CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0006-0016
DOI: 10.1055/s-0036-1591891
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Copyright with the author

Thiocyanation of Pyrazoles Using KSCN/K2S2O8 Combination

T. Songsichan
,
P. Katrun
,
O. Khaikate
,
D. Soorukram
,
M. Pohmakotr
,
V. Reutrakul
,
We thank the Thailand Research Fund (BRG5850012 and IRN58W0005), the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Postgraduate Education Research Development Office, Office of the Higher Education Commission, Ministry of Education, Mahidol University under the National Research Universities Initiative, PICS6663 ISMA (France/Thailand), and the Franco–Thai Cooperation Program in Higher Education and Research (PHC Siam 2017) for financial support.
Further Information

Publication History

Received: 17 October 2017

Accepted after revision: 16 December 2017

Publication Date:
23 January 2018 (online)

 

Abstract

A convenient and practical thiocyanation of pyrazoles is reported employing a combination of KSCN and K2S2O8 in dimethyl sulfoxide (DMSO). The salient features of the present reaction include environmentally benign reagents and solvents, and simple operation. The reaction shows wide functional group tolerance and gives moderate to excellent yields.


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Sulfur-containing organic molecules are important structural motifs in organic synthesis, organic materials, agrochemicals, nanotechnology and pharmaceutically important compounds in which the unique properties stem from the enhanced physical and chemical features of the sulfur atom.[1] Therefore, there are continuing efforts in the development of convenient methods for the introduction of sulfur moieties into organic molecules and materials as well as pharmaceuticals. Among various sulfur-containing substances, thiocyanate derivatives, particularly aryl- and heteroaryl thiocyanates, are an important class of compounds exhibiting pharmacological potential[2] and serving as versatile synthetic precursors for the synthesis of various organosulfur derivatives such as thiols,[3] thioethers,[4] thiocarbamates,[5] thioesters,[6] disulfides,[7] sulfonic acids,[6] sulfonyl chlorides,[8] and sulfonyl cyanides.[9] A number of synthetic routes are available for the synthesis of aryl- and heteroaryl thiocyanates including coupling of diazonium salts with metal thiocyanates under Sandmeyer type conditions,[10] cyanation of organosulfur and organometallic compounds,[11] metal-catalyzed coupling reaction of arylboronic acids with trimethylsilylisothiocyanate (TMSNCS) or aryl halides with thiocyanate salts[12] and the direct thiocyanation of C–H bonds with thiocyanates.[13] Pyrazoles and their derivatives have attracted increasing interest in the fields of medicine and pharmacology because of their interesting biological properties including antifungal,[14] antibacterial,[15] anticancer,[16] anti-inflammatory,[17] antiviral,[18] antioxidant,[19] cytotoxic,[20] antihypertensive,[21] antitubercular,[22] analgesic,[23] antipyretic,[24] anticonvulsant,[25] and A3 adenosine receptor antagonistic activities.[26] Additionally, pyrazole derivatives are also important in agricultural chemistry.[27] Although thiocyanation of arenes and heterocyclic compounds such as indoles, pyrroles, carbazoles, 8-aminoquinolines and imidazopyridines has been reported,[28] the thiocyanation of pyrazoles has been little explored.[29] Most recently, and during the preparation of this manuscript, Bhat and co-workers reported thiocyanation of phenols, anilines and indoles using K2S2O8/NH4SCN in CH2Cl2.[28r] This prompts us to report our study on a direct regioselective C4-thiocyanation of pyrazoles with commercially available and inexpensive potassium thiocyanate (KSCN) in the presence of K2S2O8 under environmentally friendly conditions and with short reaction times.

Table 1 Optimization of the Reaction Conditionsa

Entry

SCN source (2)

Oxidant

Solvent

1a (%)

3a (%)b

1

KSCN (2a)

K2S2O8

H2O

98

trace

2

KSCN (2a)

K2S2O8

1,4-dioxane

93

trace

3

KSCN (2a)

K2S2O8

THF

98

trace

4

KSCN (2a)

K2S2O8

DMF

91

1

5

KSCN (2a)

K2S2O8

CH2Cl2

85

2

6

KSCN (2a)

K2S2O8

EtOH

66

34

7

KSCN (2a)

K2S2O8

CH3OH

15

75

8

KSCN (2a)

K2S2O8

EtOAc

80

17

9

KSCN (2a)

K2S2O8

CH3CN

47

47

10

KSCN (2a)

K2S2O8

DCE

54

35

11

KSCN (2a)

K2S2O8

DMSO

1

96

12

NaSCN (2b)

K2S2O8

DMSO

7

91

13

NH4SCN (2c)

K2S2O8

DMSO

12

86

14

KSCN (2a)

OXONE®

DMSO

31

66

15

KSCN (2a)

Na2S2O8

DMSO

2

95

16

KSCN (2a)

DIB

DMSO

85

14

17

KSCN (2a)

IBX

DMSO

90

8

18

KSCN (2a)

TBHP

DMSO

96

trace

19

KSCN (2a)

CAN

DMSO

53

43

20

KSCN (2a)

DMSO

98

21 c

KSCN (2a)

K2S2O8

DMSO

0

99

22d

KSCN (2a)

K2S2O8

DMSO

5

95

23e

KSCN (2a)

K2S2O8

DMSO

19

79

a Reaction conditions: 1a (0.5 mmol), 2 (2.0 equiv) and oxidant (1.5 equiv) in solvent (3 mL), open air at room temperature for 24 h.

b Isolated yield after column chromatography.

c Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv) and oxidant (1.5 equiv) in DMSO (3 mL), open air at 60 °C for 2 h.

d Reaction conditions: entry 21 and in the presence of TsOH (1 equiv).

e Reaction conditions: entry 21 and in the presence of K2CO3 (1 equiv).

We began our study by employing 1-methyl-3,5-diphenyl-1H-pyrazole (1a) as a model substrate to screen for optimum reaction conditions. Various reaction parameters including solvent, thiocyanate source, oxidizing agent, reagent stoichiometry, temperature and reaction time were screened and the results are summarized in Table [1]. First, various solvents were evaluated using 1-methyl-3,5-diphenyl-1H-pyrazole (1a; 0.5 mmol), KSCN (2a; 2 equiv) and K2S2O8 (1.5 equiv) at room temperature for 24 h (entries 1–11). It was found that only trace amounts of 3a were observed when H2O, 1,4-dioxane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF) and CH2Cl2 were employed as the solvents (entries 1–5). Better results were observed when the reactions were performed in EtOH, CH3OH, EtOAc, CH3CN, 1,2-dichloroethane (DCE) and DMSO (entries 6–11), and DMSO provided the highest yield of the desired product 3a of 96% (entry 11). Under the optimized conditions (entry 11), the source of thiocyanate was next examined and KSCN gave the optimal results (entries 11–13). Among oxidizing agents screened including K2S2O8, OXONE®, Na2S2O8, (diacetoxyiodo)benzene (DIB), 2-iodoxybenzoic acid (IBX), tert-butyl hydroperoxide (TBHP) and cerium(IV) ammonium nitrate (CAN), K2S2O8 was optimum (entries 11, 14–19). Finally, no desired product 3a was observed when the oxidizing agent was excluded from the reaction (entry 20). After the optimal solvent, thiocyanate source and oxidizing agent were identified, we further optimized the reagent stoichiometry, temperature and reaction time. We were pleased to observe that 3a was obtained in excellent yield (99% yield) when the reaction was performed in DMSO at 60 °C for 2 h, employing KSCN (1.5 equiv) and K2S2O8 (1.5 equiv) (entry 21). Notably, the yield slightly dropped when p-toluenesulfonic acid (TsOH, 1 equiv) was added as an additive (entry 22). In contrast, the presence of K2CO3 (1 equiv) significantly lowered the yield of 3a (entry 23). Finally, no improvement was observed when the stoichiometry of KSCN or K2S2O8 was increased. After extensive experimentations, the optimum reaction conditions were chosen as: 1 (0.5 mmol; 1.0 equiv), KSCN (1.5 equiv) and K2S2O8 (1.5 equiv) in DMSO at 60 °C for 2 h (entry 21).

With optimized reaction conditions established (Table [1], entry 21), the substrate scope and limitations of the reaction were evaluated; the results are summarized in Scheme [1]. A variety of N-substituted-3,5-diphenyl- and N-substi­tuted-3,5-dimethylpyrazoles was first examined. The reactions of N-substituted-3,5-diphenylpyrazoles including N-methyl-, N-phenyl-, N-allyl-, N-alkyl- and N-(2,2-dimethoxyethyl)-3,5-diphenylpyrazoles proceeded smoothly to yield the corresponding thiocyanated products 3af in moderate to excellent yields (52–99%). N-Benzyl-3,5-dimethylpyrazole (1g) also worked well to provide the corresponding product 3g in 95% yield. On the other hand, the reaction of N-(1-propenyl)-3,5-dimethylpyrazole (1h) proceeded with lower efficiency, yielding 3h in 50% yield. N-Aryl-3,5-dimethylpyrazoles bearing electronically different substituents on the phenyl ring were also investigated. N-Aryl-3,5-dimethylpyrazoles bearing electron-donating groups (4-CH3 and 4-OCH3) afforded 3ik in high yields (92–97%). The reaction of N-(4-fluorophenyl)-3,5-dimethylpyrazole (1l) provided 3l in 98% yield. A low yield was observed when N-(2,4-dinitrophenyl)-3,5-dimethylpyrazole (1m) was employed as a substrate. Next, the reactions of 1H-pyrazoles, including symmetrical 3,5-dialkyl-1H-pyrazoles 1nq, symmetrical 3,5-diaryl-1H-pyrazoles 1rv and unsymmetrical 3,5-disubstituted-1H-pyrazoles 1wac, were also evaluated. Gratifyingly, it was found that the corresponding thiocyanated products 3nac were isolated in good to excellent yields (81–99%). Notably, the N-unprotected-1H-pyrazoles are potentially useful for further synthetic manipulation. 3-Phenyl-1H-pyrazol-5-ol (1ad) and 3-phenyl-1H-pyrazol-5-amine (1ae) gave moderate yields of 3ad (53% yield) and 3ae (55% yield). Pyrazole, N-methylpyrazole and N-benzylpyrazole (1afah) smoothly underwent the reaction to yield C4-thiocynated products (3afah) in low to moderate yields (13–57%). These results implied that the present thiocyanation reaction took place regioselectively at C4 of the pyrazole core. Moreover, the reactions of bis(3,5-dimethylpyrazol-1-yl)methane (1ai) and 1,3-bis(3,5-dimethylpyrazol-1-yl)propane (1aj) proceeded readily under standard reaction conditions (with the use of KSCN and K2S2O8, 3.0 equiv each) to yield the corresponding products in high yields (89% and 86%, respectively). Finally, the reaction of curcumin-derived pyrazole (1ak) provided the thiocyanated product 3ak in 28% yield.

Zoom Image
Scheme 1 Substrate scope of C4 thiocyanation of pyrazoles. Reaction conditions: 1 (0.5 mmol), KSCN (1.5 equiv) and K2S2O8 (1.5 equiv) in DMSO (3 mL), open air, 60 °C, 2 h. Isolated yield after column chromatography given in parentheses. a KSCN (3.0 equiv) and K2S2O8 (3.0 equiv) were used.

To demonstrate the utility of the present reaction further, a scale-up reaction was carried out. Under standard reaction conditions, 1a (1.17 g, 5 mmol) was efficiently converted into 3a in 99% yield (Scheme [2]). Additionally, further synthetic manipulations of 3a were also demonstrated (Scheme [3]).[3b] [28p] [30] The thiocyanate group of 3a can be transformed into thiocarbamate 4a in 95% yield. Cycloaddition reaction of 3a with NaN3 mediated by ZnCl2 provided thiotetrazole 5a in 91% yield. Finally, upon treatment of 3a with LiAlH4, the disulfide 6a was obtained in 71% yield.

Zoom Image
Scheme 2 Gram-scale synthesis of thiocyanated pyrazole 3a
Zoom Image
Scheme 3 Synthetic applications of thiocyanated pyrazole 3a

To understand the reaction mechanism better, control experiments were carried out (Scheme [4]). The yields of 3a dropped significantly when the reactions of 1a were carried out in the presence of either 2,6-di-tert-butyl-4-methylphenol (BHT) or hydroquinone. In the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), the reaction was totally closed down. Finally, styrene, commonly used as a radical trapping compound, was found to react competitively with reactive species formed in the reaction. Compound 1a was recovered in 58% yield and 3a was obtained as an inseparable mixture contaminated with unidentified materials. The observed experimental results imply that the reaction process is likely to involve a radical pathway.

Zoom Image
Scheme 4 Control experiments

On the basis of the control experiments and the previous related reports,[28f] [28m] a possible reaction pathway can be proposed (Scheme [5]). First, a thiocyanate radical is generated­ by the oxidation of KSCN with K2S2O8. This thiocyanate radical then reacts with pyrazole 1 to give a radical intermediate A, which could be oxidized to carbocationic intermediate B by K2S2O8. Finally, deprotonation of intermediate B takes place to provide the desired product 3.

Zoom Image
Scheme 5 Possible reaction mechanism

In conclusion, we have demonstrated a facile method for thiocyanation of pyrazole derivatives. The reaction was found to be general and pyrazole derivatives bearing a wide variety of substituents are well tolerated. The use of commercially available and inexpensive reagents and the possibility of reaction scale-up make this protocol attractive for future development. Initial efforts to prove the reaction mechanism suggest that the reaction proceeds via radical intermediates.

All isolated compounds were characterized on the basis of 1H NMR, 13C NMR, IR spectroscopic spectra, and HRMS data. 1H NMR and 13C NMR spectra were recorded with a Bruker Ascend™ spectrometer. 1H NMR and 13C NMR chemical shifts are reported in ppm using tetramethylsilane or the residual non-deuterated solvent peak as an internal standard. Infrared spectra were recorded with a Bruker ALPHA FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded with a Bruker micro TOF spectrometer in ESI mode. Melting points were recorded with a Sanyo Gallenkamp apparatus. Reactions were monitored by thin-layer chromatography and visualized by UV and KMnO4 solution. Solvents and some pyrazoles (1af and 1ag) were obtained from commercial sources and used without further purification. Other pyrazoles were synthesized according to reported procedures (see the Supporting Information). Purification of the reaction products was carried out by column chromatography on silica gel (0.063–0.200 mm). After column chromatography, analytically pure solids were obtained by crystallization from CH2Cl2–hexanes.


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C4 Thiocyanation of Pyrazoles; General Procedure

A 10 mL round-bottom flask was charged with pyrazole 1 (0.5 mmol), KSCN (72.9 mg, 0.75 mmol), K2S2O8 (202.7 mg, 0.75 mmol) and DMSO (3 mL). The resulting solution was stirred under air (open flask) at 60 °C for 2 h. After completion of the reaction, the mixture was cooled to r.t. and was diluted with H2O (10 mL). The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated on a rotary evaporator. The residue was purified by column chromatography on silica gel to provide the desired product 3.


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1-Methyl-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3a)

Prepared from 1-methyl-3,5-diphenyl-1H-pyrazole (1a, 117.1 mg). Purification by column chromatography (20% EtOAc/hexanes) afforded 3a (99%, 144.4 mg) as a white solid.

Mp 137.0–138.0 °C; Rf = 0.57 (30% EtOAc/hexanes).

IR (neat): 2154 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 2 H), 7.62–7.57 (m, 3 H), 7.55–7.44 (m, 5 H), 3.87 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 153.1 (C), 149.2 (C), 131.2 (C), 130.0 (CH), 129.8 (2×CH), 129.0 (2×CH), 128.8 (CH), 128.6 (2×CH), 128.2 (2×CH), 127.5 (C), 111.9 (C), 94.3 (C), 38.2 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H14N3S: 292.0908; found: 292.0918.


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1,3,5-Triphenyl-4-thiocyanato-1H-pyrazole (3b)

Prepared from 1,3,5-triphenyl-1H-pyrazole (1b, 148.2 mg). Purification by column chromatography (10% EtOAc/hexanes) afforded 3b (63%, 111.6 mg) as a pale-yellow solid.

Mp 130.5–132.0 °C; Rf = 0.64 (30% EtOAc/hexanes).

IR (neat): 2161 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 7.2 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.51–7.43 (m, 4 H), 7.40–7.37 (m, 2 H), 7.34–7.30 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 154.3 (C), 148.6 (C), 139.2 (C), 131.0 (C), 130.2 (2×CH), 129.9 (CH), 129.2 (CH), 129.1 (2×CH), 128.9 (2×CH), 128.7 (2×CH), 128.5 (2×CH), 128.3 (CH), 127.8 (C), 125.0 (2×CH), 111.8 (C), 96.7 (C).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H15N3NaS: 376.0884; found: 376.0888.


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1-Allyl-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3c)

Prepared from 1-allyl-3,5-diphenyl-1H-pyrazole (1c, 130.2 mg). Purification by column chromatography (10% EtOAc/hexanes) afforded 3c (77%, 122.2 mg) as a white solid.

Mp 110.5–112.0 °C; Rf = 0.61 (30% EtOAc/hexanes).

IR (neat): 2153 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.3 Hz, 2 H), 7.61–7.44 (m, 8 H), 6.06–5.96 (m, 1 H), 5.25 (dd, J = 10.3, 1.0 Hz, 1 H), 5.08 (dd, J = 17.1, 1.0 Hz, 1 H), 4.73 (t, J = 1.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 153.2 (C), 149.2 (C), 132.3 (CH), 131.1 (C), 130.0 (CH), 129.7 (2×CH), 128.9 (2×CH), 128.7 (CH), 128.5 (2×CH), 128.2 (2×CH), 127.3 (C), 118.3 (CH2), 111.8 (C), 94.4 (C), 53.0 (CH2).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H16N3S: 318.1065; found: 318.1076.


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2-(3,5-Diphenyl-4-thiocyanato-1H-pyrazol-1-yl)ethanol (3d)

Prepared from 2-(3,5-diphenyl-1H-pyrazol-1-yl)ethanol (1d, 132.2 mg). Purification by column chromatography (40% EtOAc/hexanes) afforded 3d (92%, 148.2 mg) as a white solid.

Mp 130.0–132.0 °C; Rf = 0.40 (40% EtOAc/hexanes).

IR (neat): 3498 (O–H), 2158 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.4 Hz, 2 H), 7.60–7.54 (m, 3 H), 7.53–7.44 (m, 5 H), 4.15 (t, J = 5.2 Hz, 2 H), 3.98 (t, J = 5.2 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 153.3 (C), 149.9 (C), 130.8 (C), 130.04 (CH), 129.95 (2×CH), 128.9 (3×CH), 128.5 (2×CH), 128.1 (2×CH), 127.0 (C), 111.8 (C), 94.5 (C), 61.0 (CH2), 51.9 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H15N3NaOS: 344.0834; found: 344.0835.


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2-(2-(3,5-Diphenyl-4-thiocyanato-1H-pyrazol-1-yl)ethoxy)ethanol (3e)

Prepared from 2-(2-(3,5-diphenyl-1H-pyrazol-1-yl)ethoxy)ethanol (1e, 154.2 mg). Purification by column chromatography (60% EtOAc­/hexanes) afforded 3e (83%, 150.8 mg) as a pale-yellow solid.

Mp 63.0–64.5 °C; Rf = 0.43 (60% EtOAc/hexanes).

IR (neat): 3400 (O–H), 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.0 Hz, 2 H), 7.61–7.43 (m, 8 H), 4.27 (t, J = 5.3 Hz, 2 H), 3.88 (t, J = 5.3 Hz, 2 H), 3.62 (t, J = 4.8 Hz, 2 H), 3.47 (t, J = 4.8 Hz, 2 H), 2.53 (br s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 153.4 (C), 150.1 (C), 131.0 (C), 130.0 (3×CH), 128.94 (2×CH), 128.89 (CH), 128.6 (2×CH), 128.2 (2×CH), 127.4 (C), 111.9 (C), 94.6 (C), 72.2 (CH2), 69.0 (CH2), 61.4 (CH2), 50.1 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H19N3NaO2S: 388.1096; found: 388.1104.


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1-(2,2-Dimethoxyethyl)-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3f)

Prepared from 1-(2,2-dimethoxyethyl)-3,5-diphenyl-1H-pyrazole (1f, 154.2 mg). Purification by column chromatography (20% EtOAc/ hexanes­) afforded 3f (52%, 94.5 mg) as a white solid.

Mp 75.0–76.5 °C; Rf = 0.57 (20% EtOAc/hexanes).

IR (neat): 2152 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.5 Hz, 2 H), 7.61–7.44 (m, 8 H), 4.91 (t, J = 5.6 Hz, 1 H), 4.18 (d, J = 5.6 Hz, 2 H), 3.32 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 153.5 (C), 150.4 (C), 131.2 (C), 130.3 (2×CH), 130.0 (CH), 129.1 (3×CH), 128.6 (2×CH), 128.3 (2×CH), 127.3 (C), 112.0 (C), 103.1 (CH), 94.6 (C), 55.1 (2×CH3), 51.9 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H19N3NaO2S: 388.1096; found: 388.1094.


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1-Benzyl-3,5-dimethyl-4-thiocyanato-1H-pyrazole (3g)

Prepared from 1-benzyl-3,5-dimethyl-1H-pyrazole (1g, 93.1 mg). Purification by column chromatography (100% CH2Cl2) afforded 3g (95%, 115.0 mg) as a white solid.

Mp 82.5–83.5 °C; Rf = 0.50 (100% CH2Cl2).

IR (neat): 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 3 H), 7.10 (d, J = 6.6 Hz, 2 H), 5.22 (s, 2 H), 2.36 (s, 3 H), 2.29 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 150.8 (C), 143.8 (C), 135.4 (C), 128.7 (2×CH), 127.8 (CH), 126.7 (2×CH), 110.9 (C), 94.9 (C), 53.7 (CH2), 11.8 (CH3), 10.0 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H13N3NaS: 266.0728; found: 266.0729.


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3,5-Dimethyl-1-(prop-1-en-1-yl)-4-thiocyanato-1H-pyrazole (3h)

Prepared from 3,5-dimethyl-1-(prop-1-en-1-yl)-1H-pyrazole (1h, 68.1 mg). Purification by column chromatography (30% EtOAc/ hexanes­) afforded 3h (50%, 47.9 mg) as a yellow solid.

Mp 56.0–58.0 °C; Rf = 0.48 (20% EtOAc/hexanes).

IR (neat): 2151 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.66 (dd, J = 13.7, 1.7 Hz, 1 H), 6.27 (dq, J = 13.7, 6.9 Hz, 1 H), 2.39 (s, 3 H), 2.35 (s, 3 H), 1.83 (dd, J = 6.9, 1.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 151.8 (C), 142.6 (C), 124.0 (CH), 117.3 (CH), 110.8 (C), 95.5 (C), 15.0 (CH3), 11.9 (CH3), 10.1 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H12N3S: 194.0752; found: 194.0752.


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3,5-Dimethyl-1-phenyl-4-thiocyanato-1H-pyrazole (3i)

Prepared from 3,5-dimethyl-1-phenyl-1H-pyrazole (1i, 86.1 mg). Purification by column chromatography (100% CH2Cl2) afforded 3i (92%, 106.0 mg) as white crystals.

Mp 89.0–90.0 °C; Rf = 0.62 (100% CH2Cl2).

IR (neat): 2151 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.51–7.39 (m, 5 H), 2.43 (s, 3 H), 2.42 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 152.0 (C), 144.3 (C), 139.1 (C), 129.4 (2×CH), 128.6 (CH), 125.0 (2×CH), 110.8 (C), 96.6 (C), 12.0 (CH3), 11.5 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H12N3S: 230.0752; found: 230.0766.


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3,5-Dimethyl-4-thiocyanato-1-(p-tolyl)-1H-pyrazole (3j)

Prepared from 3,5-dimethyl-1-(p-tolyl)-1H-pyrazole (1j, 93.1 mg). Purification by column chromatography (10% EtOAc/hexanes) afforded 3j (97%, 118.5 mg) as colorless crystals.

Mp 85.5–88.0 °C; Rf = 0.66 (30% EtOAc/hexanes).

IR (neat): 2151 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.18 (s, 4 H), 2.32 (s, 3 H), 2.31 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 151.5 (C), 144.0 (C), 138.4 (C), 136.3 (C), 129.6 (2×CH), 124.5 (2×CH), 110.7 (C), 95.9 (C), 20.9 (CH3), 11.8 (CH3), 11.2 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14N3S: 244.0908; found: 244.0908.


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1-(4-Methoxyphenyl)-3,5-dimethyl-4-thiocyanato-1H-pyrazole (3k)

Prepared from 1-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole (1k, 101.1 mg). Purification by column chromatography (20% EtOAc/ hexanes­) afforded 3k (95%, 123.5 mg) as colorless needles.

Mp 89.0–91.0 °C; Rf = 0.34 (20% EtOAc/hexanes).

IR (neat): 2149 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.9 Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2 H), 3.74 (s, 3 H), 2.32 (s, 3 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 159.4 (C), 151.3 (C), 144.2 (C), 131.8 (C), 126.2 (2×CH), 114.2 (2×CH), 110.7 (C), 95.6 (C), 55.3 (CH3), 11.7 (CH3), 11.1 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14N3OS: 260.0858; found: 260.0860.


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1-(4-Fluorophenyl)-3,5-dimethyl-4-thiocyanato-1H-pyrazole (3l)

Prepared from 1-(4-fluorophenyl)-3,5-dimethyl-1H-pyrazole (1l, 95.1 mg). Purification by column chromatography (30% EtOAc/hexanes) afforded 3l (98%, 120.9 mg) as a pale-yellow solid.

Mp 77.0–79.0 °C; Rf = 0.37 (20% EtOAc/hexanes).

IR (neat): 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.38–7.33 (m, 2 H), 7.18–7.12 (m, 2 H), 2.378 (s, 3 H), 2.375 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.1 (d, J = 247.7 Hz, C), 151.8 (C), 144.2 (C), 135.0 (C), 126.8 (d, J = 8.8 Hz, 2×CH), 116.1 (d, J = 23.0 Hz, 2×CH), 110.5 (d, J = 6.7 Hz, C), 96.6 (C), 11.8 (CH3), 11.2 (CH3).

19F NMR (376 MHz, CDCl3): δ = –112.03.

HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H11FN3S: 248.0658; found: 248.0658.


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1-(2,4-Dinitrophenyl)-3,5-dimethyl-4-thiocyanato-1H-pyrazole (3m)

Prepared from 1-(2,4-dinitrophenyl)-3,5-dimethyl-1H-pyrazole (1m, 131.1 mg). Purification by column chromatography (10% EtOAc/ hexanes­) afforded 3m (33%, 51.5 mg) as a pale-yellow solid.

Mp 79.0–81.5 °C; Rf = 0.41 (30% EtOAc/hexanes).

IR (neat): 2160 (C≡N), 1535 and 1349 (N–O) cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 2.5 Hz, 1 H), 8.63 (dd, J = 8.7, 2.5 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 2.41 (s, 3 H), 2.40 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 154.3 (C), 147.4 (C), 146.0 (C), 145.7 (C), 136.8 (C), 130.1 (CH), 127.9 (CH), 121.2 (CH), 109.9 (C), 99.4 (C), 12.0 (CH3), 10.9 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H9N5NaO4S: 342.0273; found: 342.0268.


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3,5-Dimethyl-4-thiocyanato-1H-pyrazole (3n)

Prepared from 3,5-dimethyl-1H-pyrazole (1n, 48.1 mg). Purification by column chromatography (20% EtOAc/CH2Cl2) afforded 3n (87%, 66.3 mg) as a white solid

Mp 57.0–59.0 °C; Rf = 0.43 (30% EtOAc/CH2Cl2).

IR (neat): 3272 (N–H), 2163 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.33 (br s, 1 H), 2.40 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 148.5 (2×C), 110.8 (C), 94.9 (C), 11.0 (2×CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C6H7N3NaS: 176.0258; found: 176.0251.


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3,5-Diethyl-4-thiocyanato-1H-pyrazole (3o)

Prepared from 3,5-diethyl-1H-pyrazole (1o, 62.1 mg). Purification by column chromatography (20% EtOAc/CH2Cl2) afforded 3o (93%, 84.0 mg) as a colorless oil.

Rf = 0.43 (30% EtOAc/CH2Cl2).

IR (neat): 3174 (N–H), 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.82 (br s, 1 H), 2.75 (q, J = 7.6 Hz, 4 H), 1.26 (t, J = 7.6 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 153.7 (2×C), 111.3 (C), 92.8 (C), 19.0 (2×CH2), 12.8 (CH3), 12.6 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H12N3S: 182.0752; found: 182.0761.


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3,5-Diisopropyl-4-thiocyanato-1H-pyrazole (3p)

Prepared from 3,5-diisopropyl-1H-pyrazole (1p, 76.1 mg). Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 3p (97%, 101.0 mg) as a colorless oil.

Rf = 0.47 (30% EtOAc/CH2Cl2).

IR (neat): 3178 (N–H), 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.41 (br s, 1 H), 3.27 (sept, J = 7.0 Hz, 2 H), 1.34 (d, J = 7.0 Hz, 12 H).

13C NMR (100 MHz, CDCl3): δ = 157.6 (2×C), 111.6 (C), 91.2 (C), 26.0 (2×CH), 21.6 (4×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H16N3S: 210.1065; found: 210.1073.


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3,5-Di-tert-butyl-4-thiocyanato-1H-pyrazole (3q)

Prepared from 3,5-di-tert-butyl-1H-pyrazole (1q, 90.1 mg). Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 3q (89%, 105.4 mg) as a colorless solid.

Mp 155.5–157.5 °C; Rf = 0.61 (30% EtOAc/CH2Cl2).

IR (neat): 3259 (N–H), 2150 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.11 (br s, 1 H), 1.51 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 160.3 (2×C), 112.7 (C), 90.6 (C), 33.0 (2×C), 29.3 (6×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H20N3S: 238.1378; found: 238.1385.


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3,5-Diphenyl-4-thiocyanato-1H-pyrazole (3r)

Prepared from 3,5-diphenyl-1H-pyrazole (1r, 110.1 mg). Purification by column chromatography (10% EtOAc/CH2Cl2) afforded 3r (99%, 137.5 mg) as a white solid.

Mp 171.5–174.5 °C; Rf = 0.39 (30% EtOAc/CH2Cl2).

IR (neat): 3185 (N–H), 2157 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.04 (br s, 1 H), 7.64 (dd, J = 7.6, 1.6 Hz, 4 H), 7.48–7.40 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 152.1 (2×C), 129.7 (2×CH), 128.9 (4×CH), 128.7 (2×C), 128.3 (4×CH), 111.7 (C), 93.4 (C).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H12N3S: 278.0752; found: 278.0757.


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4-Thiocyanato-3,5-di-p-tolyl-1H-pyrazole (3s)

Prepared from 3,5-di-p-tolyl-1H-pyrazole (1s, 124.2 mg). Purification by column chromatography (10% EtOAc/CH2Cl2) afforded 3s (99%, 150.5 mg) as a white solid.

Mp 186.5–188.5 °C; Rf = 0.58 (30% EtOAc/CH2Cl2).

IR (neat): 3185 (N–H), 2157 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.99 (br s, 1 H), 7.56 (d, J = 8.1 Hz, 4 H), 7.23 (d, J = 7.9 Hz, 4 H), 2.41 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 152.1 (2×C), 139.7 (2×C), 129.6 (4×CH), 128.1 (4×CH), 125.8 (2×C), 111.9 (C), 92.8 (C), 21.4 (2×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H16N3S: 306.1065; found: 306.1060.


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3,5-Bis(4-methoxyphenyl)-4-thiocyanato-1H-pyrazole (3t)

Prepared from 3,5-bis(4-methoxyphenyl)-1H-pyrazole (1t, 140.2 mg). Purification by column chromatography (10% EtOAc/CH2Cl2) afforded 3t (90%, 152.6 mg) as a white solid.

Mp 188.0–189.0 °C; Rf = 0.43 (60% EtOAc/CH2Cl2).

IR (neat): 3187 (N–H), 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.7 Hz, 4 H), 6.89 (d, J = 8.7 Hz, 4 H), 3.84 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 160.5 (2×C), 151.8 (2×C), 129.6 (4×CH), 121.1 (2×C), 114.3 (4×CH), 112.1 (C), 92.2 (C), 55.3 (2×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H16N3O2S: 338.0963; found: 338.0962.


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3,5-Bis(2-methoxyphenyl)-4-thiocyanato-1H-pyrazole (3u)

Prepared from 3,5-bis(2-methoxyphenyl)-1H-pyrazole (1u, 140.2 mg). Purification by column chromatography (10% EtOAc/CH2Cl2) afforded 3u (84%, 142.5 mg) as a pale-yellow solid.

Mp 132.5–134.0 °C; Rf = 0.43 (60% EtOAc/CH2Cl2).

IR (neat): 3154 (N–H), 2154 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.59 (br s, 1 H), 7.73 (dd, J = 7.6, 1.6 Hz, 2 H), 7.44 (td, J = 7.6, 1.6 Hz, 2 H), 7.09 (td, J = 7.6, 0.7 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 2 H), 3.83 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 156.9 (2×C), 148.1 (2×C), 130.9 (2×CH), 130.7 (2×CH), 120.8 (2×CH), 118.0 (2×C), 111.9 (C), 111.1 (2×CH), 95.7 (C), 55.4 (2×CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H15N3NaO2S: 360.0783; found: 360.0782.


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3,5-Bis(2-(benzyloxy)phenyl)-4-thiocyanato-1H-pyrazole (3v)

Prepared from 3,5-bis(2-(benzyloxy)phenyl)-1H-pyrazole (1v, 216.3 mg). Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 3v (99%, 242.2 mg) as a pale-yellow solid.

Mp 104.5–106.5 °C; Rf = 0.39 (30% EtOAc/CH2Cl2).

IR (neat): 3187 (N–H), 2153 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 11.00 (br s, 1 H), 7.73 (d, J = 7.5 Hz, 2 H), 7.44–7.29 (m, 12 H), 7.13–7.06 (m, 4 H), 5.11 (s, 4 H).

13C NMR (100 MHz, CDCl3): δ = 155.8 (2×C), 147.6 (2×C), 136.2 (2×C), 130.7 (2×CH), 130.6 (2×CH), 128.3 (4×CH), 127.7 (2×CH), 126.8 (4×CH), 121.1 (2×CH), 118.4 (2×C), 113.0 (2×CH), 111.7 (C), 96.0 (C), 70.4 (2×CH).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H24N3O2S: 490.1589; found: 490.1597.


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5-Phenyl-4-thiocyanato-3-(m-tolyl)-1H-pyrazole (3w)

Prepared from 5-phenyl-3-(m-tolyl)-1H-pyrazole (1w, 117.2 mg). Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 3w (99%, 144.2 mg) as a white solid.

Mp 167.0–169.0 °C; Rf = 0.51 (5% EtOAc/CH2Cl2).

IR (neat): 3206 (N–H), 2153 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 11.29 (br s, 1 H), 7.56 (d, J = 8.3 Hz, 2 H), 7.42–7.32 (m, 5 H), 7.26–7.19 (m, 2 H), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 152.1 (C), 151.9 (C), 138.6 (C), 130.4 (CH), 129.5 (CH), 128.8 (2×CH), 128.73 (CH), 128.69 (CH), 128.3 (2×C), 128.1 (2×CH), 125.3 (CH), 111.8 (C), 93.0 (C), 21.3 (CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H14N3S: 292.0908; found: 292.0904.


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3-(3-Methoxyphenyl)-5-phenyl-4-thiocyanato-1H-pyrazole (3x)

Prepared from 3-(3-methoxyphenyl)-5-phenyl-1H-pyrazole (1x, 125.2 mg). Purification by column chromatography (40% EtOAc/ hexanes­) afforded 3x (96%, 148.0 mg) as a pale-yellow solid.

Mp 92.5–94.0 °C; Rf = 0.55 (40% EtOAc/hexanes).

IR (neat): 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 11.14 (br s, 1 H), 7.54 (d, J = 7.0 Hz, 2 H), 7.41–7.31 (m, 3 H), 7.23 (t, J = 8.1 Hz, 1 H), 7.13 (d, J = 6.7 Hz, 2 H), 6.92 (dd, J = 8.5, 1.6 Hz, 1 H), 3.69 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 159.6 (C), 151.9 (2×C), 129.9 (CH), 129.7 (C), 129.6 (CH), 128.8 (2×CH), 128.4 (C), 128.1 (2×CH), 120.3 (CH), 115.6 (CH), 113.2 (CH), 111.8 (C), 93.1 (C), 55.1 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H13N3NaOS: 330.0677; found: 330.0675.


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3-(3-Chlorophenyl)-5-phenyl-4-thiocyanato-1H-pyrazole (3y)

Prepared from 3-(3-chlorophenyl)-5-phenyl-1H-pyrazole (1y, 127.4 mg). Purification by column chromatography (40% EtOAc/hexanes) afforded 3y (81%, 126.0 mg) as a white solid.

Mp 139.0–141.0 °C; Rf = 0.64 (40% EtOAc/hexanes).

IR (neat): 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 11.81 (br s, 1 H), 7.57–7.54 (m, 3 H), 7.51–7.43 (m, 2 H), 7.42–7.36 (m, 3 H), 7.30 (t, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 151.7 (C), 151.1 (C), 134.7 (C), 130.7 (C), 130.05 (CH), 129.98 (CH), 129.6 (CH), 129.0 (2×CH), 128.1 (CH), 128.0 (2×CH), 127.5 (C), 126.3 (CH), 111.3 (C), 93.6 (C).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H10ClN3NaS: 334.0182; found: 334.0182.


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3-Cyclohexyl-5-phenyl-4-thiocyanato-1H-pyrazole (3z)

Prepared from 3-cyclohexyl-5-phenyl-1H-pyrazole (1z, 113.2 mg). Purification by column chromatography (40% EtOAc/hexanes) afforded 3z (99%, 139.6 mg) as a pale-yellow solid.

Mp 87.0–89.0 °C; Rf = 0.66 (40% EtOAc/hexanes).

IR (neat): 3158 (N–H), 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.63 (br s, 1 H), 7.65 (dd, J = 7.6, 2.0 Hz, 2 H), 7.44–7.38 (m, 3 H), 2.96–2.90 (m, 1 H), 1.90 (d, J = 10.7 Hz, 2 H), 1.79–1.71 (m, 3 H), 1.48–1.28 (m, 4 H), 1.18–1.10 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 156.8 (C), 152.0 (C), 129.6 (C), 129.2 (CH), 128.6 (2×CH), 128.1 (2×CH), 111.6 (C), 92.2 (C), 35.6 (CH), 31.7 (2×CH2), 26.1 (2×CH2), 25.5 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H18N3NaS: 306.1041; found: 306.1053.


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5-Hexyl-3-phenyl-4-thiocyanato-1H-pyrazole (3aa)

Prepared from 5-hexyl-3-phenyl-1H-pyrazole (1aa, 114.2 mg). Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 3aa (94%, 134.2 mg) as a colorless oil.

Rf = 0.68 (5% EtOAc/CH2Cl2).

IR (neat): 3165 (N–H), 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 11.70 (br s, 1 H), 7.69–7.67 (m, 2 H), 7.45–7.44 (m, 3 H), 2.62 (t, J = 7.7 Hz, 2 H), 1.58–1.53 (m, 2 H), 1.30–1.21 (m, 6 H), 0.88 (t, J = 6.5 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 152.8 (C), 151.9 (C), 129.6 (C), 129.3 (CH), 128.7 (2×CH), 128.0 (2×CH), 111.3 (C), 93.3 (C), 31.2 (CH2), 28.8 (CH2), 28.4 (CH2), 25.2 (CH2), 22.3 (CH2), 13.9 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H19N3NaS: 308.1197; found: 308.1199.


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5-Benzyl-3-phenyl-4-thiocyanato-1H-pyrazole (3ab)

Prepared from 5-benzyl-3-phenyl-1H-pyrazole (1ab, 117.2 mg). Purification by column chromatography (40% EtOAc/hexanes) afforded 3ab (88%, 127.8 mg) as a yellow solid.

Mp 121.5–122.5 °C; Rf = 0.56 (40% EtOAc/hexanes).

IR (neat): 3211 (N–H), 2154 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.90 (br s, 1 H), 7.56 (dd, J = 7.4, 1.3 Hz, 2 H), 7.41–7.33 (m, 3 H), 7.21–7.13 (m, 3 H), 7.08 (d, J = 7.8 Hz, 2 H), 3.95 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 152.3 (C), 150.7 (C), 136.3 (C), 129.5 (CH), 128.8 (2×CH), 128.7 (C), 128.6 (2×CH), 128.5 (2×CH), 127.9 (2×CH), 126.9 (CH), 110.9 (C), 93.7 (C), 31.6 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+calcd for C17H13N3NaS: 314.0728; found: 314.0732.


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5-((Benzyloxy)methyl)-3-phenyl-4-thiocyanato-1H-pyrazole (3ac)

Prepared from 5-((benzyloxy)methyl)-3-phenyl-1H-pyrazole (1ac, 132.2 mg). Purification by column chromatography (40% EtOAc/ hexanes­) afforded 3ac (86%, 137.6 mg) as a pale-yellow solid.

Mp 146.5–150.0 °C; Rf = 0.52 (40% EtOAc/hexanes).

IR (neat): 3156 (N–H), 2155 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.72 (br s, 1 H), 7.68–7.65 (m, 2 H), 7.47–7.43 (m, 3 H), 7.34–7.30 (m, 5 H), 4.66 (s, 2 H), 4.58 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 150.2 (C), 149.9 (C), 136.8 (C), 133.2 (C), 129.5 (CH), 128.8 (2×CH), 128.3 (2×CH), 127.9 (CH), 127.86 (2×CH), 127.82 (2×CH), 110.9 (C), 93.8 (C), 73.0 (CH2), 62.5 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H15N3NaOS: 344.0834; found: 344.0831.


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3-Phenyl-4-thiocyanato-1H-pyrazol-5-ol (3ad)

Prepared from 3-phenyl-1H-pyrazol-5-ol (1ad, 80.1 mg). Purification by column chromatography (10% MeOH/CH2Cl2) afforded 3ad (53%, 57.2 mg) as a green solid.

Mp 170.0 °C (decomp.); Rf = 0.46 (20% MeOH/CH2Cl2).

IR (neat): 3290 (O–H), 2157 (C≡N) cm–1.

1H NMR (500 MHz, CD3OD): δ = 7.65–7.64 (m, 2 H), 7.42 (t, J = 7.3 Hz, 2 H), 7.36 (d, J = 7.4 Hz, 1 H).

13C NMR (125 MHz, CD3OD): δ = 161.8 (C), 145.7 (C), 130.3 (C), 128.5 (2×CH), 128.4 (C), 128.1 (2×CH), 125.0 (CH), 86.9 (C).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H7N3NaOS: 240.0208; found: 240.0214.


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3-Phenyl-4-thiocyanato-1H-pyrazol-5-amine (3ae)

Prepared from 3-phenyl-1H-pyrazol-5-amine (1ae, 79.6 mg). Purification by column chromatography (5.0% EtOAc/hexanes) afforded 3ae (55%, 59.0 mg) as a pale-yellow solid.

Mp 94.5–96.0 °C; Rf = 0.52 (100% EtOAc).

IR (neat): 3275 (N–H), 2152 (C≡N) cm–1.

1H NMR (500 MHz, CD3OD): δ = 7.65–7.63 (m, 2 H), 7.40–7.37 (m, 2 H), 7.32–7.29 (m, 1 H).

13C NMR (125 MHz, CD3OD): δ = 153.8 (C), 146.4 (C), 131.0 (C), 128.4 (2×CH), 127.8 (2×CH), 126.8 (C), 125.2 (CH), 88.8 (C).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H9N4S: 217.0548; found: 217.0548.


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4-Thiocyanato-1H-pyrazole (3af)

Prepared from pyrazole (1af, 34.0 mg). Purification by column chromatography (30% EtOAc/hexanes) afforded 3af (13%, 7.9 mg) as a white solid.

Mp 165.5–167.0 °C; Rf = 0.47 (50% EtOAc/hexanes).

IR (neat): 3211 (N–H), 2154 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 2 H), 6.52 (br s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 138.5 (2×CH), 111.2 (C), 98.1 (C).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C4H3N3NaS: 147.9945; found: 147.9935.


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1-Methyl-4-thiocyanato-1H-pyrazole (3ag)

Prepared from 1-methyl-1H-pyrazole (1ag, 41.0 mg). Product 3ag (57%, 42.6 mg) was afforded as a colorless liquid.

IR (neat): 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 1 H), 7.68 (s, 1 H), 3.94 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 143.2 (CH), 134.9 (CH), 111.2 (C), 97.0 (C), 39.5 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C5H5N3NaS: 162.0102; found: 162.0107.


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1-Benzyl-4-thiocyanato-1H-pyrazole (3ah)

Prepared from 1-benzyl-1H-pyrazole (1ah, 79.1 mg). Purification by column chromatography (5% acetone/hexanes) afforded 3ah (30%, 29.6 mg) as a colorless oil.

Rf = 0.40 (30% acetone/hexane).

IR (neat): 2156 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H), 7.64 (s, 1 H), 7.41–7.36 (m, 3 H), 7.27–7.24 (m, 2 H), 5.30 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 143.4 (CH), 134.7 (C), 134.1 (CH), 129.1 (2×CH), 128.7 (CH), 128.1 (2×CH), 111.2 (C), 97.6 (C), 56.9 (CH2).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H9N3NaS: 238.0415; found: 248.0414.


#

Bis(3,5-dimethyl-4-thiocyanato-1H-pyrazol-1-yl)methane (3ai)

Prepared from bis(3,5-dimethyl-1H-pyrazol-1-yl)methane (1ai, 102.1 mg). Purification by column chromatography (40% EtOAc/hexanes) afforded 3ai (89%, 141.1 mg) as colorless crystals.

Mp 87.5–89.5 °C; Rf = 0.53 (40% EtOAc/hexanes).

IR (neat): 2154 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.05 (s, 2 H), 2.59 (s, 6 H), 2.28 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 151.9 (2×C), 145.5 (2×C), 110.3 (2×C), 96.6 (2×C), 60.9 (CH2), 11.8 (2×CH3), 10.2 (2×CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H14N6NaS2: 341.0619; found: 341.0624.


#

1,3-Bis(3,5-dimethyl-4-thiocyanato-1H-pyrazol-1-yl)propane (3aj)

Prepared from 1,3-bis(3,5-dimethyl-1H-pyrazol-1-yl)propane (1aj, 116.2 mg). Purification by column chromatography (40% EtOAc/ hexanes­) afforded 3aj (86%, 148.3 mg) as a white solid.

Mp 71.0–73.0 °C; Rf = 0.50 (100% EtOAc).

IR (neat): 2157 (C≡N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.95 (t, J = 6.7 Hz, 4 H), 2.31 (quin, J = 6.7 Hz, 2 H), 2.254 (s, 6 H), 2.249 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 150.8 (2×C), 143.6 (2×C), 110.7 (2×C), 94.3 (2×C), 46.1 (2×CH2), 28.6 (CH2), 11.6 (2×CH3), 9.7 (2×CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H18N6NaS2: 369.0932; found: 369.0933.


#

4,4′-(1E,1′E-(4-Thiocyanato-1H-pyrazole-3,5-diyl)bis(ethene-2,1-diyl))bis(2-methoxyphenol) (3ak)

Prepared from 4,4′-((1E,1′E)-(1H-pyrazole-3,5-diyl)bis(ethene-2,1-diyl))bis(2-methoxyphenol) (1ak, 182.2 mg). Purification by column chromatography (4% MeOH/CH2Cl2) afforded 3ak (28%, 51.6 mg) as a yellow solid.

Mp 197.0–198.0 °C; Rf = 0.30 (10% MeOH/CH2Cl2).

IR (neat): 3239 (O–H), 2158 (C≡N) cm–1.

1H NMR (400 MHz, acetone-d6 ): δ = 7.87 (s, 1 H), 7.38 (d, J = 16.6 Hz, 2 H), 7.19 (d, J = 1.7 Hz, 2 H), 7.02 (s, 1 H), 6.70–6.97 (m, 3 H), 6.75 (d, J = 8.2 Hz, 2 H), 3.80 (s, 6 H).

13C NMR (100 MHz, acetone-d6 ): δ = 147.9 (2×C), 147.8 (2×C), 133.3 (2×C), 128.5 (C), 121.1 (2×CH), 114.9 (4×CH), 112.0 (C), 110.8 (C), 109.5 (4×CH), 92.5 (C), 55.4 (2×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H20N3O4S: 422.1175; found: 422.1165.


#

Synthesis of S-(1-Methyl-3,5-diphenyl-1H-pyrazol-4-yl)carbamothioate (4a)[5a]

A solution of 1-methyl-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3a, 145.7 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added to concentrated sulfuric acid (0.8 mL). The resulting solution was stirred at 0 °C for 5 h. The reaction mixture was allowed to warm to r.t. and diluted with H2O (10 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator.

Product 4a (95%, 146.7 mg) was obtained as a pale-yellow solid.

Mp 178.0–179.0 °C; Rf = 0.39 (30% EtOAc/hexanes).

IR (neat): 3454 (N–H), 1656 (C=O) cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.81 (d, J = 7.2 Hz, 2 H), 7.67 (br s, 1 H), 7.53–7.48 (m, 5 H), 7.47–7.43 (m, 2 H), 7.40–7.38 (m, 1 H), 3.81 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 166.7 (C), 152.2 (C), 148.6 (C), 132.8 (C), 129.9 (2×CH), 129.3 (CH), 128.8 (C), 128.6 (2×CH), 128.3 (2×CH), 128.0 (CH), 127.7 (2×CH), 101.1 (C), 38.0 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15N3NaOS: 332.0834; found: 332.0842.


#

Synthesis of 5-((1-Methyl-3,5-diphenyl-1H-pyrazol-4-yl)thio)-1H-tetrazole (5a)[30]

NaN3 (39.0 mg, 0.6 mmol) and ZnCl2 (68.2 mg, 0.5 mmol) were added to a solution of 1-methyl-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3a, 145.7 mg, 0.5 mmol) in i-PrOH (2 mL) at 50 °C. The resulting solution was stirred at 50 °C for 24 h, then the solvent was evaporated. Then, 5% NaOH (25 mL) was added and the mixture was stirred at r.t. for 20 min until the original precipitate had dissolved and a suspension of Zn(OH)2 was observed. The precipitate was filtered and washed with 5% NaOH (10 mL). The pH of filtrate was adjusted to pH 1.0 with concentrated HCl, which caused the product to form. The product was filtered, washed with 9% HCl (2 × 10 mL) and dried.

Product 5a (91%, 152.0 mg) was obtained as a white solid.

Mp 178.1–180.9 °C; Rf = 0.33 (100% EtOAc).

IR (neat): 1476 (C–N) cm–1.

1H NMR (400 MHz, CD3OD): δ = 7.76–7.74 (m, 2 H), 7.48–7.36 (m, 8 H), 3.87 (s, 3 H).

13C NMR (100 MHz, CD3OD): δ = 157.8 (C), 154.2 (C), 151.1 (C), 133.0 (C), 131.1 (CH), 131.0 (2×CH), 130.0 (2×CH), 129.8 (CH), 129.5 (2×CH), 129.3 (C), 129.2 (2×CH), 99.1 (C), 38.5 (CH3).

HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H14N6NaS: 357.0898; found: 357.0905.


#

Synthesis of 1,2-Bis(1-methyl-3,5-diphenyl-1H-pyrazol-4-yl)disulfane (6a)[3b]

A solution of 1-methyl-3,5-diphenyl-4-thiocyanato-1H-pyrazole (3a, 145.7 mg, 0.5 mmol) in anhydrous THF (2 mL) was added to a suspension of LiAlH4 (20.9 mg, 0.55 mmol) in anhydrous THF (4 mL) at 0 °C. The resulting mixture was stirred at r.t. overnight. After that time, water and 1.0 M HCl were added and the mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator.

Purification by column chromatography (30–70% EtOAc/hexanes) afforded 6a (71%, 94.2 mg) as a pale-yellow solid.

Mp 223.5–224.0 °C; Rf = 0.57 (60% EtOAc/hexanes).

IR (neat): 1461 (C–N) cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.76 (dd, J = 7.9, 2.1 Hz, 2 H), 7.42–7.41 (m, 3 H), 7.36–7.34 (m, 3 H), 7.10 (dd, J = 7.5, 2.0 Hz, 2 H), 3.64 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 152.7 (2×C), 148.7 (2×C), 132.1 (2×C), 130.1 (4×CH), 128.9 (2×CH), 128.15 (2×C), 128.13 (6×CH), 128.0 (4×CH), 127.9 (2×CH), 107.5 (2×C), 37.6 (2×CH3).

HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15N2S: 553.1497; found: 553.1579.


#
#

Acknowledgment

We also acknowledge the Institute for the Promotion of Teaching Science and Technology through the Development and Promotion of Science and Technology Talents Project (DPST), and Science Achievement Scholarship of Thailand (SAST) for student scholarships to T.S. and O.K., respectively and the National Research Council of Thailand (NRCT) for a postdoctoral research assistantship to P.K.

Supporting Information

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    • Some examples of Sandmeyer type reactions to prepare thiocyanates:
    • 10a Guy RG. Lau R. Rahman AU. Swinbourne FJ. Spectrochim. Acta, Part A 1997; 53: 361
    • 10b Butt N. Guy RG. Winbourne FJ. Spectrochim. Acta, Part A 1995; 51: 1715
    • 10c Bangher A. Guy RG. Pichot Y. Sillence JM. Steel CJ. Swinbourne FJ. Tamiatti K. Spectrochim. Acta, Part A 1995; 51: 1703
    • 10d Whiteker GT. Lippard SJ. Tetrahedron Lett. 1991; 32: 5019
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    • 10f Barbero M. Degani I. Diulgheroff N. Dughera S. Fochi R. Synthesis 2001; 585
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    • 11c Teng F. Yu J.-T. Yang H. Jiang Y. Cheng J. Chem. Commun. 2014; 12139
    • 12a Suzuki H. Abe H. Synth. Commun. 1996; 18: 3413
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Scheme 1 Substrate scope of C4 thiocyanation of pyrazoles. Reaction conditions: 1 (0.5 mmol), KSCN (1.5 equiv) and K2S2O8 (1.5 equiv) in DMSO (3 mL), open air, 60 °C, 2 h. Isolated yield after column chromatography given in parentheses. a KSCN (3.0 equiv) and K2S2O8 (3.0 equiv) were used.
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Scheme 2 Gram-scale synthesis of thiocyanated pyrazole 3a
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Scheme 3 Synthetic applications of thiocyanated pyrazole 3a
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Scheme 4 Control experiments
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Scheme 5 Possible reaction mechanism