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Synlett 2013; 24(2): 173-176
DOI: 10.1055/s-0032-1317958
letter
© Georg Thieme Verlag Stuttgart · New York

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

Makthala Ravi
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
,
Devireddy Anand
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
,
Ranjani Maurya
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
,
Parul Chauhan
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
,
Niraj K. Naikade
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
,
Sanjeev K. Shukla
b   Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow 226001, India
,
Prem P. Yadav*
a   Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India, Fax: +91(522)2623405   Fax: +91(522)2623938   Email: pp_yadav@cdri.res.in   Email: ppy_cdri@yahoo.co.in
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Further Information

Publication History

Received: 29 October 2012

Accepted after revision: 08 December 2012

Publication Date:
21 December 2012 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

  • 1 World Malaria Report. World Health Organization; Geneva: 2011. ; http://www.who.int/-malaria/world_malaria_report_2011/en/
    Google Scholar
  • 2 Klayman DL. Science 1985; 228: 1049
    CrossrefPubMed
    • 3a Jefford CW, Jaggi D, Boukouvalas J, Kohmoto S. J. Am. Chem. Soc. 1983; 105: 6498
      Crossref
    • 3b Kepler JA, Philip A, Lee YW, Morey MC, Caroll FI. J. Med. Chem. 1988; 31: 713
      CrossrefPubMed
    • 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
      Crossref
    • 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
      Crossref
    • 3h O’Neill PM, Mukhtar A, Ward SA, Bickley JF, Davies J, Bachi MD, Stocks PA. Org. Lett. 2004; 6: 3035
      Crossref
  • 4 Singh C, Verma VP, Naikade NK, Singh AS, Hassam M, Puri SK. J. Med. Chem. 2008; 51: 7581
    Crossref
  • 5 Singh C, Pandey S, Sharma M, Puri SK. Bioorg. Med. Chem. 2008; 16: 1816
    CrossrefPubMed
  • 6 Adam W, Duran N. J. Chem. Soc., Chem. Commun. 1972; 798
  • 7 Singh C. Tetrahedron Lett. 1990; 31: 6901
    Crossref
  • 8 Dussault PH, Trullinger TK, Noor-e-Ain F. Org. Lett. 2002; 4: 4591
    CrossrefPubMed
    • 9a Dussault PH, Davies DR. Tetrahedron Lett. 1996; 37: 463
      Crossref
    • 9b Ushigoe Y, Torao Y, Masuyama A, Nojima M. J. Org. Chem. 1997; 62: 4949
      Crossref
    • 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
      CrossrefPubMed
    • 10a Singh C, Misra D, Saxena G, Chandra S. Bioorg. Med. Chem. Lett. 1992; 2: 497
      Crossref
    • 10b Singh C, Misra D, Saxena G, Chandra S. Bioorg. Med. Chem. Lett. 1995; 5: 1913
      Crossref
    • 10c Singh C, Malik H, Puri SK. Bioorg. Med. Chem. Lett. 2004; 14: 459
      Crossref
    • 10d Singh C, Malik H, Puri SK. J. Med. Chem. 2006; 49: 2794
      CrossrefPubMed
    • 10e Singh C, Kanchan R, Sharma U, Puri SK. J. Med. Chem. 2007; 50: 521
      CrossrefPubMed
  • 11 Wong HN. C, Hon MY, Tse CW, Yip YC, Tanko J, Hudlicky T. Chem. Rev. 1989; 89: 165
    Crossref
  • 12 Singh C, Srivastav NC, Srivastav N, Puri SK. Tetrahedron Lett. 2005; 46: 2757
    Crossref
  • 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