Received: February 2018

DOI 10.17677/fn20714807.2018.01.05

Fluorine Notes, 2018, 116, 9-10

Synthesis of 5-nitro-pyrazole triflones via [3+2] cycloaddition reaction and its application for potential insecticide

Pulakesh Das,¹ Hiroto Uno, ¹ Etsuko Tokunaga, ¹ Yuji Sumii ¹ and Norio Shibata^1,2*

¹Department of Nanopharmaceutical Sciences, and Department of Life Science and Applied Chemistry,

Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan, E-mail: nozshiba@nitech.ac.jp; TEL; +81-52-735-7543

²Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China

Abstract: Synthesis of 5-nitro-pyrazole triflones 6 was achieved via [3+2] cycloaddition reaction of 2-diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (3) and α-bromonitrostyrene derivatives 7 under basic conditions in moderate to good yields. An agrochemically attractive 5-amino-N-pyrimidinyl-pyrazole triflone 2a was successfully prepared from 5-nitro-pyrazole triflone 6c in two steps.

Key words: 5-nitro-pyrazole triflones, α-bromonitrostyrene, [3+2] cycloaddition

Introduction: Pyrazoles are often found as an integral part of biologically active molecules [1]. In particular, pyrazoles with aryl or heteroaryl substituents at N-1 position and a free NH₂ group at C-5 position have gathered much attention because of their promising pharmaceutical [2] and agrochemical [3] properties. More precisely, 1-arylpyrazoles having substituents like alkyl, thioalkyl, acyl or cyano- group at the C-3 and C-4 positions exhibit potent insecticidal activities [4]. Amongst the pyrazole-type pesticides, Fipronil^® (5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulfinyl-1H-pyrazole-3-carbonitrile) is a highly effective broad-spectrum insecticide and veterinary medicine to get rid of fleas and ticks [5] (Figure 1). However, the use of Fipronil^® is the matter of discussion due to the recent food safety incident [6]. Thus, the development of safer derivatives of Fipronil^® is of great importance. Bayer CropScience AG has filed patents on the sulfur-derivatized pyrimidinyl-pyrazol-5-amines 1 which showed potent activities as insecticides and/or parasiticides [3a,7]. Inspired by their patents, we are interested in triflyl (trifluoromethanesulfonyl, SO₂CF₃) variants (triflones) 2 as potential pesticides.

Figure 1. Fipronil^® and its biologically attractive derivatives containing aryl or heteroaryl substituent at N-1 position and a free NH₂ group at C-5 position.

The introduction of fluorine(s) and fluorinated functional groups into organic compounds is one of the effective strategies to improve/alter biological activity and metabolic stability of original molecules [8]. In the case of our target 5-amino-pyrazole triflones 2, the incorporation of a lipophilic triflyl group (π = 0.55) to C-3 position in 2 could potentially perturb the chemical, physical and biological properties of the parent heterocyclic 5-amino-pyrazoles. Besides, the triflone variants 2 are also expected to have a reduced basicity of the amine moiety in 2 due to the strong electron withdrawing effect by the triflyl group (σ_m = 0.79, σ_p = 0.93) [9]. For decades, our group has been focusing on the development of novel shelf-stable reagents for fluoro-functionalization reactions [10,11]. One such kind of unique compounds is 2-diazo-1-phenyl-2-((trifluoromethyl)-sulfonyl)ethan-1-one (3) [12]. The compound 3 was originally developed by us as a regent for electrophilic trifluoromethylthiolation reactions. A wide variety of nucleophiles such as enamines, indoles, β-ketoesters, and pyrroles are nicely trifluoromethylthiolated by 3 in the presence of a copper catalyst under mild conditions [12a]. Aromatic coupling reaction is also available by using 3. On the other hand, 3 also acts as a powerful building block for the preparation of variety of triflones such as β-lactam triflones [12c]. Recently, we have reported the synthesis of pyrazole triflones 4 via [3+2] cycloaddition of 3 with nitrostyrenes 5 (Scheme 1a) [12d]. In the presence of NaOMe, reagent 3 generates a reactive anionic triflyl-diazomethane species A in situ to react with nitrostyrenes 5. As an extension of our research work on heterocyclic triflones [12], we herein report the novel strategy for the preparation of 5-amino-N-pyrimidinyl-pyrazole triflones 2. The important precursors to access 2 are the 5-nitro-pyrazole triflones 6, which can be synthesized by the reaction of 3 with α-bromonitrostyrenes 7 under basic conditions (Scheme 1b). The selective elimination of the bromo group rather than nitro group in 7 during the cyclization step to suppress the formation of 5-bromo-pyrazole triflones 8 is the key for the success [13]. Substrate scope of 7 for the preparation of 6 was examined. Subsequently, the 5-nitro-pyrazole triflone 6c was successfully transformed to the targeted 5-amino-N-pyrimidinyl-pyrazole triflone 2a via two steps in moderated yield (Scheme 1b).

Scheme 1. a) Synthesis of pyrazole triflons 4 via [3+2] cycloaddition of 3 with nitrostyrenes 5 (previous work); b) Selective synthesis of 5-nitro-pyrazole triflons 6 and transformation of 6c to 5-amino-N-pyrimidinyl-pyrazole triflone 2a (this work).

Based on our previous work [12d], we initiated to optimize the reaction temperatures for the reactions between 3 and α-bromonitrostyrene 7a in the presence of 10 equiv of NaOMe in MeOH (Table 1). Desired 5-nitro-pyrazole triflone 6a was obtained in 62% yield along with 5-bromo-pyrazole triflone 8a in 17% yield at 0 °C for 20 min (entry 1). While, decreasing the reaction temperature to –10 °C, did not affect the yield and products distribution (entry 2). Increasing the amount of 3 from 1.2 to 1.5 equiv, slightly increased the yields of 6a to 64% and 8a to 19% (entry 3) were detected, whereas lowering the temperature with 1.5 equiv of 3 did not affect the formation of nitro product 6a with slightly increased the yield of bromo 8a to 21% (entry 4). Thus, the combination of 3 (1.5 equiv) and α-bromonitrostyrenes 7 (1.0 equiv) in the presence of NaOMe (10.0 equiv) in MeOH at 0 °C for 20 min, was selected as the optimized reaction condition (entry 3).

Table 1. Optimization of [3+2] cycloaddition reaction^a

entry	3 (equiv)	7a (equiv)	temp. (°C)	yield (%)
				6a	8a
1	1.2	1.0	0	62	17
2	1.2	1.0	–10	63	20
3	1.5	1.0	0	64	19
4	1.5	1.0	–10	64	21

^aReaction conditions: Experiments were performed with 3 (1.2 or 1.5 equiv), 7a (1.0 equiv), NaOMe (10 equiv), MeOH (1.0 mL) at given temperature for 20 min.

With the optimized reaction conditions in hand, the substrate scope of the [3+2] cyclization reaction was explored as shown in Table 2. All the reactions proceeded smoothly to furnish the desired 5-nitro-pyrazole triflones 6b—e as major products in good yields with similar selectivity as 7a. Electron donating 4-Me-C₆H₄ substituted substrate 7b provided the product in similar yield and selectivity (6b: 67%, 8b: 23%). The halogen substituted α-bromonitrostyrenes (7c: 4-Cl-C₆H₄; 7d: 3-Br-C₆H₄; 7e: 4-F-C₆H₄) provided the corresponding 5-nitro-pyrazole triflones 6 with higher yields (6c: 77%; 6d: 76%; 6e: 69%) along with corresponding bromo by-products 8 (8c: 15%; 8d: 18%; 8e: 17%) (Table 2).

Next, we examined the synthesis of 5-amino-N-pyrimidinyl-pyrazole triflone 2a. The reduction of nitro group in 6c by hydrogenation in the presence of Pd-C in MeOH gave the 5-amino-pyrazole triflone 9, followed by the nucleophilic addition to 2-chloropyrimidine in the presence of NaH under heating condition to afford the potential biological active 5-amino-N-pyrimidinyl-pyrazole triflone 2a in 35% yield for two steps (Scheme 2).

Table 2. Scope of the reaction of diazotriflone 3 with α-bromonitroalkenes 7a-e^a

entry	7	Ar	Yield (%)
			6	8
1	7a	Ph	6a: 64	8a: 19
2	7b	4-Me-C6H4	6b: 67	8b: 23
3	7c	4-Cl-C6H4	6c: 77	8c: 15
4	7d	3-Br-C6H4	6d: 76	8d: 18
5	7e	4-F-C6H4	6e: 69	8e: 17

^aExperiments were performed with 3 (1.5 equiv), 7a-e (1.0 equiv) and NaOMe (10 equiv) in dry MeOH at 0 °C for 20–25 min.

Scheme 2. Synthesis of 5-amino-N-pyrimidinyl-pyrazole triflone 2a.

In conclusion, we have disclosed the synthesis of 5-nitro-pyrazole triflones 6 via [3+2] cycloaddition reaction of 2-diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one 3 and α-bromonitrostyrene derivatives 7 under basic conditions in moderate to good yields. The transformation of 5-nitro-pyrazole triflone 6 to an agrochemically attractive 5-amino-N-pyrimidinyl-pyrazole triflone 2a was successfully demonstrated in two steps. The synthesis of a series of 5-amino-N-pyrimidinyl-pyrazole triflones and their evaluation of the insecticide property are underway.

Experimental

All reactions were performed in oven-dried glassware under positive pressure of nitrogen or argon unless mentioned otherwise. Solvents were transferred via syringe and were introduced into reaction vessels though a rubber septum. All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel (60-F₂₅₄). The TLC plates were visualized with UV light and KMnO₄ in water/heat. Column chromatography was carried out on columns packed with silica gel (60N spherical neutral size 40-50 µm) for flash column chromatography. The ¹H NMR (300 MHz), ¹⁹F NMR (282 MHz), and ¹³C NMR (126 MHz) spectra for solution in CDCl_3, CD₃OD were recorded on Varian Mercury 300, and Bruker Avance 500 NMR spectrometers. Chemical shifts (δ) are expressed in ppm downfield from TMS (δ = 0.00) or C₆F₆ [δ = −162.2 (CDCl₃)] as an internal standard. Mass spectra were recorded on a SHIMAZU LCMS-2020 (ESI-MS). High resolution mass spectrometric measurements were recorded on a Waters Synapt G2 HDMS (ESI-MS), a Waters GCT premier (EI-MS). Solvents CH₃CN, CH₂Cl₂, DMF were dried and distilled before use. 2-Diazo-1-phenyl-2-((trifluoromethyl)-sulfonyl)ethan-1-one (3) [12c] and (Z)- α-bromonitrostyrenes 7a—e [14] were prepared according to the known procedures.

Typical procedure for the synthesis of 5-nitro-4-aryl-pyrazole triflon (6) and 5-bromo-4-aryl-pyrazole triflon (8) from 3 and (Z)-1-(2-bromo-2-nitrovinyl) benzene (7) (Procedure A)

To a stirred solution of (Z)-α-bromonitrostyrenes 7 (0.1 mmol, 1.0 equiv) and 2-diazo-1-phenyl-2-((trifluoromethyl)-sulfonyl)ethan-1-one (3) (0.15 mmol, 1.5 equiv) in dry MeOH (1.0 mL), NaOMe (10.0 equiv) was added at 0 °C and the resulting mixture was stirred for 20-25 minutes under Ar atmosphere (progress of the reaction was monitored by TLC). After completion, the reaction mixture was concentrated under reduced pressure. Water was added and neutralized the solution with 5% HCl and extracted with ethyl acetate. The combined organic phase was washed with brine and dried over Na₂SO₄, and the mixture was evaporated in vacuo. The crude product was purified by flash column chromatography (DCM/MeOH = 10:1) to obtain the desired substituted 5-nitro-4-phenyl-3-((trifluoromethyl)sulfonyl)-1H-pyrazole 6 and 5-bromo-4-phenyl-3-((trifluoromethyl)sulfonyl)-1H-pyrazole 8.

5-Nitro-4-phenyl-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (6a) and 5-Bromo-4-phenyl-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (8a):

(Z)-(2-Bromo-2-nitrovinyl) benzene 7a (0.1 mmol, 0.023 g, 1.0 equiv), 3 (0.15 mmol, 0.042 g, 1.5 equiv) and NaOMe (1.0 mmol, 0.054 g, 10.0 equiv) in dry MeOH (1.0 mL) at 0 °C for 20 min provided the pure product 6a (0.0205 g, 64 %) as a pale yellow solid and 8a (0.0068 g, 19 %) as a brown solid.

6a: Mp: 313–315 °C (methanol); ¹H NMR (CDCl₃, 300 MHz) δ: 7.56–7.44 (m, 3H), 7.40–7.31 (m, 2H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –77.96 (s, 3F); ¹³C NMR (CD₃OD, 126 MHz) δ: 151.51, 138.17, 131.37, 130.22, 128.86, 127.58, 125.48, 120.81 (q, J = 324.8 Hz); IR (KBr): 3581, 3334, 3066, 1963, 1673, 1560, 1506, 1378, 1232, 1110, 921 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₅F₃N₃O₄S [M–H]^– 319.9953; found 319.9981.

8a: Mp: 152–155 °C (DCM); ¹H NMR (CDCl₃, 300 MHz) δ: 7.49–7.43 (m, 3H), 7.41–7.36 (m, 2H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.30 (s, 3F); ¹³C NMR (CDCl₃, 126 MHz) δ: 130.49, 129.92, 129.55, 129.28, 128.49, 127.82, 126.77, 119.51 (q, J = 326.0 Hz); IR (KBr): 3642, 3210, 3116, 2672, 1959, 1654, 1533, 1386, 1114, 987, 717 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₆F₃N₂O₂SBrNa [M+Na]⁺ 376.9183; found 376.9177.

5-Nitro-4-(p-tolyl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (6b) and 5-Bromo-4-(p-tolyl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (8b):

(Z)-1-(2-Bromo-2-nitrovinyl)-4-methylbenzene 7b (0.3 mmol, 0.0726 g, 1.0 equiv), 3 (0.45 mmol, 0.125 g, 1.5 equiv) and NaOMe (3.0 mmol, 0.162 g, 10.0 equiv) in dry MeOH (3.0 mL) at 0 °C for 25 min provided the pure product 6b (0.0677 g, 67%) as a pale yellow solid and 8b (0.0251 g, 23%) as a brown solid.

6b: Mp: 305–308 °C (methanol); ¹H NMR (CDCl₃, 300 MHz) δ: 7.34–7.15 (m, 4H), 2.43 (s, 3H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.12 (s, 3F); ¹³C NMR (CD₃OD, 126 MHz) δ: 155.17, 139.39, 139.21, 131.23, 129.18, 126.95, 125.27, 121.20 (q, J = 325.0 Hz), 21.37; IR (KBr): 3596, 3210, 3035, 1720, 1670, 1529, 1371, 1224, 1110, 995 cm^-1; HRMS (ESI–TOF): calcd for C₁₁H₇F₃N₃O₄S [M–H]^– 334.0109, found 334.0108.

8b: Mp: 133–134 °C (DCM); ¹H NMR (CDCl₃, 300 MHz) δ: 7.29–7.25 (m, 4H), 2.41 (s, 3H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.33 (s, 3F); ¹³C NMR (CDCl₃, 126 MHz) δ: 139.55, 130.33, 129.72, 129.23, 127.77, 125.33, 123.79, 119.53 (q, J = 325.7 Hz), 21.56; IR (KBr): 3612, 3237, 3097, 2350, 1901, 1662, 1498, 1382, 1106, 975, 717 cm^-1; HRMS (ESI–TOF): calcd for C₁₁H₈F₃N₂O₂SBrNa [M+Na]⁺ 390.9340, found 390.9333.

4-(4-Chlorophenyl)-5-nitro-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (6c) and 5-Bromo-4-(4-chlorophenyl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (8c):

(Z)-1-(2-Bromo-2-nitrovinyl)-4-chlorobenzene 7c (0.3 mmol, 0.0787 g, 1.0 equiv), 3 (0.45 mmol, 0.125 g, 1.5 equiv) and NaOMe (3.0 mmol, 0.162 g, 10.0 equiv) in dry MeOH (3.0 mL) at 0 °C for 20 min provided the pure product 6c (0.0825 g, 77 %) as a brownish yellow solid and 8c (0.0177 g, 15 %) as a brown solid.

6c: Mp: 271–273 °C (methanol); ¹H NMR (CDCl₃, 300 MHz) δ: 7.38 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 3.04 (br s, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.47 (s, 3F); ¹³C NMR (CD₃OD, 126 MHz) δ: 156.09, 139.82, 135.04, 132.99, 129.66, 128.60, 123.65, 121.26 (q, J = 325.2 Hz); IR (KBr): 3507, 3241, 3073, 2609, 1897, 1635, 1529, 1367, 1220, 1106, 848 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₄F₃N₃O₄SCl [M–H]^– 353.9563; found 353.9581.

8c: Mp: 136–138 °C (DCM); ¹H NMR (CDCl₃, 300 MHz) δ: 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.32 (s, 3F); ¹³C NMR (CDCl₃, 126 MHz) δ: 135.73, 133.76, 131.71, 130.22, 128.75, 126.43, 125.12, 119.34 (q, J = 325.9 Hz); IR (KBr): 3619, 3131, 2923, 2327, 1540, 1459, 1390, 1110, 987, 829, 717 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₄F₃N₂O₂SClBr [M–H]^– 386.8817; found 386.8824.

4-(3-Bromophenyl)-5-nitro-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (6d) and 5-Bromo-4-(3-bromophenyl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (8d):

(Z)-1-Bromo-3-(2-bromo-2-nitrovinyl)benzene 7d (0.3 mmol, 0.092 g, 1.0 equiv), 3 (0.45 mmol, 0.125 g, 1.5 equiv) and NaOMe (3.0 mmol, 0.162 g, 10.0 equiv) in dry MeOH (3.0 mL) at 0 °C for 20 min provided the pure product 6d (0.0917 g, 76 %) as a brownish yellow solid and 8d (0.024 g, 18%) as a brown solid.

6d: Mp: 266–268 °C (methanol); ¹H NMR (CDCl₃, 300 MHz) δ: 7.59 (d, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.36–7.26 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.54 (s, 3F); ¹³C NMR (CD₃OD, 126 MHz) δ: 156.12, 139.87, 134.13, 133.27, 131.95, 130.31, 130.17, 123.17, 122.15, 121.26 (q, J = 325.3 Hz); IR (KBr): 3569, 3226, 3085, 2613, 1743, 1552, 1521, 1378, 1205, 1106, 840, 624 cm^-1. HRMS (ESI–TOF): calcd for C₁₀H₄F₃N₃O₄SBr [M–H]^– 397.9058; found 397.9055.

8d: Mp: 115–116 °C (DCM); ¹H NMR (CDCl₃, 300 MHz) δ: 7.61 (d, J = 5.9 Hz, 1H), 7.54 (s, 1H), 7.40–7.31 (m, 2H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.27 (s, 3F); ¹³C NMR (CD₃OD, 126 MHz) δ: 134.51, 134.04, 133.04, 131.41, 130.96, 130.67, 129.47, 126.43, 122.86, 120.90 (q, J = 325.3 Hz); IR (KBr): 3667, 3139, 2938, 2373, 1556, 1459, 1375, 1106, 987, 871, 790, 655 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₄F₃N₂O₂SBr₂ [M–H]^– 430.8312; found 430.8305.

4-(4-Fluorophenyl)-5-nitro-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (6e) and 5-Bromo-4-(4-fluorophenyl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazole (8e):

(Z)-1-(2-Bromo-2-nitrovinyl)-4-fluorobenzene 7e (0.3 mmol, 0.0738 g, 1.0 equiv), 3 (0.45 mmol, 0.125 g, 1.5 equiv) and NaOMe (3.0 mmol, 0.162 g, 10.0 equiv) in dry MeOH (3.0 mL) at 0 °C for 20 min provided the pure product 6e (0.0706 g, 69 %) as a brownish yellow solid and 8e (0.0188 g, 17 %) as a brown solid.

6e: Mp: 352–354 °C (methanol); ¹H NMR (CDCl₃, 300 MHz) δ: 7.26–7.23 (m, 2H), 7.18–7.07 (m, 2H), 2.20 (br s, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.65 (s, 3F), –111.50 (s, 1F); ¹³C NMR (CD₃OD, 126 MHz) δ: 162.65 (d, J = 245.3 Hz), 155.03, 138.54, 131.98 (d, J = 8.6 Hz), 125.71 (d, J = 3.8 Hz), 122.47, 119.91 (q, J = 325.2 Hz), 113.82 (d, J = 22.0 Hz); IR (KBr): 3519, 3318, 3097, 2562, 1654, 1521, 1375, 1224, 1106, 991 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₄F₄N₃O₄S [M–H]^– 337.9859; found 337.9861.

8e: Mp: 116–118 °C (DCM); ¹H NMR (CDCl₃, 300 MHz) δ: 7.40–7.33 (m, 2H), 7.19–7.12 (m, 2H); ¹⁹F NMR (CDCl₃, 282 MHz) δ: –78.35 (s, 3F), –111.67– –111.86 (m, 1F); ¹³C NMR (CD₃OD, 126 MHz) δ: 164.57 (d, J = 247.0 Hz), 133.89 (d, J = 8.7 Hz), 130.72, 129.47, 127.02, 125.31 (d, J = 3.6 Hz), 120.92 (q, J = 325.1 Hz), 116.10 (d, J = 22.1 Hz); IR (KBr): 3679, 3127, 2931, 2377, 1548, 1475, 1382, 1228, 1114, 983, 755, 640 cm^-1; HRMS (ESI–TOF): calcd for C₁₀H₄F₄N₂O₂SBr [M–H]^– 370.9113; found 370.9113.

Synthesis of 4-(4-chlorophenyl)-1-(pyrimidin-2-yl)-3-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-amine (2a)

To a solution of 4-(4-chlorophenyl)-5-nitro-3-((trifluoromethyl)sulfonyl)-1H-pyrazole 6c (0.0355 g, 0.1 mmol) in MeOH was added Pd/C (0.006 g), and the mixture was stirred at rt under H₂ atmosphere (balloon) for 2.5 h. The mixture was filtered through a pad of Celite® to give the amine 9. The crude product was used for the next reaction without further purification.

The crude amine 9 was dissolved in DMF (1.0 mL). NaH (60% w/w in mineral oil, 0.0024 g, 0.1 mmol) was added to the mixture at 0 °C, and the mixture was stirred at rt for 30 min. 2-Chloropyrimidine (0.0115 g, 0.1 mmol) was added to the mixture and the mixture was stirred at 100 °C for 12 h. H₂O was added to the mixture and the mixture was extracted with EtOAc. The combined organic phase was washed with brine and dried with Na₂SO₄, and the mixture was evaporated in vacuo. The crude product was purified with flash column chromatography (eluted with CH₂Cl₂:MeOH = 20:1, the silica gel was neutralized with 1% ammonia solution in DCM prior to using) to give the 5-amino-N-pyrimidinyl-pyrazole triflone 2a (0.014 g, 35% yield) as a white solid.

Mp (DCM): 150–151 °C; ¹H NMR (300 MHz, CDCl₃) δ: 8.90 (d, J = 4.9 Hz, 2H), 7.48–7.41 (m, 3H), 7.40–7.34 (m, 2H), 6.09 (br s, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ: –78.18 (s, 3F).; ¹³C NMR (126 MHz, CDCl₃) δ: 158.96, 157.28, 148.99, 143.03, 130.72, 129.02, 128.75, 128.20, 119.74, 119.68 (q, J = 326.3 Hz), 106.98; IR (KBr): 3411, 3255, 3060, 1600, 1567, 1511, 1428, 1376, 1297, 1213, 1120, 979, 838, 794, 701, 657 cm^–1; HRMS (ESI–TOF): calcd for C₁₄H₈F₃N₅O₂SCl [M–H]^– 402.0039; found 402.0029.

Acknowledgements

This work was supported by JSPS KAKENHI grants JP 16H01142 (Middle Molecular Strategy) and JP16H01017 (Precisely Designed Catalysts with Customized Scaffolding), and ACT-C from the JST (JPMJCR12Z7). ET thanks the Pesticide Science Society of Japan for support.

See Supporting Information (¹H, ¹⁹F, ¹³C NMR Spectra) in PDF version

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Recommended for publication by Prof. Norio Shibata

Fluorine Notes, 2018, 116, 9-10