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

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

Publication History

Received: 27 April 2024

Accepted after revision: 22 July 2024

Accepted Manuscript online:
22 July 2024

Article published online:
12 August 2024

• References and Notes

• 1 Abdelli A, Azzouni S, Plais R, Gaucher A, Efrit ML, Prim D.. Tetrahedron Lett. 2021; 86: 153518
• 2 Strzelecka M, Swiatek P. Pharmaceuticals 2021; 14: 224
• 3 Sadeghian S, Emami L, Mojaddami A, Khabnadideh S, Faghih Z, Zomorodian K, Rashidi M, Rezaei Z. J. Mol. Struct. 2023; 1271: 134039
• 4 Karczmarzyk Z, Swatko-Ossor M, Wysocki W, Drozd M, Ginalska G, Pachuta-Stec A, Pitucha M. Molecules 2020; 25: 6033
• 5 Pachuta-Stec A. Mini-Rev. Med. Chem. 2022; 22: 1081
• 6 Rathod B, Kumar K. Chem. Biodiversity 2022; 19: e202200679
• 7 Gajanan KhanageS, Raju A, Baban MohiteP, Bhanudas PandhareR. Adv. Pharm. Bull. 2013; 3: 13
• 8 Paprocka R, Wiese M, Eljaszewicz A, Helmin-Basa A, Gzella A, Modzelewska-Banachiewicz B, Michalkiewicz J. Bioorg. Med. Chem. Lett. 2015; 25: 2664
• 9 Sahoo S, Sindhu KN, Sreeveena K. Res. J. Pharm. Technol. 2019; 12: 5071
• 10a Einhorn A, Bischkopff E, Szelinski B, Schupp G, Spröngerts E, Ladisch C, Mauermayer T. Justus Liebigs Ann. Chem. 1905; 343: 207
• 10b Brunner K. Ber. Dtsch. Chem. Ges. 1914; 47: 2671
• 10c Brunner K. Monatsh. Chem. 1915; 36: 509
• 11 Pellizzari G. Chem. Zentralbl. 1894; 65: 67
• 12 Atkinson MR, Polya JB. J. Chem. Soc. 1952; 3418
• 13 Huisgen R, Wulff J. Chem. Ber. 1969; 102: 1848
• 14 Yavari I, Khaledian O. Chem. Commun. 2020; 56: 9150
• 15 Plenkiewicz J, Zdrojewski T. Bull. Soc. Chim. Belg. 1987; 96: 675
• 16 Tsai S.-E, Chiang K.-H, Tseng C.-C, Chen N.-W, Chern C.-Y, Wong FF. Eur. J. Org. Chem. 2019; 1754
• 17 Paulvannan K, Chen T, Hale R. Tetrahedron 2000; 56: 8071
• 18 Curtis AD. M. Product Class 14: 1,2,4-Triazoles . In Science of Synthesis, Vol 13. Storr RC, Gilchrist TL. Thieme; Stuttgart: 2004. 603
• 19 Bruché L, Garanti L, Zecchi G. Synthesis 1985; 304
• 20 Tam A, Armstrong IS, La Cruz TE. Org. Lett. 2013; 15: 3586
• 21 Huang H, Guo W, Wu W, Li CJ, Jiang H. Org. Lett. 2015; 17: 2894
• 22 Liu JQ, Shen X, Wang Y, Wang XS, Bi X. Org. Lett. 2018; 20: 6930
• 23 Tian YT, Zhang FG, Nie J, Cheung CW, Ma JA. Adv. Synth. Catal. 2020; 363: 227
• 24 Ugi I, Fetzer U, Eholzer U, Knupfer H, Offermann K. Angew. Chem., Int. Ed. Engl. 1965; 4: 472
• 25 Lin Y.-I, Lang SA, Lovell MF, Perkinson NA. J. Org. Chem. 1979; 44: 4160
• 26 Yang N, Yuan G. J. Org. Chem. 2018; 83: 11963
• 27 Chudinov MV, Konstantinova ID, Ryzhova OI, Esipov RS, Yurkevich AM, Shvets VI, Miroshnikov AI. Pharm. Chem. J. 2005; 39: 212
• 28a Ikegami H, Jachmann M, Nokura Y, Iwata C. WO2007043677, 2007
• 28b Kamenecka TM, Jiang R, Song X, Lograsso P, Cameron MD. WO2009032861, 2009
• 28c Benbow JW, Lou J, Pfefferkorn JA, Tu MM. US20100063063, 2010
• 28d Antons S, Lui N. WO2011020579, 2011
• 28e Yates CM, Shaver SR, Hoekstra WJ. WO2017117393, 2017
• 28f Collin-Kroepelin M.-P, Kolkhof P, Neubauer T, Fuerstner C, Pook E, Wittwer MB, Lustig K, Tinel H, Lindner N, Schirmer H. WO2019081307, 2019
• 28g Horii T, Suzuki S, Roupany AJ. A, Mui JJ. B, Lewis-Marshall JP, Devan FA, Cartwright MW. WO2021149692, 2021
• 28h Liu G, Ran B, Wang Q, Zhang W, Qian G, Wang P. CN115466227, 2022
• 28i Kushida I, Komura F, Shibuguchi N. WO2023002965, 2023
• 28j Qin T, Kuang Y, Wang X, Guo P. CN117447353, 2024
• 29a Francis JE, Gorczyca LA, Mazzenga GC, Meckler H. Tetrahedron Lett. 1987; 28: 5133
• 29b Katritzky AR, Qi M, Feng D, Zhang G, Griffith MC, Watson K. Org. Lett. 1999; 1: 1189
• 29c Beyzaei H, Malekraisi F, Aryan R, Ghasemi B. Chem. Heterocycl. Compd. 2020; 56: 482
• 30 Dandia A, Singh R, Joshi J, Kumari S. Mini-Rev. Org. Chem. 2014; 11: 462
• 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]⁺.