Synthèse des composés A et B

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Chapitre I Utilisation de doubles émulsions sensibles aux ultrasons pour la

I. 4.5.3.(2) Expériences avec contact de 72 h

I.7. Partie expérimentale

I.7.2 Synthèse des composés A et B

91 3-Azido-7-hydroxycoumarin (A):84

Chemical formula: C9H5N3O3 Molecular weight: 203.15 g.mol-1

A mixture of 2,4-dihydroxybenzaldehyde (3 g, 21.7 mmol, 1 equiv), N-acetylglycine (2.54 g, 21.7 mmol, 1 equiv) and sodium acetate (8.86 g, 65.1 mmol, 3 equiv) in acetic anhydride (100 mL) was refluxed under stirring for 4 h. The reaction mixture was then poured onto ice to give a yellowish precipitate, which was filtered, washed with ice water and dried under vacuum to give 1.9 g of a crude yellowish solid (1.9 g, 7.33 mmol, 34%). The crude residue was then refluxed in a mixture of concentrated HCl and ethanol (15 mL, 2:1 v/v) for 1 h. Ice water (20 mL) was then added to dilute the solution. The latter was eventually cooled in an ice bath before NaNO2 (1.01 g 14.66 mmol, 2 equiv) was added. After 15 min of stirring, NaN3 (1.43 g, 22.0 mmol, 3 equiv) was added in portions. After stirring for an additional 15 min, the resulting precipitate was filtered off, washed with water and dried under reduced pressure to give 1 (860 mg, 4.23 mmol, 20% overall yield, 58% on the last step) as a brownish solid. The spectroscopic and physical data of 1 were consistent with those reported in the literature for the same compound.

IR: 3054, 2830, 2112, 1681, 1613, 1463, 1303, 1154, 1125, 1066, 875 cm-1.

1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H, HOH), 7.57 (s, 1H, H8), 7.46 (d, J= 8.7 Hz, 1H, H6), 6.79 (dd, J= 8.5, 2.3 Hz, 1H, H5), 6.75 (d, J = 2.3 Hz, 1H, H3).

13C NMR (100 MHz, DMSO) δ 160.3 (s, C1 or C7 or C9), 157.3 (s, C1 or C7 or C9), 152.8 (s, C1 or C7 or C9), 129.1 (d, C6), 127.9 (d, C8), 121.1 (s, C2 or C4), 113.8 (d, C5), 111.4 (s, C2 or C4), 102.1 (d, C3).

3-Hydroxy-2’,3’,2”,3”-tetramethoxy-7,8-didehydro-1,2:5,6-dibenzocyclocta-1,5,7-triene (TMDIBO B):83

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2-(3,4-Dimethoxyphenyl)ethyl alcohol (5)103

Chemical formula: C10H14O3 Molecular weight: 182.22 g.mol-1

To a flame-dried round-bottom flask charged with LiAlH4 (3.9 g, 102 mmol, 2 equiv) was added THF (60 mL). The resulting mixture was cooled to 0 °C, and a solution of 3,4-(dimethoxyphenyl)acetic acid (10 g, 51 mmol, 1 equiv) in THF (60 mL) was added dropwise, over 15 min. The resulting reaction mixture was then stirred at the same temperature for 3 h and refluxed for an additional 3 h. The mixture was eventually cooled to 0 °C and EtOAc (10 mL) was slowly added, followed by the addition of H2O (20 mL). The resulting mixture was diluted with more ethyl acetate and washed first with a 2N aqueous solution of HCl, then with a saturated solution of brine. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure, to give, after flash column chromatography on silica gel (CH2Cl2/EtOAc: 10/0 to 8/2), compound 5 as a white solid. The spectroscopic and physical data of 5 were consistent with those reported in the literature for the same compound.

Rf: 0.24 (CH2Cl2/EtOAc = 9:1)

IR: 3240, 2930, 2890, 1590, 1515, 1450, 1420 cm-1.

1H NMR (400 MHz, CDCl3) δ 6.77 (m, 1H, H7), 6.72 (m, 2H, H4 or H8), 3.82 (s, 3H, H9 or H10), 3.81 (s, 3H, H9 or H10), 3.77 (t, J = 6.4 Hz, 2H, H1), 2.76 (t, J = 6.4 Hz, 2H, H2), proton from –OH was not visible on spectrum.

103 Zhao, Y.; Gu, P.; Zhang, H.; Zhang, Q.; Fan, C. J. Org. Chem. 2010, 75, 5289-5295.

93

13C NMR (100 MHz, CDCl3) δ 148.9 (s, C5 or C6), 147.5 (s, C5 or C6), 131.1 (s, C3), 120.9 (d, C8), 112.2 (d, C4 or C7), 111.3 (d, C4 or C7), 63.6 (t, C1), 55.9 and 55.8 (q, C9 and C10), 38.6 (t, C2).

(3,4-Dimethoxyphenyl)acetaldehyde (6)104

Chemical formula: C10H12O3 Molecular weight: 180.20 g.mol-1

Dess-Martin Periodinane (5.0 g, 11.78 mmol, 1.5 equiv) was added to a solution of alcohol 5 (1.4 g, 7.85 mmol, 1 equiv) in dry CH2Cl2 (15 mL). The reaction mixture was stirred at rt for 3 h, then 2 mL of a saturated aqueous solution of NaHCO3 and 2 mL of a saturated aqueous solution of Na2S2O3 were added. The resulting mixture was stirred for an additional 30 min. The pale suspension was filtered, and the organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. After flash column chromatography on silica gel (CH2Cl2/EtOAc: 10/0 à 8/2), the desired compound 6 (1.21 g, 6.71 mmol, 86%) was obtained as a colorless oil. The spectroscopic and physical data of 6 were consistent with those reported in the literature for the same compound.

Rf: 0.67 (CH2Cl2/AcOEt = 9:1)

IR: 2937, 2835, 2724, 1720, 1590, 1513, 1463, 1420, 1257, 1140, 1024 cm-1.

1H NMR (400 MHz, CDCl3) δ 9.72 (t, J = 2.5 Hz, 1H, H1), 6.86 (d, J = 8.0 Hz, 1H,H7), 6.76 (dd, J = 8.0, 2.0 Hz, 1H, H8), 6.69 (d, J = 2.0 Hz, 1H, H4), 3.87 (s, 6H, H9 and H10), 3.61 (d, J = 2.5 Hz, 2H, H2).

13C NMR (100 MHz, CDCl3) δ 199.6 (d, C1), 149.4 (s, C5 or C6), 148.5 (s, C5 or C6), 124.2 (s, C3), 121.9 (d, C8), 112.6 (d, C4), 111.7 (d, C7), 56.0 and 56.0 (q, C9 and C10), 50.2 (t, C2).

2’,3’,2”,3”-Tetramethoxy-2,3:6,7-dibenzo-9-oxabicyclo[3.3.1]nona-2,6-diene (7)105

Chemical formula: C20H22O5 Molecular weight: 342.39 g.mol-1

104 Pelphrey, P. M.; Popov, V. M.; Joska, T. M.; Beierlein, J. M.; Bolstad, E. S. D.; Fillingham, Y. A.; Wright, D. L.; Anderson, A. C. J. Med. Chem. 2007, 50, 940-950.

105 Jung, M. E.; Miller, S. J. J. Am. Chem. Soc. 1981, 103, 1984-1992.

94

To a solution of aldehyde 6 (1.2 g, 6.66 mmol, 1 equiv) in CH2Cl2 (40 mL) at –78 °C was added slowly, under vigorous stirring, iodotrimethylsilane (966 μL, 6.79 mmol, 1.02 equiv). The resulting solution was stirred for 2 h at –78 °C and then allowed to warm slowly to rt. The reaction was quenched upon reaching rt by addition of 40 mL of a 1M aqueous solution of Na2S2O3. After the color of idodine had been discharged, the reaction mixture was extracted with CH2Cl2, and combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried over anhydrous MgSO4 and concentrated under reduced pressure. After recrystallization in MeOH, the expected compound 7 (760 mg, 2.22 mmol, 67%) was obtained as a white solid. The spectroscopic and physical data of 7 were consistent with those reported in the literature for the same compound.

Rf: 0.53 (CH2Cl2/EtOAc = 9:1)

Compound 7 (110 mg, 0.32 mmol, 1 equiv), TBSOTf (75 μL, 0.32 mmol, 1 equiv) and a few crystals of phenanthroline were dissolved in THF (4 mL) à 0 °C. MeLi was added dropwise until the color of the mixture turned to reddish. n-BuLi (2.5M in THF, 260 μL, 0.64 mmol, 2 equiv) was slowly added at 0 °C and the resulting mixture was stirred at 0 °C for 2 h. A few mL of a saturated aqueous solution of NH4Cl were added to the mixture, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, and concentrated under reduced pressure. Flash column chromatography on silica gel (CH2Cl2/EtOAc: first with CH2Cl2 to remove impurities, then with EtOAc) gave compound 8 (104 mg, 0.30 mmol, 95%). The spectroscopic and physical data of 8 were consistent with those reported in the literature for the same compound.

Rf: 0.18 (CH2Cl2/EtOAc = 9:1)

95

Chemical formula: C26H36O5Si Molecular weight: 456.65 g.mol-1

To a solution of compound 8 (110 mg, 0.32 mmol, 1 equiv) in DMF (8 mL) at 0 °C, were added TBSCl (97 mg, 0.64 mmol, 2 equiv) and then imidazole (66 mg, 0.96 mmol, 3 equiv). The resulting solution was stirred at rt for 18 h. EtOAc was then added and the mixture was washed 3 times with a large amount of H2O. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give, after flash column chromatography on silica gel (PE/EtOAc = 9:1 then 8:2 then 7:3) compound 9 (94 mg, 0.21 mmol, 64%). The spectroscopic and physical data of 9 were consistent with those reported in the literature for the same compound.

Rf: 0.76 (CH2Cl2/AcOEt = 9:1)

96

Compound 9 (120 mg, 0.26 mmol, 1 equiv) was dissolved in CH2Cl2 (8 mL) and the mixture was cooled to –40 °C. Bromine (14 μL, 0.26 mmol, 1 equiv) was then added dropwise, until the brownish color persisted. The solvent was evaporated in vacuo, and the residue was directly dissolved in THF (8 mL).

N-Methylpiperazine (432 μL, 3.9 mmol, 15 equiv) was added, and then t-BuOK (117 mg, 1.04 mmol, 4 equiv). The resulting suspension was stirred for 18 h before it was poured into ice water and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The yellowish crude residue was dissolved in THF (8 mL) at 0 °C and TBAF (1M in THF, 340 μL, 0.34 mmol, 1.3 equiv) was added dropwise. The resulting mixture was finally allowed to reach rt and was stirred for an additional 45 min. A saturated aqueous solution of NaHCO3 was then added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was washed with methanol to afford compound 2 (53 mg, 0.16 mmol, 60%) as a pale yellowish solid. The spectroscopic and physical data of 2 were consistent with those reported in the literature for the same compound.

Rf: 0.32 (Hexane/EtOAc = 1:1)

IR: 3507, 3457, 1993, 1937, 1830, 2140, 1600, 1560, 1500, 1463 cm-1.

1H NMR (400 MHz, DMSO) δ 7.32 (s, 1H, H7), 7.09 (s, 1H, H14), 6.92 (d, J = 2.7 Hz, 2H, H17), 5.77

97 7-hydroxy-3-(9-hydroxy-5,6,11,12-tetramethoxy-8,9-dihydro-1H-dibenzo[3,4:7,8] cycloocta[1,2-d][1,2,3]triazol-1-yl)-2H-chromen-2-one (A-B)

Chemical Formula: C29H25N3O8 Molecular weight : 543.52 g.mol-1

Compound 1 (30 mg, 0.15 mmol, 1 equiv) and compound 2 (50 mg, 0.15 mmol, 1 equiv) were suspended in a EtOH/H2O mixture (4 mL in total, 1:1) and stirred in the dark for 1 h. EtOH was removed under reduced pressure. H2O was added and the resulting suspension was cooled in an ice bath, filtered and dried under vacuum to give a brownish solid 3 as a mixture of isomers.

IR: 2937, 1721, 1606, 1224, 1036 cm-1.

1H NMR (400 MHz, DMSO) δ 8.77 (m, 1H), 7.69-6.48 (m, 8H), 5.51 (brs, 1H), 5.07-4.92 (m, 1H), 3.82-3.70 (m, 12H, HOMe), 3.18-3.00 (m, 2H)

13C NMR (100 MHz, DMSO) δ 163.6 (s), 157.1 (s), 155.5 (s), 149.8 (s), 148.7 (s), 148.5 (s), 147.0 (s), 146.9 (s), 146.1 (s), 143.9 (d), 138.3 (s), 134.4 (s), 131.2 (d), 128.9 (s), 120.8 (s), 118.1 (s), 114.7 (d), 114.6 (d), 113.7 (d), 112.9 (d), 111.4 (d), 109.8 (d), 109.1 (d), 102.5 (d), 102.4 (d), 79.0 (s), 67.3 (d), 55.5 (q, COMe), 45.6 (t), 23.1 (t), 19.2 (t), 13.5 (d).

We were unable to separate and purify the mixture of isomers obtained, and the NMR spectra were thus almost impossible to attribute (see below for spectra).

HRMS (ESI) m/z: calculated for C29H25N3O8Na [M+Na]+: 566.1539, found: 566.1534.

Ammonium salt of Krytox:

98

Commercial Krytox® 157 FSH by DuPont™ (10 g) was dissolved in perfluorohexane FC-72 oil by 3M™ (100 mL). NH3 was bubbled under stirring for 1 h at 0 °C. NH3 bubbling was then replaced by argon to evacuate the residual ammoniac from the medium. The resulting solution of Krytox’s ammonium salt was stored at 4 °C.

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