Thiocyanation of Pyrazoles Using KSCN/K₂S₂O₈ Combination

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.

Key words

thiocyanation - pyrazoles - potassium thiocyanate - potassium persulfate - heterocycle

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 Conditions^a

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 3a–f 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 3i–k 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 1n–q, symmetrical 3,5-diaryl-1H-pyrazoles 1r–v and unsymmetrical 3,5-disubstituted-1H-pyrazoles 1w–ac, were also evaluated. Gratifyingly, it was found that the corresponding thiocyanated products 3n–ac 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 (1af–ah) smoothly underwent the reaction to yield C4-thiocynated products (3af–ah) 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.

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.

Scheme 2 Gram-scale synthesis of thiocyanated pyrazole 3a

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.

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.

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.

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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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.

R_f = 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.

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.

R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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; R_f = 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.

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.

R_f = 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.

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; R_f = 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.

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; R_f = 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.

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.); R_f = 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.

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; R_f = 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.

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; R_f = 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.

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.

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.

R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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.

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