Synthesis of 1,2,4-Trioxepanes and 1,2,4-Trioxanes via H₂O₂-Mediated Reaction of Tertiary Carbinols

Abstract

A facile and efficient method for the synthesis of 1,2,4-trioxepanes and 1,2,4-trioxanes from different carbinols having cyclopropyl and phenyl substituents has been developed. The corresponding hydroxyhydroperoxides were synthesized from 30% H₂O₂ mediated reaction of carbinols in acidic conditions. This method provided access to novel 6,6-diaryl-substituted 1,2,4-trioxanes derived from benzilic acid.

Key words

1,2,4-trioxanes - 1,2,4-trioxepanes - hydrogen peroxide - carbinols - antimalarial

• References and Notes

• 1 World Malaria Report. World Health Organization; Geneva: 2011. ; http://www.who.int/-malaria/world_malaria_report_2011/en/
• 2 Klayman DL. Science 1985; 228: 1049
• 3a Jefford CW, Jaggi D, Boukouvalas J, Kohmoto S. J. Am. Chem. Soc. 1983; 105: 6498
• 3b Kepler JA, Philip A, Lee YW, Morey MC, Caroll FI. J. Med. Chem. 1988; 31: 713
• 3c Fujisaku T, Miura M, Nojima M, Kasabayashi S. J. Chem. Soc., Perkin Trans. 1 1989; 1031
• 3d Bloodworth AJ, Shah A. J. Chem. Soc., Chem. Commun. 1991; 947
• 3e Bunelle WH, Isbell TA, Barnes CL, Qualls S. J. Am. Chem. Soc. 1991; 113: 8168
• 3f Bloodworth AJ, Johnson KA. Tetrahedron Lett. 1994; 35: 8057
• 3g O’Neill PM, Pugh M, Davies J, Ward SA, Park BK. Tetrahedron Lett. 2001; 42: 4569
• 3h O’Neill PM, Mukhtar A, Ward SA, Bickley JF, Davies J, Bachi MD, Stocks PA. Org. Lett. 2004; 6: 3035
• 4 Singh C, Verma VP, Naikade NK, Singh AS, Hassam M, Puri SK. J. Med. Chem. 2008; 51: 7581
• 5 Singh C, Pandey S, Sharma M, Puri SK. Bioorg. Med. Chem. 2008; 16: 1816
• 6 Adam W, Duran N. J. Chem. Soc., Chem. Commun. 1972; 798
• 7 Singh C. Tetrahedron Lett. 1990; 31: 6901
• 8 Dussault PH, Trullinger TK, Noor-e-Ain F. Org. Lett. 2002; 4: 4591
• 9a Dussault PH, Davies DR. Tetrahedron Lett. 1996; 37: 463
• 9b Ushigoe Y, Torao Y, Masuyama A, Nojima M. J. Org. Chem. 1997; 62: 4949
• 9c Ushigoe Y, Kano Y, Nojima M. J. Chem. Soc., Perkin Trans. 1 1997; 5
• 9d Ahmed A, Dussault PH. Org. Lett. 2004; 6: 3609
• 10a Singh C, Misra D, Saxena G, Chandra S. Bioorg. Med. Chem. Lett. 1992; 2: 497
• 10b Singh C, Misra D, Saxena G, Chandra S. Bioorg. Med. Chem. Lett. 1995; 5: 1913
• 10c Singh C, Malik H, Puri SK. Bioorg. Med. Chem. Lett. 2004; 14: 459
• 10d Singh C, Malik H, Puri SK. J. Med. Chem. 2006; 49: 2794
• 10e Singh C, Kanchan R, Sharma U, Puri SK. J. Med. Chem. 2007; 50: 521
• 11 Wong HN. C, Hon MY, Tse CW, Yip YC, Tanko J, Hudlicky T. Chem. Rev. 1989; 89: 165
• 12 Singh C, Srivastav NC, Srivastav N, Puri SK. Tetrahedron Lett. 2005; 46: 2757
• 13 Representative Procedure for the Synthesis of 1,2,4-Trioxepane 5 To an ice-cooled (0–5 °C) solution of 1,3-diol 4 (1.00 g, 5.2 mmol) in CH₂Cl₂ (50 mL) was added 30% H₂O₂ (0.64 mL, 20.8 mmol) followed by dropwise addition of concd H₂SO₄ (0.14 mL, 2.6 mmol) with constant stirring, and the mixture was stirred at 0–5 °C for 3 h. The reaction mixture was diluted with cold H₂O (25 mL), and the aqueous layer was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with sat. aq NaHSO₃ solution (25 mL) and H₂O (2 × 25 mL). The combined organic layer was dried (Na₂SO₄), the solution reduced to 50 mL under reduced pressure, and the crude hydroxyhydroperoxide was reacted with cyclohexanone (0.74 mL, 7.2 mmol) in the presence of PTSA (0.2 g, 1 mmol) with stirring for 1.5 h at 0–5 °C. The reaction mixture was concentrated in vacuo at r.t., and the crude product was purified by column chromatography over silica gel using 1.0% EtOAc–hexane as eluent to furnish 0.97g (65%) of 5 as a white solid.
• 14 Compound 5: mp 94–95 °C. FT-IR (KBr): 2933.9, 1659.3, 755.6 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.14–0.37 (m, 4 H), 1.03 (br s, 1 H), 1.33–1.57 (m, 8 H), 1.96 (br d, 2 H), 2.28 (br d, 1 H), 2.57 (br d, 1 H), 3.73–3.85 (m, 2 H), 7.25–7.37 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 1.02 (CH₂), 1.36 (CH₂), 20.43 (CH), 22.81 (CH₂), 23.07 (CH₂), 25.5 (2 × CH₂), 32.73 (CH₂), 41.12 (CH₂), 59.17 (CH₂), 87.86 (C), 106.19 (C),126.85 (CH), 127.05 (CH), 127.64 (CH), 141.31 (C). APCI-MS: m/z = 287 [M + H⁺]. Anal. Calcd for C₁₈H₂₄O₃: C, 74.97; H, 8.39. Found: C, 74.91; H, 8.43.
• 15 Compound 13: yield 62%, white solid, mp 100–101 °C. FT-IR (KBr): 2937, 1661.2, 764.9 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.46–1.76 (m, 10 H), 4.54 (s, 2 H), 7.26–7.37 (m, 6 H), 7.43–7.46 (m, 4 H). ¹³C NMR (75MHz, CDCl₃): δ = 24.01 (2 × CH₂), 25.23 (CH₂), 36.12 (2 × CH₂), 74.80 (CH₂), 85.72 (C), 111.33 (C), 126.22 (4 × CH), 127.16 (2 × CH), 128.16 (4 × CH), 144.88 (2 × C). APCI-MS: m/z = 311 [M + H]⁺. Anal. Calcd for C₂₀H₂₂O₃: C, 77.39; H, 7.14. Found: C, 77.43; H, 7.20