Download PDF
Synlett 2009(2): 263-267  
DOI: 10.1055/s-0028-1087665
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Approach to Original Substituted 2-Arylidene-2H-[1,4]-oxazin-3(4H)-ones via a Tandem Intramolecular P(O→C) Migration/Horner-­Wadsworth-Emmons Olefination Sequence

Elise Claveau, Isabelle Gillaizeau*, Gérard Coudert*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, Rue de Chartres, B.P. 6759, 45067 Orléans, Cedex 2, France
Fax: +33(2)38417281; e-Mail: isabelle.gillaizeau@univ-orleans.fr; e-Mail: gerard.coudert@univ-orleans.fr;
Further Information

Publication History

Received 23 September 2008
Publication Date:
15 January 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

A useful tool for the synthesis of 2-arylidene-2H-[1,4]-oxazin-3(4H)-one derivatives is described. Starting from bisvinylphosphate intermediate, the key step is an intramolecular P(O→C) migration combined with a Horner-Wadsworth-Emmons olefination as a one-pot procedure.

Key words

vinylphosphate - Horner-Wadsworth-Emmons olefination - 1,3-phosphorus migration - oxazine - arylidene

    References and Notes

  • 1a Lichtenthaler FW. Chem. Rev.  1961,  61:  607 
    Google Scholar
  • 1b Ebran J.-P. Hansen AL. Gøgsig TM. Skrydstrup T. J. Am. Chem. Soc.  2007,  129:  6931 
    Google Scholar
  • 1c Sasaki M. Fuwa H. Ebine M. Org. Lett.  2008,  10:  2275 
    Google Scholar
  • 1d Dugovic B. Reissig H.-U. Synlett  2008,  769 
    Google Scholar
  • 2a Gezginci H. Salman S. Okyar A. Baktir G. Farmaco  1997,  52:  255 
    Google Scholar
  • 2b Croce PD. Ferraccioli R. La Rosa C. Heterocycles  1995,  40:  349 
    Google Scholar
  • 2c Turk CF. Krapcho J. Michel IM. Weinryb I. J. Med. Chem.  1977,  20:  729 
    Google Scholar
  • 3a Yu H. Wang Z. Zhang L. Zhang J. Huang Q. Bioorg. Med. Chem. Lett.  2007,  17:  2126 
    Google Scholar
  • 3b Sun L. Tran N. Liang C. Hubbard S. Tang F. Lipson K. Schreck R. Zhou Y. Waltz K. McMahon G. Tang C. J. Med. Chem.  2000,  43:  2655 
    Google Scholar
  • 3c Stopeck A. Sheldon M. Vahedian M. Cropp G. Gosalia R. Hannah A. Clin. Cancer Res.  2002,  8:  2798 
    Google Scholar
  • 3d Andreani A. Burnelli S. Granaiola M. Leoni A. Locatelli A. Morigi R. Rambaldi M. Varoli L. Landi L. Prata C. Berridge MV. Grasso C. Fiebig H.-H. Kelter G. Burger AM. Kunkel MW. J. Med. Chem.  2008,  51:  4563 
    Google Scholar
  • 4a Belaud C. Roussakis C. Letourneux Y. Alami N. Villiéras J. Synth. Commun.  1985,  15:  1233 
    Google Scholar
  • 4b Kornet MJ. J. Pharm. Sci.  1979,  68:  350 
    Google Scholar
  • 4c Ikuta H. Shirota S. Kobayashi Y. Yamagishi K. Yamada K. Yamatsu I. Katayama K. J. Med. Chem.  1987,  30:  1995 
    Google Scholar
  • 4d Kim SY. Lee J. Bioorg. Med. Chem.  2004,  12:  2639 
    Google Scholar
  • 4e Janecki T. Baszczyk E. Studzian K. Janecka A. Krajewska U. Różalski M. J. Med. Chem.  2005,  48:  3516 
    Google Scholar
  • 4f Krawczyk H. Albrecht L. Wojciechowski J. Wolf WM. Krajewska U. Różalski M. Tetrahedron  2008,  64:  6307 
    Google Scholar
  • 5a Mousset D. Gillaizeau I. Sabatié A. Bouyssou P. Coudert G. J. Org. Chem.  2006,  71:  5993 
    Google Scholar
  • 5b Mousset D. Gillaizeau I. Hassan J. Lepifre F. Bouyssou P. Coudert G. Tetrahedron Lett.  2005,  46:  3703 
    Google Scholar
  • 5c Claveau E. Gillaizeau I. Blu J. Bruel A. Coudert G. J. Org. Chem.  2007,  72:  4832 
    Google Scholar
  • 5d Cottineau B. Gillaizeau I. Farard J. Auclair M.-L. Coudert G. Synlett  2007,  1925 
    Google Scholar
  • 5e Chaignaud M. Gillaizeau I. Ouhamou N. Coudert G. Tetrahedron  2008,  64:  805 
    Google Scholar
  • 6a Hammond GB. Calogeropoulou T. Wiemer DF. Tetrahedron Lett.  1986,  27:  4265 
    Google Scholar
  • 6b Calogeropoulou T. Hammond GB. Wiemer DF. J. Org. Chem.  1987,  52:  4185 
    Google Scholar
  • 7 Du Y. Wiemer DF. J. Org. Chem.  2002,  67:  5709 ; and references cited therein
    CrossrefGoogle Scholar
  • 8 Baker TJ. Wiemer DF. J. Org. Chem.  1998,  63:  2613 
    CrossrefGoogle Scholar
  • α-Phosphonolactams analogous to 3 (Scheme 1) have been prepared previously, in a number of different ways, and used in olefination processes. For recent representative examples, see:
  • 9a Gois PMP. Afonso CAM. Eur. J. Org. Chem.  2003,  3798 
    Google Scholar
  • 9b Gois PMP. Afonso CAM. Tetrahedron Lett.  2003,  44:  6571 
    Google Scholar
  • 9c Bower JF. Svenda J. Williams AJ. Charmant JPH. Lawrence RM. Szeto P. Gallagher T. Org. Lett.  2004,  6:  4727 
    Google Scholar
  • 9d Sudau A. Münch W. Bats J.-W. Nubbemeyer U. Eur. J. Org. Chem.  2002,  3315 
    Google Scholar
  • 12a Yu JS. Wiemer DF. J. Org. Chem.  2007,  72:  6263 
    Google Scholar
  • 12b Vögeli U. Von Philipsborn W. Nagarajan K. Nair MD. Helv. Chim. Acta  1978,  61:  607 
    Google Scholar
  • 12c Cabiddu S. Floris C. Melis S. Sotgiu F. Cerioni G. J. Heterocycl. Chem.  1986,  23:  1815 
    Google Scholar
  • 14 Scott WJ. Stille JK. J. Am. Chem. Soc.  1986,  108:  3033 
    CrossrefGoogle Scholar
  • 16 Minireview: Soos TJ. Meijer L. Nelson PJ. Drug News Perspect.  2006,  19:  325 
    CrossrefGoogle Scholar
  • 18a Bach S. Knockaert M. Reinhardt J. Lozach O. Schmitt S. Baratte B. J. Biol. Chem.  2005,  280:  31208 
    Google Scholar
  • 18b Bettayeb K. Tirado OM. Marionneau-Lambert S. Ferandin Y. Lozach O. Morris JC. Mateo-Lozano S. Drueckes P. Schächtele C. Kubbutat M. Liger F. Marquet B. Joseph B. Echalier A. Endicott J. Notario V. Meijer L. Cancer Res.  2007,  67:  8325 
    Google Scholar
  • 18c Reinhardt J. Ferandin Y. Meijer L. Protein Expr. Purif.  2007,  54:  101 
    Google Scholar
10

The 1,3-phosphorus migration reaction was easily followed by TLC.
Synthesis of 4-( tert -Butoxycarbonyl)-2-(diphenoxy-phosphoryl)-5-(diphenoxyphosphoryloxy)-3-oxo-2,3-dihydro-4 H -[1,4]-oxazine (3)
A solution of KHMDS (13.94 mL, 0.5 M in toluene, 6.97 mmol) in THF (20 mL) was cooled to -78 ˚C under argon. Subsequently, a solution of 1 (0.500 g, 2.32 mmol), distilled diphenyl chlorophosphate (1.373 g, 5.11 mmol), and distilled HMPA (1.041 g, 5.81 mmol) in THF (15 mL) was added dropwise over 5 min. After 15 min at -78 ˚C, KHMDS was added (4.65 mL, 2.32 mmol). After an additional hour at -78 ˚C, the reaction mixture was diluted with Et2O (85 mL). Water (125 mL) was then added, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over anhyd MgSO4, and concentrated. Flash chromatography (PE-EtOAc, 7:3) afforded 3 (0.315 g, 20%) as a pale yellow oil; R f  = 0.56 (PE-EtOAc, 6:4). IR (NaCl): 3068, 2988, 2930, 1790, 1489, 1206 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.07-7.26 (m, 20 H), 6.65 (d, 4 J HP = 2.8 Hz, 1 H), 4.92 (d, ² J HP = 16.0 Hz, 1 H), 1.42 (s, 9 H). ¹³C NMR (62.5 MHz, CDCl3): δ = 160.1 (s, J C,P = 4.5 Hz), 150.5 (s, J C,P = 7.5 Hz), 150.4 (s, J C,P = 6.5 Hz), 150.3 (s, J C,P = 7.6 Hz), 150.0 (s, J C,P = 9.6 Hz), 146.3 (s), 132.5 (s, J C,P = 8.9 Hz), 130.4 (d), 130.3 (d), 126.4 (d), 126.2(d), 122.9 (d, J C,P = 5.1 Hz), 121.1 (d), 121.0(d), 120.4 (d, J C,P = 2.1 Hz), 120.3 (d, J C,P = 2.1 Hz), 87.0(s), 74.8 (d, J C,P = 160.1 Hz), 28.0(q). MS (IS): m/z = 680.5 [M + H]+, 702.0 [M + Na]+.

11

As previously reported, the synthesis of bisvinylphosphate 2 from N-Boc morpholine-3,5-dione 1 was optimal by using KHMDS as a base (cf. ref. [5c] )

13

General Procedure for the Wiemer Rearrangement Followed by the Horner-Wadsworth-Emmons Reaction - Synthesis of (6 Z )-4-( tert -Butoxycarbonyl)-6-(3,4,5-trimethoxybenzylidene)-5,6-dihydro-5-oxo-4 H -[1,4]-oxazin-3-yl Diphenyl Phosphate (4a)
A solution of the bisvinylphosphate 2 [5c] (0.500 g, 0.74 mmol) in THF (7.5 mL) was cooled to -78 ˚C under argon. Subsequently, n-BuLi (0.552 mL, 1.6 M in hexane, 0.88 mmol) was added dropwise, and the reaction mixture was stirred for 10 min at -78 ˚C. A solution of 3,4,5-trimethoxy-benzaldehyde (0.722 g, 3.68 mmol) in THF (2 mL), previously dried over MS 4 Å, was then added dropwise. After 15 min at -78 ˚C and 150 min at 0 ˚C, the reaction mixture was diluted with Et2O (10 mL). Water (10 mL) was then added, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over anhyd MgSO4, and concentrated. Flash chromatog-raphy (PE-EtOAc, 8:2) afforded 4a (0.193 g, 42%) as a yellow oil. IR (NaCl): 2926, 1693, 1446, 1240, 1043 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 7.20-7.41 (m, 20 H), 6.90 (s, 2 H), 6.71 (d, 4 J HP = 3.3 Hz, 1 H), 6.66 (s, 1 H), 3.87 (s, 3 H), 3.85 (s, 6 H), 1.50 (s, 9 H). ¹³C NMR (62.5 MHz, CDCl3): δ = 156.2(s), 152.6 (s), 150.1 (s, J C,P = 7.4 Hz), 146.7 (s), 139.1 (s), 138.7 (s), 130.4 (s, J C,P = 7.6 Hz), 130.1(d), 127.1(s), 126.1(d), 124.5 (d), 121.4 (d, J C,P = 4.9 Hz), 120.0 (d, J C,P = 4.9 Hz), 108.0(d), 86.2 (s), 60.9 (q), 56.1 (q), 27.6(q). MS (IS): m/z = 626.5 [M + H]+, 648.5 [M + Na]+.

15

General Procedure for Stille-Type Coupling Reactions - Synthesis of (2 Z )-4-( tert -Butoxycarbonyl)-2-(3,4,5-trimethoxybenzylidene)-5-{benzo[ b ][1,4]dioxin-2-yl}-2,3-dihydro-3-oxo-[1,4]-oxazine (5a)
To a stirred solution of enol phosphate 4a (0.517 g, 0.83 mmol) in THF (16 mL), {benzo[b][1,4]dioxin-2-yl}tributyl-stannane (0.874 g, 2.07 mmol) and LiCl (0.105 g, 2.48 mmol) were added under argon. Then, the flask was evacuated and backfilled with argon three times. Under argon, Pd(PPh3)4 (0.096 g, 0.08 mmol) was added, and the mixture was heated at reflux during 150 min. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried over anhyd MgSO4, and concentrated. Flash chromatography (PE-EtOAc, 9:1 then 8:2) afforded 5a (0.247 g, 59%) as a yellow solid; mp 151-152 ˚C. IR (NaCl): 2978, 2942, 2836, 1759, 1702, 1493, 1246 cm-¹. ¹H NMR (250 MHz, CDCl3) δ = 6.95 (s, 1 H), 6.89 (s, 1 H), 6.83-6.87 (m, 2 H), 6.63-6.70 (m, 3 H), 6.20 (s, 1 H), 3.88 (s, 3 H), 3.87 (s, 6 H), 1.55 (s, 9 H). ¹³C NMR (62.5 MHz, CDCl3): δ = 156.1(s), 153.1(s), 148.0(s), 141.7 (s), 141.6(s), 140.2 (s), 139.1(s), 130.0(s), 128.5 (s), 128.0(d), 125.2 (d), 124.6 (d), 124.5 (d), 116.4 (d), 115.6 (d), 113.3 (s), 107.8 (d), 85.8 (s), 61.0(q), 56.2(q), 27.8 (q). ESI-HRMS: m/z calcd for C27H27NO9 ²³Na [M +Na]+: 532.15835; found: 532.1582.
Compound 5b: yellow solid; mp 140-141 ˚C. HRMS (EI): m/z calcd for C19H13NO4 [M - C4H8 - CO2]+ : 319.08446; found: 319.0838.
Compound 5c: yellow oil. HRMS (EI): m/z calcd for C17H11NO5 [M - C4H8 - CO2]+ : 309.06372; found: 309.0642.
Compound 5d: yellow oil. HRMS (EI): m/z calcd for C19H13NO2 [M - C4H8 - CO2]+ : 287.09463; found: 287.0969.
Compound 5e: yellow oil. HRMS (EI): m/z calcd for C16H17NO4 [M]+ : 287.11576; found: 287.1166.

17

Kinase activities assay were performed as reported in ref. [¹5] and [¹7] .