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

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 
• 1b Ebran J.-P. Hansen AL. Gøgsig TM. Skrydstrup T. J. Am. Chem. Soc.  2007,  129:  6931 
• 1c Sasaki M. Fuwa H. Ebine M. Org. Lett.  2008,  10:  2275 
• 1d Dugovic B. Reissig H.-U. Synlett  2008,  769 
• 2a Gezginci H. Salman S. Okyar A. Baktir G. Farmaco  1997,  52:  255 
• 2b Croce PD. Ferraccioli R. La Rosa C. Heterocycles  1995,  40:  349 
• 2c Turk CF. Krapcho J. Michel IM. Weinryb I. J. Med. Chem.  1977,  20:  729 
• 3a Yu H. Wang Z. Zhang L. Zhang J. Huang Q. Bioorg. Med. Chem. Lett.  2007,  17:  2126 
• 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 
• 3c Stopeck A. Sheldon M. Vahedian M. Cropp G. Gosalia R. Hannah A. Clin. Cancer Res.  2002,  8:  2798 
• 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 
• 4a Belaud C. Roussakis C. Letourneux Y. Alami N. Villiéras J. Synth. Commun.  1985,  15:  1233 
• 4b Kornet MJ. J. Pharm. Sci.  1979,  68:  350 
• 4c Ikuta H. Shirota S. Kobayashi Y. Yamagishi K. Yamada K. Yamatsu I. Katayama K. J. Med. Chem.  1987,  30:  1995 
• 4d Kim SY. Lee J. Bioorg. Med. Chem.  2004,  12:  2639 
• 4e Janecki T. Baszczyk E. Studzian K. Janecka A. Krajewska U. Różalski M. J. Med. Chem.  2005,  48:  3516 
• 4f Krawczyk H. Albrecht L. Wojciechowski J. Wolf WM. Krajewska U. Różalski M. Tetrahedron  2008,  64:  6307 
• 5a Mousset D. Gillaizeau I. Sabatié A. Bouyssou P. Coudert G. J. Org. Chem.  2006,  71:  5993 
• 5b Mousset D. Gillaizeau I. Hassan J. Lepifre F. Bouyssou P. Coudert G. Tetrahedron Lett.  2005,  46:  3703 
• 5c Claveau E. Gillaizeau I. Blu J. Bruel A. Coudert G. J. Org. Chem.  2007,  72:  4832 
• 5d Cottineau B. Gillaizeau I. Farard J. Auclair M.-L. Coudert G. Synlett  2007,  1925 
• 5e Chaignaud M. Gillaizeau I. Ouhamou N. Coudert G. Tetrahedron  2008,  64:  805 
• 6a Hammond GB. Calogeropoulou T. Wiemer DF. Tetrahedron Lett.  1986,  27:  4265 
• 6b Calogeropoulou T. Hammond GB. Wiemer DF. J. Org. Chem.  1987,  52:  4185 
• 7 Du Y. Wiemer DF. J. Org. Chem.  2002,  67:  5709 ; and references cited therein
• 8 Baker TJ. Wiemer DF. J. Org. Chem.  1998,  63:  2613 
• 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 
• 9b Gois PMP. Afonso CAM. Tetrahedron Lett.  2003,  44:  6571 
• 9c Bower JF. Svenda J. Williams AJ. Charmant JPH. Lawrence RM. Szeto P. Gallagher T. Org. Lett.  2004,  6:  4727 
• 9d Sudau A. Münch W. Bats J.-W. Nubbemeyer U. Eur. J. Org. Chem.  2002,  3315 
• 12a Yu JS. Wiemer DF. J. Org. Chem.  2007,  72:  6263 
• 12b Vögeli U. Von Philipsborn W. Nagarajan K. Nair MD. Helv. Chim. Acta  1978,  61:  607 
• 12c Cabiddu S. Floris C. Melis S. Sotgiu F. Cerioni G. J. Heterocycl. Chem.  1986,  23:  1815 
• 14 Scott WJ. Stille JK. J. Am. Chem. Soc.  1986,  108:  3033 
• 16 Minireview: Soos TJ. Meijer L. Nelson PJ. Drug News Perspect.  2006,  19:  325 
• 18a Bach S. Knockaert M. Reinhardt J. Lozach O. Schmitt S. Baratte B. J. Biol. Chem.  2005,  280:  31208 
• 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 
• 18c Reinhardt J. Ferandin Y. Meijer L. Protein Expr. Purif.  2007,  54:  101 

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] .