ): δ

NMR (400 MHz, CDCl ): δ 7.84−7.80 (m, 1H), 7.45−7.43 (m, 3H),

C−F

246.4 Hz), 139.8, 131.6 (C−F, J

7.38−7.36 (m, 1H), 7.23−7.17 (m, 2H), 7.11−7.09 (m, 2H), 5.90 (d,

C−F

21.7 (C−F, J

= 21.0 Hz),

J = 16.8 Hz, 0.59H), 5.43 (d, J = 34.0 Hz, 0.37H), 2.37 (s, 3H), 2.30

C−F

03.6 (C−F, J

(s, 3H). C{ H} NMR (125 MHz, CDCl

): δ 168.0 (C−F, JC−F

C−F

−

86.83 (s, 1F), −119.71 (s, 1F). GC-MS (EI, 70 eV) m/z (%): 291

306.1 Hz), 166.0, 163.4 (C−F, JC−F = 25.3 Hz), 160.3, 140.6, 139.9,

(

27), 199 (49), 127 (51), 93 (100), 83 (9). HRMS (ESI) m/z: [M +

134.9, 134.2, 130.7, 130.0, 129.5, 129.4, 123.7, 123.2 (C−F, JC−F =

H] Calcd for C H F NOS 292.0602; found 292.0594.

8.5 Hz), 120.4, 120.0, 106.2 (C−F, JC−F = 9.0 Hz), 102.1 (C−F,

12 2

(

Z)-3-Fluoro-N-phenyl-3-(thiophen-2-ylthio)acrylamide (3k).

JC−F = 22.2 Hz), 21.3, 20.9. F NMR (470 MHz, CDCl ): δ −74.95

White solid obtained by column chromatography (petroleum ether/

ethyl acetate = 15:1), 10.0 mg, yield: 36%; m.p.: 139.0−142.0 °C. H

NMR (400 MHz, DMSO-d ): δ 10.18 (s, 1H), 7.91−7.89 (m, 1H),

(s, 0.60F), −77.96 (s, 0.40F). GC-MS (EI 70 eV) m/z (%): 301 (12)₊,

195 (27), 178 (90), 91 (100), 77 (28). HRMS (ESI) m/z: [M + H]

Calcd for C H FNOS 302.1009, found: 302.1024.

17 17

596

J. Org. Chem. 2021, 86, 1591−1600

The Journal of Organic Chemistry

Article

-Fluoro-N-(4-methoxyphenyl)-3-(p-tolylthio)acrylamide (3q).

Both isomers: white solid obtained by column chromatography

petroleum ether/ethyl acetate = 8:1), 20.9 mg, yield: 66%; m.p.:

N-(4-Bromophenyl)-3-ﬂuoro-3-(p-tolylthio)acrylamide (3u).

Both isomers: yellow solid obtained by column chromatography

(petroleum ether/ethyl acetate = 8:1), 26.8 mg, yield: 73%; m.p.:

(

19.8−121.7 °C. H NMR (400 MHz, CDCl ): δ 7.78 (s, 1H), 7.47−

146−148 °C. H NMR (500 MHz, CDCl ): δ 7.79−7.77 (m, 0.32H),

.37 (m, 4H), 7.22−7.16 (m, 2H), 6.84−6.81 (m, 2H), 5.88 (d, J =

6.8 Hz, 0.60H), 5.43 (d, J = 34.4 Hz, 0.34H), 3.77−3.76 (m, 3H),

7.60 (s, 0.65H), 7.48−7.40 (m, 6H), 7.24−7.19 (m, 2H), 5.87 (d, J =

16.5 Hz, 0.65H), 5.37 (d, J = 34.5 Hz, 0.35H), 2.39−2.38 (m, 3H).

.37 (s, 3H). ¹³C{ H} NMR (125 MHz, CDCl ): δ 167.9 (C−F,

C{ H} NMR (125 MHz, CDCl ): δ 169.3 (C−F, J

= 306.1

C−F

J_C₋_F= 305.8 Hz), 165.7, 163.1 (C−F, J

= 14.4 Hz), 160.3, 156.7,

Hz), 160.2, 140.9, 140.2, 137.0, 136.6, 135.0, 134.4, 131.99, 131.95,

C−F

56.4, 140.6, 139.9, 134.9, 134.1, 130.7, 130.0, 123.2 (C−F, J

130.8, 130.1, 122.7 (C−F, J

= 8.5 Hz), 121.7, 121.3, 105.4 (C−F,

C−F

2 19

C−F

.0 Hz), 122.2, 121.8, 114.2, 114.1, 106.2 (C−F, J

= 9.0 Hz),

= 18.5 Hz), 101.3 (C−F, J = 9.0 Hz), 21.34, 21.29.

C−F

02.0 (C−F, J

= 21.9 Hz), 55.5, 21.2. F NMR (470 MHz,

NMR (470 MHz, CDCl ): δ −73.18 (s, 0.65F), −77.73 (s, 0.35F).

C−F

CDCl ): δ −75.14 (s, 0.61F), −78.00 (s, 0.39F). GC-MS (EI 70 eV)

GC-MS (EI 70 eV) m/z (%): 367 (3), 365 (2), 286 (22), 207 (21),

m/z (%): 317 (10), 195 (29), 123 (100), 91 (12). HRMS (ESI) m/z:

195 (100). HRMS (ESI) m/z: [M + Na] Calcd for

C H FBrNOSNa 387.9777, found: 387.9778.

[

M + Na] Calcd for C H FNO SNa 340.0778, found: 340.0777.

mers: yellow oil obtained by column chromatography (petroleum

ether/ethyl acetate = 8:1), 20.2 mg, yield: 67%. H NMR (400 MHz,

16 13

-Fluoro-N-(m-tolyl)-3-(p-tolylthio)acrylamide (3r). Both iso-

N-(3-Chlorophenyl)-3-ﬂuoro-3-(p-tolylthio)acrylamide (3v). Both

isomers: white solid obtained by column chromatography (petroleum

ether/ethyl acetate = 8:1), 21.2 mg, yield: 66%; m.p.: 184.1−186.2

CDCl ): δ 7.92−7.90 (m, 1H), 7.54−7.38 (m, 3H), 7.34−7.33 (m,

°C. H NMR (400 MHz, CDCl ): δ 7.83−7.76 (m, 1H), 7.65 (s,

H), 7.27−7.22 (m, 3H), 6.98−6.96 (m, 1H), 5.96 (d, J = 16.8 Hz,

1H), 7.50−7.48 (m, 2H), 7.43−7.36 (m, 1H), 7.29−7.23 (m, 3H),

.55H), 5.48 (d, J = 34.0 Hz, 0.42H), 2.42 (s, 3H), 2.35 (s, 3H).

7.13−7.11(m, 1H), 5.90 (d, J = 16.4 Hz, 0.37H), 5.42 (d, J = 34.4 Hz,

C{ H} NMR (125 MHz, CDCl ): δ 168.3 (C−F, J

= 305.0

0.63H), 2.43−2.42 (m, 3H). C{ H} NMR (125 MHz, CDCl ): δ

C−F

Hz), 166.1, 163.4 (C−F, J

= 18.4 Hz), 160.3, 140.6, 139.9, 138.9,

166.6, 165.8 (C−F, J

= 302.3 Hz), 160.2, 140.8, 140.1, 139.1,

C−F

(

37.9, 137.4, 134.9, 134.2, 130.7, 130.0, 128.8, 128.7, 125.5, 125.1,

138.7, 134.9, 134.70, 134.67, 134.4, 130.8, 130.04, 129.95, 129.91,

23.7, 123.1 (C−F, J

= 8.6 Hz), 120.9, 120.6, 117.4, 117.0, 106.1

124.8, 124.3, 123.3, 122.7 (C−F, J

(C−F, J

= 8.4 Hz), 120.2, 118.1, 105.4

C−F

C−F, J

= 9.3 Hz), 102.0 (C−F, J

= 16.6 Hz), 24.42, 21.41,

= 16.9 Hz), 21.26, 21.25. F NMR (470 MHz, CDCl ):

C−F 3

C−F

1.3. ¹⁹F NMR (470 MHz, CDCl ): δ −74.69 (s, 0.47F), −77.81 (s,

δ −72.88 (s, 0.36F), −77.54 (s, 0.64F). GC-MS (EI 70 eV) m/z (%):

321 (11), 195 (100), 127 (66), 91 (27). HRMS (ESI) m/z: [M +

.53F). GC-MS (EI 70 eV) m/z (%): 301 (14), 207 (37), 195 (32),

78 (100), 91 (93). HRMS (ESI) m/z: [M + H] Calcd for

C H FNOS 302.1009, found: 302.1020.

Na] Calcd for C H FClNOSNa 344.0283, found: 344.0277.

16 13

N-(2-Bromophenyl)-3-ﬂuoro-3-(p-tolylthio)acrylamide (3w).

(

Z)-3-Fluoro-N-(2-methoxyphenyl)-3-(p-tolylthio)acrylamide (Z-

s). White solid obtained by column chromatography (petroleum

ether/ethyl acetate = 8:1), 14.6 mg, yield: 46%; m.p.: 105.4−107.2

Both isomers: yellow solid obtained by column chromatography

(petroleum ether/ethyl acetate = 20:1), 25.3 mg, yield: 69%; m.p.:

105.0−107.0 °C. H NMR (400 MHz, CDCl ): δ 8.47−8.45 (m,

C. H NMR (400 MHz, CDCl ): δ 8.50−8.48 (m, 1H), 7.92 (s,

1H), 8.43−8.41 (m, 0.66H), 7.79 (s, 0.35H), 7.59−7.56 (m, 1H),

7.52−7.50 (m, 2H), 7.38−7.24 (m, 3H), 7.04−6.99 (m, 1H), 5.98 (d,

J = 16.4 Hz, 0.38H), 5.47 (d, J = 34.4 Hz, 0.63H), 2.44−2.43 (m,

H), 7.48−7.46 (m, 2H), 7.21−7.19 (m, 2H), 7.07−7.03 (m, 1H),

.99−6.95 (m, 1H), 6.89−6.86 (m, 1H), 5.93 (d, J = 16.4 Hz, 1H),

.87 (s, 3H), 2.38 (s, 3H). C{ H} NMR (125 MHz, CDCl ): δ

3H). C{ H} NMR (125 MHz, CDCl ): δ 165.7 (C−F, J

C−F

68.1 (C−F, J

= 306.1 Hz), 162.9 (C−F, J

= 20.0 Hz), 147.8,

= 8.0 Hz), 121.2,

302.8 Hz), 160.6, 140.7, 140.1, 135.9, 135.8, 134.9, 134.3, 132.3,

C−F

39.9, 134.9, 130.0, 127.8, 123.7, 123.2 (C−F, J

130.8, 130.1, 128.4, 128.3, 125.2, 122.0, 113.3, 105.8, 101.8 (C−F,

C−F

19.9, 110.0, 102.6 (C−F, J

= 24.3 Hz), 55.7, 21.2. F NMR

= 26.5 Hz), 21.3, 18.4. F NMR (470 MHz, CDCl ): δ −72.49

C−F

(

470 MHz, CDCl ): δ −74.85. GC-MS (EI 70 eV) m/z (%): 317

(s, 0.39F), −76.94 (s, 0.61F). GC-MS (EI 70 eV) m/z (%): 367 (8),

[M + Na] Calcd for C H FBrNOSNa 387.9777, found: 387.9780.

17), 195 (47), 123 (100), 77 (32). HRMS (ESI) m/z: [M + H]

65 (7), 281 (31), 208 (20), 207 (100), 195 (99). HRMS (ESI) m/z:

Calcd for C H FNO S 318.0959, found: 318.0965.

16 13

(

E)-3-Fluoro-N-(2-methoxyphenyl)-3-(phenylthio)acrylamide (E-

N-(Benzo[d]thiazol-2-yl)-3-ﬂuoro-3-(p-tolylthio)acrylamide (3x).

Both isomers: yellow solid obtained by column chromatography

s). Yellow oil obtained by column chromatography (petroleum

ether/ethyl acetate = 8:1), 9.8 mg, yield: 31%. H NMR (400 MHz,

(

petroleum ether/ethyl acetate = 8:1), 17.5 mg, yield: 51%; m.p.:

CDCl ): δ 8.57−8.55 (m, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.52−7.50

190.0−193.0 °C. H NMR (400 MHz, DMSO-d ): δ 12.52 (s, 1H),

(

m, 2H), 7.31−7.27 (m, 2H), 7.11−7.07 (m, 1H), 7.01−6.98 (m,

.99 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.52−7.50 (m,

H), 7.46−7.43 (m, 1H), 7.34−7.28 (m, 3H), 6.28 (d, J = 16.8 Hz,

H), 6.93−6.91 (m, 1H), 5.51 (d, J = 34.0 Hz, 1H), 3.91 (s, 3H),

.44 (s, 3H). ¹³C{ H} NMR (125 MHz, CDCl ): δ 165.8 (C−F,

1H), 2.35 (s, 3H). C{ H} NMR (125 MHz, DMSO-d ): δ 169.3

^JC−F = 304.0 Hz), 159.9, 147.9, 140.4, 134.0, 130.7, 127.7, 123.9,

(C−F, J

= 305.8 Hz), 163.1 (C−F, J

= 21.9 Hz), 157.7,

C−F

23.8, 121.1, 120.0, 110.0, 107.0 (C−F, J

= 13.2 Hz), 55.8, 21.3.

C−F

148.6, 140.1, 134.9, 131.5, 130.2, 129.6, 126.1, 123.5, 121.6, 120.5,

F NMR (470 MHz, CDCl ): δ −78.30. GC-MS (EI 70 eV) m/z

99.8 (C−F, J

= 28.1 Hz), 20.8. F NMR (470 MHz, DMSO-d ):

−

(

%): 317 (23), 195 (37), 123 (100), 91 (12). HRMS (ESI) m/z: [M

δ −72.57. GC-MS (EI 70 eV) m/z (%): 344 (23), 195 (100), 123

H] Calcd for C H FNO S 318.0959, found: 318.0948.

N-(4-Chlorophenyl)-3-ﬂuoro-3-(p-tolylthio)acrylamide (3t). Both

isomers: yellow solid obtained by column chromatography (petro-

(54), 77 (32). HRMS (ESI) m/z: [M + Na] Calcd for

C H FN OS Na 367.0346, found: 367.0340.

N-Benzyl-3-ﬂuoro-3-(p-tolylthio)acrylamide (3y). Both isomers:

leum ether/ethyl acetate = 8:1), 25.0 mg, yield: 78%; m.p.: 128.1−

yellow solid obtained by column chromatography (petroleum ether/

31.5 °C. H NMR (400 MHz, CDCl ): δ 7.95 (s, 1H), 7.57−7.54

ethyl acetate = 8:1), 16.9 mg, yield: 56%; m.p.: 102.4−104.6 °C. H

(

m, 1H), 7.48−7.46 (m, 2H), 7.31−7.22 (m, 5H), 5.95 (d, J = 16.4

NMR (400 MHz, CDCl ): δ 7.48−7.45 (m, 2H), 7.38−7.30 (m, 5H),

Hz, 0.69H), 5.42 (d, J = 34.0 Hz, 0.32H), 2.44−2.42 (m, 3H).

7.26−7.21 (m, 2H), 6.40 (brs, 0.15H), 6.07 (s, 0.69H), 5.80 (d, J =

16.4 Hz, 0.75H), 5.42 (d, J = 34.8 Hz, 0.20H) 4.55 (d, J = 5.6 Hz,

C{ H} NMR (125 MHz, CDCl ): δ 169.0 (C−F, J

= 305.3

C−F

Hz), 163.5 (C−F, J

C−F

= 21.3 Hz), 140.8, 140.1, 136.5, 136.1 (C−F,

= 21.9 Hz), 135.0, 134.3, 130.8, 130.7, 130.0, 129.7, 129.0,

1.51H), 4.51 (d, J = 5.6 Hz, 0.48H), 2.41 (s, 3H). C{ H} NMR

C−F

(125 MHz, CDCl ): δ 167.1 (C−F, J

= 305.1 Hz), 164.7 (C−F,

C−F

28.9, 122.7, 121.2, 105.2, 101.5 (C−F, J

= 16.6 Hz), 21.27,

JC−F = 19.5 Hz), 162.1, 161.5, 140.4, 139.8, 138.1, 138.0, 134.7,

C−F

1.26. ¹⁹F NMR (470 MHz, CDCl ): δ −73.43 (s, 0.70F), −77.30 (s,

134.1, 130.6, 130.0, 128.7, 127.9, 127.7, 127.5, 123.3 (C−F, J

C−F

.30F). GC-MS (EI 70 eV) m/z (%): 321 (13), 195 (92), 127 (100),

7.9 Hz), 105.9, 101.8 (C−F, J

= 24.8 Hz), 100.0, 43.6, 21.2.

C−F

1 (27). HRMS (ESI) m/z: [M + Na] Calcd for C H FClNOSNa

44.0283, found: 344.0285.

NMR (470 MHz, CDCl ): δ −75.83 (s, 0.76F), −78.73 (s, 0.24F).

GC-MS (EI 70 eV) m/z (%): 301 (12), 195 (27), 178 (90), 91 (100),

597

J. Org. Chem. 2021, 86, 1591−1600

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c02436.

Article

1 (28). HRMS (ESI) m/z: [M + H]⁺Calcd for C H FNOS

MHz, DMSO-d ): δ 7.78−7.69 (m, 2H), 7.51−7.49 (m, 2H), 7.40−

02.1009, found: 302.1016.

-Fluoro-N-hexyl-3-(p-tolylthio)acrylamide (3z). Both isomers:

yellow oil obtained by column chromatography (petroleum ether/

7.38(m, 2H), 7.28−7.26 (m, 2H), 6.81 (d, J = 15.6 Hz, 1H), 2.33 (s,

3H). C{ H} NMR (125 MHz, DMSO-d ): δ 163.5 (C−F, J

C−F

305.2 Hz), 158.9 (C−F, J

= 18.8 Hz), 149.6, 141.3, 139.8, 134.1,

= 5.6 Hz), 119.4, 110.6, 97.4

= 35.6 Hz), 20.7. F NMR (470 MHz, DMSO-d ): δ

C−F

ethyl acetate = 30:1), 14.2 mg, yield: 48%. H NMR (400 MHz,

130.3, 125.3, 124.8, 122.5 (C−F, J

C−F

CDCl ): δ 7.47−7.44 (m, 2H), 7.26−7.20 (m, 2H), 6.12 (s, 0.14H),

(C−F, J

−

(

.78 (d, J = 16.8 Hz, 0.79H), 5.42 (d, J = 34.8 Hz, 0.21H), 3.39−3.29

−125.0. LRMS (EI 70 eV) m/z (%): 285 (100), 286 (20), 284 (15),

m, 2H), 2.41−2.40 (m, 3H), 1.61−1.50 (m, 2H), 1.41−1.32 (m,

265 (14). 252 (63), HRMS (ESI) m/z: [M + H] Calcd for

H), 0.94−0.90 (m, 3H). C{ H} NMR (125 MHz, CDCl ): δ 166.2

C H FNOS 286.0696, found: 286.0696.

16 13

(C−F, J

= 305.4 Hz), 164.7 (C−F, J

= 19.1 Hz), 162.2,

C−F

40.3, 139.7, 134.6, 133.9, 130.6, 129.9, 124.1, 123.6, 106.8, 106.7,

= 24.3 Hz), 39.7, 39.6, 31.5, 31.4, 29.6, 29.4, 26.6,

6.5, 22.52, 22.48, 21.3, 21.2, 13.95, 13.93. F NMR (470 MHz,

ASSOCIATED CONTENT

■

02.4 (C−F, J

C−F

sı

* Supporting Information

CDCl ): δ −74.08 (s, 0.48F), −76.41 (s, 0.52F). GC-MS (EI 70 eV)

The Supporting Information is available free of charge at

m/z (%): 295 (14), 294 (63), 134 (84), 293 (45), 183 (100). HRMS

(

ESI) m/z: [M + H]⁺Calcd for C H FNOS 296.1479, found:

Copies of H spectra for products 1a−1c, 1k, and 1n;

96.1484.

-Fluoro-N-(naphthalen-2-yl)-3-(p-tolylthio)acrylamide (3aa).

Both isomers: yellow solid obtained by column chromatography

petroleum ether/ethyl acetate = 8:1), 25.3 mg, yield: 75%; m.p.:

copies of H, F, and C NMR spectra for products 1d,

1f, 1h, 1j, 1l, and 1m; and products 3 and X-ray data for

compound 3a; supplementary crystallographic data

deposited at the Cambridge Crystallographic Data

Centre (CCDC) under the number CCDC-1970986

(

23.9−126.5 °C. H NMR (400 MHz, CDCl ): δ 8.37−8.23 (m,

H), 8.02−8.00 (m, 1H), 7.82−7.80 (m, 3H), 7.51−7.42 (m, 5H),

.28−7.23 (m, 2H), 5.99 (d, J = 16.8 Hz, 0.45H), 5.53 (d, J = 34.0

(3a ) and can be obtained free of charge via www.ccdc.

Hz, 0.55H), 2.42 (s, 3H). C{ H} NMR (125 MHz, CDCl ): δ 165.2

cam.ac.uk (PDF )

(

C−F, J

= 297.1 Hz), 160.43 (C−F, J

= 13.3 Hz), 160.38,

40.7, 140.0, 135.4, 134.99, 134.95, 134.3, 133.9, 133.8, 130.8, 130.7,

30.0, 128.8, 128.7, 127.72, 127.71, 127.54, 127.53, 126.52, 126.49,

= 8.5 Hz), 120.1, 117.1, 106.1

= 20.4 Hz), 101.9, 21.3. F NMR (470 MHz, CDCl ): δ

73.92 (s, 0.44F), −77.72 (s, 0.56F). GC-MS (EI 70 eV) m/z (%):

37 (13), 195 (100), 125 (84), 93 (56), 71 (32). HRMS (ESI) m/z:

M + Na] Calcd for C H FNOSNa 360.0829, found: 360.0831.

Z)-N-Ethyl-3-ﬂuoro-N-phenyl-3-(p-tolylthio)acrylamide (3ab).

Yellow oil obtained by column chromatography (petroleum ether/

ethyl acetate = 15:1), 7.6 mg, yield: 24%. H NMR (400 MHz,

C−F

Accession Codes

CCDC 1970986 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

25.1, 125.0, 123.6, 123.0 (C−F, J

C−F

(C−F, J

−

[

20 16

(

AUTHOR INFORMATION

CDCl ): δ 7.41−7.32 (m, 3H), 7.26 (s, 1H), 7.14−7.04 (m, 5H), 5.08

■

(

d, J = 24.4 Hz, 1H), 3.76 (q, J = 6.0 Hz, 2H), 2.32 (s, 3H), 1.11 (t, J

Corresponding Authors

5.6 Hz, 3H). ¹³C{ H} NMR (125 MHz, CDCl ): δ 170.7 (C−F,

Xing-Guo Zhang − College of Chemistry and Materials

Engineering, Wenzhou University, Wenzhou 325035, China;

Guangxi Key Laboratory of Calcium Carbonate Resources

Comprehensive Utilization, Hezhou University, Hezhou

542899, China; orcid.org/0000-0002-4539-7166;

Email: zxg@wzu.edu.cn

J_C₋_F= 306.4 Hz), 166.5, 142.0, 139.4, 133.2, 130.2, 129.4, 128.2,

(

27.6, 124.8, 104.4 (C−F, J

= 23.1 Hz), 21.2, 13.0. F NMR

470 MHz, DMSO-d ): δ −78.17. GC-MS (EI 70 eV) m/z (%): 315

7), 192 (82), 152 (22), 121 (100), 106 (34). HRMS (ESI) m/z: [M

C−F

H] Calcd for C H FNOS 316.1166, found: 316.1172.

18 19

(

E)-3-Fluoro-N-phenyl-3-(p-tolylsulﬁnyl)acrylamide (E-4). White

solid obtained by column chromatography (petroleum ether/ethyl

acetate = 3:1), 9.7 mg, yield: 16%; m.p.: 142.2−142.6 °C. H NMR

Hai-Yong Tu − College of Chemistry and Materials

Engineering, Wenzhou University, Wenzhou 325035, China;

orcid.org/0000-0002-6561-8579; Email: hytu@

wzu.edu.cn

(

400 MHz, DMSO-d ): δ 10.47 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H),

.60 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz,

H), 7.08 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 32.8 Hz, 1H), 2.41 (s, 3H).

C{ H} NMR (125 MHz, DMSO-d ): δ 165.4 (C−F, J

= 237.9

C−F

Authors

Hz), 158.2, 143.4, 138.4, 136.6, 130.5, 128.8, 125.7, 123.9, 119.3,

Xiao-Qin Shen − College of Chemistry and Materials

Engineering, Wenzhou University, Wenzhou 325035, China

Sui-Qian Wang − College of Chemistry and Materials

Engineering, Wenzhou University, Wenzhou 325035, China

Dongfeng Fan − Zhejiang Huafon Thermoplastic

Polyurethane Company Limited, Ruian 325200, China

04.7 (C−F, J

= 14.8 Hz), 21.0. F NMR (470 MHz, DMSO-

C−F

d ): δ −91.12. LRMS (EI 70 eV) m/z (%): 303 (7), 163 (37), 123

(

29), 93 (100), 91 (23). HRMS (ESI) m/z: [M + H] Calcd for

C H FNO S 304.0802, found: 304.0794.

(Z)-3-Fluoro-N-phenyl-3-(p-tolylsulﬁnyl)acrylamide (Z-4). White

solid obtained by column chromatography (petroleum ether/ethyl

acetate = 3:1), 35.1 mg, yield: 58%; m.p.: 184.0−185.8 °C. H NMR

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02436

(

400 MHz, DMSO-d ): δ 10.55 (s, 1H), 7.75 (d, J = 7.6 Hz, 2H),

.63 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz,

H), 7.13 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 15.2 Hz, 1H), 2.37 (s, 3H).

Notes

C{ H} NMR (125 MHz, DMSO-d ): δ 168.6 (C−F, J

= 326.6

C−F

The authors declare no competing ﬁnancial interest.

Hz), 160.3 (C−F, J

= 18.4 Hz), 141.9, 138.5, 138.2, 130.1, 128.9,

C−F

24.9, 124.2, 119.5, 110.1 (C−F, J

= 16.1 Hz), 20.9. F NMR

C−F

(470 MHz, DMSO-d ): δ −79.83. LRMS (EI 70 eV) m/z (%): 303

(9), 211 (100), 207 (73), 163 (94), 93 (91). HRMS (ESI) m/z: [M +

ACKNOWLEDGMENTS

■

We thank the Natural Science Foundation of Guangxi Province

No. 2018GXNSFDA281011) and Plan Project of Wenzhou

H] Calcd for C H FNO S 304.0802, found: 304.0794.

(

-(2-Fluoro-2-(p-tolylthio)vinyl)benzo[d]oxazole (5). White solid

obtained by column chromatography (petroleum ether/ethyl acetate

Municipal Science and Technology (No. ZG2019026) for

ﬁnancial support.

15:1), 35.9 mg, yield: 63%; m.p.: 76.7−78.7 °C. H NMR (400

598

J. Org. Chem. 2021, 86, 1591−1600

The Journal of Organic Chemistry

Convenient and Effective Method to Synthesize CF -Containing

Article

Oxindoles Bearing a Quaternary Carbon Center. Chem. - Eur. J. 2013,

REFERENCES

■

(

1) Fraus

to da Silva, J. R.; Williams, R. J. P. The Biological Chemistry

9, 14039−14042. (f) Zhang, Z.; Zhang, L.; Cao, Y.; Li, F.; Bai, G.;

of the Elements; Oxford University Press: NewYork, 2001.

Liu, G.; Yang, Y.; Mo, F. Mn-Mediated Electrochemical Trifluor-

omethylation/C(sp )−H Functionalization Cascade for the Synthesis

b) Chauhan, P.; Mahajan, S.; Enders, D. Organocatalytic Carbon −

2) For reviews see: (a) Kondo, T.; Mitsudo, T.-A. Metal-Catalyzed

Carbon −Sulfur Bond Formation. Chem. Rev. 2000 , 100 , 3205 −3220.

Sulfur Bond-Forming Reactions. Chem. Rev. 2014, 114, 8807 −8864.

c) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Recent

Advances in C −S Bond Formation via C −H Bond Functionalization

and Decarboxylation. Chem. Soc. Rev. 2015, 44, 291 −314 For selected

examples see:. (d) Sun, J. W.; Fu, G. C. Phosphine-Catalyzed

Formation of Carbon −Sulfur Bonds: Catalytic Asymmetric Synthesis

of γ -Thioesters. J. Am. Chem. Soc. 2010, 132, 4568−4569. (e) Tian,

X.; Cassani, C.; Liu, Y. K.; Moran, A.; Urakawa, A.; Galzerano, P.;

Arceo, E.; Melchiorre, P. Diastereodivergent Asymmetric Sulfa-

Michael Additions of α -Branched Enones using a Single Chiral

Organic Catalyst. J. Am. Chem. Soc. 2011, 133, 17934 −17941. (f) Xia,

Y.; Lin, L.; Chang, F.; Fu, X.; Liu, X.; Feng, X. Asymmetric Ring-

Opening of Cyclopropyl Ketones with Thiol, Alcohol, and Carboxylic

Acid Nucleophiles Catalyzed by a Chiral N, N ’-Dioxide-Scandium-

of Azaheterocycles. Org. Lett. 2019, 21, 762−766. (g) Ruan, Z.;

Huang, Z.; Xu, Z.; Mo, G.; Tian, X.; Yu, X.-Y.; Ackermann, L.

Catalyst-Free, Direct Electrochemical Tri- and Difluoroalkylation/

Cyclization: Access to Functionalized Oxindoles and Quinolinones.

Org. Lett. 2019 , 21 , 1237 −1240. (h) Shi, Y.; Xiao, H.; Xu, X.-H.;

Huang, Y. Transition Metal Free Decarboxylative Fluoroalkylation of

N -Acrylamides with 3,3,3-Trifluoro-2,2-dimethylpropanoic Acid

H.; Liu, J.-K. Synthesis of Difluoromethylated 2-Oxindoles and

(TFDMPA). Org. Biomol. Chem. 2018, 16, 8472−8476. (i) Sun, H.;

Jiang, Y.; Yang, Y.-S.; Li, Y.-Y.; Li, L.; Wang, W.-X.; Feng, T.; Li, Z.-

Quinoline-2,4-diones via Visible Light-Induced Tandem Radical

Cyclization of N -Arylacrylamides. Org. Biomol. Chem. 2019, 17,

5) (a) Hinterberger, S.; Hofer, O.; Greger, H. Synthesis of Amides

629−6638.

from Glycosmis Species: Methylthiopropenoic Acid, Methylsulfonyl-

propenoic Acid, Thiocarbamic Acid S -Methyl Ester, and Senecioic

Acid Amides. Tetrahedron 1998, 54, 487−496. (b) Hansen, B. K.;

Loveridge, C. J.; Thyssen, S.; Wørmer, G. J.; Nielsen, A. D.; Palmfeldt,

J.; Johannsen, M.; Poulsen, T. B. STEFs: Activated Vinylogous

Protein-Reactive Electrophiles. Angew. Chem., Int. Ed. 2019, 58,

g) Denmark, S. E.; Chi, H. M. Catalytic, Enantioselective,

III) Complex. Angew. Chem., Int. Ed. 2015 , 54 , 13748 −13752.

Intramolecular Carbosulfenylation of Olefins. Mechanistic Aspects:

A Remarkable Case of Negative Catalysis. J. Am. Chem. Soc. 2014,

36, 3655 −3663. (h) Denmark, S. E.; Hartmann, E.; Kornfilt, D. J. P.;

3533−3537. (c) Van Herck, N.; Maes, D.; Unal, K.; Guerre, M.;

Wang, H. Mechanistic, Crystallographic, and Computational Studies

on the Catalytic, Enantioselective Sulfenofunctionalization of Alkenes.

Nat. Chem. 2014, 6, 1056−1064. (i) Li, L.; Chen, Q.; Xu, H.-H.;

Zhang, X.-H.; Zhang, X.-G. DBU-Promoted Demethoxylative

Thioannulation of Alkynyl Oxime Ethers with Sulfur for the Synthesis

of Bisisothiazole-4-yl Disulfides. J. Org. Chem. 2020 , 85 , 10083 −

Winne, J. M.; Du Prez, F. E. Covalent Adaptable Networks with

Tunable Exchange Rates Based on Reversible Thiol −yne Cross-

Linking. Angew. Chem., Int. Ed. 2020, 59, 3609−3617.

(6) Ikegami, F.; Sekine, T.; Aburada, M.; Fujii, Y.; Komatsu, Y.;

Murakoshi, I. Synthesis of Entadamide A and Entadamide B Isolated

from Entada phaseoloides and Their Inhibitory Effects on 5-

Lipoxygenase. Chem. Pharm. Bull. 1989, 37, 1932−1933.

0090. (j) Wang, S.-Q.; Hu, B.-L.; Zhang, X.-G. Copper-Catalyzed

Thioannulation of Propynamides with Sodium Sulfide for the

(7) (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;

Synthesis of Isothiazol-3-ones. Adv. Synth. Catal. 2019, 361, 1459−

Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-

Containing Pharmaceuticals, Compounds Currently in Phase II −III

Clinical Trials of Major Pharmaceutical Companies: New Structural

Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518.

(

462.

3) (a) Chen, X.; Xiao, J.-W.; Cao, P.; Zhang, Y.; Cai, W.-J.; Song, J.-

Y.; Gao, W.-M.; Li, B. Brain-Derived Neurotrophic Factor Protects

Against Acrylamide-Induced Neuronal and Synaptic Injury via the

TrkB-MAPK-Erk1/2 Pathway. Neural Regener. Res. 2021, 16, 150−

(

b) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,

N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.

015 , 58 , 8315 −8359. (c) Meanwell, N. A. Synopsis of Some Recent

Tactical Application of Bioisosteres in Drug Design. J. Med. Chem.

011 , 54 , 2529 −2591. (d) Jeschke, P. The Unique Role of Fluorine in

57. (b) Bogdanova, L. R.; Valiullina, Y. A.; Faizullin, D. A.;

Kurbanov, R. K.; Ermakova, E. A. Spectroscopic, Zeta Potential and

Molecular Dynamics Studies of the Interaction of Antimicrobial

Peptides with Model Bacterial Membrane. Spectrochim. Acta, Part A

the Design of Active Ingredients for Modern Crop Protection.

ChemBioChem 2004 , 5 , 570 −589. (e) Leroux, F.; Jeschke, P.;

Schlosser, M. α -Fluorinated Ethers, Thioethers, and Amines:

Anomerically Biased Species. Chem. Rev. 2005, 105, 827−856.

020, 242, 118785. (c) Bologna, L. S.; Andrawes, F. F.; Barvenik, F.

W.; Lentz, R. D.; Sojka, R. E. Analysis of Residual Acrylamide in Field

Crops. J. Chromatogr. Sci. 1999, 37, 240−244. (d) Pogorelova, S. P.;

Bourenko, T.; Kharitonov, A. B.; Willner, I. Selective Sensing of

Triazine Herbicides in Imprinted Membranes Using Ion-sensitive

Field Effect Transistors and Microgravimetric Quartz Crystal

Microbalance Measurements. Analyst 2002, 127, 1484−1491.

e) Dos Santos, L. A.; Carrodeguas, R. G.; Boschi, A. O.; De

Arruda, A. C. Dual-setting Calcium Phosphate Cement Modified with

Ammonium Polyacrylate. Artif. Organs 2003, 27, 412−418.

4) For selected examples for the synthesis of oxindoles, see:

(f) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.;

Leroux, F. R. Synthesis of Diversely Fluorinated Pyrazoles as Novel

Active Agrochemical Ingredients. J. Fluorine Chem. 2013, 152, 2−11.

(g) Fedorov, P. P.; Luginina, A. A.; Kuznetsov, S. V.; Osiko, V. V.

Nanofluorides. J. Fluorine Chem. 2011 , 132 , 1012 −1039. (h) O'Hagan,

D. Understanding Organofluorine Chemistry. An Introduction to the

C −F Bond. Chem. Soc. Rev. 2008, 37, 308−319.

(8) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J.

Organic Fluorine Compounds: a Great Opportunity for Enhanced

Materials Properties. Chem. Soc. Rev. 2011 , 40 , 3496 −3508.

(9) (a) Bello, D.; O ’Hagan, D. Lewis Acid-Promoted Hydro-

fluorination of Alkynyl Sulfides to Generate α -Fluorovinyl Thioethers.

Beilstein J. Org. Chem. 2015, 11 , 1902 −1909. (b) Bello, D.;

Cormanich, R. A.; O ’Hagan, D. Fluorovinyl Thioethers as Putative

Steric and Electronic Thioester Enolate Mimetics: Chemoselective

HF Addition to Acetylene Thioethers. Aust. J. Chem. 2015, 68, 72−79.

(10) (a) Ichikawa, J.; Kobayashi, M.; Yokota, N.; Noda, Y.; Minami,

T. Reaction of 2,2-Difluorovinyl Ketones with Heteroatom

Nucleophiles: A General One-Pot Synthesis of α -Oxoketene Acetals.

Tetrahedron 1994 , 50 , 11637 −11646. (b) Timperley, C. M. Highly-

toxic Fluorobutenes and Their Mode of Toxicity: Reactions of

Perfluoroisobutene and Polyfluorinated Cyclobutenes with Thiols. J.

(

a) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R. Photoredox-

Catalyzed Tandem Radical Cyclization of N -Arylacrylamides: General

Methods to Construct Fluorinated 3,3-Disubstituted 2-Oxindoles

Using Fluoroalkylsulfonyl Chlorides. Org. Lett. 2014, 16, 4594 −4597.

b) Yang, F.; Klumphu, P.; Liang, Y.-M.; Lipshutz, B. H. Copper-

Catalyzed Trifluoromethylation of N -Arylacrylamides “On Water ” at

Room Temperature. Chem. Commun. 2014, 50, 936−938. (c) Li, L.;

Deng, M.; Zheng, S.-C.; Xiong, Y.-P.; Tan, B.; Liu, X.-Y. Metal-Free

Direct Intramolecular Carbotrifluoromethylation of Alkenes to

Functionalized Trifluoromethyl Azaheterocycles. Org. Lett. 2014, 16,

04 −507. (d) Mu, X.; Wu, T.; Wang, H.-y.; Guo, Y.-l.; Liu, G.

Palladium-Catalyzed Oxidative Aryltrifluoromethylation of Activated

Alkenes at Room Temperature. J. Am. Chem. Soc. 2012, 134 , 878 −

81. (e) Xu, P.; Xie, J.; Xue, Q.; Pan, C.; Cheng, Y.; Zhu, C. Visible-

Light-Induced Trifluoromethylation of N -Aryl Acrylamides: a

599

J. Org. Chem. 2021, 86, 1591−1600

The Journal of Organic Chemistry

M. J.; Greenall, J. A. Reactions of Arylthiols with Perfluoroisobutene,

Article

Fluorine Chem. 2004 , 125 , 685 −693. (c) Timperley, C. M.; Waters,

Perfluoropropene and Chlorotrifluoroethene. J. Fluorine Chem. 2006,

acetoxyphenyl Sulfides and Sulfones as Cyclooxygenase-2 Inhibitors.

Bioorg. Med. Chem. 2005 , 13 , 1715. (b) Evindar, G.; Batey, R. A.

Parallel Synthesis of a Library of Benzoxazoles and Benzothiazoles

Using Ligand-Accelerated Copper-Catalyzed Cyclizations of ortho -

Halobenzanilides. J. Org. Chem. 2006, 71, 1802−1808. (c) Ishikawa,

T.; Sonehara, T.; Minakawa, M.; Kawatsura, M. Copper-Catalyzed

Intermolecular Hydroamination of Internal Alkynes with Anilines and

Amines. Org. Lett. 2016, 18, 1422−1425. (d) Katagiri, T.; Handa, M.;

Asano, H.; Asanuma, T.; Mori, T.; Jukurogi, T.; Uneyama, K.

Preparations and Reactions of 2-Trifluoromethylketenimines. J.

Fluorine Chem. 2009 , 130 , 714 −717. (e) Xiao, J.-C.; Chen, Q.-Y.

The Chemistry of Tetrafluoroallene: Nucleophilic Addition Reactions

with Phenols and Amines. J. Fluorine Chem. 2003, 123, 189−195.

127 , 249 −256. (d) Huang, T.; Zhao, X.; Ji, X.; Wu, W.; Cao, S.

Synthesis of Fluorovinyl Pyrazolyl (Thio)ethers by the Reaction of

gem -Difluoroalkenes with Pyrazolin-5-ones (Thiones). J. Fluorine

Chem. 2016 , 182 , 61 −68. (e) Li, J.; Rao, W.; Wang, S.-Y.; Ji, S.-J.

Nickel-Catalyzed Defluorinative Reductive Cross-Coupling Reaction

of gem -Difluoroalkenes with Thiosulfonate or Selenium Sulfonate. J.

Org. Chem. 2019, 84, 11542−11552. (f) Cong, Z.-S.; Li, Y.-G.; Chen,

L.; Xing, F.; Du, G.-F.; Gu, C.-Z.; He, L. N -Heterocyclic Carbene-

Catalyzed Stereoselective Construction of Olefinic Carbon −Sulfur

Bonds via Cross-Coupling Reaction of gem -Difluoroalkenes and

Thiols. Org. Biomol. Chem. 2017 , 15 , 3863 −3868. (g) Wang, J.;

Huang, B.; Yang, C.; Xia, W. Visible-Light-Mediated Defluorinative

Cross-Coupling of gem -Difluoroalkenes with Thiols. Chem. Commun.

Y.-G.; Liu, C.; Xiao, J.-C.; Chen, Q.-Y.; Guo, Y. Review of Recent

019, 55, 11103−11106.

11) (a) Amii, H.; Uneyama, K. C −F Bond Activation in Organic

Synthesis. Chem. Rev. 2009, 109, 2119−2183. (b) Shen, Q.; Huang,

Advances in C −F Bond Activation of Aliphatic Fluorides. J. Fluorine

Chem. 2015 , 179 , 14 −22. (c) Ahrens, T.; Kohlmann, J.; Ahrens, M.;

Braun, T. Functionalization of Fluorinated Molecules by Transition-

Metal-Mediated C −F Bond Activation to Access Fluorinated Building

Blocks. Chem. Rev. 2015 , 115 , 931 −972. (d) Zhang, X.-X.; Cao, S.

Recent Advances in the Synthesis and C −F Functionalization of gem -

Difluoroalkenes. Tetrahedron Lett. 2017, 58, 375 −392. (e) Wu, Y.;

Zhang, B.; Zheng, Y.; Wang, Y.; Lei, X. Cs CO -Promoted

Defluorination and Functionalization of α -CF Carbonyl Compounds

in the Presence of N -, O -, and/or S -Nucleophiles. RSC Adv. 2018 , 8 ,

6019 −16023. (f) Li, X.-F.; Shi, L.-F.; Zhang, X.-G.; Zhang, X.-H. Pd-

Catalyzed C(sp )−H Aminocarbonylation Using the Langlois

Reagent as A Carbonyl Source. Org. Biomol. Chem. 2018, 16,

6438 −6442. (g) Li, X.-F.; Zhang, X.-G.; Chen, F.; Zhang, X.-H.

Copper-Catalyzed N -Formylation of Amines through Tandem

Amination/Hydrolysis/Decarboxylation Reaction of Ethyl Bromodi-

fluoroacetate. J. Org. Chem. 2018, 83, 12815−12821. (h) Wei, F.;

Shen, X.-Q.; Zhang, X.-H.; Zhang, X.-G. Copper-Catalyzed

Defluorinative Thioannulation of Trifluoropropynes for the Synthesis

of 1,2-Dithiole-3-thiones. Adv. Synth. Catal. 2018 , 360 , 3911 −3915.

(i) Feng, W.; Zhang, X.-G. Organophosphine-Free Copper-Catalyzed

Isothiocyanation of Amines with Sodium Bromodifluoroacetate and

Sulphur. Chem. Commun. 2019, 55, 1144−1147.

(12) Wang, F.; Zhang, T.; Tu, H.-Y.; Zhang, X.-G. Transition-Metal-

Free Conversion of Trifluoropropanamides into Cyanoformamides

through C −CF Bond Cleavage and Nitrogenation. J. Org. Chem.

13) (a) Zhou, M.; Zhang, J.; Zhang, X.-G.; Zhang, X.-G. Ni-

017, 82, 5475−5480.

Catalyzed Defluorination for the Synthesis of gem -Difluoro-1,3-dienes

and Their [4 + 2] Cycloaddition Reaction. Org. Lett. 2019 , 21 , 671 −

674. (b) He, S.-Y.; Zhang, X.-G. Palladium-Catalyzed Selective

Defluorinative Sulfenylation for the Synthesis of Fluorovinylth-

ioethers. Org. Chem. Front. 2020, 7, 3174−3178.

(14) (a) Banerjee, S.; Adak, L.; Ranu, B. C. Ionic Liquid/PPh

Promoted Cleavage of Diphenyl Disulfide and Diselenide: A Straight-

forward Metal-Free One-Pot Route to the Synthesis of Unsym-

metrical Sulfides and Selenides. Tetrahedron Lett. 2012, 53, 2149−

2152. (b) Overman, L. E.; Matzinger, D.; O'Connor, E. M.; Overman,

J. D. Nucleophilic Cleavage of the Sulfur-Sulfur Bond by Phosphorus

Nucleophiles. Kinetic Study of the Reduction of Aryl Disulfides with

Triphenylphosphine and Water. J. Am. Chem. Soc. 1974, 96, 6081−

15) Zhang, H.; Lin, J.-H.; Xiao, J.-C.; Gu, Y.-C. Rh-Catalyzed

089.

Allylic C-F Bond Activation: The Stereoselective Synthesis of

Trisubstituted Monofluoroalkenes and A Mechanism Study. Org.

Biomol. Chem. 2014, 12, 581−588.

(16) (a) Reddy, M. V. R.; Mallireddigari, M. R.; Pallela, V. R.;

Venkatapuram, P.; Boominathan, R.; Bell, S. C.; Reddy, E. P. Design,

Synthesis, and Biological Evaluation of (E )- and (Z )-Styryl-2-

600