Access to 1,3- and 1,5-Disubstituted 1,2,4-Triazoles by Condensation of Acyl Hydrazides with Formamidinium Acetate

Maximilian Bremerich

doi:10.1055/a-2370-6323

Synlett, Table of Contents

Synlett 2025; 36(05): 496-503
DOI: 10.1055/a-2370-6323

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Access to 1,3- and 1,5-Disubstituted 1,2,4-Triazoles by Condensation of Acyl Hydrazides with Formamidinium Acetate

Maximilian Bremerich ∗

Abstract

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Abstract

A simple redox-neutral method for the regioselective preparation of 1,3- and 1,5-disubstituted 1,2,4-triazoles from the corresponding unactivated acyl hydrazides and the inexpensive, non-toxic, and shelf-stable formamidinium acetate was developed. The addition of zinc salts proved to be pivotal to ensure full regioselectivity for the 1,3-disubstitution pattern, while 1,5-disubstituted 1,2,4-triazoles could be accessed without. A variety of sensitive functional groups were tolerated, and [1,2,4]triazolo[4,3-a]pyridines were obtained from the corresponding 2-hydrazopyridines without Dimroth rearrangement.

Key words

1,2,4-triazoles - formamidinium acetate - condensation - heterocycles - regioselective

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References

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31 General Procedure for the Preparation of 1,3-Disubstituted 1,2,4-Triazoles 5 from N-Alkyl/Aryl-N′-acyl Hydrazides 2 and FAc (1) A 25 mL sealable tube with magnetic stirrer bar was charged with the corresponding hydrazide 2 (3 mmol, 1 equiv), FAc 1 (9 mmol, 3 equiv), and zinc pivalate (9 mmol, 3 equiv) on air at room temperature. Non-dried 2,2,2-trifluoroethanol (9 mL, 3 v/n) was added, and the tube was sealed. It was heated to 110 °C with a heating mantle for 24 h. After cooling back to room temperature, the reaction mixture was concentrated under reduced pressure, and the semisolid residue taken up in a mixture of dichloromethane (15 mL) and 4 M aq. NaOH (15 mL). After shaking vigorously in a separation funnel, the layers were separated, and the aqueous layer was washed with dichloromethane (2 × 15 mL). The combined organic layers were washed with 4 M aq. NaOH (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column chromatography of the obtained crude product then gave the desired products. Notes: Commercial formamidinium acetate was often found to contain up to 20 mol% formamide and acetic acid as impurities and was therefore recrystallized from ethanol prior to use. For aromatic hydrazides, 6 equiv of 1 and zinc pivalate were used. The use of lower concentrated aq. NaOH in the workup led to the precipitation of zinc hydroxide, which gave inseparable emulsions. 3-Methyl-1-phenyl-1,2,4-triazole (5a)Purification by recrystallization from water/EtOH 9:1 (at 80 °C) gave the desired product (402 mg, 2.52 mmol, 84%) as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (1 H, s), 7.60–7.68 (2 H, m), 7.44–7.54 (2 H, m), 7.33–7.41 (1 H, m), 2.50 (3 H, s) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 162.2, 141.0, 137.1, 129.7, 127.8, 119.8, 14.0 ppm. LC–MS: t _Ret = 0.84 min, m/z (+) = 160 [M + H]⁺. TLC: R_f = 0.31 (silica, n-heptane/EtOAc 1:1). 3-(Isopropyl)-1-phenyl-1,2,4-triazole (5b)Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 80:20 to 50:50, 10 CV gradient) gave the desired product (470 mg, 2.51 mmol, 84%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.44 (s, 1 H), 7.62–7.71 (m, 2 H), 7.49 (t, J = 7.79 Hz, 2 H), 7.36 (m, 1 H), 3.11–3.25 (m, 1 H), 1.40 (d, J = 6.98 Hz, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 170.6, 140.8, 137.2, 129.6, 127.27, 119.8, 28.3, 21.6 ppm. LC–MS: t _Ret = 1.07 min, m/z (+) = 188 [M + H]⁺. TLC: R_f = 0.35 (silica, n-heptane/EtOAc 1:1). 3-(tert-Butyl)-1-phenyl-1,2,4-triazole (5c)Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 80:20 to 50:50, 10 CV gradient) gave the desired product (477 mg, 2.37 mmol, 79%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.67 (dd, J = 8.7, 1.2 Hz, 2 H), 7.48 (t, J = 7.9 Hz, 2 H), 7.36 (m, 1 H), 1.45 (s, 9 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 173.1, 140.7, 129.6, 127.6, 119.9, 33.0, 29.5 ppm. LC–MS: t _Ret = 1.21 min, m/z (+) = 202 [M + H]⁺. TLC: R_f = 0.44 (silica, n-heptane/EtOAc 1:1).1,3-Diphenyl-1,2,4-triazole (5d)Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 100:0 to 50:50, 10 CV gradient) gave the desired product (449 mg, 2.03 mmol, 68%) as off-white solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.38 (1 H, s), 8.10–8.17 (2 H, m), 7.91–7.99 (2 H, m), 7.57–7.64 (2 H, m), 7.42–7.56 (4 H, m) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 161.8, 143.4, 136.8, 130.4, 129.8, 129.6, 128.8, 127.8, 126.0, 119.3 ppm. LC–MS: t _Ret = 1.26 min, m/z (+) = 222 [M + H]⁺. TLC: R_f = 0.51 (silica, n-heptane/EtOAc 1:1).3-Trifluoromethyl-1-phenyl-1,2,4-triazole (5e) Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 100:0 to 50:50, 10 CV gradient) gave the desired product (416 mg, 1.95 mmol, 65%) as orange oil. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.59 (1 H, s), 7.88–7.93 (2 H, m), 7.63 (2 H, t, J = 7.4 Hz), 7.53 (1 H, t, J = 7.2 Hz) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 153.0–154.0 (q, 36.1 Hz, 1 H), 145.5, 136.5, 130.4, 129.5, 120.7 ppm. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –64.01 (3 F, s) ppm. LC–MS: t _Ret = 1.19 min, m/z (+) = 214 [M + H]⁺. TLC: R_f = 0.40 (silica, n-heptane/EtOAc 4:1).3-(2-Propenyl)-1-phenyl-1,2,4-triazole (5f)Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 100:0 to 50:50, 10 CV gradient) gave the desired product (315 mg, 1.80 mmol, 60%) as colorless crystals. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (1 H, s), 7.69–7.71 (2 H, m), 7.50 (2 H, t, J = 7.2 Hz), 7.38 (1 H, t, J = 7.2 Hz), 6.13 (1 H, quint, J = 1.0 Hz), 5.34 (1 H, quint, J = 1.6 Hz), 2.26 (3 H, t, J = 1.1 Hz) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 164.3, 141.1, 137.1, 134.5, 129.7, 127.9, 119.9, 116.6, 19.5 ppm. LC–MS: t _Ret = 1.14 min, m/z (+) = 186 [M + H]⁺. TLC: R_f = 0.30 (silica, n-heptane/EtOAc 1:1).3-(Furan-2-yl)-1-phenyl-1H-1,2,4-triazole (5g)Starting from 2 mmol of 2g, purification by FCC (25 g silica cartridge, liquid loading with DCM, DCM/MeCN 100:0 to 90:10, 10 CV gradient) gave the desired product (271 mg, 1.28 mmol, 64%) as off-white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.56 (1 H, s), 7.76 (1 H, s), 7.73–7.75 (1 H, m), 7.58 (1 H, dd, J = 1.6, 0.8 Hz), 7.53 (2 H, t, J = 7.6 Hz), 7.39–7.44 (1 H, m), 7.08 (1 H, dd, J = 3.5, 0.8 Hz), 6.56 (1 H, dd, J = 3.4, 1.7 Hz) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 156.4, 146.0, 143.5, 141.4, 136.8, 129.7, 128.2, 120.0, 111.5, 110.0 ppm. LC–MS: t _Ret = 1.06 min, m/z (+) = 212 [M + H]⁺. TLC: R_f = 0.29 (silica, DCM/MeCN 9:1).2-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine (5h)Purification by FCC (80 g silica cartridge, liquid loading with DCM, DCM/MeCN 100:0 to 90:10, 10 CV gradient) gave the desired product (222 mg, 1.14 mmol, 38%) as light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 9.03 (1 H, s), 7.75–7.85 (2 H, m), 7.29 (1 H, d, J = 7.5 Hz), 2.50 (3 H, s) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 162.9, 150.1, 149.0, 142.1, 141.5, 122.8, 110.9, 14.1 ppm. LC–MS: t _Ret = 0.93 min, m/z (+) = 195 [M + H]⁺. TLC: R_f = 0.29 (silica, DCM/MeCN 9:1). Main side product was the unmethylated derivative (167 mg, 0.93 mmol, 31%), R_f = 0.34 (silica, DCM/MeCN 9:1).
32 General Procedure for the Preparation of 1,5-Disubstituted 1,2,4-Triazoles 7 from N-Alkyl/Aryl-N-acyl Hydrazides 4 and FAc 1 or [1,2,4]Triazolo[4,3-a]pyridines 6 from 2-Hydrazopyridines 3A 25 mL sealable tube with magnetic stirrer bar was charged with the corresponding hydrazide 6 or 7 (3 mmol, 1 equiv) and FAc 1 (9 mmol, 3 equiv) on air at room temperature. Non-dried 2,2,2-trifluoroethanol (9 mL, 3 v/n) was added, and the tube was sealed. It was heated to 110 °C with a heating mantle for 1–4 h. After cooling back to room temperature, the reaction mixture was concentrated under reduced pressure, and the semisolid residue taken up in a mixture of dichloromethane (15 mL) and 10% aq. sodium carbonate solution (15 mL). After shaking vigorously in a separation funnel, the layers were separated, and the aqueous layer was washed with dichloromethane (2 × 15 mL). The combined organic layers were washed with 10% aq. sodium carbonate solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column chromatography of the obtained crude product then gave the desired products.6-Methyl-[1,2,4]triazolo[4,3-a]pyridine (6a)Purification by FCC (25 g silica cartridge, liquid loading with DCM, DCM/MeOH 95:5, 10 CV) gave the desired product (320 mg, 2.40 mmol, 80%) as off-white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.73 (1 H, s), 7.90 (1 H, s), 7.70 (1 H, d, J = 9.4 Hz), 7.12 (1 H, dd, J = 1.3, 9.4 Hz), 2.35 (3 H, s) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 148.5, 135.0, 130.9, 123.8, 120.4, 115.1, 17.7 ppm. LC–MS: t _Ret = 0.28 min (br), m/z (+) = 134 [M + H]⁺. TLC: R_f = 0.16 (silica, DCM/MeOH 95:5).5-Methyl-1-phenyl-1,2,4-triazole (7a)Purification by FCC (25 g silica cartridge, liquid loading with DCM, n-heptane/EtOAc 100:0 to 50:50, 10 CV gradient) gave the desired product (396 mg, 2.49 mmol, 83%) as yellowish oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (1 H, s), 7.41–7.58 (5 H, m), 2.54 (3 H, s) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 152.0, 151.0, 137.4, 129.4, 128.8, 124.6, 13.1 ppm. LC–MS: t _Ret = 0.77 min, m/z (+) = 160 [M + H]⁺. TLC: R_f = 0.28 (silica, n-heptane/EtOAc 1:1).5-(2-Furyl)-1-phenyl-1,2,4-triazole (7b)Purification by FCC (25 g silica cartridge, liquid loading with DCM, 3-heptane/EtOAc 100:0 to 50:50, 10 CV gradient) gave the desired product (436 mg, 2.07 mmol, 69%) as white fluffy solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (1 H, s), 7.49–7.54 (3 H, m), 7.44–7.49 (3 H, m), 6.52 (1 H, d, J = 3.5 Hz), 6.43 (1 H, dd, J = 3.5, 1.9 Hz) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 151.7, 146.2, 144.3, 142.4, 137.9, 129.6, 129.3, 126.0, 112.7, 111.6 ppm. LC–MS: t _Ret = 0.97 min, m/z (+) = 212 [M + H]⁺. TLC: R_f = 0.35 (silica, n-heptane/EtOAc 1:1).6,7-Dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (7c)320 mg (2.40 mmol, 80%) as light yellow crystalline solid without purification. ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (1 H, s), 4.14 (2 H, t, J = 7.3 Hz), 2.89–2.98 (2 H, m), 2.69–2.79 (2 H, m) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 161.1, 156.4, 45.4, 25.3, 21.3 ppm. LC–MS: t _Ret = 0.17–0.30 min (br), m/z (+) = 110 [M + H]⁺.

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