Development of a Purely Isolable (Dimorpholino)triazine-Based Reagent for the Epoxidation of Alkenes

Abstract

A triazine-based reagent, 2-hydroperoxy-4,6-dimorpholino-1,3,5-triazine (Triazox-II), was developed for alkene epoxidation. This reagent can be prepared from inexpensive starting materials (cyanuric chloride and morpholine) on a 15 mmol scale in two steps with 54% overall yield and isolated as a pure, bench-stable solid with low sensitivity to impact and friction. Triazox-II exhibited higher solubility in chlorinated solvents than the previously reported reagent Triazox. Epoxidation using Triazox-II was conducted in various solvents, with a preference for CH₂Cl₂ at 0.5 M concentration, resulting in epoxides in 83–94% yield. The reaction was conducted under mild conditions owing to the low acidity of the reaction coproduct.

Key words

Triazox-II - triazine - morpholine - epoxidation - alkenes

Publication History

Received: 26 May 2024

Accepted after revision: 27 June 2024

Accepted Manuscript online:
28 June 2024

Article published online:
18 July 2024

• References and Notes

• 1 Yamada K, Igarashi Y, Betsuyaku T, Kitamura M, Hirata K, Hioki K, Kunishima M. Org. Lett. 2018; 20: 2015
• 2 Yamada K, Liu J, Kunishima M. Org. Biomol. Chem. 2018; 16: 6569
• 3 Kunishima M, Kawachi C, Hioki K, Terao K, Tani S. Tetrahedron 2001; 57: 1551
• 4 Kunishima M, Morita J, Kawachi C, Iwasaki F, Terao K, Tani S. Synlett 1999; 1255
• 5 Kunishima M, Kawachi C, Morita J, Terao K, Iwasaki F, Tani S. Tetrahedron 1999; 55: 13159
• 6 Kunishima M, Kawachi C, Iwasaki F, Terao K, Tani S. Tetrahedron Lett. 1999; 40: 5327
• 7 Fujita H, Hayakawa N, Kunishima M. J. Org. Chem. 2018; 83: 10684
• 8 Fujita H, Kakuyama S, Fukuyoshi S, Hayakawa N, Oda A, Kunishima M. J. Org. Chem. 2018; 83: 4568
• 9 Yamada K, Hayakawa N, Fujita H, Kitamura M, Kunishima M. Chem. Pharm. Bull. 2017; 65: 112
• 10 Yamada K, Hayakawa N, Fujita H, Kitamura M, Kunishima M. Eur. J. Org. Chem. 2016; 4093
• 11 Yamada K, Yoshida S, Fujita H, Kitamura M, Kunishima M. Eur. J. Org. Chem. 2015; 7997
• 12 Yamada K, Fujita H, Kitamura M, Kunishima M. Synthesis 2013; 45: 2989
• 13 Yamada K, Fujita H, Kunishima M. Org. Lett. 2012; 14: 5026
• 14 Hussain H, Al-Harrasi A, Green IR, Ahmed I, Abbas G, Rehman NU. RSC Adv. 2014; 4: 12882
• 15 Rao AS, Mohan HR, Charette A. In Encyclopedia of Reagents for Organic Synthesis, Wiley . 2005.
• 16 Schwartz NN, Blumbergs JH. J. Org. Chem. 1964; 29: 1976
• 17 Mikula H, Svatunek D, Lumpi D, Glöcklhofer F, Hametner C, Fröhlich J. Org. Process Res. Dev. 2013; 17: 313
• 18 Crandall JK, Curci R, D’Accolti L, Fusco C, Schomaker JM, Nicastri KA. In Encyclopedia of Reagents for Organic Synthesis. Wiley,; 2021.
• 19 Murray RW. Chem. Rev. 1989; 89: 1187
• 20 Sato D, Wu Z, Fujita H, Lindsey JS. Organics 2021; 2: 161
• 21 Afonso C, Lourenco N, Rosatella A. Molecules 2006; 11: 81
• 22 Steffensen MB, Hollink E, Kuschel F, Bauer M, Simanek EE. J. Polym. Sci., Part A: Polym. Chem. 2006; 44: 3411
• 23 Armarego WL. F. Purification of Laboratory Chemicals, 8th ed. Butterworth-Heinemann; Oxford: 2017
• 24 El-Faham A, Soliman SM, Ghabbour HA, Elnakady YA, Mohaya TA, Siddiqui MR. H, Albericio F. J. Mol. Struct. 2016; 1125: 121
• 25 Ando T, Fujimoto Y, Morisaki S. J. Hazard. Mater. 1991; 28: 251
• 26 Japanese Industrial Standards K 4810, Testing Methods of Explosives; Japanese Standards Association: Tokyo; 2019.
• 27 UN recommendations on the transport of dangerous goods: Manual of Tests and Criteria, 8th ed. . United Nations; New York/Geneva: 2023. accessed July 11, 2024 https://unece.org/transport/standards/transport/dangerous-goods/un-manual-tests-and-criteria-rev8-2023
• 28 Marcus Y. The Properties of Solvents . John Wiley & Sons; Chichester: 1998
• 29 Hoveyda AH, Evans DA, Fu GC. Chem. Rev. 1993; 93: 1307
• 30 General Procedure for the Epoxidation of Alkenes Using Triazox-II Triazox-II (1.1–1.2 equiv.) was added to a solution of alkene 2 (1 equiv.) in CH₂Cl₂ (0.5 M) at room temperature. The reaction mixture was stirred until TLC monitoring indicated complete conversion. The reaction mixture was quenched by adding 2-methyl-2-butene (10 equiv.). After 30 min, the reaction mixture was passed through a pad of silica gel. The eluent was concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired epoxide 3.
• 31 Synthesis of 1-Phenyl-1,2-epoxycyclohexane (3a) The general procedure was followed using 2a (80 μL, 0.50 mmol), Triazox-II (156 mg, 0.55 mmol), CH₂Cl₂ (1.00 mL), and 2-methyl-2-butene (530 μL, 5 mmol). The reaction mixture was stirred at room temperature for 3 h. Column chromatography (silica gel, hexane/EtOAc = 19:1) afforded a colorless oil (78.4 mg, 90%). ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.29 (m, 4 H), 7.29–7.23 (m, 1 H), 3.10–3.05 (m, 1 H), 2.28 (ddd, J = 14.9, 8.8, 5.6 Hz, 1 H), 2.12 (ddd, J = 14.9, 5.4, 5.4 Hz, 1 H), 2.06–1.93 (m, 2 H), 1.66–1.42 (m, 3 H), 1.38–1.25 (m, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 142.6, 128.4, 127.3, 125.4, 62.0, 60.3, 29.0, 24.8, 20.2, 19.9. LRMS (DART-TOF): m/z = 175 ([M + H]⁺). The NMR spectra were identical with those previously reported.¹