Mechanochemical Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazoles Mediated by PPh3-TCCA

Dolnapa Yamano; Nittaya Wiriya; Wong Phakhodee; Sirawit Wet-osot; Mookda Pattarawarapan

doi:10.1055/s-0040-1719867

Synlett, Table of Contents

Synlett 2022; 33(14): 1458-1462
DOI: 10.1055/s-0040-1719867

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Organic Chemistry in Thailand

Mechanochemical Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazoles Mediated by PPh₃-TCCA

Dolnapa Yamano

^aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

,

Nittaya Wiriya

^aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

,

Wong Phakhodee

^aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

^bResearch Center on Chemistry for Development of Health Promoting Products from Northern Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand

,

Sirawit Wet-osot

^cMedical Life Science Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand

,

Mookda Pattarawarapan∗

^aDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

^bResearch Center on Chemistry for Development of Health Promoting Products from Northern Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand

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Abstract

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Abstract

Mechanochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles was developed as an environmentally benign alternative to conventional solvent-based methods. In the presence of triphenylphosphine and trichloroisocyanuric acid, N-acylbenzotriazoles condense with acylhydrazides leading to oxadiazoles derivatives in good to excellent yields within minutes. The approach circumvents the need for strictly anhydrous conditions, external heating, long reaction times, as well as tedious multistep procedures. A range of substrates with reactive functionalities was also well tolerated.

Keywords

N-acylbenzotriazole - liquid-assisted grinding - mechanosynthesis - 1,3,4-oxadiazoles - triphenylphosphine - trichloroisocyanuric acid

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References

References and Notes

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18 Synthesis of 2; General Procedure: N-Acylbenzotriazole (0.54 mmol) was mixed with acylhydrazide (0.54 mmol) and ground in mortar for 2–5 min, during which a few drops of acetone/CH₂Cl₂ (1:2 v/v, less than 1 μL/mg solids) were added to aid the homogeneous mixing. TCCA (0.0502 g, 0.216 mmol), PPh₃ (0.1699 g, 0.648 mmol), and NaHCO₃ (0.1361 g, 1.62 mmol) were then added before further grinding until completion of the reaction as indicated by TLC. It is noted that the grinding was stopped intermittently for TLC analysis using a glass capillary tube filled with ethanol for TLC sampling. The semi-solid mixture was then dissolved in acetone (ca. 2 mL), followed by filtration of the solids before solvent removal in vacuo. The crude material was purified by column chromatography using ethyl acetate/hexanes as the eluent to afford pure product. Note: Five new compounds including 2k, 2m, 2n, 2t, 2u were fully characterized, while the spectral data for the known products were consistent with the reported data. tert-Butyl (S)-(1-(5-Phenyl-1,3,4-oxadiazol-2-yl)ethyl)carbamate(2k). Yield: 0.1217g (78%); white solid; mp 117–119 °C; R_f 0.31 (20% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 8.02–7.99 (m, 2 H), 7.53–7.44 (m, 3 H), 5.35 (d, J = 8.4 Hz, 1 H), 5.16 (quint, J = 7.2 Hz, 1 H), 1.63 (d, J = 7.2 Hz, 3 H), 1.44 (s, 9 H). Benzyl (S)-(2-Phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)carbamate(2l). Yield: 0.1702g (79%); yellow solid; mp 109–111 °C; R_f 0.31 (20% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (d, = 7.2 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.33–7.19 (m, 10 H), 6.10 (br s, 1 H), 5.49 (dd, J = 15.2, 7.6 Hz, 1 H), 5.13 (dd, J = 15.2, 12.4 Hz, 2 H), 3.43–3.31 (m, 2 H). (9H-Fluoren-9-yl)methyl (S)-(2-(4-(tert-Butoxy)phenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)carbamate (2m). Yield: 0.2446g (81%); colorless oil; R_f 0.30 (20% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.4 Hz, 2 H), 7.75 (d, J = 7.6 Hz, 2 H), 7.58 (t, J = 7.6 Hz, 2 H), 7.53 (t, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 2 H), 7.05 (d, J = 7.6 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 6.06 (d, J = 9.2 Hz, 1 H), 5.42 (q, J = 7.6 Hz, 1 H), 4.46–4.35 (m, 2 H), 4.19 (t, J = 6.8 Hz, 1 H), 3.29 (d, J = 6.8 Hz, 2 H), 1.27 (s, 9 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 166.0, 165.0, 155.6, 154.6, 143.74, 143.68, 141.3, 131.9, 130.1, 129.9, 129.0, 127.7, 127.1, 126.9, 125.1, 124.3, 123.5, 120.0, 78.5, 67.2, 49.2, 47.1, 39.3, 28.8. HRMS (ESI/QTOF): m/z [M + H]⁺ calcd for C₃₅H₃₄N₃O₄: 560.2544; found: 560.2541.2-(5-(4-Fluorobenzyl)-1,3,4-oxadiazol-2-yl)phenol (2t). Yield: 0.0904 g (62%); white solid; mp 97–99 °C; R_f 0.41(10% EtOAc/hexanes).¹H NMR (400 MHz, CDCl₃): δ = 10.06 (s, 1 H), 7.66 (dd, J = 8.0, 1.6 Hz, 1 H), 7.41 (ddd, J = 8.0,7.2, 1.6 Hz, 1 H), 7.36–7.31 (m, 2 H), 7.10–7.03 (m, 3 H), 6.96 (ddd, J = 8.0,7.2, 1.6 Hz, 1 H), 4.26 (s, 2 H).¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 164.9, 164.0, 163.61, 161.16 (d, ¹ J _C–F = 345.0 Hz), 157.6, 133.7, 130.63, 130.55 (d, ³ J _C–F = 8.0 Hz), 129.23, 129.20 (d, ⁴ J _C–F = 3.0 Hz), 126.6, 119.9, 117.6, 116.16, 115.95 (d, ² J _C–F = 21.0 Hz), 108.0, 31.0. HRMS (ESI/QTOF): m/z [M + H]⁺ calcd for C₁₅H₁₂FN₂O₂: 271.0877; found: 271.0875.2-(5-(Pyridin-3-yl)-1,3,4-oxadiazol-2-yl)phenol(2u). Yield: 0.0839 g (65%); white solid; mp 132–134 °C; R_f 0.37(20% EtOAc/hexanes 2× developed). ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (s, 1 H), 9.31 (dd, J = 2.4, 1.2 Hz, 1 H), 8.78 (dd, J = 4.8, 1.2 Hz, 1 H), 8.38 (dt, J = 8.0, 4.8, 1.6 Hz, 1 H), 7.80 (dd, J = 8.0, 7.2, 1.6 Hz, 1 H), 7.49–7.40 (m, 2 H), 7.09 (dd, J = 8.4, 1.2 Hz, 1 H), 7.00 (ddd, J = 8.4,7.2, 1.2 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 164.7, 161.2, 157.8, 152.8, 148.0, 134.3, 134.1, 126.6, 124.0, 120.1, 119.9, 117.8, 107.7.

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