Les réactions sensibles à l’air et/ou à l’eau ont été réalisées sous argon et suivies par
chromatographie sur couche mince (CCM) en utilisant les plaques de silice 60 F254 (SDS) de 0,25 mm d’épaisseur. Les produits ont été visualisés sous lumière UV (254 et 366 nm) ou révélés à
l’aide de différents réactifs tels que l’acide phosphomolybdique, le permanganate de potassium, la vaniline ou encore la ninhydrine.
Les solvants de réactions utilisés étaient soit anhydres à plus de 99% sous septum et azote, soit purifiés par distillation. Le THF a été distillé sur sodium en présence de benzophénone sous argon, CH2Cl2 a été distillé sur P2O5. La triéthylamine et la diisopropylamine ont été distillées sur hydrure de calcium. Les autres solvents commerciaux, de qualité «purex» ou «HPLC», ont été utilisés tels quels.
Les réactifs, achetés chez Sigma-Aldrich, VWR, Fisher, TCI et Carbosynth, ont été utilisés sans purification préalable.
Les purifications ont été réalisées dans des conditions de «flash-chromatographie», sur un gel de silice (colonnes prépaquée Redi Sep, 35-70 μm) sous pression moyenne de 20 psi à l’aide d’un CombiFlash Companion.
Les spectres RMN ont été réalisés à l’aide de spectromètres Avance Bruker 300 MHz et 500 MHz et à l’aide du programme d’acquisition Topspin 2.1. Pour chaque composé, le solvant et le champ sont précisés. Les données ont été traitées avec le logiciel nmrNotebook. Des expériences à une dimension (1H, 13C, 31P) comme à deux dimensions ont pu être réalisées (corrélation homonucléaire
1
H-1H COSY et hétéronucléaire 1H-13C HMQC et HMBC).
Les déplacements chimiques (δ) sont exprimés en ppm (partie par million) relativement au solvant utilisé comme référence interne :
- chloroforme-d : 7,26 ppm pour la RMN 1H ; 77,16 ppm pour la RMN 13C. - méthanol-d4 : 3,31 ppm pour la RMN 1H ; 49,00 ppm pour la RMN 13C. - benzène-d6 : 7,16 ppm pour la RMN 1H ; 128,06 ppm pour la RMN 13C.
Les constantes de couplage (J) sont exprimées en hertz (Hz). La multiplicité des signaux est désignée comme suit : s (singulet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br s (singulet élargi).
Les spectres de masse ont été realisés avec une UPLC Acquity Waters, équipée d’un détecteur PDA Acquity Waters sur une plage de longueur d’onde allant de 210 à 410 nm. La séparation est réalisée sur colonne C18 BEH avec un débit de 0,6 mL/min et un gradient en eau/acétonitrile allant de 95:5 à 0:100 en 5 min. L’UPLC est couplée à un spectromètre de masse Waters LCT Premier XE, équipé d’une ionisation ESI ou APCI en mode positif ou négatif sur une gamme de masse de 80 à 1500 m/z.
Les spectres d’absorption infrarouge ont été enregistrés à l’aide d’un spectromètre à transformée de Fourier Perkin-Elmer Spectrum 100 équipé de l’accessoire ATR Diamant qui permet d’utiliser tout type de produit solide ou liquide sans dilution. Les nombres d’onde des bandes d’absorption sont exprimés en cm-1.
Les pouvoirs rotatoires ont été mesurés, à température ambiante, à l’aide du polarimètre Jasco P-1010, dans des cellules de 1 mL. La concentration (c) et le solvant sont précisés pour chaque mesure.
Les points de fusion ont été pris sur un appareil à point de fusion digital Büch B-540 au moyen de tubes capillaires.
La nomenclature est cohérente avec les règles IUPAC pour la majorité des composés décrits. La numérotation est, quant à elle, arbitraire et n’a pas de rapport avec la nomenclature officielle.
1-(4-Bromobutyl)-4-methoxybenzene132a
C11H15BrO 242.14 g.mol-1
To a solution of 4-(4-methoxyphenyl)butan-1-ol (0.29 mL, 1.66 mmol) in CH2Cl2 (10.4 mL), at 0 °C, was added CBr4 (717.6 mg, 2.16 mmol) and PPh3 (742.1 mg, 2.83 mmol) in portions. After 15 min at this temperature, the reaction mixture was diluted with hexane and filtered through a Celite® pad, concentrated and purified on a silica gel cartridge (98:2 Heptane/AcOEt) to give the desired product as a colorless oil (400 mg, 100%). IR υmax (cm-1): 2934, 1611, 1512. 1 H NMR (300 MHz, CDCl3): δ 7.11 (d, J = 8.5 Hz, 2 H, H4), 6.85 (d, J = 8.5 Hz, 2 H, H3), 3.80 (s, 3 H, H1), 3.42 (t, J = 6.6 Hz, 2 H, H9), 2.59 (t, J = 7.4 Hz, 2 H, H6), 1.87 (quint., J = 7.0 Hz, 2 H, H8), 1.76 (quint., J = 7.0 Hz, 2 H, H7). 13 C NMR (75 MHz, CDCl3): δ157.8 (C2), 133.9 (C5), 129.2 (2 C, C4), 113.8 (2 C, C3), 55.3 (C1), 34.1 (C6), 33.7 (C9), 32.2 (C7), 30.1 (C8). MS ES+/-: No answer I-029
1-(4-Iodobutyl)-4-methoxybenzene132b
C11H15IO 290.14 g.mol-1
Imidazole (280.4 mg, 4.12 mmol) and PPh3 (518.6 mg, 1.98 mmol) were added to a solution of 4-(4-methoxyphenyl)butan-1-ol (0.19 mL, 1.09 mmol) in dry CH2Cl2 (27 mL). A solution of iodine (487.9 mg, 1.92 mmol) in dry CH2Cl2 (4.8 mL) was added dropwise. The mixture was stirred for 1.5 h at room temperature. The mixture was extracted with HCl/AcOEt and washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. Purification on a silica gel cartridge (98:2 Heptane/AcOEt) gave the desired product as a colorless oil (316.1 mg, 100%).
IR υmax (cm-1): 2931, 1611, 1510. 1 H NMR (300 MHz, CDCl3): δ 7.11 (d, J = 8.6 Hz, 2 H, H4), 6.85 (d, J = 8.6 Hz, 2 H, H3), 3.80 (s, 3 H, H1), 3.23 (t, J = 7.0 Hz, 2 H, H9), 2.59 (t, J = 7.4 Hz, 2 H, H6), 1.86 (quint., J = 7 Hz, 2 H, H8), 1.72 (quint., J = 7 Hz, 2 H, H7). 13 C NMR (75 MHz, CDCl3): δ157.8 (C2), 133.8 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 55.2 (C1), 33.8 (C6), 32.9 (C7), 32.4 (C8), 6.8 (C9). MS ES+/-: No answer I-030
6-(4-Methoxyphenyl)hex-5-enoic acid135
C13H16O3 220.26 g.mol-1
To a solution of 97% (3-carboxy)triphenylphosphonium bromide (10.6 g, 23.9 mmol) in 1:1 DMSO/THF (96 mL) was added 4-methoxybenzaldehyde (2.9 mL, 23.8 mmol). Then NaH (60% dispersion in mineral oil, 1.91 g, 47.8 mmol) was added in one portion at 0 °C. The resulting suspension was stirred at this temperature for 30 min, allowed to slowly warm up to room temperature and stirred at this temperature for 7 h. At 0 °C, ice and water were added followed by 1 M HCl. The product was extracted with ether and dried over Na2SO4 and the solvent was evaporated under vacuum. The desired product was obtained after chromatography on a silica gel cartridge (60:40 Heptane/AcOEt) as a yellow solid and as a 60:40 mixture of isomers E/Z (5.05 g, 96%, mp: 40.5-41.8 °C). IR υmax (cm-1): 3100, 1605. 1 H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.3 Hz, 1.2 H, H4E), 7.23 (d, J = 8.3 Hz, 0.8 H, H4Z), 6.90 (d, J = 8.3 Hz, 0.8 H, H3Z), 6.86 (d, J = 8.3 Hz, 1.2 H, H3E), 6.43 (d, J = 11.7 Hz, 0.4 H, H6Z), 6.38 (d, J = 15.6 Hz, 0.6 H, H6E), 6.06 (dt, J = 15.6, 7.3 Hz, 0.6 H, H7E), 5.56 (dt, J = 11.7, 7.3 Hz, 0.4 H, H7E), 3.83 (s, 1.2 H, H1Z), 3.82 (s, 1.8 H, H1E), 2.36-2.46 (m, 2.8 H, H10, H8Z), 2.28 (q, J = 7.3 Hz, 1.2 H, H8E), 1.78-1.88 (m, 2 H, H9). 13 C NMR (75 MHz, CDCl3): δ179.9 (0.6 C, C11E), 179.7 (0.4 C, C11Z), 158.7 (0.6 C, C2E), 158.3 (0.4 C, C2Z), 130.34 (0.8 C, C4Z), 130.28 (1.2 C, C4E), 130.1 (0.6 C, C5E), 129.9 (0.4 C, C5Z), 129.8 (0.6 C, C6E), 129.3 (0.4 C, C6Z), 127.13 (0.6 C, C7E), 127.10 (0.4 C, C7Z), 113.9 (1.2 C, C3E), 113.6 (0.8 C, C3Z), 55.24 (0.6 C1E), 55.21 (0.4 C1z), 33.5 (0.4 C, C10Z), 33.3 (0.6 C, C10E), 32.2 (0.6 C, C8E), 27.8 (0.4 C, C8Z), 24.8 (0.4 C, C9Z), 24.3 (0.6 C, C9E). MS ES-: m/z 219.1 (100, [M-H]-).
HRMS: calculated for C13H15O3 (M-H) 219.1021, found 219.1014. I-035
6-(4-Methoxyphenyl)hexanoic acid135
C13H18O3 222.28 g.mol-1
To a solution of compound I-035 (E/Z 65:35) (3.74 g, 17.0 mmol) in THF (85 mL) was added 10% palladium on carbon (1.8 g). The mixture was stirred under hydrogen atmosphere until the reactant was completely consumed. The mixture was then filtered through a pad of Celite® and the solvent
was removed under vacuum. The desired compound was obtained as a white solid (mp: 41.5-42.1 °C, 3.66 g, 97%). IR υmax (cm-1): 3100. 1 H NMR (500 MHz, CDCl3): δ 10.74 (brs, 1 H, H12), 7.11 (d, J = 8.7 Hz, 2 H, H4), 6.84 (d, J = 8.7 Hz, 2 H, H3), 3.81 (s, 3 H, H1), 2.58 (t, J = 8.0 Hz, 2 H, H6), 2.37 (t, J = 8.0 Hz, 2 H, H10), 1.69 (quint., J = 8.0 Hz, 2 H, H7), 1.63 (quint., J = 8.0 Hz, 2 H, H9), 1.40 (quint., J = 7.1 Hz, 2 H, H8). 13 C NMR (75 MHz, CDCl3): δ 179.1 (C11), 157.7 (C2), 134.5 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 55.3 (C1), 34.8 (C6), 33.8 (C10), 31.3 (C7), 28.6 (C8), 24.5 (C9). MS ES-: m/z 221.1 (100, [M-H]-), 443.2 (40, [2M-H]-).
HRMS: calculated for C13H17O3 (M-H) 221.1178, found 221.1175. I-036
S-Pyridin-2-yl 6-(4-methoxyphenyl)hexanethioate
C18H21NO2S 315.43 g.mol-1
To a stirred solution of compound I-036 (3.6 g, 16.2 mmol) in CH2Cl2 (81 mL) were added oxalyl chloride (2.12 mL, 24.3 mmol) and a catalytic amount of anhydrous DMF at room temperature and the reaction mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. To the oil residue was added a solution of 2-mercaptopyridine (2.16 g, 19.4 mmol) in CH2Cl2 (81 mL) followed by Et3N (4.52 mL, 32.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then quenched with 1 M HCl and neutralized by washing with saturated NaHCO3. The organic layer were combined and evaporated. After purification by flash chromatography on a silica gel cartridge (80:20 Heptane/AcOEt), the desired product was obtained as a yellow oil (3.7 g, 73%). IR υmax (cm-1): 1704. 1 H NMR (300 MHz, CDCl3): δ 8.64 (d, J = 4.3 Hz, 1 H, H16), 7.76 (t, J = 7.6 Hz, 1 H, H14), 7.62 (d, J = 7.6 Hz, 1 H, H13), 7.26-7.34 (m, 1 H, H15), 7.11 (d, J = 8.1 Hz, 2 H, H4), 6.84 (d, J = 8.1 Hz, 2 H, H3), 3.81 (s, 3 H, H1), 2.72 (t, J = 7.6 Hz, 2 H, H6), 2.58 (t, J = 7.6 Hz, 2 H, H10), 1.78 (quint., J = 7.6 Hz, 2 H, H7), 1.64 (quint., J = 7.6 Hz, 2 H, H9), 1.42 (quint., J = 7.6 Hz, 2 H, H8). 13 C NMR (75 MHz, CDCl3): δ 196.5 (C11), 157.7 (C2), 151.7 (C12), 150.4 (C16), 137.1 (C14), 134.5 (C5), 130.1 (C15), 129.2 (2 C, C4), 123.4 (C13), 113.7 (2 C, C3), 55.3 (C1), 44.2 (C10), 34.7 (C6), 31.3 (C7), 28.5 (C8), 25.3 (C9). MS ES+: m/z 316.1 (100, [M+H]+).
HRMS: calculated for C18H22NO5S (M+H) 316.1371, found 316.1375. I-037
trans-4-Ethyl-3-(4-(4-methoxyphenyl)butyl)oxetan-2-one
C16H22O3 262.34 g.mol-1
To a stirred solution of 1 M LiHMDS in hexane (3.7 mL, 3.7 mmol) at -78 °C was added dropwise compound I-037 (500 mg, 1.6 mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred for 30 min at -78 °C and TESCl (0.54 mL, 3.2 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h and then quenched with a pH 7 buffer. The organic layer was separated, dried over Na2SO4
and evaporated.
Propanal (0.1 mL, 1.39 mmol) and a solution of crude S-pyridin-2-yl 6-(4-methoxyphenyl)hexanethioate triethylsilyl enol ether (680 mg, 1.58 mmol) in CH2Cl2 (7.2 mL) were added dropwise to a suspension of ZnCl2 (393 mg, 2.88 mmol, freshly fused under vacuum) at room temperature. The reaction mixture was stirred at room temperature for 2.5 h. A PBS buffer (pH 7) was added to the reaction mixture which was stirred for 25 min. The product was extracted with CH2Cl2, dried over Na2SO4 and the solvents were evaporated. After purification on a silica gel cartridge (80:20 Heptane/AcOEt), the desired product was obtained as a colorless oil (155.3 mg, 37%). IR υmax (cm-1): 1814. 1 H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.3 Hz, 2 H, H4), 6.83 (d, J = 8.3 Hz, 2 H, H3), 4.10-4.18 (m, 1 H, H12), 3.78 (s, 3 H, H1), 3.11-3.20 (m, 1 H, H10), 2.57 (t, J = 7.7 Hz, 2 H, H6), 1.78-1.95 (m, 2 H, H9), 1.69-1.78 (m, 2 H, H7), 1.53-1.69 (m, 2 H, H13), 1.32-1.53 (m, 2 H, H8), 0.99 (t, J = 7.1 Hz, 3 H, H14). 13 C NMR (75 MHz, CDCl3): δ171.5 (C11), 157.8 (C2), 134.1 (C5), 129.2 (2 C, C4), 113.8 (2 C, C3), 79.1 (C12), 55.6 (C10), 55.3 (C1), 34.6 (C6), 31.3 (C7), 27.8 (C9), 27.5 (C13), 26.5 (C8), 9.1 (C14). MS ES+: m/z 547.3 (10, [2M+Na]+), 285.1 (100, [M+Na]+).
HRMS: calculated for C16H22NaO3 (M+Na) 285.1467, found 285.1473. I-038
(S*)-2-((S*)-(1-(Acetylthio)propyl)-6-(4-methoxyphenyl)hexanoic acid
C18H26O4S 338.46 g.mol-1
In a solution of compound I-038 (531 mg, 2.02 mmol) in DMF (4.04 mL) was added cesium ethanethioate (1.05 g, 5.07 mmol) and the reaction mixture was stirred at room temperature for 22 h. The mixture was acidified with 1 M HCl. and was extracted with ether and dried over Na2SO4. The desired product was obtained after purification on a silica gel cartridge (70:30 Heptane/AcOEt) as a yellow oil (418.8 mg, 61%). IR υmax (cm-1): 3100, 1705, 1690. 1 H NMR (500 MHz, CDCl3): δ 8.93 (br s, 1 H, H17), 7.08 (d, J = 8.0 Hz, 2 H, H4), 6.82 (d, J = 8.0 Hz, 2 H, H3), 3.78 (s, 3 H, H1), 3.70-3.77 (m, 1 H, H12), 2.50-2.65 (m, 3 H, H6, H10), 2.34 (s, 3 H, H16), 1.71-1.82 (m, 2 H, H13), 1.54-1.67 (m, 4 H, H9 and H7), 1.30-1.49 (m, 2 H, H8), 0.97 (t, J = 7.4 Hz, 3 H, H14). 13 C NMR (75 MHz, CDCl3): δ195.2 (C15), 179.4 (C11), 157.7 (C2), 134.5 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 55.3 (C1), 49.5 (C12), 47.4 (C10), 34.7 (C6), 31.5 (C7), 30.7 (C16), 29.5 (C9), 27.1 (C8), 25.5 (C13), 11.5 (C14). MS ES-: m/z 337.1 (100, [M-H]-).
HRMS: calculated for C18H25O4S (M-H) 337.1474, found 337.1459. I-039
(S*)-2-((S*)-1-Mercaptopropyl)-6-(4-methoxyphenyl)hexanoic acid
C16H24O3S 296.42 g.mol-1
To a solution of compound I-039 (410 mg, 1.2 mmol) in CH3CN (24 mL) was added hydrazine monohydrate (0.12 mL, 2.4 mmol) and the reaction mixture was stirred at 0 °C for 1.5 h. The mixture was acidified with 1 M HCl. The product was extracted with CH2Cl2, dried over Na2SO4 and the solvent was evaporated. The desired product was obtained as a yellow oil (342.4 mg, 96%).
IR υmax (cm-1): 3100, 2856, 1703. 1 H NMR (300 MHz, CDCl3): δ 9.67 (br s, 1 H, H16), 7.11 (d, J = 8.1 Hz, 2 H, H4), 6.84 (d, J = 8.1 Hz, 2 H, H3), 3.81 (s, 3 H, H1), 2.95-3.06 (m, 1 H, H10), 2.52-2.63 (m, 1 H, H12), 2.51 (t, J = 7.4 Hz, 2 H, H6), 2.00 (s, 1 H, H15), 1.72-1.86 (m, 2 H, H7), 1.24-1.71 (m, 6 H, H8, H9, H13), 1.08 (t, J = 7.4 Hz, 3 H, H14). 13 C NMR (75 MHz, CDCl3): δ 180.4 (C11), 157.7 (C2), 134.5 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 55.3 (C1), 52.4 (C10), 44.4 (C12), 34.7 (C6), 31.5 (C7), 29.8 (C13), 29.0 (C9), 27.1 (C8), 11.8 (C14). MS ES-: m/z 589.3 (100, [2M-3H]-).
HRMS: calculated for C32H45O6S2 (2M-3H) 589.2658, found 589.2648. I-040
Cis-4-ethyl-3-(4-(4-methoxyphenyl)butyl)thietan-2-one
C16H22O2S 278.41 g.mol-1
Compound I-040 (330 mg, 1.11 mmol) in CH2Cl2 (5.6 mL) was added to EDCI.HCl (427.3 mg, 2.23 mmol) and pentafluorophenol (246.1 mg, 1.34 mmol) at 0 °C and the mixture was stirred at 0 °C for 1.5 h. The mixture was quenched with 1 M HCl and extracted with CH2Cl2, dried over Na2SO4 and the solvent was removed. The desired product was obtained after purification on a silica gel cartridge (90:10 Heptane/AcOEt) as a colorless oil (302.8 mg, 98%).
IR υmax (cm-1): 1749. 1 H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.6 Hz, 2 H, H4), 6.82 (d, J = 8.6 Hz, 2 H, H3), 4.12 (q, J = 7.5 Hz, 1 H, H10), 3.79 (s, 3 H, H1), 3.53 (ddd, J = 11.4, 7.4, 4.1 Hz, 1 H, H12), 2.56 (t, J = 7.6 Hz, 2 H, H6), 1.27-2.08 (m, 8 H, H7,H8, H9, H13), 1.06 (t, J = 7.0 Hz, 3 H, H14). 13 C NMR (75 MHz, CDCl3): δ195.3 (C11), 157.7 (C2), 134.3 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 70.4 (C10), 55.3 (C1), 40.9 (C12), 34.6 (C6), 31.5 (C9), 27.4 (C7), 26.2 (C8), 25.8 (C13), 13.1 (C14). MS ES+: m/z 579.3 (15, [2M+Na]+), 301.1 (100, [M+Na]+), 296.2 (60, [M+NH4]+). HRMS: calculated for C16H22NaO2S (M+Na) 301.1238, found 301.1236.
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)thietan-2-one
C16H22O2S 278.41 g.mol-1
To a -78 °C solution of compound I-041 (270 mg, 0.97 mmol) in THF (26.9 mL) was added 1 M LiHMDS in hexane (1.46 mL, 1.46 mmol) and the reaction mixture was stirred at -78 °C for 1 h. Tetramethylethylenediamine (0.22 mL, 1.46 mmol) was then added at -78 °C and the mixture was stirred for an additional 30 min, after which the solution was quenched with acetic acid (0.17 mL, 2.97 mmol). The reaction mixture was neutralized with a saturated Na2CO3 and the product was extracted with ether. The solvent was removed under vacuum. The desired product was obtained as a colorless oil (263.8 mg, 98%, cis/trans 20:80).
IR υmax (cm-1): 1747. 1 H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.6 Hz, 2 H, H4), 6.83 (d, J = 8.6 Hz, 2 H, H3), 4.12 (q, J = 7.9 Hz, 0.2 H, H10cis), 3.81 (s, 3 H, H1), 3.62 (ddd, J = 8.4, 6.4, 3.6 Hz, 0.8 H, H10trans), 3.53 (ddd, J = 11.2, 7.4, 3.6 Hz, 0.2 H, H12cis), 3.15 (ddd, J = 8.9, 5.6, 3.5 Hz, 0.8 H, H12trans), 2.57 (t, J = 7.5 Hz, 2 H, H6), 1.53-2.05 (m, 6 H, H7,H8, H9), 1.50-1.36 (m, 2 H, H13), 1.04 (t, J = 7.5 Hz, 0.6 H, H14cis), 1.02 (t, J = 7.5 Hz, 2.4 H, H14trans). 13 C NMR (75 MHz, CDCl3): δ195.3 (0.2 C, C11cis), 194.5 (0.8 C, C11trans), 157.8 (C2), 134.3 (C5), 129.2 (2 C, C4), 113.8 (2 C, C3), 73.9 (0.8 C, C10trans), 70.4 (0.2 C, C10cis), 55.3 (C1), 42.5 (0.8 C, C12trans), 40.9 (0.2 C, C12cis), 34.7 (C6), 31.5 (C9), 30.7 (C7), 27.4 (0.2 C, C8cis), 26.2 (0.8 C, C8trans), 25.9 (0.8 C, C13trans), 25.8 (0.2 C, C13cis), 13.2 (0.2 C, C14cis), 13.0 (0.8 C, C14trans).
MS ES+: m/z 579.3 (15, [2M+Na]+), 301.1 (100, [M+Na]+), 296.2 (60, [M+NH4]+). HRMS: calculated for C16H22NaO2S (M+Na) 301.1238, found 301.1236.
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-3-methyloxetan-2-one
C17H24O3 276.37 g.mol-1
A solution of 0.6 M LDA (7.5 mL, 4.5 mmol) in THF was added dropwise to a solution of compound I-038 (534 mg, 2.04 mmol) in THF (6.7 mL) at -78 °C. The reaction was stirred at this temperature for 30 min and freshly distilled MeI (0.44 mL, 6.9 mmol) was added. The reaction was slowly warmed up to room temperature for 2.5 h. The mixture was then cooled down to -78 °C and acetic acid was added. The mixture was extracted with AcOEt, washed with saturated Na2CO3 and then brine and dried over Na2SO4. The solvent was removed under vacuum. The desired product was obtained after purification on a silica gel cartridge (85:15 Heptane/AcOEt) as a colorless oil (394.6 mg, 70%, unlike/like 80:20). IR υmax (cm-1): 1815. 1 H NMR (500 MHz, CDCl3): δ 7.08 (d, J = 8.0 Hz, 2 H, H4), 6.83 (d, J = 8.0 Hz, 2 H, H3), 4.17 (dd, J = 9.1 Hz, 5.5 Hz, 0.2 H, H12like), 4.11 (dd, J = 9.6 Hz, 4.6 Hz, 0.8 H, H12unlike), 3.79 (s, 3 H, H1), 2.50-2.63 (m, 2 H, H6), 1.67-1.85 (m, 4 H, H13, H9), 1.57-1.67 (m, 2 H, H7), 1.57-1.47 (m, 2 H, H8), 1.38 (s, 2.4 H, H15unlike), 1.24 (s, 0.6 H, H15like), 1.03 (t, J = 7.3 Hz, 2.4 H, H14unlike), 1.01 (t, J = 7.3 Hz, 0.6 H, H14like).
13
C NMR (75 MHz, CDCl3): δ175.0 (C11), 157.8 (C2), 134.3 (0.8 C, C5unlike), 134.2 (0.2 C, C5like), 129.2 (2 C, C4), 113.8 (2 C, C3), 85.4 (0.8 C, C12unlike), 82.9 (0.2 C, C12like), 57.0 (0.2 C, C10like), 56.4 (0.8 C, C10unlike), 55.3 (C1), 35.7 (0.2 C, C6like), 34.7 (0.8 C, C6unlike), 32.1 (0.8 C, C7unlike), 31.8 (0.2 C, C7like), 30.0 (C9), 23.8 (C15), 23.4 (0.8 C, C13unlike), 19.8 (C8), 14.1 (0.2 C, C13like), 10.0 (0.8 C, C14unlike), 9.8 (0.2 C, C14like).
MS APCI: m/z 277.2 (85, [M+H]+), 318.2 (100, [M+H+CH3CN]+). HRMS: calculated for C17H25O3 (M+H) 277.1804, found 277.1794.
(E)-S-Methyl 6-(4-methoxyphenyl)-2-propylidenehexanethioate
C17H24O2S 292.44 g.mol-1
To a solution of compound I-041 (50 mg, 0.18 mmol) in THF (1.8 mL), at -78 °C, was added 1 M LiHMDS in hexane (0.36 mL, 0.36 mmol) and the solution was stirred at this temperature for 1.5 h. Distilled MeI (22.2 µL, 0.35 mmol) was added at -78 °C and the reaction mixture was allowed to warm up to -40 °C and was stirred at this temperature for 12 h. Acetic acid was added at this temperature. The organic layer was washed with saturated Na2CO3, dried over Na2SO4 and the solvent was removed in vacuum. I-045 was obtained as a colorless oil after purification on a silica gel plate (90:10 Heptane/AcOEt) (6.3 mg, 12%). 1 H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.6 Hz, 2 H, H4), 6.81 (d, J = 8.6 Hz, 2 H, H3), 6.67 (t, J = 7.6 Hz, 1 H, H11), 3.78 (s, 3 H, H1), 2.55 (t, J = 7.4 Hz, 2 H, H6), 2.36 (t, J = 7.4 Hz, 2 H, H9), 2.32 (s, 3 H, H15), 2.20 (t, J = 7.6 Hz, 2 H, H12), 1.58 (quint., J = 7.4 Hz, 2 H, H7), 1.42 (quint., J = 7.4 Hz, 2 H, H8), 1.05 (t, J = 7.6 Hz, 3 H, H13). 13 C NMR (75 MHz, CDCl3): δ 194.4 (C14), 157.7 (C2), 142.3 (C10), 140.3 (C11), 134.6 (C5), 129.2 (2 C, C4), 113.7 (2 C, C3), 55.3 (C1), 34.8 (C6), 31.6 (C7), 29.7 (C8), 28.8 (C9), 26.9 (C12), 21.9 (C15), 13.3 (C13). MS ES+/- or APCI: no answer. I-045
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-3-methylthietan-2-one
C17H24O2S 292.44 g.mol-1
To a solution of compound I-041 (168 mg, 0.6 mmol) in THF (16.7 mL) was added to 1 M LiHMDS in hexane (0.9 mL, 0.93 mmol) at -78 °C and the mixture was stirred at this temperature for 1 h. TMEDA (0.14 mL, 0.93 mmol) and distilled MeI (0.19 mL, 3.0 mmol) were added at -78 °C and the reaction mixture was allowed to warm up to -40 °C and was stirred at this temperature for 12 h. Acetic acid was added at this temperature. The organic layer was washed with saturated Na2CO3, dried over Na2SO4 and the solvent was removed under vacuum. The desired product was obtained as a yellow oil without further purification (164.7 mg, 94%, 70:30 unlike/like).
IR υmax (cm-1): 1740. 1 H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.4 Hz, 2 H, H4), 6.83 (d, J = 8.4 Hz, 2 H, H3), 3.79 (s, 3 H, H1), 3.24 (dd, J = 10.6, 4.5 Hz, 0.3 H, H12like), 3.17 (dd, J = 11.5, 4.1 Hz, 0.7 H, H12unlike), 2.50-2.64 (m, 2 H, H6), 1.41-2.02 (m, 8 H, H7, H8, H9, H13), 1.35 (s, 2.1 H, H15unlike), 1.24 (s, 0.9 H, H15like), 1.00 (t, J = 7.3 Hz, 3 H, H14). RMN 13C NMR (75 MHz, CDCl3): δ198.8 (0.3 C, C11like), 198.5 (0.7 C, C11unlike), 157.8 (C2), 134.5 (0.7 C, C5unlike), 134.4 (0.3 C, C5like), 129.3 (2 C, C4), 113.9 (2 C, C3), 74.8 (0.3 C, C10like), 74.3 (0.7 C, C10unlike), 55.4 (C1), 50.0 (0.7 C, C12unlike), 47.1 (0.3 C, C12like), 38.0 (C9), 34.9 (C6), 32.3 (0.7 C, C7unlike), 32.1 (0.3 C, C7like), 25.9 (0.3 C, C8like), 25.1 (0.7 C, C8unlike), 24.4 (0.7 C, C13unlike), 23.6 (0.3 C, C13like), 22.4 (0.7 C, C15unlike), 16.6 (0.3 C, C15like), 13.5 (C14).
MS ES+: m/z 310.2 (100, [M+NH4]+).
HRMS: calculated for C17H28NO2S (M+NH4) 310.1841, found 310.1827. I-048
S-Phenyl 6-(4-methoxyphenyl)hexanethioate
C19H22O2S 314.13 g.mol-1
To a stirred solution of compound I-036 (4 g, 18.00 mmol) in CH2Cl2 (90 mL) was added oxalyl chloride (2.4 mL, 27.96 mmol) and a catalytic amount of anhydrous DMF at room temperature. The reaction mixture was stirred for 30 min and the solvent was evaporated under reduced pressure. To the stirred oil residue was added thiophenol (2.21 mL, 21.59 mmol) in CH2Cl2 (90 mL) followed by Et3N (5 mL, 35.87 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then quenched with 1 M HCl and neutralized by washing with saturated NaHCO3. The organic layers were combined and evaporated. After purification on a silica gel cartridge (50:50 Heptane/CH2Cl2), the desired product was obtained as a yellow oil (5.16 g, 91%).
IR υmax (cm-1): 1707. 1 H NMR (300 MHz, CDCl3): δ 7.40 (s, 5 H, H13, H14, H15), 7.09 (d, J = 8.3 Hz, 2 H, H4), 6.83 (d, J = 8.3 Hz, 2 H, H3), 3.79 (s, 3 H, H1), 2.65 (t, J = 7.5 Hz, 2 H, H6), 2.56 (t, J = 7.5 Hz, 2 H, H10), 1.74 (quint., J = 7.5 Hz, 2 H, H7), 1.62 (quint., J = 7.5 Hz, 2 H, H9), 1.42 (quint., J = 7.5 Hz, 2 H, H8). 13 C NMR (75 MHz, CDCl3): δ 197.6 (C11), 157.8 (C2), 134.3 (3 C, C13, C5), 129.5 (2 C, C14), 129.4 (3 C, C12, C4), 129.3 (C15), 113.9 (2 C, C3), 55.4 (C1), 43.8 (C6), 34.9 (C10), 31.4 (C9), 28.6 (C8), 25.6 (C7). MS ES+: m/z 332.1 (100, [M+NH4]+).
HRMS: calculated for C19H26NO2S (M+NH4) 332.1684, found 332.1670. I-049
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-4-methyloxetan-2-one
C17H24O3 276.37 g.mol-1
To a stirred solution of 0.6 M LDA in THF (4.7 mL, 2.82 mmol) at -78 °C was added dropwise a solution of compound I-049 (809 mg, 2.57 mmol) in THF (1.2 mL). The reaction mixture was stirred for 30 min at -78 °C and 2-butanone (0.23 mL, 2.57 mmol) was added dropwise. The reaction was stirred at -78 °C for 30 min and then allowed to warm up to 0 °C. The reaction was quenched with half saturated aqueous ammonium chloride. The mixture was poured into a separatory funnel containing hexane/water (1:1). The aqueous layer was extracted with hexane and the combined organic layers were washed successively with aqueous NaHCO3 and brine and then was dried over Na2SO4 and evaporated. After a purification on a silica gel cartridge (95:5 Heptane/AcOEt), the desired product was obtained as a colorless oil (70:30 unlike/like, 511.4 mg, 60%).
IR υmax (cm-1): 1811.
RMN 1H (500 MHz, CDCl3): δ 7.08 (d, J = 8.6 Hz, 2 H, H4), 6.83 (d, J = 8.6 Hz, 2 H, H3), 3.79 (s, 3 H, H1), 3.18 (dd, J = 8.6, 7.2 Hz, 0.3 H, H10like), 3.14 (t, J = 8.0 Hz, 0.7 H, H10unlike), 2.57 (t, J = 7.5 Hz, 2 H, H6), 1.73-1.91 (m, 4 H, H13 and H9), 1.55-1.71 (m, 4 H, H7 and H8), 1.52 (s, 1 H, H15like), 1.42 (s, 2 H, H15unlike), 1.02 (t, J = 7.3 Hz, 1 H, H14like), 0.96 (t, J = 7.3 Hz, 2 H, H14unlike).
RMN 13C (75 MHz, CDCl3): δ171.8 (C11), 157.9 (C2), 134.3 (C5), 129.4 (2 C, C4), 113.9 (2 C, C3), 82.8 (0.7 C, C12unlike), 82.5 (0.3 C, C12like), 59.0 (0.3 C, C10like), 56.6 (0.7 C, C10unlike), 55.4 (C1), 34.7 (C6), 33.9 (0.7 C, C13unlike), 33.8 (0.3 C, C13like), 31.5 (0.7 C, C8unlike), 28.0 (0.3 C, C8like), 27.4 (0.3 C, C7like), 27.2 (0.7 C, C7unlike), 25.0 (0.7 C, C9unlike), 24.4 (0.3 C, C9like), 24.3 (0.3 C, C15like), 19.1 (0.7 C, C15unlike), 8.5 (0.7 C, C14unlike), 8.1 (0.3 C, C14like).
MS ES+: m/z 277.1 (100, [M+H]+).
HRMS: calculated for C17H25O3 (M+H) 277.1804, found 277.1802. I-050
2-(2-Hydroxybutan-2-yl)-6-(4-methoxyphenyl)hexanoic acid
C17H26O4 294.39 g.mol-1
To a stirred solution of compound I-050 (like/unlike 70:30) (1.45 g, 5.2 mmol) in THF (10.5 mL) was added aqueous solution of NaOH (3 M) (10.5 mL, 31.5 mmol). The mixture was stirred at room temperature for 18 h, then acidified and the desired product was extracted with AcOEt, dried over Na2SO4 and the solvent was evaporated under vacuum to give the desired product as a yellowish oil (unlike/like 70:30, 1.5 g, 97%).
IR υmax (cm-1): 3100, 2933, 1704.
1
H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 8.3 Hz, 2 H, H4), 6.82 (d, J = 8.3 Hz, 2 H, H3), 5.01 (bs, 1 H, H15), 3.78 (s, 3 H, H1), 2.50-2.61 (m, 2 H, H6), 2.40-2.50 (m, 1 H, H10), 1.70-1.88 (m, 2 H, H9), 1.50-1.70 (m, 4 H, H7, H13), 1.29-1.50 (m, 2 H, H8), 1.28 (s, 0.3 H, H16like), 1.27-1.22 (m, 1.6 H, H16unlike and H15like), 1.19 (s, 2.1 H, H15unlike), 0.84-0.99 (m, 3 H, H14).
13C NMR (75 MHz, CDCl3): δ180.3 (C11), 157.7 (C2), 134.6 (C5), 129.3 (2 C, C4), 113.8 (2 C, C3), 73.8 (0.7 C, C12unlike), 73.5 (0.3 C, C12like), 56.6 (0.3 C, C10like), 55.8 (C1), 53.8 (0.7 C, C10unlike), 34.9 (C6), 34.5 (0.7 C, C13unlike), 33.8 (0.3 C, C13like), 31.7 (0.7 C, C7unlike), 31.4 (0.3 C, C7like), 27.8 (0.7 C, C8unlike), 27.7 (0.3 C, C8like), 27.2 (0.7 C, C9unlike), 26.7 (0.3 C, C9like), 25.0 (0.3 C, C15like), 22.9 (0.7 C, C15unlike), 8.5 (0.3 C, C14like), 8.2 (0.7 C, C14unlike).
MS ES-: m/z 293.2 (100, [M-H]-), 587.4 (20, [2M-H]-).
HRMS: calculated for C17H25O4 (M-H) 293.1753, found 293.1749. I-051
Methyl 2-(2-hydroxybut-2-yl)-6-(4-methoxyphenyl)hexanoate
C18H28O4 308.41 g.mol-1
To a stirred solution of compound I-050 (like/unlike 70:30) (500 mg, 1.8 mmol) in MeOH (9 mL) was added at 0 °C NaH 60% (150 mg, 3.75 mmol). The mixture was stirred at room temperature for 1 h. The reaction was poured into an ice bath and quenched with 1 M HCl, extracted with AcOEt and washed successively with H2O and brine. After evaporation under vacuum, the desired product was obtained as a colorless oil (70:30 unlike/like, 558.1 mg, 100%).
IR υmax (cm-1): 3515, 2932, 1730.
1
H NMR (300 MHz, CDCl3): δ 7.06 (d, J = 8.7 Hz, 2 H, H4), 6.81 (d, J = 8.7 Hz, 2 H, H3), 3.77 (s, 3 H, H1), 3.68 (s, 3 H, H17), 2.69 (br s, 1 H, H16), 2.49-2.62 (m, 2 H, H6), 2.39-2.49 (m, 1 H, H10), 1.69-1.88 (m, 2 H, H9), 1.39-1.69 (m, 4 H, H7, H13), 1.18-1.33 (m, 2 H, H8), 1.15 (s, 1.1 H, H15like), 1.14 (s, 1.9 H, H15unlike), 0.91 (t, J = 7.2 Hz, 2.1 H, H14unlike), 0.88 (t, J = 7.2 Hz, 0.9 H, H14like).
13C NMR (75 MHz, CDCl3): δ 176.6 (0.3 C, C11like), 176.5 (0.7 C, C11unlike), 157.6 (C2), 134.4 (C5), 129.1 (2 C, C4), 113.6 (2 C, C3), 73.2 (0.7 C, C12unlike), 72.9 (0.3 C, C12like), 55.1 (C1), 53.7 (0.7 C, C10unlike), 53.5 (0.3 C, C10like), 51.3 (C17), 34.7 (1.7 C, C6, C13unlike), 34.5 (0.3 C, C13like), 31.6 (0.3 C, C7like), 31.4 (0.7 C, C7unlike), 27.5 (0.7 C, C8unlike), 27.4 (0.3 C, C8like), 27.2 (0.7 C, C9unlike), 26.5 (0.3 C, C9like), 25.2 (0.3 C, C15like), 22.7 (0.7 C, C15unlike), 8.0 (0.3 C, C14like), 7.9 (0.7 C, C14unlike).
MS ES+: m/z 291.2 (100, [M-H2O+H]+), 309.2 (57, [M+H]+). HRMS: calculated for C18H29O4 (M+H) 309.2066, found 309.2067.
1-Methoxy-4-(6-methyloct-5-en-1-yl)benzene
C16H24O 232.36 g.mol-1
Compound I-050 (like/unlike 70:30) (57.9 mg, 0.21 mmol) was heated in FC-70 (1 mL) at 120 °C overnight to give, after purification on a silica cartridge (98:2 Heptane/AcOEt), the desired product as a colorless oil (29.4 mg, 60%, Z/E (70:30)) and the starting material (23.2 mg).
IR υmax (cm-1): 1613. 1 H NMR (300 MHz, CDCl3): δ 7.10 (d, J = 8.6 Hz, 2 H, H4), 6.83 (d, J = 8.6 Hz, 2 H, H3), 5.05-5.16 (m, 1 H, H10), 3.79 (s, 3 H, H1), 2.57 (t, J = 7.7 Hz, 2 H, H6), 2.08-1.94 (m, 4 H, H9,H13), 1.69 (s, 1 H, H12E), 1.54-1.67 (m, 2 H, H7), 1.64 (s, 2 H, H12Z), 1.29-1.44 (m, 2 H, H8), 0.99 (t, J = 7.5 Hz, 2 H, H14Z), 0.97 (t, J = 7.5 Hz, 1 H, H14E). 13 C NMR (75 MHz, CDCl3): δ 157.6 (C2), 137.1 (0.3 C, C11E), 136.9 (0.7 C, C11Z), 135.0 (C5), 129.2 (2 C, C4), 124.3 (0.3 C, C10E), 123.1 (0.7 C, C10Z), 113.7 (2 C, C3), 55.2 (C1), 35.0 (C6), 32.4 (0.3 C, C13E), 31.4 (C7), 29.7(0.3 C, C8E), 29.5 (0.7 C, C8Z), 27.7 (0.7 C, C9Z), 27.5 (0.3 C, C9E), 24.8 (0.7 C, C13Z), 22.9 (0.7 C, C12Z), 15.9 (0.3 C, C12E), 12.8 (C14). MS APCI: 274.2 (100, [M+H+CH3CN]+), 233.2 (50, [M+H]+), 232.2 (30, [M+.]. HRMS: calculated for C16H25O (M+H) 233.1905, found 233.1907.
To a stirred solution of compound I-052 (59 mg, 0.19 mmol) in CH2Cl2 (1 mL, 0.2 M) was added triethylamine (59 µL, 0.42 mmol) and MsCl (18 µL, 0.23 mmol). The mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with 1 M HCl and the crude was extracted with CH2Cl2. The solution was dried over Na2SO4 and the solvent was removed under vacuum. After purification on a silica gel cartridge (70:30 Heptane/AcOEt), the mixture of alkenes was obtained as a colorless oil (12.7 mg, 23%).
To a stirred solution of compound I-052 (80 mg, 0.26 mmol) in pyridine (0.9 mL) was added POCl3
(29 µL, 0.31 mmol) at 0 °C. The mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with 1 M HCl and the crude was extracted with CH2Cl2 and the organic layer was washed with NaHCO3 and brine, dried over Na2SO4 and the solvent was removed under vacuum. After purification (70:30 Heptane/AcOEt), the mixture of alkenes was obtained as a colorless oil (66.9 mg, 89%). RMN 1H (300 MHz, CDCl3): δ 7.08 (d, J = 8.8 Hz, 2 H, H4), 6.82 (d, J = 8.8 Hz, 2 H, H3), 5.32-5.44 (m, 0.7 H, H13), 4.93 (br t, J = 0.9 Hz, 0.4 H, H15), 4.89 (br s, 0.4 H, H15’), 3.78 (s, 3 H, H1), 3.66 (s, 0.9 H, H17, H17), 3.65 (s, 2.1 H, H17), 3.49 (t, J = 7.8 Hz, 0.2 H, H10), 3.04-2.90 (2 t, J = 7.8 Hz, 0.7 H, H10), 2.54 (t, J = 7.5 Hz, 2 H, H6), 1.99-2.15 (m, 0.6 H, H13, H13), 1.71-1.94 (m, 2 H, H9), 1.69-1.71 (m, 6.2 H, H7, H14, H15), 1.16-1.36 (m, 2 H, H8), 1.04 (t, 0.9 H, H14,H14). RMN 13C (75 MHz, CDCl3): δ174.8, 174.4 (C11), 157.7 (C2), 148.7 (0.3 C, C12, C12), 134.7 (1.7 C, C5, C12), 132.9 (0.05 C, C10), 129.2 (2 C, C4), 123.1, 122.6 (0.7 C, C13), 113.7 (2 C, C3), 110.7 (0.25 C, C15), 55.3 (C1), 54.4 (0.7 C, C10), 52.1 (0.25 C, C17), 51.7 (0.75 C, C17, C17), 45.8 (0.25 C, C10), 34.9 (C6), 31.6 (0.25 C, C9), 31.5 (0.75 C, C9, C9), 30.8 (0.25 C, C7), 29.8 (0.75 C, C7, C7), 29.1 (C8), 27.2 (0.05 C, C13), 26.9 (0.3 C, C15, C15), 19.6 (0.7 C, C15), 13.5 (0.7 C, C14), 13.3 (0.05 C, C14), 12.1 (0.25 C, C14). MS APCI: m/z 291.2 (100, [M+H]+).
HRMS: calculated for C18H27O3 (M+H) 291.1960, found 291.1953. I-054
Methyl 3-methylpent-2-enoate353
C7H12O2 128.17 g.mol-1
To DMF (69 mL) at 0 °C were added NaH 60% (1.8 g, 45.8 mmol) and trimethyl phosphonoacetate (7.4 mL, 45.8 mmol). After 10 min, ethyl methyl ketone (3.7 mL, 41.3 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water was added and the organic product was extracted with MTBE, which was dried over Na2SO4 and filtered. The solvent was removed under vacuum. A distillation (50 mm Hg, 100 °C) gave the desired product as a colorless oil (7:3 E/Z, 4.5 g, 85%). IR υmax (cm-1): 1740. 1 H NMR (300 MHz, CDCl3): δ 5.65-5.67 (m, 0.7 H, H5E), 5.62-5.64 (br s, 0.3 H, H5Z), 3.68 (s, 2.1 H, H7E), 3.67 (s, 0.9 H, H7Z), 2.63 (q, J = 7.5 Hz, 0.6 H, H2Z), 2.16 (q, J = 7.5 Hz, 1.4 H, H2E), 2.16 (s, 2.1 H, H4E), 1.88 (s, 0.9 H, H4Z), 1.070 (t, J = 7.5 Hz, 0.9 H, H1Z), 1.065 (t, J = 7.5 Hz, 2.1 H, H1E). 13 C NMR (75 MHz, CDCl3): δ166.7 (0.3 C, C6Z), 167.4 (0.7 C, C6E), 162.4 (0.3 C, C3Z), 161.9 (0.7 C, C3E), 115.0 (0.3 C, C5Z), 114.0 (0.7 C, C5E), 50.8 (C7), 33.7 (0.7 C, C2E), 26.5 (0.3 C, C4Z), 24.6 (0.3 C, C2Z), 18.8 (0.7 C, C4E), 12.5 (0.3 C, C1Z), 11.9 (0.7 C, C1E). MS ES+/-: m/z no answer 353
McGreer, D. E.; et al. Can. J. Chem. 1963, 41, 726.
3-Methylpent-2-enoic acid354
C6H10O2 114.14 g.mol-1
To a solution of I-055 (3.74 g, 29.2 mmol) in THF/H2O (5:4) (187 mL) was added LiOH (3.5 g, 146.0 mmol). The reaction mixture was stirred at room temperature overnight. Water was added and the organic product was extracted with MTBE. The aqueous layer was acidified to pH = 2-3 with 2 M HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and filtered. The solvent was removed under vacuum to give the desired product as a colorless oil (7:3 E/Z, 2.33 g, 70%). The starting material I-055 was recovered (930 mg, 25%).
IR υmax (cm-1): 2975, 1690. 1 H NMR (300 MHz, CDCl3): δ 11.37 (br s, 1 H, H7), 5.67-5.71 (m, 0.7 H, H5E), 5.64-5.67 (m, 0.3 H, H5Z), 2.64 (q, J = 7.5 Hz, 0.6 H, H2Z), 2.20 (q, J = 7.5 Hz, 1.4 H, H2E), 2.17 (s, 2.1 H, H4E), 1.92 (s, 0.9 H, H4Z), 1.08 (t, J = 7.5 Hz, 2.1 H, H1E), 1.07 (t, J = 7.5 Hz, 0.9 H, H1Z). 13 C NMR (75 MHz, CDCl3): δ171.9 (C6), 164.8 (C3), 114.9 (0.3 C, C5Z), 113.9 (0.7 C, C5E), 34.0 (0.7 C, C2E), 26.7 (0.3 C, C2Z), 25.0 (0.3 C, C4Z), 19.1 (0.7 C, C4E), 12.6 (0.3 C, C1Z), 11.9 (0.7 C, C1E). MS ES-: m/z 113.1 (100, [M-H]-).
HRMS: calculated for C6H9O2 (M-H) 113.0603, found 113.0598.
354
Mori, K.; et al. Leibigs Ann. Chem. 1990, 159.
3-(Benzylthio)-3-methylpentanoic acid
C13H18O2S 238.35 g.mol-1
To a solution of I-056 (261.1 mg, 2.29 mmol) in dry piperidine (0.5 mL) was added benzyl mercaptan (0.27 mL, 2.29 mmol). The reaction mixture was stirred at reflux for 24 h. The mixture was acidified with 1 M HCl and extracted with CH2Cl2, dried over Na2SO4 and filtered. The solvent was removed under vacuum. The desired product was obtained after purification on a silica gel cartridge (100% Heptane) as a yellow oil (334.7 mg, 61%) together with I-058 as a yellow oil (164.5 mg, 35%).
IR υmax (cm-1): 2970, 1705. 1 H NMR (300 MHz, CDCl3): δ 9,14 (br s, 1 H, H7), 7.18-7.38 (m, 5 H, Ph), 3.77 (d, J = 12.0 Hz, 1 H, H8a), 3.72 (d, J = 12.0 Hz, 1 H, H8b), 2.65 (s, 2 H, H5), 1.74 (q, J = 7.5 Hz, 2 H, H2), 2.43 (s, 3 H, H4), 1.01 (t, J = 7.5 Hz, 3 H, H1). 13 C NMR (75 MHz, CDCl3): δ175.3 (C6), 137.5, 129.1, 128.6, 127.1 (6 C, Ph), 48.0 (C3), 44.7 (C5), 32.8 (C8), 32.6 (C2), 25.5 (C4), 8.7 (C1). MS ES-: m/z 237.1 (100, [M-H]-).
HRMS: calculated for C13H17O2S (M-H) 237.0949, found 237.0955. I-057
Phenyl(piperidin-1-yl)methanethione355 C12H15NS 205.32 g.mol-1 IR υmax (cm-1): 2937, 1241. 1 H NMR (300 MHz, CDCl3): δ 7.21-7.41 (m, 5 H, Ph), 4.38 (dd, J = 6.0, 5.0 Hz, 2 H, H2 ou H2’), 3.53 (dd, J = 5.7, 5.5 Hz, 2 H, H2’ ou H2), 1.72-1.89 (m, 4 H, H3, H3’), 1.53-1.63 (m, 2 H, H4). 13 C NMR (75 MHz, CDCl3): δ199.6 (C1), 143.4, 128.4, 125.5 (6 C, Ph), 53.2, 50.7 (2 C, C2, C2’), 26.9 (C4), 25.5, 24.2 (2 C, C3, C3’). MS ES+: m/z 206.1 (100, [M+H]+).
HRMS: calculated for C12H16NS (M+H) 206.1003, found 206.1013.
355
Koduri, N. D.; et al. Org. Lett. 2011, 14, 440.