Iodine-Catalyzed Odorless Synthesis of S-Thiocarbamates with

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Iodine-Catalyzed Odorless Synthesis of SThiocarbamates with Sulfonyl Chlorides as a Sulfur Source Wen-Hu Bao, Min He, Jing-Ting Wang, Xin Peng, Men Sung, Zilong Tang, Si Jiang, Zhong Cao, and Wei-Min He J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00178 • Publication Date (Web): 19 Apr 2019 Downloaded from http://pubs.acs.org on April 19, 2019

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The Journal of Organic Chemistry

Iodine-Catalyzed Odorless Synthesis of SThiocarbamates with Sulfonyl Chlorides as a Sulfur Source Wen-Hu Baoa, Min Hea,, Jing-Ting Wanga, Xin Penga, Men Sungb, Zilong Tangb, Xing-Xing Wangc, Zhong Caoc and Wei-Min Hea,* aDepartment

of Chemistry, Hunan University of Science and Engineering, Yongzhou 425100,

China bSchool

of Chemistry and Chemical Engineering, Hunan University of Science and Technology,

Xiangtan 411201, China cHunan

Provincial Key Laboratory of Materials Protection for Electric Power and Transportation,

Changsha University of Science and Technology, Changsha, 410114, China [email protected]

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT R1SO2Cl 1

+ R2NC

O

I2 (15 mol%) PPh3, NMP/H2O

R1S

C

NHR2

2

R , R : aryl, alkyl Excellent Group Tolerability 27 Examples, 64-90% Yields Short reaction time and Large-scale synthesis Odorless, Base-free, Mild and Simple Coditions Dual role of water: co-solvent & H and O source

A general and efficient protocol for the direct preparation of various S-thiocarbamates with readily available and inexpensive sulfonyl chlorides as an odorless sulfur source was developed. The employment of easily available reactants, excellent functional group tolerability, mild reaction conditions make this process very practical. ACS Paragon Plus Environment

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INTRODUCTION S-Thiocarbamates are valuable synthetic intermediates and have been found in many natural biologically active compounds as well as synthetic pharmaceuticals (Scheme 1).1 Over the past several years, a tremendous amount of effort and energy have been spent on the establishment of various protocols to construct such motifs. The classical methodologies for S-thiocarbamate synthesis involve the thiocarboxylation of amines, carbon monoxide and sulfur as well as subsequent alkylation,2 the two-step reaction of thiols with phosgene (or its derivatives) and primary amines (or the reverse),3 one-pot two-step synthesis from primary amides, oxalyl chloride and hazardous thiols,4 and the addition of hazardous thiols to isocyanates.5 However, all of the aforementioned synthetic protocols require the employment of highly hazardous chemical reactants (monoxide, phosgene, and isocyanides).6 Scheme 1 S-thiocarbamate motif in biologically active compounds O

O S

N

N

Cl

Me

Me

S

Me

O

Thiobencarb

Me

Me

Me Molinate

Orbencarb

O

O O H2N

O

S NH

N

S

N H

Me

NCp7 inhibitor

Me

S

N

Me Me

Eradicane

In order to circumvent these drawbacks, novel methods to S-thiocarbamates formation are therefore being developed. The alternative protocols include the NaI-catalyzed reaction of thiosulfonates (prepared from thiols7 or sulfonyl chlorides8) with isocyanides (Scheme 2a),9 the reaction of sulfoxides (prepared from thiosulfonates10) with isocyanides (Scheme 2b),11 and the visible-light/Rose Bengal12 or molecular iodine13-promoted multicomponent reaction of thiols, isocyanides and water (Scheme 2c). For its inherent importance, the development of an efficient and general route for the construction and enriching of the library of S-thiocarbamate compounds is an ACS Paragon Plus Environment

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urgent task for chemists and will be beneficial for organic synthesis, pharmaceuticals and agrochemicals.14 Sulfonyl chlorides are odorless, easily available, and have been demonstrated as useful reactants in the field of organic and medicinal chemistry as well as material science.15 In contrast to the impressive progress in the construction of organosulfur compounds with sulfonyl chlorides as sulfone reactants,8, 16 there is no example of direct preparation of S-thiocarbamates from abundant and easy-to-handle sulfonyl chlorides. We have reported the construction of several sulfurcontaining compounds.13a,

17

In this paper, we report a practical protocol for the iodine-catalyzed

synthesis of various S-thiocarbamates by directly using sulfonyl chlorides as a sulfur source under metal-free and mild reaction conditions (Scheme 2d). Scheme 2 Preparation of S-Thiocarbamates Previous work: secondary S-thiocarbamates synthesis from RSH O O O NaI (5 mol%) 1 (a) R S S R2 + R2NC + S i C isopropanol R1S NHR2 R2 O Pr O R3Br, BuLi, -78 oC O (b)

R3

S

t

Bu

2 + R NC

O

toluene, 100 oC R3S

C

Rose Bengal, EtOAc/H2O 3 W blue LED lamps (c) R4SH + R2NC or I2 (1 equiv.), DMSO/H2O

NHR2 O R4S

C

NHR2

This work: odorless, commercial, easy-to-handle sulfur sources O I2 (15 mol%) (d) R5SO2Cl + R2NC C PPh3, NMP/H2O R5S NHR2

RESULTS AND DISCUSSION As a model reaction, we chose tosyl chloride (1a) and tert-butyl isocyanide (2a) as standard substrates to screen optimal reaction conditions for the thiocarbamatation (Table 1). Treatment of a mixture of 1a, 2a (1.3 equiv.), triphenylphosphine (PPh3, 2 equiv.) with molecular iodine (15 mol%) in DMF/H2O as the catalyst at 40 ℃ under air atmosphere resulted in the formation of the desired Sthiocarbamate (3aa) in 76% yield (Table 1, entry 1). Screening of various iodine reagents, such as KI, NH4I, and TBAI, revealed that molecular iodine provides the best result for this transformation (entries ACS Paragon Plus Environment


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2 - 4). The test on the optimal amount of catalyst (entries 5 - 7) indicated that 15 mol% of molecular iodine was an appropriate amount. With 5 mol% I2 as the catalyst, a 41% yield of 3aa was obtained, and a large amount of 1a remained completely unconsumed (entry 6). Among all of the reductants analyzed (entries 8 - 10), we found that PPh3 was the most suitable for this transformation. The ideal amount of PPh3 was also investigated and these results suggested that 2 equiv. of PPh3 is still the best choice (entries 11 and 12). When we examined different reaction mediums (entries 13 - 23), the reaction in NMP/H2O (50/1) gave the best yield (entry 18). No benefit was obtained by increasing the amount of 2a, however, decreasing the loading of 2a from 1.3 equiv. to 1.1 equiv. led to a slightly lower yield of 3aa (entries 24 and 25). Elevating the reaction temperature to 60 ℃ did not improve the yield of 3aa (entry 26), whereas a slightly decrease in the product yield was observed when the temperature was decreased to room temperature (entry 27). Performed the reaction under oxygen or nitrogen atmosphere did not influence the outcome of the transformation (entries 28 and 29). As a control experiment, no reaction occurred in the absence of I2 or PPh3 (entries 30 and 31). No benefit was obtained by increasing the reaction time to 8 h at room temperature (entry 32). After the above screening, the optimal reaction conditions selected for the construction of S-thiocarbamates included sulfonyl chloride (1), isonitrile (2, 1.3 equiv.), I2 (15 mol%) and PPh3 (2 equiv.)18 in NMP/H2O (50/1) as the solvent at 40 ℃. Table 1. Optimization of the reaction conditionsa O S Cl + t BuNC O

Me 1a

2a

Me

O

Catalyst

t

Reductant Solvent/H2O, Temp.

S 3aa

N H

Bu

Entry

Catalyst (mol%)

Reductant (equiv.)

Solvent

Temp.

Yieldb

1

I2 (15)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

76%

2

KI (15)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

13%

3

NH4I (15)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

8%

4

TBAI (15)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

10%

5

I2 (10)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

72%

6

I2 (5)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

41%

7

I2 (20)

PPh3 (2)

DMF/H2O (50/1)

40 ℃

76%

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8

I2 (15)

HPPh2 (2)

DMF/H2O (50/1)

40 ℃

trace

9

I2 (15)

HPPh(OMe)2 (2)

DMF/H2O (50/1)

40 ℃

31%

10

I2 (15)

HPPh(OBn)2 (2)

DMF/H2O (50/1)

40 ℃

25%

11

I2 (15)

PPh3 (2.5)

DMF/H2O (50/1)

40 ℃

30%

12

I2 (15)

PPh3 (1.5)

DMF/H2O (50/1)

40 ℃

61%

13

I2 (15)

PPh3 (2)

THF/H2O (50/1)

40 ℃

49%

14

I2 (15)

PPh3 (2)

DMSO/H2O (50/1)

40 ℃

trace

15

I2 (15)

PPh3 (2)

DCE/H2O (50/1)

40 ℃

23%

16

I2 (15)

PPh3 (2)

1,4-dioxane/H2O (50/1)

40 ℃

64%

17

I2 (15)

PPh3 (2)

MeCN/H2O (50/1)

40 ℃

34%

18

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

40 ℃

87%

19

I2 (15)

PPh3 (2)

EtOAc/H2O (50/1)

40 ℃

41%

20

I2 (15)

PPh3 (2)

EtOH /H2O (50/1)

40 ℃

21%

21

I2 (15)

PPh3 (2)

EtOH

40 ℃

17%

22

I2 (15)

PPh3 (2)

NMP

40 ℃

trace

23

I2 (15)

PPh3 (2)

H2O

40 ℃

38%

24c

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

40 ℃

78%

25d

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

40 ℃

87%

26

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

60 ℃

86%

27

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

r.t.

82%

28e

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

40 ℃

87%

29f

I2 (15)

PPh3 (2)

NMP/H2O (50/1)

40 ℃

87%

30

-

PPh3 (2)

NMP/H2O (50/1)

40 ℃

trace

31

I2 (15)

-

NMP/H2O (50/1)

40 ℃

0

NMP/H2O (50/1) r.t. 82% 32g I2 (15) PPh3 (2) a Unless otherwise specified, the reactions were carried out in a sealed tube in the presence of 1a (0.2 mmol), 2a (1.3 equiv.), catalyst (15 mol%), reductant (2 equiv.), solvent (1.02 mL), 40℃, 4 h. NMP: N-methyl pyrrolidone b Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal reference. c 1.1 equiv. of 2a was used. d 1.5 equiv. of 2a was used. e Perform the reaction under oxygen atmosphere. f Perform the reaction under nitrogen atmosphere. g Reaction time: 8 h.

With the optimal reaction conditions in hand (Table 1, entry 18), the generality of this reaction was evaluated. As shown in Table 2, a series of benzenesulfonyl chlorides bearing electron-rich and electron-withdrawing substituents at the 4- or 3-position of phenyl ring reacted well with tert-butyl isocyanide to afford the expected products in good to excellent yields (3aa – 3ka). Sterically hindered benzenesulfonyl chlorides survived the optimal conditions to generate the desired S-



Page 6 of 22

thiocarbamates in good yields (3la – 3na). Moreover, a wide range of important functional groups are well tolerated, including alkyl (3aa, 3ja and 3la), phenyl (3ca), alkoxy (3da), free hydroxyl (3ea), halogen (3fa – 3ha, 3ka and 3ma), and trifluoromethyl (3ia and 3na) groups. Multiple substituted benzenesulfonyl chlorides and naphthalenesulfonyl chloride can also be employed as the reaction substrates, furnishing the corresponding products (3oa – 3pa) with good yields. Heterocycle units are present in a number of biologically active molecules and the direct synthesis of N/O–heteroaromatic thiocarbamates has previously not been reported. Pleasingly, the commercially available heteroaromatic sulfonyl chlorides could work well under the standard conditions to afford the corresponding S-thiocarbamates of good yields (3qa – 3sa). Aliphatic sulfonyl chlorides were also suitable reaction substrates for this present transformation (3ta and 3ub). Furthermore, the generality of isocyanides was tested. Besides tert-butyl isocyanide, primary isocyanides, electron-poor and aromatic isocyanides were also viable in this developed transformation, providing the expected products in moderate to good yields (3ab-3ac, 3ae-3af, 3bd and 3ve). For the cases of electron-poor isocyanides (1b, 1d and 1e), relatively lower yields were obtained; this could be mitigated by employing MeCN/H2O mixed solution as the solvent. Notably, a one-gram-scale synthesis of 3aa was achieved successfully, demonstrating the synthetic practicality of this developed reaction. Table 2.Reaction Scopea


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R1SO2Cl

R

I2 (15 mol%) PPh3 (2 equiv.) NMP/H2O (50/1), 40 oC

R2NC

+

R = H, 4-Me, 4-Ph, 4-OMe, 4-OH, 4-F, H S N 4-Cl, t Bu 4-Br, O 4-CF3, 3ba, 84% 3-Me, 3-Br, 2-Me, 2-Cl 2-CF3, 3,5-di-Me,

3ba, 84% 3aa, 85% 3ca, 78% 3da, 90% 3ea, 87% 3fa, 64% 3ga, 75% 3ha, 72% 3ia, 70% 3ja, 72% 3ka, 76% 3la, 83% 3ma, 69% 3na, 61% 3oa, 78%

H N

S O

Me

CO2Me

S

Ph

O

Me

t

Bu

O 3qa,84%

t

H N

S

Bu

t

Bu

O

O

N 3sa, 68%

H N

S

H N

S

Bu

3ra, 75% t

Bu

n-Bu

H N

S

O

Ts

O 3ubb

3ta, 54%

, 56%

H N

S

CO2Et

CO2Me

O

Me

3aeb, 71%

H N

S

3veb, 67% a

H N

S

NHR2

O

3bdb, 73% H N

S

t

3pa, 81%

O

3ac, 84%

EtO2C

O

H N

S

R1S H N

S

O C

O

H N

S

Ts

O

Me

3abb, 71%

Me

3af, 73%

All reactions were carried out in a vial in the presence of 1 (0.2 mmol), 2 (0.26 mmol), PPh3 (0.4 mmol), I2

(0.03 mmol), NMP/H2O (1.02 mL), 40 ℃ , air atmosphere, 4 h.

b

CH3CN instead of NMP, 100 ℃ , air

atmosphere, 8 h

To understand the reaction mechanism of this transformation, some control experiments were performed as shown in Scheme 3. When radical scavenger (TEMPO, BHT or 1,1-diphenylethylene) was added to the reaction mixture under the standard reaction conditions, the yield of 3aa was not significantly influenced (Scheme 3a). These results indicated that a free-radical mechanism or single electron transfer might not be involved in these processes. To fully rule out the possibility of the free radical

mechanism,

we

next

conducted

radical

clock

experiments.

Starting

with

(1-

cyclopropylvinyl)benzene (4a), and no ring-opening reaction was observed (Scheme 3b-c). Taken together, the radical intermediate is not likely to be involved in this current transformation. When H218O



was added under the standard conditions, the

18O-3aa

Page 8 of 22

was detected, suggesting the carbonyl oxygen

atom of S-thiocarbamate originated from water (Scheme 3d). Scheme 3. Control Experiments I2 (15 mol% ) Ph3P (2 equiv.) radical scavenger (2 equiv.) + t BuNC NMP/H2O (50/1), 40 °C, 4h

(a) TsCl 1a

radical scavenger TEMPO BHT 1,1-diphenylethylene

(b) TsCl + Ph 1a

(d) TsCl

Bu

3aa

3aa 79% 80% 81%

standard conditions

no reaction

standard conditions

no reaction

4a

(c) t BuNC + Ph 2a

t

O

Me

2a

H N

S

4a

I2 (15 mol% ) Ph 3P (2 equiv.) + t BuNC NMP/H218O (50/1), 40 °C, 4h

1a

H N

S

t

Bu

18O

Me 18

2a

O-3aa

A plausible reaction mechanism is proposed based upon the above-mentioned experimental results and literature reports13a,

18-19

(Scheme 4). Initially, the reduction of sulfonyl chlorides 1 with

triphenylphosphine produces the intermediate R1S-Cl (A),18b which reacts with molecular iodine to generates the highly active ArS-I (B). The addition of intermediate B to isocyanide 2 forms an intermediate C, which subsequently undergoes nucleophilic attack with water on the more electrondeficient carbon atom to deliver an intermediate E20. Finally, the intermediate E quickly tautomerized to generate the more stable product 3. HI further reacts with ICI to regenerate molecular iodine and HCl. Scheme 4. Plausible Reaction Mechanism O R1 S Cl O

1 ICl + HI

Ph3P Ph3P=O

R1 S Cl

R1 S

ICl A

H

2

I2

I

2

R NC

1

R

S

C

I

B

C

N

2

R

H2O

R1

S I

I2 + HCl


O C

D

H N R2

OH R1

HI

S

C

E

N R2

O NHR2

R1S

3

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CONCLUSIONS In conclusion, we have developed a facile and general protocol for the synthesis of Sthiocarbamates. By the employment of inexpensive, abundant and readily available sulfonyl chlorides as the sulfone reactants, a variety of S-thiocarbamates bearing a broad range of functionalgroups have been efficiently constructed under mild reaction conditions. In this protocol the water has a dual role: oxygen and hydrogen source as well as the co-solvent. This protocol is free of foul, hazardous and unstable thiols, making it suitable for the large-scale synthesis of various bioactive complex S-thiocarbamate and derivatives. These characteristics make our process potentially attractive both in academia and industry.

EXPERIMENTAL SECTION General Information Commercially available reagents were purchased from commercial suppliers and used without further purification. Reactions were monitored by thin layer chromatography (TLC) using silicycle precoated silica gel plates. Flash column chromatography was performed over silica gel (200-300 mesh). 1H

NMR and

13C{1H}

NMR spectra were recorded on 400 MHz NMR or 500 MHz NMR plus

spectrometer. Chemical shifts (δ) are expressed in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). Chemical shifts are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1 H} NMR) as an internal standard. High resolution mass spectra were obtained using GCT-TOF instrument with ESI source. General Procedure for the Synthesis of Products 3 In a pressure tube (or round-bottomed flask) was consecutively placed sulfuryl chloride 1 (0.2 mmol), isocyanide 2 (0.26 mmol), PPh3 (0.4 mmol, 104.8 mg), I2 (0.03 mmol, 7.6 mg) and NMP/H2O (50:1, 1.02 mL), then the mixtures were heated at 40 ℃ by oil bath under air atmosphere. The progress of the reaction was monitored by TLC. The reaction typically took 4



Page 10 of 22

h. Upon completion, the reaction was cooled to room temperature, then water (20 mL) was added to the reaction mixture, it was extracted with CH2Cl2 (5 mL x 3) and the organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with petroleum/ethyl acetate (20:1) to obtain secondary S-thiocarbamates 3. Procedure of Gram-Scale Synthesis In a round-bottomed flask (50mL) was consecutively placed tosyl chloride (6 mmol, 1143.9 mg), tert-butylisonitrile (7.8 mmol, 647.4 mg), PPh3 (12 mmol, 3147 mg), I2 (0.9 mmol, 228.6 mg) and NMP/H2O (50:1, 20.4 mL), then the mixtures were heated at 40 ℃ by oil bath under air atmosphere. The progress of the reaction was monitored by TLC. Upon completion, the reaction was cooled to room temperature, then saturated Na2S2O3 solution (100 mL) was added to the reaction mixture, it was extracted with CH2Cl2 (10 mL x 3) and the organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain S-(p-tolyl) tertbutylthiocarbamate in 80% yield (1.07 g). S-(p-tolyl)tert-butylthiocarbamate (3aa). White solid (36.5 mg, yield of 85%, purity ≥ 95% by 1H NMR analysis); m.p.: 116-117 °C (lit. 116-117 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 38.1 mg 1a, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.18 (s, 1H), 2.36 (s, 3H), 1.31 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 139.7, 135.4, 130.1, 125.6, 53.4, 28.8, 21.3. The spectral data are in accordance with the literature.11 S-phenyl tert-butylthiocarbamate (3ba). White solid (35.1 mg, yield of 84%, purity ≥ 95% by 1H NMR analysis); m.p.: 114-115 °C (lit. 114-115 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 35.3 mg 1b, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 6.4, 3.2 Hz, 2H), 7.45 –


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7.36 (m, 3H), 5.22 (s, 1H), 1.32 (s, 9H);

13C

NMR (100 MHz, CDCl3) δ 164.0, 135.4, 129.3, 129.2,

129.1, 53.5, 28.9. The spectral data are in accordance with the literature.11 S-([1,1'-biphenyl]-4-yl)tert-butylthiocarbamate (3ca). White solid (44.5mg, yield of 78%, purity ≥ 95% by 1H NMR analysis); m.p.: 132-133 °C (lit. 131-132 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 50.5 mg 1c, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.57 (m, 6H), 7.42 (m, 3H), 5.28 (s, 1H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9, 142.3, 140.2, 135.7, 128.9, 128.0, 127.9, 127.8, 127.2, 53.6, 28.9. The spectral data are in accordance with the literature.11 S-(4-methoxyphenyl)tert-butylthiocarbamate (3da). Yellow solid (43.1 mg, yield of 90%, purity ≥ 95% by 1H NMR analysis); m.p.: 84-85 °C (lit. 83-84 °C); Rf = 0.3 in Hexane/EtOAc (10:1); 41.3 mg 1d, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 5.16 (s, 1H), 3.82 (s, 3H), 1.31 (s, 9H);

13C{1H}

NMR (125 MHz, CDCl3) δ 164.5,

160.2, 136.7, 119.3, 114.4, 54.9, 52.9, 28.4. S-(4-hydroxyphenyl)tert-butylthiocarbamate (3ea). White solid (39.2 mg, yield of 87%, purity ≥ 95% by 1H NMR analysis); m.p.: 142-143 °C (lit. 142-143 °C); Rf = 0.2 in Hexane/EtOAc (10:1); 38.5 mg 1e, 1.02 mL NMP/H2O (50/1), 40 °C, 3 h; 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 2H), 6.93 (s, 1H), 6.66 (d, J = 8.5 Hz, 2H), 5.35 (s, 1H), 1.35 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.5, 157.45, 136.95, 117.4, 116.3, 53.2, 28.4. The spectral data are in accordance with the literature.11 S-(4-fluorophenyl)tert-butylthiocarbamate (3fa). White solid (31.6 mg, yield of 64%, purity ≥ 95% by 1H NMR analysis); m.p.: 97-98 °C (lit. 98-99 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 38.9 mg 1f, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.48 (m, 2H), 7.09 (t, J = 8.5 Hz, 2H), 5.19 (s, 1H), 1.34 (s, 9H);

13C{1H}

NMR (125 MHz, CDCl3) δ 163.9, 162.3 (d, J = 130

Hz), 137.1 (d, J = 8.5 Hz), 123.7, 115.8 (d, J = 10.0 Hz), 53.2, 28.34. The spectral data are in accordance with the literature.11 S-(4-chlorophenyl)tert-butylthiocarbamate (3ga). White solid (36.4 mg, yield of 75%, purity ≥ 95% by 1H NMR analysis); m.p.: 145-146 °C (lit. 145-146 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 42.2 mg ACS Paragon Plus Environment


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1g, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 5.21 (s, 1H), 1.35 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.7, 136.1, 135.2, 128.9, 126.9, 53.3, 28.4. The spectral data are in accordance with the literature.9 S-(4-bromophenyl)tert-butylthiocarbamate (3ha). White solid (41.4 mg, yield of 72%, purity ≥ 95% by 1H NMR analysis); m.p.: 152-153 °C (lit. 154-155 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 51.1 mg 1h, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 5.23 (s, 1H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 136.7, 132.3, 128.1, 123.9, 53.7, 28.8. The spectral data are in accordance with the literature.11 S-(4-(trifluoromethyl)phenyl)tert-butylthiocarbamate (3ia). White solid (38.8 mg, yield of 70%, purity ≥ 95% by 1H NMR analysis); m.p.: 115-116 °C (lit. 114-115 °C); Rf = 0.25 in Hexane/EtOAc (20:1); 48.9 mg 1i, 1.02 mL NMP/H2O (50/1), 40 °C, 5 h; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 4H), 5.27 (s, 1H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 135.1, 133.7, 131.1 (q, J = 32.4 Hz), 125.8 (q, J = 3.7 Hz), 124.0 (q, J = 272.4 Hz), 54.0, 28.9; 19F NMR (376 MHz, CDCl3) δ -62.85. The spectral data are in accordance with the literature.11 S-(m-tolyl)tert-butylthiocarbamate (3ja). Yellow solid (35.8 mg, yield of 72 %, purity ≥ 95% by 1H NMR analysis); m.p.: 109-110 °C (lit. 111-112 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 38.1 mg 1j, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 11.6 Hz, 2H), 7.25 – 7.21 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H), 5.17 (s, 1H), 2.32 (s, 3H), 1.28 (s, 9H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 164.3, 139.1, 135.9, 132.4, 130.2, 129.1, 128.8, 53.4, 28.9, 21.3. The spectral data are in accordance with the literature.13b S-(3-bromophenyl)tert-butylthiocarbamate (3ka). Yellow solid (43.6 mg, yield of 76%, purity ≥ 95% by 1H NMR analysis); m.p.: 141-142 °C (lit. 140-141 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 51.1 mg 1k, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (500 MHz, CDCl3) δ 7.68 (t, J = 1.5 Hz, 1H), 7.51 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.47 – 7.44 (m, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.21 (s, 1H), 1.35 (s, 9H);


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13C{1H}


NMR (125 MHz, CDCl3) δ 162.3, 137.2, 133.4, 131.7, 130.5, 129.9, 122.1, 53.3, 28.4. The

spectral data are in accordance with the literature.13b S-(o-tolyl)tert-butylthiocarbamate (3la). White solid (37.1 mg, yield of 83%, purity ≥ 95% by 1H NMR analysis); m.p.: 107-108 °C; Rf = 0.3 in Hexane/EtOAc (20:1); 38.1 mg 1l, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.5 Hz, 1H), 7.32 (dd, J = 5.0, 2.0 Hz, 2H), 7.23 (dd, J = 7.5, 3.0 Hz, 1H), 5.17 (s, 1H), 2.45 (s, 3H), 1.31 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 163.4, 142.2, 136.4, 130.4, 129.7, 128.2, 126.3, 52.9, 28.3, 20.6. The spectral data are in accordance with the literature12. S-(2-chlorophenyl)tert-butylthiocarbamate (3ma). White solid (33.4 mg, yield of 69%, purity ≥ 95% by 1H NMR analysis); m.p.: 133-134 °C; Rf = 0.3 in Hexane/EtOAc (20:1); 42.2 mg 1m, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.33 – 7.16 (m, 2H), 5.22 (s, 1H), 1.28 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3) δ 162.1,

139.1, 137.8, 130.8, 130.2, 128.6, 127.3, 53.7, 28.8. The spectral data are in accordance with the literature.12 S-(2-(trifluoromethyl)phenyl)tert-butylthiocarbamate (3na). Yellow solid (33.8 mg, yield of 61%, purity ≥ 95% by 1H NMR analysis); m.p.: 111-112 °C; Rf = 0.25 in Hexane/EtOAc (20:1); 48.9 mg 1n, 1.02 mL NMP/H2O (50/1), 40 °C, 5 h; 1H NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 11.0, 7.8 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 5.26 (s, 1H), 1.34 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9, 139.4, 133.0 (q, J = 30.5 Hz), 131.7, 129.1, 126.4, 125.7 (q, J = 5.5 Hz), 122.8 (q, J = 272.5 Hz), 53.3, 28.2. The spectral data are in accordance with the literature.12 S-(3,5-dimethylphenyl)tert-butylthiocarbamate (3oa). White solid (36.8 mg, yield of 78%, purity ≥ 95% by 1H NMR analysis); m.p.: 109-110 °C; Rf = 0.3 in Hexane/EtOAc (20:1); 40.9 mg 1o, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 2H), 7.02 (s, 1H), 5.23 (s, 1H), 2.32 (s, 6H), 1.32 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 138.9, 133.1, 131.3, 128.4, 53.4, 28.8, 21.2; Elemental analysis calcd for C13H19NOS: C, 65.78; H, 8.07; N, 5.90; O, 6.74; S, 13.51,



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Found: C, 65.94; H, 8.10; N, 5.94; O, 6.93; S, 13.63 ; HRMS (ESI) calcd for C13H20NOS [M + H]+: 238.1260, found: 238.1262. S-(naphthalen-2-yl)tert-butylthiocarbamate (3pa). Yellow solid (41.8 mg, yield of 81%, purity ≥ 95% by 1H NMR analysis); m.p.: 89-90 °C; Rf = 0.25 in Hexane/EtOAc (20:1); 45.3 mg 1p, 1.02 mL NMP/H2O (50/1), 40 °C, 6 h; 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.88 – 7.82 (m, 3H), 7.58 (dd, J= 8.4, 1.6Hz, 1H), 7.54 – 7.50 (m, 2H), 5.25 (s, 1H), 1.34 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 163.6, 134.7, 133.1, 132.8, 131.3, 128.4, 127.5, 127.3, 126.7, 126.1, 125.8, 53.1, 28.4. The spectral data are in accordance with the literature.12 S-(2,3-dihydrobenzofuran-5-yl)tert-butylthiocarbamate (3qa). White solid (42.2 mg, yield of 84%, purity ≥ 95% by 1H NMR analysis); m.p.: 101-102 °C; Rf = 0.3 in Hexane/EtOAc (10:1); 43.7 mg 1q, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 4.53 (t, J = 8.8 Hz, 2H), 3.16 (t, J = 8.8 Hz, 2H), 1.25 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3) δ 165.3, 161.5, 136.2, 132.6, 128.5, 119.2, 110.2, 71.8, 53.3,

29.4, 28.8; Elemental analysis calcd for C13H17NO2S: C, 62.12; H, 6.82; N, 5.57; O, 12.73; S, 12.76, Found: C, 62.20; H, 6.89; N, 5.64; O, 12.84; S, 12.82 ; HRMS (ESI) calcd for C13H18NO2S [M + H]+: 252.1053, found: 252.1054. S- (thiophen-2-yl)tert-butylthiocarbamate (3ra). White solid (32.3 mg, yield of 75%, purity ≥ 95% by 1H

NMR analysis); m.p.: 106-107 °C; Rf = 0.3 in Hexane/EtOAc (5:1); 36.5 mg 1r, 1.02 mL NMP/H2O

(50/1), 40 °C, 5 h; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 5.2, 1.2 Hz, 1H), 7.19 (dd, J = 3.2, 1.2 Hz, 1H), 7.02 (dd, J = 5.2, 3.6 Hz, 1H), 5.22 (s, 1H), 1.24 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.7, 137.1, 132.6, 128.1, 127.2, 53.6, 28.7. The spectral data are in accordance with the literature.12 S-(pyridin-4-yl)tert-butylthiocarbamate (3sa). White solid (28.5 mg, yield of 68%, purity ≥ 95% by 1H

NMR analysis); m.p.: 97-98 °C; Rf = 0.2 in Hexane/EtOAc (3:1); 35.5 mg 1s, 1.02 mL NMP/H2O

(50/1), 40 °C, 6 h; 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 1.6 Hz, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 (dt, J = 8.0, 2.0 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5.46 (s, 1H), 1.35 (s, 9H); 13C{1H}


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NMR (100 MHz, CDCl3) δ 162.1, 154.6, 149.7, 142.8, 126.6, 123.8, 53.9, 28.8; Elemental analysis calcd for C10H14N2OS: C, 57.12; H, 6.71; N, 13.32; O, 7.61; S, 15.25, Found: C, 57.23; H, 6.81; N, 13.41; O, 7.69; S, 15.29; HRMS (ESI) calcd for C10H15N2OS [M + H]+: 211.0900, found: 211.0900. S-benzyl tert-butylthiocarbamate (3ta). White solid (24.1mg, yield of 54%, purity ≥ 95% by 1H NMR analysis); m.p.: 75-76 °C (lit. 74-75 °C); Rf = 0.3 in Hexane/EtOAc (20:1); 38.1 mg 1t, 1.02 mL NMP/H2O (50/1), 40 °C, 6 h; 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 5H), 5.12 (s, 1H), 4.03 (s, 2H), 1.27 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3) δ 164.8, 138.6, 128.8, 128.6, 127.1, 53.4, 34.3, 29.0.

The spectral data are in accordance with the literature.9 S-butyl (tosylmethyl)thiocarbamate (3ub). White solid (33.6mg, yield of 56%, purity ≥ 95% by 1H NMR analysis); m.p.: 88-89 °C; Rf = 0.3 in Hexane/EtOAc (3:1); 31.3 mg 1u, 1.02 mL CH3CN /H2O (50/1), 100 °C, 8 h; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.47 (s, 1H), 4.66 (d, J = 6.7 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.45 – 1.36 (m, 2H), 1.29 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 145.4, 133.7, 129.9, 129.0, 61.4, 32.2, 29.7, 21.7, 21.6, 13.6. The spectral data are in accordance with the literature.13a S-(p-tolyl) cyclohexylthiocarbamate (3ac). White solid (41.8mg, yield of 84%, purity ≥ 95% by 1H NMR analysis); m.p.: 114-115 °C; Rf = 0.3 in Hexane/EtOAc (20:1); 38.1 mg 1a, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.20 (s, 1H), 3.73 (s, 1H), 2.38 (s, 3H), 1.87 (d, J = 9.2 Hz, 2H), 1.58 (m, 3H), 1.34 – 1.27 (m, 2H), 1.11 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.4, 139.9, 135.4, 130.3, 125.4, 50.4, 32.8 25.4, 24.6, 21.3. The spectral data are in accordance with the literature.12 methyl ((p-tolylthio)carbonyl)glycinate (3ae). White solid (33.8mg, yield of 71%, purity ≥ 95% by 1H NMR analysis); m.p.: 120-121 °C; Rf = 0.3 in Hexane/EtOAc (3:1); 35.3 mg 1b, 1.02 mL CH3CN /H2O (50/1), 100 °C, 8 h; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.88 (s, 1H), 4.03 (d, J = 5.2 Hz, 2H), 3.74 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ



Page 16 of 22

169.8, 167.4, 140.4, 135.59 , 130.5 , 124.4, 52.5, 42.5, 21.4. The spectral data are in accordance with the literature.12 ethyl ((phenylthio)carbonyl)glycinate (3bd). White solid (34.9 mg, yield of 73%, purity ≥ 95% by 1H NMR analysis); m.p.: 118-119 °C; Rf = 0.3 in Hexane/EtOAc (3:1); 38.1 mg 1a, 1.02 mL CH3CN/H2O (50/1), 100 °C, 8 h; 1H NMR (500 MHz, CDCl3) δ 7.63 – 7.52 (m, 2H), 7.43 (d, J = 5.5 Hz, 3H), 5.98 (s, 1H), 4.19 (q, J = 7.0 Hz, 2H), 4.02 (d, J = 5.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 168.8, 166.4, 135.1, 129.4, 129.1, 127.5, 61.3, 42.2, 13.6. The spectral data are in accordance with the literature.12 ethyl 4-(((2-methoxy-2-oxoethyl)carbamoyl)thio)benzoate (3ve). Yellow solid (39.6mg, yield of 67%, purity ≥ 95% by 1H NMR analysis); m.p.: 122-123 °C (lit. 120-121 °C); Rf = 0.2 in Hexane/EtOAc (3:1); 49.7 mg 1v, 1.02 mL CH3CN /H2O (50/1), 100 °C, 8 h; 1H NMR (400 MHz, CDCl3) δ 8.13 – 7.98 (m, 2H), 7.68 – 7.57 (m, 2H), 6.04 (t, J = 5.2 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.07 (d, J = 5.2 Hz, 2H), 3.76 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 165.8, 165.4, 134.7, 133.5, 131.3, 130.2, 61.3, 52.62 , 42.6, 14.3. The spectral data are in accordance with the literature.11 S-(p-tolyl) (tosylmethyl)thiocarbamate (3ab). White solid (47.6mg, yield of 71%, purity ≥ 95% by 1H NMR analysis); m.p.: 105-106 °C; Rf = 0.2 in Hexane/EtOAc (3:1); 35.3 mg 1b, 1.02 mL CH3CN /H2O (50/1), 100 °C, 8 h; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.51 (t, J = 6.7 Hz, 1H), 4.53 (d, J = 6.8 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 167.2, 145.6, 140.6, 135.4, 133.6, 130.4,

130.1, 129.1, 123.5, 61.4, 21.8, 21.4. The spectral data are in accordance with the literature.13a S-(p-tolyl) p-tolylthiocarbamate (3af). White solid (33.4 mg, yield of 73%, purity ≥ 95% by 1H NMR analysis); m.p.: 87-88 °C (lit. 89-90 °C); Rf = 0.2 in Hexane/EtOAc (20:1); 35.3 mg 1b, 1.02 mL NMP/H2O (50/1), 40 °C, 4 h; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 8.4, 2.4 Hz, 4H), 7.07 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 2.31 (s, 3H), 2.22 (s, 3H); 13C{1H} NMR (100 MHz,


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CDCl3) δ 164.8, 140.4, 135.7, 135.4, 134.3, 130.4, 129.5, 124.7, 119.7, 21.4, 20.8. The spectral data are in accordance with the literature.11 ACKNOWLEDGMENT We are grateful for financial support from the Hunan Provincial Natural Science Foundation of China (No. 2019JJ20008). Supporting Information: 1H

and

13C

NMR spectra of compounds 3. This material is available free of charge via the Internet at

http://pubs.acs.org. REFERENCES 1. (a) Chen, Y. S.; Schuphan, I.; Casida, J. E. S-Chloroallyl thiocarbamate herbicides: mouse hepatic microsomal oxygenase and rat metabolism of cis- and trans-[14C:O]diallate. J. Agric. Food. Chem. 1979, 27, 709-712; (b) Lindgren, B.; Lindgren, G.; Artursson, E.; Puu, G.; Fredriksson, J.; Andersson, M. Acetylcholinesterase Inhibition by Sulphur and Selenium Heterosubstituted Isomers of N, NDiethylcarbamyl Choline and Carbaryl. J. Enzym Inhib. 1985, 1, 1-11; (c) Bowden, K.; Chana, R. S. Structure–activity relations. Part 6. The alkaline hydrolysis of 3-methyl-5-methylidene- and 3,5dimethylthiazolidine-2,4-diones. The addition of thiols to 3-methyl-5-methylidenethiazolidine-2,4dione. J. Chem. Soc., Perkin Trans. 2 1990, 2163-2166; (d) Mizuno, T.; Nishiguchi, I.; Okushi, T.; Hirashima, T. Facile synthesis of S-alkyl thiocarbamates through reaction of carbamoyl lithium with elemental sulfur. Tetrahedron Lett. 1991, 32, 6867-6868; (e) Erian, A. W.; Sherif, S. M. The chemistry of thiocyanic esters. Tetrahedron 1999, 55, 7957-8024. 2. (a) Mizuno, T.; Nishiguchi, I.; Sonoda, N. Novel synthesis of S-alkyl thiocarbamates from amines, carbon monoxide, elemental sulfur, and alkyl halides in the presence of a selenium catalyst. Tetrahedron 1994, 50, 5669-5680; (b) Mizuno, T.; Iwai, T.; Ito, T. Practical synthesis of S-alkyl thiocarbamate herbicides by carbonylation of amines with carbon monoxide and sulfur. Tetrahedron ACS Paragon Plus Environment


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