S1 Supporting Information Sterereochemical Evidence for Stabilization of a Nitrogen Cation by Neighboring Chlorine or Bromine Tomohiko Ohwada 1,* , Norihiko Tani 1 Yuko Sakamaki 1 , Yoji Kabasawa 1 , Yuko Otani 1 , Masatoshi Kawahata 2 , Kentaro Yamaguchi 2.* 1 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, 2 Department of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan. *To whom correspondence should be addressed. E-mail: [email protected] E-mail: [email protected] Table of Contents Materials and Methods Figure S1 Figure S2 Figure S3 Table S1-S4 Single-crystal X-ray diffraction Experiments Table 5 SI Appendix: Materials and Methods General Methods All the melting points were measured with a Yanaco Micro Melting Point Apparatus and are uncorrected. Proton (400 MHz) NMR and carbon (100 MHz) spectra were measured on a Bruker Avance400 NMR spectrometer with TMS as an internal reference in CDCl 3 as the solvent, unless otherwise specified. Chemical shifts δ are shown in ppm. Coupling constants are given in hertz. Electron-spray ionization time- of-flight mass spectra (ESI-TOF MS, ESI + ) were recorded on a microTOF05, Bruker Daltonics. The combustion analyses were carried out in the microanalytical laboratory of Graduate School of Pharmaceutical Sciences, the University of Tokyo. Compounds Synthesis of some of the starting materials were carried out as described previously (16,18,25-31). Synthesis of Chemical Compounds Synthesis of O-tosyl-oxime of methyl 7-oxo-dehydroabietate 2a CO 2 Me H 2a-1 CO 2 Me H 2a-2 CrO 3 Ac 2 O, AcOH O CO 2 Me H 2a-3 N OH NH 2 OH/HCl pyridine 1) NaH, THF 2) TsCl, THF CO 2 Me H 2a N OTs
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S1
Supporting Information
Sterereochemical Evidence for Stabilization of a Nitrogen Cation by Neighboring Chlorine or Bromine
Tomohiko Ohwada1,*, Norihiko Tani1 Yuko Sakamaki1, Yoji Kabasawa1,
Yuko Otani1, Masatoshi Kawahata2, Kentaro Yamaguchi2.*
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,
2Department of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan.
*To whom correspondence should be addressed. E-mail: [email protected]
E-mail: [email protected]
Table of Contents Materials and Methods Figure S1 Figure S2 Figure S3 Table S1-S4 Single-crystal X-ray diffraction Experiments Table 5
SI Appendix: Materials and Methods General Methods All the melting points were measured with a Yanaco Micro Melting Point Apparatus and are uncorrected. Proton (400 MHz) NMR and carbon (100 MHz) spectra were measured on a Bruker Avance400 NMR spectrometer with TMS as an internal reference in CDCl3 as the solvent, unless otherwise specified. Chemical shifts δ are shown in ppm. Coupling constants are given in hertz. Electron-spray ionization time-of-flight mass spectra (ESI-TOF MS, ESI+) were recorded on a microTOF05, Bruker Daltonics. The combustion analyses were carried out in the microanalytical laboratory of Graduate School of Pharmaceutical Sciences, the University of Tokyo. Compounds Synthesis of some of the starting materials were carried out as described previously (16,18,25-31). Synthesis of Chemical Compounds Synthesis of O-tosyl-oxime of methyl 7-oxo-dehydroabietate 2a
CO2MeH
2a-1CO2MeH
2a-2
CrO3Ac2O, AcOH
OCO2MeH
2a-3
NOH
NH2OH/HCl
pyridine
1) NaH, THF
2) TsCl, THFCO2MeH
2a
NOTs
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S2
CO2HH
CO2MeH
2a-1
MeOH H2SO4
To a solution of reagent grade dihydroabietic acid (6.5292 g) in dry MeOH (80 mL) concentrated H2SO4 (8 mL) was added dropwise (25). The whole was heated at reflux at 85 °C for 22 hrs. The solvent was evaporated and the residue was dissolved into CH2Cl2 (80 mL), and washed with water (50 mL), saturated aqueous NaHCO3 solution (60 mL), brine (80 mL) dried over MgSO4. Evaporation of the solvent gave the residue which was repeatedly flash-column chromatographed (ethyl acetate: n-hexane =1:20 or 1:50) to afford 2a-1 (4.7032g, yield 69%) as a white powder. 2a-1: Mp: 62-63°C colorless amorphous).1H NMR (CDCl3): δ 7.161 (1H, d, J=8.0 Hz), 6.994 (1H, d, d, J=8.0, 1.6), 6.877 (1H, d, J=1.2), 3.654 (3H, s), 2.899-2.800 (2H, m), 2.293 (1H, d, J = 12.4 Hz), 2.2368 (1H, d, J = 12.6, 2.0 Hz), 1.845-1.619 (4H, m), 1.497 (2H, m), 1.403 (1H, m), 1.269 (3H, s), 1.254 (3H, s), 1.245 (6H, d, J=6.8), 1.216 (3H, d, J=8.4). 13C- NMR (CDCl3): 179.1, 146.9, 145.7, 134.7, 126.9, 124.1, 123.9, 51.9, 47.6, 44.8, 38.0, 36.9, 36.6, 33.4, 30.0, 25.1, 24.0, 21.7, 18.6, 16.5. Anal. Calcd. for C21H30O2: C, 80.21; H, 9.62; N, 0.00. Found: C, 80.04; H, 9.49; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C21H30NNaO2: 337.21380. Found: 337.21304.
CO2MeH
2a-1CO2Me
H
2a-2
CrO3Ac2O, AcOH
O
A solution of CrO3 (1.2149g, 1.2 equiv.) in Ac2O (20 mL) and AcOH (10 mL) was added dropwise to a solution of methyl ester 2a-1 (3.1471 g, 10 mmol) in AcOH (10 mL) at 3 oC over 15 min (26). The reaction mixture was stirred at 3-7 oC for 1 hr, and the whole was stirred at rt for 21 hrs. To an ice-cooled saturated aqueous NaHCO3 solution (400 mL), the reaction mixture was added dropwise with stirring. The whole was extracted with Et2O (350 mL), the organic layer was washed with saturated aqueous NaHCO3 solution (125 mL) and brine (100 mL), and dried over MgSO4. The solvent was evaporated to give a residue which was flash-column chromatographed (ethyl acetate: n-hexane=1:11) to give 2.1840 g (66 % yield) of 2a-2 as a viscous coreless oil. A small fraction of an undefined material was contaminated, but the ketone was used for the next step without further purification. 2a-2: 1H NMR (CDCl3): δ: 7.868 (1H, d, J = 2.0 Hz), 7.410 (1H, d, d, J = 8.0, 2.0 Hz), 7.294 (1H, d, J = 8.4 Hz), 3.645 (3H, s), 2.923 (1H, septet, J=6.8 Hz), 2.716 (2H, d, d, J = 7.2, 3.6 Hz), 2.346 (2H, m), 1.799 (3H, m), 1.726 (1H, m), 1.664-1.634 (1H, m), 1.339 (3H, s), 1.254 (3H, s), 1.245 (6H, d, J=6.8 Hz). 13C-NMR (CDCl3): 198.50, 177.76, 152.95, 146.88, 132.55, 130.65, 124.97, 123.44, 52.15, 46.64, 43.73, 37.80, 37.25, 37.06, 36.49, 33.55, 23.78, 23.71, 23.65, 18.12, 16.34. HRMS (ESI+, [M + Na]+): Calcd. for C21H28NaO3: 351.19307. Found: 351.19242.
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CO2MeH
2a-2
OCO2MeH
2a-3
NOH
NH2OH/HCl
pyridine
The oxime 2a-3 was synthesized from ketone 2a-2 by the action of NH2OH•HCl in dry ethanol in the presence of pyridine (16, 30). 2a-3: Mp. 98-99 °C (in a sealed test tube). Colorless amorphous. 1H NMR (CDCl3): δ 8.649 (1Η, brs, ΟΗ), 7.697 (1H, s), 7.259 (2H, s), 2.906 (1H, septet, J=6.8), 2.678 (1H, d, J=6.0), 2.655 (1H, s), 2.336 (1H, d, d, J=6.8, 9.5), 2.299 (1H, brd, J=14.0), 1.773-1.613 (5H, m), 1.379 (3H, s), 1.255 (6H, d, J=6.8Hz), 1.117 (3H, s). 13C-NMR (CDCl3) δ: 178.31, 155.69, 148.68, 146.59, 128.80, 127.99, 122.90, 122.11, 52.09, 46.55, 41.60, 37.16, 37.05, 36.54, 33.66, 24.05, 23.78, 23.70, 22.96, 18.12, 16.54. Anal. Calcd. for C21H29NO3+0.1H2O: C, 73.05; H, 8.52; N, 4.06. Found: C, 72.93; H, 8.42; N, 4.03. HRMS (ESI+, [M + Na]+): Calcd. for C21H29NNaO3: 366.20396. Found: 366.20309.
CO2MeH
2a-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2a
NOTs
TO a Solution of 2a-3 (204.8 mg, 0.60 mmol) in dry THF (4 mL), NaH (60% in oil, 55.6 mg, 1.4 mmol, 2.3 equiv.) was added at 0 °C. Then, the whole was stirred at 0 °C for 120 min and was added TsCl (120.6 mg, 0.63 mmol, 1.05 equiv.) in one portion at 0 °C. The mixture was stirred at 0 °C for 100 min. Water (5 mL) was added and the whole was diluted with water (30 mL) and extracted with CH2Cl2 (100 mL) and the organic layer was washed with brine (40 mL) and dried over MgSO4. The solvent was evaporated to give the residue, which was washed with n-hexane and dried in vacuum to give 2a (270.6 mg, 91 % yield) as a white powder. 2a: Mp. 159.5-161.0°C. 1H NMR (CDCl3) δ: 7.947 (2H, d, J = 8.4Hz), 7.581 (1H, d, J = 1.6 Hz), 7.344 (2H, d, J=8.0Hz), 7.245 (1H, d, d J=8.0, 2.0), 7.172 (1H, d, J=8.0), 3.652 (3H, s), 2.856 (1H, septet, J=6.8), 2.641 (2H, m), 2.437 (3H, s), 2.254 (2H, t, J = 9.2 Hz), 1.732-1.646 (5H, m), 1.331 (3H, s), 1.216 (3H, d, J=6.8Hz), 1.210 (3H, d, J=6.8Hz), 1.032 (3H, s). 13C NMR (CDCl3) δ: 177.83, 162.64, 150.00, 146.57, 144.96, 132.84, 129.99, 129.46, 129.09, 126.41, 123.29, 123.08, 52.22, 46.20, 41.34, 37.21, 36.93, 36.47, 33.48, 25.02, 23.83, 23.63, 23.02, 21.66, 17.95, 16.50. Anal. Calcd. for C28H35NO5S: C, 67.58; H, 7.09; N, 2.81. Found: C, 67.69; H, 7.16; N, 2.74. HRMS (ESI+, [M + Na]+): Calcd. for C28H35NO5SNa+: 530.21282. Found: 520.21334.
CO2MeH O
N
CO2Me OTsH N
TFA20 °C, 1 hr
2a3a
H
84 %
4
To weighted 2a (74.6 mg, 0.15 mmol) TFA (3.0 mL) was added at 0°C (in an ice-water bath). Then the reaction mixture was stirred at 20°C (in a water bath) for 60 min. At 0 °C, 5 mL of ice-water was added, the whole was diluted with 25 mL of
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water, and extracted with CH2Cl2 (90 mL), and the organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give a crude product (53.8 mg), which was flash-column chromatographed (ethyl acetate : n-hexane = 1 : 1) to give 3a (43.4 mg (84 % yield) as a colorless solid. 3a: Mp. 149.0-151.0 °C (colorless needles, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.499 (1H, brs, NH), 7.308 (1H, d, J=8.4), 6.997 (1H, d, d, J=8.0 Hz, 2.0 Hz), 6.691 (1H, d, J=2.0 Hz), 3.639 (3H, s), 2.848 (1H, sectet, J=7.2), 2.777 (1H, d, d, J=3.6, 8.4 Hz), 2,537 (1H, d, d, J = 14.8, 8.4 Hz), 2.156 (1H, d, d, J = 4.8, 14.8 Hz), 1.938-1.810 (3H, m), 1.748-1.654 (3H, m), 1.449 (3H, s), 1.415 (3H, s), 1.225 (6H, d, J=6.8 Hz). 13C NMR (CDCl3) δ: 178.03, 177.19, 148.24, 139.87, 134.79, 126.66, 123.74, 121.00, 52.19, 49.71, 48.59, 40.62, 39.52, 36.27, 36.18, 33.25, 23.72, 23.70, 22.19, 18.17, 16.95. Anal. Calcd. for C21H29NO3: C, 73.44; H, 8.51; N, 4.08. Found: C, 73.27; H, 8.50; N, 4.06. HRMS (ESI+, [M + Na]+): Calcd. for C21H29NNaO3+: 366.20396. Found: 366.20527.
CO2MeH
2b-1CO2Me
H
2b-2
CrO3Ac2O, AcOH
OCO2Me
H
2b-3
NOH
pyridine
1) NaH, THF
2) TsCl, THFCO2Me
H
2c
NOTs
NH2OH/HCl
Cl ClCl Cl
CO2MeH
2b-1
Cl
CO2HH
Cl
CO2HH
CH3OH
H2SO4
FeCl3, DDQsilica gel
Cl2 in CCl4
CO2HH
+
Cl
+
CO2MeH
2c-1
Cl
12- and 14-chlorodehydroabietic acid (16, 26): To a suspension of dehydroabietic acid (3.7425 g, 12.46 mmol), 2% (w/w) FeCl3 on SiO2 (1.8832 g), and 2% (w/w) DDQ on SiO2 (189.2 mg) in 11 mL of CCl4 was added a solution of 8.2 mL of 2.0 M Cl2 in CCl4 (16.4 mmol, 1.3 equiv.) in one portion at 0 oC (in an ice-water bath). The reaction mixture was vigorously stirred at 0 °C for 75 min under protection from light exposure. The reaction was quenched with saturated aqueous Na2SO3 (60 mL) at 0 °C, and the whole was extracted with CH2Cl2 (250 mL). The organic layer was washed with brine (80 mL), and dried over MgSO4. Evaporation of the solvent gave a white foam (4.1876 g), a mixture of 12- and 14-chlorodehydroabietic acids (14-Cl: 12-Cl =2.34 :1, the ratio estimated from the integration values of the 1H NMR spectra). 14-chlorodehydroabietic acid: 1H NMR (CDCl3): δ 7.162 (1H, d, J=8.8Hz), 7.102 (1H, d, J=8.4), 3.419 (1H, septet, J=7.2Hz), 2.993 (1H, d, d, J = 18.0, 6.4 Hz, 1H), 2.895-2.767 (1H. m), 2.301 (1H, d, J = 13.2 Hz), 2.183 (1H, d, d, J = 11.4, 4.4 Hz), 1.838-1.628 (7H, m), 1.282 (3H, s), 1.237-1.179 (3Hx3, m). 12-chlorodehydroabietic acid: 1H NMR (CDCl3): δ 7.173 (1H, s), 6.918 (1H, s), 3.299 (1H, septet, J=6.8Hz), 2.895-2.767 (1H. m), 2.301 (1H, d, J = 13.2 Hz), 2.242 (1H, d, J=10.4), 2.183 (1H, d, d, J = 11.4, 4.4 Hz), 1.838-1.628 (7H, m), 1.282 (3H, s), 1.237-1.179 (3Hx3, m).
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The crude mixture of two mono-chlorinated carboxylix acids was esterificated with methanol in the presence of an acid (16): To a solution of a mixture of mono-chlorinated compounds (4.1876 g) in 60 mL of metanol, 6mL of concentrated sulfuric acid (6mL) was added at 0 °C (ice-water) over 2 min. The whole was heated at reflux for 19 hrs. The white precipitate (mainly 14-Cl ester) was collected by suction and the solid was washed with methanol to give 14-Cl ester 2c-1 (2.1358 g, 49 % yield). The solvent of the filtrate was evaporated and the residue was dissolved with CH2Cl2 (175 mL), washed with water (180 mL) and brine (60 mL), and the organic layer was dried over MgSO4. Evaporation of the solvent gave the residue (1.4211 g), which was flash-column chromatographed (ethyl acetate: n-hexane=1:12) to give 12-Cl ester 2b-1 (344.0 mg, 8 % yield). 2b-1 (12-Cl): Mp. 126-127 °C (colorless needles). 1H NMR (CDCl3) δ: 7.161 (1H, s)), 6.904 (1H, s), 3.638 (3H, s), 3.286 (1H, sectet, J=6.8Hz), 2.825 (2H, m), 2.193 (2H, d, d, J = 12.8, 19.8 Hz), 1.841-1.619 (5H, m), 1.495-1.373 (2H, m), 1.249 (3H, s), 1.207 (3H, s), 1.182 (6H, d, J=6.8Hz). 13C NMR (CDCl3) δ: 178.76, 148.37, 142.29, 133.59, 130.59, 126.92, 125.04, 51.81, 47.45, 44.50, 37.80, 36.92, 36.51, 29.59, 29.36, 24.88, 22.71, 22.53, 21.45, 18.37, 16.40. Anal. Calcd. for C21H29ClO2: C, 72.29; H, 8.38; N, 0.00. Found: C, 71.94; H, 8.16; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C21H29ClO2Na+: 374.17523. Found: 371.17420. 2c-1 (14-Cl): Mp. 162-164 °C (colorless plates, recrystallized from CH2Cl2/methanol). 1H NMR (CDCl3): δ 7.157 (1H, d, J=8.4Hz), 7.095 (1H, d, J=8.4), 3.662 (3H, s), 3.413 (1H, septet, J=6.8Hz), 2.968 (1H, d, d, J = 18.0, 6.4 Hz), 2.765 (1H. m), 2.287 (1H, d, J = 11.6 Hz), 2.169 (1H, d, d, J = 12.8, 2.0 Hz), 1.821-1.625 (5H, m), 1.517-1.447 (2H, m), 1.264 (3H, s), 1.223 (3H, d, J=6.8 Hz), 1.199 (3H, s), 1.198 (3H, d, J=6.8 Hz). 13C NMR (CDCl3) δ: 178.89. 148.91, 142.79, 133.55, 133.14, 123.51, 122.52, 51.92, 47.50, 43.98, 38.17, 37.16, 36.45, 30.06, 29.10, 25.00, 22.79, 22.52, 21.40, 18.54, 16.43. Anal. Calcd. for C21H29ClO2: C, 72.29; H, 8.38; N, 0.00. Found: C, 72.07; H, 8.22; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C21H29ClO2Na+: 374.17523. Found: 371.17420.
CO2MeH
2b-1CO2Me
H
2b-2
CrO3Ac2O, AcOH
O
Cl Cl
A solution of CrO3 (107.0 mg, 1.2 equiv.) in Ac2O (2 mL) was added dropwise to a mixture of methyl ester 2b-1 (300.2 mg, 0.86 mmol) and AcOH (2 mL) and Ac2O (2mL) at 0 oC (26). The reaction mixture was stirred at 0 oC to 21 °C (water temperature) for 14 hrs. Water (20 mL) was added and the whole was extracted with CH2Cl2 (130 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (40 mL) and brine (40 mL) and dried over MgSO4. The solvent was evaporated to give a residue, which was flash-column chromatographed (ethyl acetate: n-hexane=1:8) to give 258.3 mg (83 % yield) of 2b-2 as a viscous coreless oil. 2b-2: 1H NMR (CDCl3): δ 7.937 (1H, s), 7.328 (1H, s), 3.650 (3H, s), 3.354 (1H, sectet, J=6.8 Hz), 2.680 (2H, m), 2.387-2.289 (2H, m), 1.811-1.704 (3H, m), 1.704-1.625 (2H, m), 1.332 (3H, s), 1.269 (9H, CH3x3). 13C-NMR (CDCl3): δ 197.42, 177.57, 153.82, 144.06, 139.79, 129.52, 125.80, 124.74, 52.18, 46.59, 43.64, 37.64, 37.34, 36.94, 36.43, 29.89, 23.53, 22.51, 22.37, 18.00, 16.32. HRMS (ESI+, [M +
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Na]+): Calcd. for C21H27ClNaO3: 385.15409. Found: 385.15481. Anal. Calcd. for C21H27ClO3+0.2 C6H14 (n-hexane): C, 70.14; H, 7.90; N, 0.00. Found: C, 70.33; H, 7.71; N, 0.00.
CO2MeH
2b-2
OCO2MeH
2b-3
NOH
pyridine
NH2OH/HCl
Cl Cl
A mixture of the ketone 2b-2 (258.3 mg, 0.71 mmol), NH2OH·HCl (84.4mg, 1.21 mmol, 1.7 eq), pyridine (1 mL) in EtOH (5 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane = 1：4) to give the oxime 2b-3 (238.6 mg, 89% yield) as a white foam. 2b-3: Mp. 223.0-224.0 °C (colorless cubes, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.773 (1H, s), 7.232 (1H, s), 3.655 (3H, s), 3.339 (1H, sectet, J=6.8 Hz), 2.629 (2H, m), 2.314-2.226 (2H, m), 1.766-1.728 (5H, m), 1.364 (3H, s), 1.260 (3H, d, J=6.8Hz), 1.237 (3H, d, J=6.8 Hz), 1.116 (3H, s). 13C NMR (CDCl3) δ: 178.10, 155.06, 149.82, 143.43, 135.06, 127.84, 124.19, 122.51, 52.11, 46.50, 41.54, 37.04, 36.99, 36.58, 29.93, 23.42, 22.81, 22.61, 22.56, 18.00, 16.52. Anal. Calcd. for C21H28ClNO3: C, 66.74; H, 7.47; N, 3.71. Found: C, 66.54; H, 7.33; N, 3.69. HRMS (ESI+, [M + Na]+): Calcd. for C21H28ClNO3Na+: 400.16499. Found: 400.16528.
CO2MeH
2b-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2c
NOTs
Cl Cl
TO a suspension of NaH (60% in oil, 41.9 mg, 1.05mmol, 3.7 equiv.) in dry THF (2 mL), 2b-3 (107.6 mg, 0.28 mmol) was added in one portion at 0 °C. Then, the whole was stirred at 0 °C for 60 min and then TsCl (56.6 mg, 1.1mmol, 1.04 equiv.) was added. The mixture was stirred at 3 °C for 60 min and 5 ml of water was added. The whole was diluted with water (40 mL) and extracted with CH2Cl2 (150 mL). The organic layer was washed with brine, dried over MgSO4. The solvent was evaporated to give a crude O-tosyl oxime 2c, which was flash-column chromatographed (on silica gel, ethyl acetate: n-hexane =1:6) to give 2c (133.2 mg, 88 % yield). 2c: Mp. 131.0-132.0 °C (colorless rods, recrystallization from CH2Cl2-n-hexane). 1H NMR (CDCl3) δ: 7.948 (2H, d, J=8.4Hz), 7.629 (1H, s), 7.353 (2H, d, J=8.0 Hz), 7.208 (1H, s), 3.660 (3H, s), 3.304 (1H, septet, J = 6.8 Hz), 2.705-2.601 (2H, m), 2.446 (3H, s), 2.234 (1H, d, d, J=11.8, 6.4 Hz), 2.194 (1H, d, J=13.2Hz), 1.744-1718 (4H, m), 1.687-1.615 (1H, m), 1.327 (3H. s), 1.239 (3H, d, J=7.2Hz), 1.180 (3H, d, J=6.8 Hz), 1.046 (3H, s). 13C NMR (CDCl3) δ: 177.69, 161.59,151.08, 145.14, 143.59, 137.15, 132.65, 129.45, 129.23, 125.44, 124.43, 123.74, 52.30, 46.15, 41.25, 37.17, 36.78, 36.52, 29.84, 24.84, 22.90, 22.64, 22.50, 22.34, 21.68, 17.84. Anal. Calcd. for C28H34ClNO5S: C, 63.20; H, 6.44; N, 2.63. Found: C, 63.22; H, 6.56; N, 2.47. HRMS (ESI+, [M + Na]+): Calcd. for C28H34ClNNaO5S: 554.17384. Found: 554.17576.
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CO2MeH
N
O
Cl
CO2MeNOTs
Cl
H
12
14
2b 3b
12
HTFA
20 °C, 4.5 hrs
83 %
To weighted 2b (54.0 mg, 0.10 mmol) TFA (3.0 mL) was added at 0°C (in an ice-water bath). Then the reaction mixture was stirred at 0°C for 7 min, and then at 20°C (in a water bath) for 4.5 hrs. At 0 °C, 10 mL of ice-water was added, the whole was diluted with 10 mL of water, and extracted with CH2Cl2 (90 mL), and the organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give a crude product (37.1 mg), which was flash-column chromatographed (ethyl acetate : n-hexane = 1 : 2) to give 3b (32.0 mg, 83 % yield) as colorless plates. Mp. 243.0-244.0 °C (colorless long rods, recrystallized from n-heane/CH2Cl2). 3b: 1H NMR (CDCl3) δ: 7.760 (1H, brs, OH), 7.326 (1H, s), 6.776 (1H, s), 3.642 (3H, s), 3.283 (1H, septet, J= 7.2 Hz), 2.754 (1H, d, d, J=8.4, 3.6 Hz), 2.532 (1H, d, d, J=8.4, 6.8 Hz), 2.142 (1H, d, t, J=14.8, 1.6 Hz), 1.917-1.681 (4H, m), 1.681 (2H, m), 1.436 (3H, s), 1.404 (3H, s), 1.224 (3H, d, J=6.4 Hz), 1.208 (3H, d, J=6.8 Hz). 13C NMR (CDCl3) δ: 177.96, 175.02, 144.60, 141.26, 134.74, 129.48, 127.49, 120.83, 52.15, 49.73, 48.01, 40.56, 39.43, 36.56, 36.17, 29.79, 22.45, 22.34, 21.80, 18.09, 16.87. Anal. Calcd. for C21H28ClNO3: C, 66.74; H, 7.47; N, 3.71. Found: C, 66.50; H, 7.38; N, 3.64. HRMS (ESI+, [M + Na]+): Calcd. for C21H28ClNO3Na+: 400.16499. Found: 400.16510.
CO2MeH
2c-1CO2MeH
2c-2
CrO3Ac2O, AcOH
OCO2MeH
2c-3
NOH
pyridine
1) NaH, THF
2) TsCl, THFCO2MeH
2c
NOTs
Cl NH2OH/HClClCl Cl
CO2MeH
2c-1CO2Me
H
2c-2
CrO3Ac2O, AcOH
OCl Cl
A solution of CrO3 (126.6 mg, 1.27 mmol, 1.27 equiv.) in AcOH (2 mL) was added dropwise to a mixture of methyl ester 2c-1 (349.4 mg, 1.00 mmol) and AcOH (4 mL) and Ac2O (2 mL) at 3 oC over 3 min (26). The reaction mixture was stirred at 17 °C (water temperature) for 112 hrs. Water (10 mL) was added and the whole was diluted with water (80 mL), and was extracted with CH2Cl2 (180 mL) and the organic layer was washed with water (80 mL), saturated aqueous NaHCO3 solution (60 mL) and brine (50 mL) and dried over MgSO4. The solvent was evaporated to give a residue, which was flash-column chromatographed (ethyl acetate: n-hexane=1:8) to give 250.3 mg (69 % yield) of 2c-2 as a white solid. 2c-2: Mp. 130.5-132.0°C (white powder). 1H NMR (CDCl3): δ 7.414 (1H, d, J = 8.0 Hz), 7.236 (1H, d, J = 8.4 Hz) , 3.659 (3H, s), 3.566 (1H, septet, J=6.8 Hz), 2.743-2.534 (2H, m), 2.507 (1H, d, d, J=17.4, 4.8 Hz), 2.263 (1H, d, d, J=12.4, 2.4 Hz), 1.797-1.742 (4H, m), 1.645 (1H. m), 1.346 (3H, s), 1.247 (3H, d, J=6.8Hz), 1.211 (3H, d, J=6.8Hz), 1.178 (3H, s). 13C-NMR (CDCl3): 197.50, 177.64, 154.53, 149.98, 145.64,
-
S8
143.87, 132.02, 130.34 (Cx2), 126.99, 123.24, 121.36, 52.16, 46.03, 42.29, 38.87, 37.62, 37.44, 36.66, 29.54, 23.14, 22.73, 22.43, 18.01, 16.59. HRMS (ESI+, [M + Na]+): Calcd. for C21H27ClNaO3: 385.15409. Found: 385.15319. Anal. Calcd. for C21H27ClO3+0.1 H2O: C, 69.16; H, 7.52; N, 0.00. Found: C, 68.94; H, 7.48; N, 0.00.
CO2MeH
2c-2
OCO2MeH
2c-3
NOH
pyridine
NH2OH/HClCl Cl
A mixture of ketone 2c-2 (180.9 mg, 0.50 mmol), NH2OH·HCl (54.0 mg, 0.77 mmol, 1.55 equiv.), pyridine (1 mL) and EtOH (5 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane = 1：8) to give the oxime 2c-3 (150.5 mg, 80% yield) as a white solid. 2c-3: Mp. 142.0-143.0 °C (colorless plates, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ : 8.576 (1H, brs), 7.247 (1H, d, J = 8.0 Hz), 7.148 (1H, d, J = 8.0Hz), 3.650 (3H, s), 3.550 (1H, septet, J=6.8 Hz), 3.089 (1H, d, d, J = 18.8, 13.2 Hz), 2.792 (1H, d, d, J = 18.4, 6.4 Hz), 2.222-2.154 (2H, m), 1.738-1.708 (4H, m), 1.657-1.605 (1H, m), 1.541 (3H, s), 1.265 (3H, d, J=6.8 Hz), 1.213 (3H, d, J=6.8Hz), 1.069 (3H, s). 13C NMR (CDCl3) δ: 178.03, 153.59, 151.42, 145.13, 130.44, 128.31, 126.68, 120.94, 52.11, 46.19, 41.24, 37.68, 37.55, 37.14, 30.22, 24.45, 22.99, 22.60, 21.45, 17.98, 16.73. Anal. Calcd. for C21H28ClNO3: C, 66.74; H, 7.47; N, 3.71. Found: C, 66.53; H, 7.34; N, 3.73. HRMS (ESI+, [M + Na]+): Calcd. for C21H28ClNO3Na+: 400.16499. Found: 400.16031.
CO2MeH
2c-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2c
NOTs
Cl Cl
TO a suspension of NaH (60% in oil, 34.8 mg, 0.87 mmol, 3.7 equiv.) in dry THF (2 mL), 2c-3 (86.5 mg, 0.23 mmol) was added in one portion at 0 °C. Then the whole was stirred at 0 °C for 60 min and then TsCl (43.7 mg, 0.23mmol, 1.00 equiv.) was added. The mixture was stirred at 0 °C to 8 °C for 100 min. Water (10 mL) was added. The whole was diluted with water (10 mL) and extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give a crude O-tosyl oxime 2c, which was washed with n-hexane and dry in vacuum to give 2c (113.6 mg, 93 % yield). 2c: Mp. 166.0-166.5 °C (colorless rods, recrystallization from CH2Cl2-n-hexane). 1H NMR (CDCl3) δ: 7.948 (2H, d, J=8.4Hz), 7.336 (2H, d, J = 8.4 Hz), 7.269 (1H, d, J = 8.4Hz), 7.126 (1H, d, J=8.4 Hz), 3.660 (3H, s), 3.440 (1H, septet, J=6.8 Hz), 3.034 (1H, d, d, J=19.0, 13.2Hz), 2.512 (1H, d, d, J=18.8, 6.4 Hz), 2.445 (3H, s), 2.178 (1H, brd, J=12.4Hz), 2.103 (1H, d, d, J=13.2, 6.4Hz), 1.756-1.701 (4H, m), 1.662-1.565 (1H, m), 1.373 (3H, s), 1.228 (3H, d, J=6.8 Hz), 1.142 (3H, d, J=6.8 Hz), 1.038 (3H, s). 13C NMR (CDCl3) δ: 177.77, 161.34, 152.36, 145.38, 144.91, 133.04, 131.36, 129.43, 129.28, 128.32, 126.02, 121.13, 52.25, 45.88, 40.76, 37.55, 37.50, 37.24, 30.21, 25.97, 22.94, 22.40, 21.70, 21.67, 17.83, 16.80. Anal. Calcd. for
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S9
C28H34ClNO5S: C, 63.20; H, 6.44; N, 2.63. Found: C, 63.05; H, 6.35; N, 2.57. HRMS (ESI+, [M + Na]+): Calcd. for C28H34ClNO5SNa: 554.17384. Found: 554.17317.
CO2MeH O
N
TFA20 °C, 3 hrs
H
67 %CO2MeH N
ClO
CO2Me
Cl
NOTs
H 2c 3c
12
14
H
14Cl
14
4c
+
5 %
To weighted 2c (53.3 mg, 0.10 mmol), TFA (3.0 mL) was added at 0°C (in an ice-water bath). The reaction mixture was stirred at 15°C (in a water bath) for 3 hrs, then the whole was stirred at 18 °C (water-temperature) for 60 min. Ice-water was added, and then the whole was extracted with CH2Cl2 (100 mL), and the organic layer was washed with brine (40 mL x 2), dried over MgSO4. The solvent was evaporated to give a crude product (32.4 mg) (3c: 4c=8:92, from proton integrations of the 1H NMR spectra), which was flash-column chlomatographed (ethyl acetate: n-hexane = 1 : 3) to give less polar 3c (1.8 mg (5 % yield) as a white powder and more polar 4c (25.3 mg (67 % yield) as a white powder. 4c: Mp. 247.5-248.0 °C (colorless thin plates, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.337 (1H, brs), 7.291 (1H, d, J=8.4 Hz), 7.104 (1H, d, J=8.8 Hz), 3.621 (3H, s), 3.378 (1H, septet, J= 7.2 Hz), 2.733 (1H, d, J=10.4Hz), 2.633 (1H, d, d, J= 14.0, 10.8 Hz), 2.016 (1H, d, J=14.0 Hz), 1.950-1.821 (2H, m), 1.811-1.787 (2H, m), 1.691-1.667 (2H, m), 1.472 (3H, s), 1.466 (3H, s), 1.255 (3H, d, J=7.2Hz), 1.228 (3H, d, J = 6.8 Hz). 13C NMR (CDCl3) δ: 178.06, 174.03, 144.79, 142.70, 133.42, 126.15, 123.31, 122.51, 52.12, 50.23, 50.11, 40.29, 38.90, 36.85, 36.27, 30.46, 22.54, 22.48, 20.97, 18.14, 16.59. Anal. Calcd for C21H28ClNO3: C, 66.74; H, 7.47; N, 3.71. Found: C, 66.47; H, 7.33; N, 3.58. HRMS (ESI+, [M + Na]+): Calcd. for C21H28ClNNaO3: 400.16499. Found: 400.16498. 3c: 1H NMR (CDCl3) δ: 7.314 (1H, d, J=8.4 Hz), 7.203 (1H, d, J = 8.4 Hz), 7.044 (1H, brt, J = 6.4 Hz), 3.598 (3H, s), 3.529-3.3.473 (1H. m), 3.486 (1H, septet, J=7.2 Hz), 2.854 (1H, d, d, J=16.0, 7.2 Hz), 2.213 (1H, d, J=8.4 Hz), 1.991-1.890 (2H, m), 1.838-1.768 (2H, m), 1.682-1.658 (2H, m), 1.615 (3H, s), 1.419 (3H, s), 1.247 (3H, d, J=5.2Hz), 1.229 (3H, d, J=4.8 Hz). 13C NMR (CDCl3) δ: 178.16, 171.80, 146.41, 145.18, 133.40, 132.00, 127.84, 121.20, 60.37, 52.15, 50.09, 49.47, 42.94, 40.05, 39.18, 36.54, 29.92, 23.21, 22.77, 22.57, 21.03, 18.39, 17.40, 14.19. HRMS (ESI+, [M + Na]+): Calcd. for C21H28ClNNaO3: 400.16499. Found: 400.16508.
CO2MeH
2d-1CO2Me
H
2d-2
CrO3Ac2O, AcOH
OCO2Me
H
2d-3
NOH
pyridine
1) NaH, THF
2) TsCl, THFCO2Me
H
2d
NOTs
Cl NH2OH/HClClCl Cl
Cl ClCl Cl
CO2MeH
2d-1
Cl
CO2HH
Cl
CO2HH CH3OH
H2SO4FeCl3, DDQ
silica gel
Cl2 in CCl4 Cl Cl
12,14-chlorodehydroabietic acid (2, 6): To a stirred suspension of dehydroabietic acid (3.0029 g, 10.0 mmol), 2% (w/w) FeCl3 on SiO2 (1.5040 g), and 2% (w/w) DDQ on SiO2 (159.2 mg) in 9 mL of CCl4 was added a solution of 30 mL of 2.0 M Cl2 in
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S10
CCl4 (60 mmol, 6 equiv.) in one portion at 0 oC (in an ice-water bath) (16, 26). The reaction mixture was vigorously stirred at 0 °C for 3hrs under protection from light exposure. Saturated aqueous Na2SO3 (100 mL) solution was added at 0 °C, and the whole was extracted with CH2Cl2 (300 mL). The organic layer was washed with brine (175 mL), and dried over MgSO4. Evaporation of the solvent gave a pale yellow solid (5.6652 g), which was flash-column chromatographed (ethyl acetate: n-hexane =1:5) to give 12,14-dichlorodehydroabietic acid (2.1722 g, 59 % yield). 12,14-chlorodehydroabietic acid: Mp. 235.0-236.0 °C (white powder, recrystallized from n-hexane). 1H NMR (CDCl3,): δ 11.63 (1H, brs, OH), 7.135 (1H, brs), 3.891 (1H, brs), 2.915 (1H, d, d, J=18.2, 6.4 Hz), 2.776-2.703 (1H, m), 2.218 (1H, d, J=12.8 Hz), 2.106 (1H, d, d, J=12.8, 2.0 Hz),1.809-1.592 (6H, m), 1.373 (6H, d, 7.2 Hz), 1.252 (3H, s), 1.181 (3H, s). 13C NMR (CDCl3) δ 184.63, 149.53, 139.08, 135.33, 47.17, 43.47, 37.94, 37.14, 36.47, 31.20, 24.85, 21.34, 19.58, 19.44, 18.38, 16.15. Anal. Calcd. for C20H26Cl2O2+0.2H2O: C, 64.41; H, 7.14; N, 0.00. Found: C, 64.03; H, 6.88; N, 0.00. HRMS (ESI+, [M - H]-): Calcd. for C20H25Cl2O2: 367.12371. Found: 367.12678. HRMS (ESI+, [M + Na]+): Calcd. for C20H26Cl2O2Na: 391.12021. Found: 399.11555. To a solution of recrystallized 12,14-dichlorodehydroabietic acid (1.6977 g) in 50 mL of dry metanol, 5 mL of concentrated sulfuric acid was added (27). The whole was heated at 85°C for 39 hrs. The white precipitate was formed. Methanol was evaporated and the residue was diluted with water. The whole was basified with 10% aqueous NaOH solution, extracted with CH2Cl2 (175 mL), and the organic layer was washed with brine (70 mL), dried over MgSO4. The organic solvent was evaporated to give the white powder (1.7201 g), which was flash-column chromatographed (ethyl acetate: n-hexane=1:4) to give 1.6175 g (2d-1, 92 % yield). 2d-1: Mp. 135.0-136.0 °C (white powder, recrystallized from n-hexane). 1H NMR (400 MHz, CDCl3) δ: 7.254 (1H, brs), 3.907 (1H, brs), 3.686 (3H, s), 2.912 (1H, d, d, J=18.2, 6.4 Hz), 2.751-2.658 (1H, m), 2.225 (1H, d, J=10.8 Hz), 2.118 (1H, d, d, J=12.8, 2.4 Hz), 1.777-1.577 (5H, m), 1.390 (6H, d, J=7.2 Hz), 1.256 (3H, s), 1.175 (3H, s). 13C NMR (CDCl3) δ: 178.69, 149.67, 138.98, 135.26, 51.96, 48.32, 47.39, 46.65, 43.68, 37.98, 37.18, 36.37, 31.16, 24.83, 21.26, 19.54, 19.41, 18.40, 16.40. Anal. Calcd. for C21H28Cl2O2: C, 65.79; H, 7.36; N, 0.00. Found: C, 65.69; H, 7.17; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C21H28Cl2O2Na+: 405.13586. Found: 405.13644.
CO2MeH
2d-1CO2Me
H
2d-2
CrO3Ac2O, AcOH
OCl Cl
Cl Cl
A solution of CrO3 (4.78.8 mg, 4.79 mmol, 1.23 equiv.) in AcOH (10 mL) and Ac2O (6 mL) was added dropwise to a suspension of methyl ester 2d-1 (1.5408 g, 3.88 mmol) and AcOH (8 mL) and Ac2O (4 mL) at 0 oC over 5 min (16). The reaction mixture was stirred at 10 °C (water temperature) for 15 hrs. Saturated aqueous NaHCO3 solution (220 mL) was added and the whole was extracted with CH2Cl2 (250 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (60 mL) and brine (80 mL) and dried over MgSO4. The solvent was evaporated to give a residue, which was flash-column chromatographed (ethyl acetate: n-hexane=1:10) to give 840.0 mg (53 % yield) of 2d-2 as a white foam.
-
S11
2d-2: Mp. 58.0-62.0°C (colorless plates). 1H NMR (CDCl3, 400 MHz): δ 7.232 (1H, brs), 4.092 (1H, brs), 3.662 (3H, s), 2.720-2.480 (3H, m), 2.202 (1H, d, J=12.4 Hz), 1.823-1.725 (4H, m), 1.678-1.572 (1H, m), 1.410 (6H, d, J=7.2 Hz), 1.336 (3H, s), 1.168 (3H, s). 13C-NMR (CDCl3): 196.73, 177.50, 154.50, 141.99, 140.27, 139.26, 52.24, 45.96, 42.10, 38.87, 37.63, 37.23, 36.64, 22.87, 19.41, 19.15, 17.89, 16.61. HRMS (ESI+, [M + Na]+): Calcd. for C21H26Cl2NaO3: 419.11512. Found: 419.11586. Anal. Calcd. for C21H26Cl2O3: C, 63.48; H, 6.60; N, 0.00. Found: C, 63.57; H, 6.79; N, 0.00.
CO2MeH
2d-2
OCO2MeH
2d-3
NOH
pyridine
NH2OH/HClCl Cl
Cl Cl
A mixture of ketone 2d-2 (300.7 mg, 0.76 mmol), NH2OH·HCl (81.6 mg, 1.17 mmol, 1.54 equiv.), pyridine (1 mL) and EtOH (5 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane = 1：6) to give the oxime 2d-3 (278.7 mg, 89% yield) as a white powder. 2d-3: Mp. 155.0-159.0 °C (colorless cubes, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 9.180 (1H, brs, OH), 7.153 (1H, brs), 4.129 (1H, brs), 3.660 (3H, s), 3.085 (1H, d, d, J=18.8, 13.2 Hz), 2.380 (1H, d, d, J=18.8, 6.4 Hz), 2.176-2.127 (2H, m), 1.746-1.697 (5H, m), 1.594-1.569 (1H, m), 1.432 (6H, brd, J=7.2 Hz), 1.370 (3H, s), 1.056 (3H, s). 13C NMR (CDCl3) δ: 177.89, 153.31, 151.71, 141.32, 135.51, 132.44, 127.66, 124.56, 52.21, 46.16, 41.10, 37.63, 37.49, 37.09, 31.57, 24.39, 21.15, 19.70, 19.29, 17.88, 16.76. Anal. Calcd. for C21H27Cl2NO3+0.5H2O: C, 59.86; H, 6.70; N, 3.32. Found: C, 59.56; H, 6.68; N, 3.05. HRMS (ESI+, [M + Na]+): Calcd. for C21H27Cl2NO3Na+: 434.12602. Found: 434.12748.
CO2MeH
2d-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2d
NOTs
Cl Cl
Cl Cl
NaH (60% in oil, 30.1 mg, 0.75 mmol, 3.0 equiv.) was washed with n-pentane (2 mL x 2) and the n-pentane was removed by decantation. TO a suspension of oil-free NaH in dry THF (2 mL), the oxime 2c-3 (102.7 mg, 0.25 mmol) was added in one portion at 0 °C. Then the whole was stirred at 0 °C for 75 min and then TsCl (50.4 mg, 0.264 mmol, 1.06 equiv.) was added. The mixture was stirred at 0 °C for 80 min. Water (5 mL) was added at 0 C°. The whole was diluted with water (30 mL) and extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (30 mL), dried over MgSO4. The solvent was evaporated to give the residue (131.2 mg), which was flash-column chromatographed (ethyl acetate: n-hexane = 1：6) to give 2d (128.6 mg, 91 % yield). 2d: Mp. 72.0-76.0 °C (colorless amorphous). 1H NMR (CDCl3) δ: 7.931 (2H, d, J = 8.4 Hz), 7.339 (1H, d, J = 8.0Hz), 7.128 (1H, brs, OH), 3.941 (1H, brs), 3.663 (3H, s), 3.020 (1H, d, d, J=18.8, 12.8 Hz), 2.494 (1H, d, d, J=18.8, 6.4 Hz), 2.450 (3H, s),
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S12
2.163-2.037 (2H, m), 1.764-1.693 (3H, m), 1.596-1.521 (2H, m), 1.537 (3H, s), 1.363 (6H, brs), 1.027 (3H, s). 13C NMR (CDCl3) δ: 177.60, 152.47, 145.03, 143.89, 141.61, 137.27, 133.41, 132.91, 130.20, 129.46, 129.22, 127.07, 52.30, 45.81, 40.59, 37.59, 37.29, 37.16, 31.18, 25.92, 21.70, 21.34, 19.50, 19.09, 17.70, 16.79. Anal. Calcd. for C28H33Cl2NO5S+0.2C6H14 (n-hexane): C, 60.08; H, 6.18; N, 2.40. Found: C, 60.32; H, 6.36; N, 2.30. HRMS (ESI+, [M + Na]+): Calcd. for C28H33Cl2NO5SNa: 588.13487. Found: 588.13246.
CO2MeH N
Cl
ClO
CO2Me
Cl
Cl
NOTs
H
12
14
H
1214TFA
20 °C, 1 hr
3 %2d 84 %CO2MeH O
N HCl
+
Cl
3d 4d
To weighted 2d (51.2 mg, 0.09 mmol), TFA (3.0 mL) was added at 0°C (in an ice-water bath). The reaction mixture was stirred at 20 °C (in a water bath) for 2 hrs. At 0°C, ice-water (5 mL) was added, the whole was diluted with water (30 mL), and extracted with CH2Cl2 (100 mL), and the organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give a crude product (39.6 mg) (3d: 4d=4:96, from proton integrations of the 1H NMR spectra), which was flash-column chromatographed (ethyl acetate: n-hexane = 2 : 3) to give less polar 3d (1.1 mg (3 % yield) and more polar 4d (34.7 mg, 93 % yield) as a white powder. 4d: Mp. 134.0-135.0 °C (colorless plates, recrystallized from n-heane/CH2Cl2). 1H NMR (CDCl3) δ: 7.187 (1H, brs), 6.379 (1H, brs, OH), 3.939 (1H, brs), 3.590 (3H, s), 3.460 (1H, septet, J=6.0 Hz), 2.816 (1H, d, d, J=16.2, 6.8 Hz), 2.179 (1H, d, J=8.4 Hz), 1.904-1.819 (2H, m), 1.785-1.764 (2H, m), 1.664-1.656 (2H, m), 1.560 (3H, s), 1.391 (3H, s), 1.378 (3H, d, J=7.2 Hz). 13C NMR (CDCl3): 177.93, 171.22 (br), 146.83, 141.36, 136.52, 133.86, 132.31 (very br), 124.78 (very br), 52.19, 49.77, 49.41, 42.85, 40.04, 38.99, 36.45, 31.12 (br), 22.89, 18.89, 19.25, 18.27, 17.30. Anal. Calcd. for C21H27Cl2NO3+0.8C6H14 (n-hexane): C, 64.38; H, 8.00; N, 2.91. Found: C, 64.10; H, 7.78; N, 3.01. HRMS (ESI+, [M + Na]+): Calcd. for C21H27Cl2NO3Na: 434.12602. Found: 434.12473. 3d: δ: 7.309 (1H, brs), 7.273 (1H, brs), 3.880 (1H, septet, J=7.2 Hz), 3.631 (3H, s), 2.731-2.603 (2H, m), 2.015 (1H, d, J=13.6 Hz), 1.923-1.869 (2H, m), 1.815-1.751 (2H, m), 1.688-1.654 (2H, m), 1.469 (3H, s), 1.463 (3H, s), 1.415 (3H, d, J=7.2 Hz). 13C NMR (CDCl3) δ: 177.85, 173.67, 143.48, 140.89, 128.90, 52.17, 50.26, 49.89, 40.33, 38.71, 36.78, 36.18, 31.71, 20.70, 19.38, 19.23, 18.04, 16.51 (three carbon signals cannot be identified due to the noisy spectra of a limited amount of the sample). HRMS (ESI+, [M + Na]+): Calcd. for C21H27Cl2NO3Na: 434.12602. Found: 434.12549.
CO2MeH
2a-2CO2Me
H
2a-4
NOOCH3
NH2OCH3·HCl
pyridineEtOH CO2Me
H
2e-1
NOCH3
BrNBSPd(OAc)2
AcOHCO2Me
H
2e-2
O
BrHCl
dioxane-H2O
-
S13
CO2MeH
2a-2CO2MeH
2a-4
NOOCH3
NH2OCH3·HCl
pyridineEtOH
A mixture of the ketone 2a-2 (4.3909 g, 13.37 mmol), NH2OMe·HCl (1.5612 g, 18.69 mmol, 1.40 equiv.), dry pyridine (1 mL) and dry EtOH (20 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was diluted with water and extracted with CH2Cl2 (125 mL), and the organic layer was washed with 1M aqueous HCl solution (70 mL), brine (40 mL) and dried over MgSO4. The organic solvent was evaporated to give the oil residue, which was flash-column chromatographed (ethyl acetate: n-hexane = 1：20) to give the O-methyl oxime 2a-4 (3.8485 g, 81% yield) as a colorless viscous oil. 2a-4: 1H NMR (CDCl3) δ: 7.752 (1H, brs), 7.193 (1H, brs), 7.190 (1H, brs), 4.000 (3H, s), 3.639 (3H, s), 2.904 (1H, septet, J=6.8 Hz), 2.636-2.497 (2H, m), 2.318-2.259 (2H, m), 1.758-1.614 (5H, m), 1.355 (3H, s), 1.252 (3H, d, J=6.8 Hz), 1.249 (3H, d, J=6.8 Hz), 1.101 (3H, s). 13C NMR (CDCl3) δ: 178.28, 154.21, 148.50, 146.47, 128.88, 127.62, 122.79, 122.27, 61.97, 52.04, 46.52, 41.62, 37.15, 37.05, 36.44, 33.68, 24.16, 23.66, 22.91, 18.21, 16.54. Anal. Calcd. for C22H31NO3+0.4H2O: C, 72.45; H, 8.79; N, 3.84. Found: C, 72.68; H, 8.61; N, 3.79. HRMS (ESI+, [M + Na]+): Calcd. for C22H31NO3Na+: 380.21961. Found: 380.22049.
CO2MeH
2a-4
NOCH3 CO2Me
H
2e-1
NOCH3
BrNBSPd(OAc)2
AcOHCO2Me
H
2e-2
O
BrHCl
dioxane-H2O
A mixture of 2a-4 (1.8746 g, 5.24 mmol), Pd(OAc)2 (63.8 mg, 0.284 mmol, 5 mol%), NBS (1.0768 g, 6.05 mmol, 1.15 equiv.) in AcOH (18 mL) was heated at 90 °C for 50 min under microwave irradiation with stirring, then the whole was cooled to rt., and poured into 10% aqueous NaOH solution (100 mL) (27). The aqueous layer was extracted with CH2Cl2 (120 mL), and the organic layer was washed with saturated NaHCO3 solution (40 mL) and brine (50 mL) and dried over MgSO4. The organic solvent was evaporated to give the pale orange colored foam, which was flash-column chromatographed (ethyl acetate: n-hexane = 1：20~1:16) to afford a inseparable mixture (1.2710 g) of 2e-1 (O-methyl oxime of methyl 14-bromo-7-oxo-dehydroabietate) and O-methyl oxime of methyl 12-bromo-7-oxo-dehydroabietate, the starting material (2a-4) and the ketone 2a-2 in mol% ratios (63.9:25.9:8.0: 2.1, estimated from the integration values of the 1H NMR spectra) as a pale yellow foam. The mixture was used for the next step without further isolation. 2e-1: 1H NMR (CDCl3) δ: 7.211 (1H, d, J=8.0Hz), 7.155 (1H, d, J=8.4 Hz), 4.037 (3H, s), 3.637 (3H, s), 3.561 (1H, septet, J=6.8 Hz), 3.020 (1H, d, d, J=18.4, 12.8Hz), 2.278 (1H, d, d, J=18.4, 6.4 Hz), 2.207-2.110 (2H, m), 1.748-1.607 (5H, m), 1.368 (3H, s), 1.244 (3H, d, J=6.8 Hz), 1.190 (3H, d, J=6.8 Hz), 1.062 (3H, s). 13C NMR (CDCl3) δ: 178.04, 153.62, 151.51, 147.05, 130.41, 127.42, 126.82, 122.54, 122.35, 121.56, 62.19, 52.11, 46.23, 41.48, 37.66, 37.04, 33.27, 24.62, 23.35, 22.79, 22.68, 21.68, 21.26, 17.98, 16.76.
-
S14
A solution of the mixture (mainly 2e-1 (1.2385 g)), in 1,4-dioxane (10 mL) and 6 M aqueous HCl (10 mL) was heated at 120 °C for 120 min under microwave irradiation with stirring, then the whole was cooled, and the solvent was evaporated in vacuum (28). The resultant was diluted with water (70 mL) and extracted with CH2Cl2 (180 mL). The organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated in vacuum to give the residue, which was flash-column chromatographed (ethyl acetate: n-hexane=1 : 10) to afford an inseparable mixture of ketones (760.3 mg), i.e., 2e-2, 2a-2 and 2f-2 in mol% ratios (63.0: 27.7: 9.2, estimated from the integration of the 1H NMR spectra). The mixture was suspended in n-hexane at rt and the insoluble white powder was collected by suction to provide pure 2e-2 (406.2 mg, 19 % yield, in two steps) as a white powder. 2e-2: Mp. 165.0-165.5 °C (colorless plates, recrystallized from CH2Cl2-n-hexane). 1H NMR (CDCl3) δ: 7.379 (1H, d, J=8.4 Hz), 7.260 (1H, d, J=6.4 Hz), 3.655 (3H, s), 3.599 (1H, septet, J=6.8 Hz), 2.715 (1H, d, d, J=17.4, 12.4 Hz), 2.627-2.486 (2H, m), 2.250 (1H, d, J=12.4Hz), 1.800-1.736 (5H, m), 1.662-1.615 (1H, m), 1.341 (3H, s), 1.239 (3H, d, J=6.8 Hz), 1.202 (3H, d, J=6.8 Hz), 1.161 (3H, s). 13C NMR (CDCl3) δ: 198.22, 177.69, 154.67, 147.47, 132.39, 130.36, 122.62, 122.11, 52.22, 46.03, 42.25, 38.72, 37.67, 37.47, 36.70, 32.46, 23.12, 22.99, 22.68, 18.02, 16.63. Anal. Calcd. for C21H27BrO3: C, 61.92; H, 6.68; N, 0.00. Found: C, 61.76; H, 6.06; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C21H27BrO3Na: 429.10358. Found: 429.10588.
CO2MeH
2e-3
NOH
pyridine
NH2OH/HCl Br
CO2MeH
2e-2
O
Br
A mixture of the ketone 2e-2 (150.3 mg, 0.37 mmol), NH2OH·HCl (43.2 mg, 0.62 mmol, 1.68 equiv.), pyridine (0.4 mL) and EtOH (4 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane = 1：6) to give the oxime 2e-3 (150.1 mg, 96% yield) as a white powder. 2e-3: Mp. 235.0-239.0 °C (colorless cubes, recrystallized from n-hexane). 1H NMR (CDCl3) δ: 9.176 (1H, brs), 7.234 (1H, d, J=8.4Hz), 7.171 (1H, d, J=8.0 Hz), 3.647 (3H, s), 3.576 (1H, septet, J=6.8 Hz), 3.134 (1H, d, d, J=18.6, 12.8 Hz), 2.365 (1H, d, d, J=18.4, 6.8 Hz), 2.209-2.148 (2H, m), 1.748-1.700 (4H, m), 1.624-1.574 (1H, m), 1.370 (3H, s), 1.266 (3H, d, J=6.8 Hz), 1.208 (3H, d, J=6.8Hz), 1.053 (3H, s). 13C NMR (CDCl3) δ: 178.05, 154.79, 151.65, 147.01, 130.51, 126.97, 122.17, 121.65, 52.14, 46.25, 41.47, 37.73, 37.13, 33.27, 31.57, 24.28, 23.24, 22.86, 21.35, 18.00, 16.76. Anal. Calcd. for C21H28BrNO3: C, 59.72; H, 6.68; N, 3.32. Found: C, 59.49; H, 6.57; N, 3.33. HRMS (ESI+, [M + Na]+): Calcd. for C21H28BrNO3Na+: 444.11448. Found: 444.11507.
CO2MeH
2e-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2e
NOTs
Br Br
-
S15
To a solution of the oxime 2e-3 (100.5 mg, 0.24 mmol) in THF (2 mL), NaH (60% in oil, 22.5 mg, 0.56 mmol, 2.3 equiv.) was added at 0 °C. Then the whole was stirred at 0 °C for 70 min and then TsCl (48.6 mg, 0.255 mmol, 1.06 equiv.) was added. The mixture was stirred at 0 °C for 100 min. 5 mL of water was added at 0 C°. The whole was diluted with water (25 mL) and extracted with CH2Cl2 (80 mL). The organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give the residue (147.3 mg), which was washed with n-hexane and dried in vacuum to give 2e (127.0 mg, 93 % yield) as a white powder. 2e: Mp. 139.0-142.0 °C (colorless cubes, recrystallized from CH2Cl2/n-hexane). 1H NMR (CDCl3) δ: 7.917 (2H, d, J=8.4 Hz), 7.295 (2H, d, J=8.0 Hz), 7.217 (1H, d, J=8.0 Hz), 7.123 (1H, d, J=8.4 Hz), 3.632 (3H, s), 3.396 (1H, septet, J=6.8 Hz), 3.055 (1H, d, d, J=18.8, 12.8 Hz), 2.471 (1H, d, d, J=18.8, 6.4 Hz), 2.142 (1H, d, J=12.4 Hz), 2.072 (1H, d, d, J=12.8, 6.8 Hz), 1.717-1.669 (3H, m), 1.635-1.485 (2H, m), 1.485 (3H, s), 1.185 (3H, d, J=6.8 Hz), 1.103 (3H, d, J=6.8 Hz), 0.996 (3H, s). 13C NMR (CDCl3) δ: 177.75, 162.27, 152.52, 147.24, 144.88, 133.19, 129.47, 129.36, 128.48, 128.13, 122.72, 121.83, 52.25, 45.90, 40.92, 37.70, 37.51, 37.20, 33.26, 25.94, 23.15, 22.61, 21.67, 21.54, 17.82, 16.80. Anal. Calcd. for C28H34BrNO5S: C, 58.33; H, 5.94; N, 2.43. Found: C, 58.61; H, 6.00; N, 2.42. HRMS (ESI+, [M + Na]+): Calcd. for C28H34BrNO5SNa: 598.12333. Found: 598.12327.
CO2MeH N
Br
O
CO2Me
Br
NOTs
H
12
14
H
14
12
TFA10°C, 1.5 hr
97 %2e 4e
To weighted 2e (75.8 mg, 0.13 mmol), TFA (3.0 mL) was added at 0°C (in an ice-water bath). The reaction mixture was stirred at 10 °C (in a water bath) for 2 hrs. At 0°C, ice-water (10 mL) was added, the whole was diluted with water (10 mL), and extracted with CH2Cl2 (90 mL), and the organic layer was washed with brine (30 mL), dried over MgSO4. The solvent was evaporated to give a crude product (69.7 mg), which was flash-column chromatographed (ethyl acetate: n-hexane = 1 : 1) to give 4e (53.7 mg, 97 % yield) as a white powder. 4e: Mp. 244.0-248.0 °C (colorless rods, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ : 7.294 (1H, d, J=8.0Hz), 7.242 (1H, d, J=9.2 Hz), 6.589 (1H, t, J=6.8 Hz, NH), 3.607 (3H, s), 3.537-3.459 (1H, m), 3.496 (1H, septet, J=6.8 Hz), 2.842 (1H, d, d, J=16.2, 6.8 Hz), 2.200 (1H, d, J=8.4 Hz), 2.013-1.892 (2H, m), 1.846-1.773 (2H, m), 1.691-1.608 (2H, m), 1.608 (3H, s), 1.431 (3H, s), 1.241 (3H, d, J=6.8 Hz), 1.231 (3H, d, J=6.8 Hz). 13C NMR (CDCl3) δ: 178.15, 172.38, 146.92, 146.55, 135.61, 127.87, 123.42, 121.94, 52.15, 50.06, 49.47, 42.96, 40.08, 39.24, 36.49, 32.78, 23.23, 22.93, 22.78, 18.40, 17.43. Anal. Calcd. for C21H28BrNO3: C, 59.72; H, 6.68; N, 3.32. Found: C, 59.48; H, 6.52; N, 3.27. HRMS (ESI+, [M + Na]+): Calcd. for C21H28BrNO3Na: 444.11448. Found: 444.11433.
CO2MeH
CO2MeH
2f-1
NBSCH3CN
Br
2a-1 To a solution of methyl ester 2a-1 (324.7 mg, 1.03 mmol) in 5 mL of acetonitrile,
-
S16
NBS (207.3 mg, 1.16 mmmol, 1.1 equiv.) was added in one portion at rt (20). The whole was stirred in dark at rt for 2.5 hr. After 30 min stirring, a white powder started to precipitate. The precipitate white power was filtered, washed with acetonitrile and dried in vacuum to give 185.4 mg (46 % yield) of 2f-1 as pale yellow amorphous. 2f-1: Mp. 142.0-143.5 °C (colorless needles, recrystallized from acetonitrile/Et2O). 1H NMR (CDCl3): δ 7.319 (1H, s), 6.871 (1H, s), 3.625 (3H, s), 3.223 (1H, septet, J=6.8 Hz), 2.790 (1H, d, d, J=9.2, 4.8 Hz), 2.201 (1H, brd. J=12.0Hz), 2.138 (1H, d, d, J=12.6, 2.4 Hz), 1.788-1.598 (5H, m), 1.411-1.361 (2H, m), 1.229 (3H, s), 1.176 (3H, d, J=7.2 Hz), 1.159 (3H, s), 1.158 (3H, d, J=7.2Hz). 13C-NMR(CDCl3): δ 178.92, 148.96, 144.02, 134.45, 128.49, 127.09, 121.46, 51.93, 47.56, 44.58, 37.89, 37.02, 36.60, 32.31, 29.47, 24.97, 22.97, 22.78. 21.47, 18.44, 16.48. Anal. Calcd. for C21H29BrO2: C, 64.21; H, 7.43; N, 0.00. Found: C, 63.87; H, 7.34; N, 0.00. HRMS (ESI+, [M + H]+): Calcd. for C21H30BrO2+: 393.14237. Found: 393.13886.
CO2MeH
2f-1CO2MeH
2f-2
CrO3Ac2O, AcOH
OCO2MeH
2f-3
NOH
pyridine
1) NaH, THF
2) TsCl, THFCO2MeH
2f
NOTs
NH2OH/HCl
Br BrBr Br
CO2MeH
2f-1CO2Me
H
2f-2
CrO3Ac2O, AcOH
O
Br Br
A solution of CrO3 (364.2 mg, 3.64 mmol, 1.33 equiv.) in AcOH (4 mL) and Ac2O (2 mL) was added dropwise to a suspension of methyl ester 2f-1 (1.0677 g, 2.71 mmol) and AcOH (6 mL) and Ac2O (2 mL) at 3 oC over 3 min (26). The whole was stirred at 23 °C (water temperature) for 20 hrs. To saturated aqueous NaHCO3 solution (140 mL) was added the reaction mixture. The whole was extracted with CH2Cl2 (150 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (40 mL) and brine (50 mL) and dried over MgSO4. The solvent was evaporated to give a residue which was flash-column chromatographed (ethyl acetate: n-hexane=1:8) to give 915.3 mg (83 % yield) of 2f-2 as a white amorphous powder. Mp. 236.0-236.5°C (colorless rods, recrystallized from n-hexane/CH2Cl2). 2f-2: 1H NMR (CDCl3): δ 7.899 (1H, s), 7.525 (1H, s), 3.648 (3H, s), 3.320 (1H, septet, J=6.8 Hz), 2.701-2.673 (2H, m), 2.384-2.279 (2H, m), 1.803-1.635 (5H, m), 1.329 (3H, s), 1.260 (3H, s), 1.258 (3H, d, J=6.8 Hz), 1.233 (3H, d, J=6.8 Hz). 13C-NMR(CDCl3): δ 197.67, 177.63, 153.92, 145.83, 131.38, 130.18, 128.22, 125.68, 52.24, 46.66, 43.70, 37.72, 37.38, 37.01, 36.50, 32.65, 23.62, 22.74, 22.59, 18.06, 16.38. HRMS (ESI+, [M + Na]+): Calcd. for C21H27BrNaO3+: 429.10358. Found: 429.10553. Anal. Calcd. for C21H28BrNO3: C, 59.72; H, 6.68; N, 3.32. Found: C, 59.42; H, 6.56; N, 3.33.
-
S17
CO2MeH
2f-2
OCO2MeH
2f-3
NOH
pyridine
NH2OH/HCl
Br Br
A mixture of the ketone 2f-2 (244.0 mg, 0.60 mmol), NH2OH·HCl (67.5 mg, 0.97 mmol, 1.61 equiv.), pyridine (0.5 mL) and EtOH (5 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled to rt, and the solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane = 1：6) to give the oxime (197.0 mg, 78% yield) as a white powder. 2f-3: Mp. 239.0-240.0 °C (colorless cubes, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 8.361 (1H, brs, OH), 7.745 (1H, s), 7.421 (1H, s), 3.651 (3H, s), 3.298 (1H, septet, J=6.8 Hz), 2.680-2.579 (2H, m), 2.288 (1H, d, d, J=10.4, 8.0 Hz), 2.235 (1H, brd, J=11.2Hz), 1.792-1.605 (5H, m), 1.359 (3H, s), 1.254 (3H, d, J=6.8 Hz), 1.229 (3H, d, J=6.8Hz), 1.111 (3H, s). 13C NMR (CDCl3) δ: 178.13, 155.12, 150.12, 145.12, 128.54, 127.57, 126.22, 122.51, 46.53, 41.58, 37.08, 37.02, 36.61, 32.64, 23.54, 22.84, 22.80, 22.63, 18.02. Anal. Calcd. for C21H26BrNO3: C, 59.72; H, 6.68; N, 3.32. Found: C, 59.79; H, 6.59; N, 3.37. HRMS (ESI+, [M + Na]+): Calcd. for C21H28BrNO3Na+: 444.11448. Found: 444.11570.
CO2MeH
2f-3
NOH
1) NaH, THF
2) TsCl, THFCO2Me
H
2f
NOTs
Br Br
To a solution of the oxime 2f-3 (84.4 mg, 0.20 mmol) in THF (2 mL), NaH (60% in oil, 18.1 mg, 0.45 mmol, 2.3 equiv.) was added at 3 °C in one portion. Then the whole was stirred at 3 °C for 60 min and then TsCl (40.6 mg, 0.213 mmol, 1.06 equiv.) was added. The mixture was stirred at 3 °C for 75 min. 5 mL of water was added at 3 C°. The whole was diluted with water (40 mL) and extracted with CH2Cl2 (90 mL). The organic layer was washed with brine (40 mL), dried over MgSO4. The solvent was evaporated to give the residue (147.3 mg), which was washed with n-hexane and dried in vacuum to give 2f (107.7 mg, 93 % yield) as a white powder. 2f: Mp. 145.0-146.0 °C (colorless cubes, recrystallized from CH2Cl2/n-hexane). 1H NMR (CDCl3) δ: 7.948 (2H, d, J=8.0 Hz), 7.606 (1H, s), 7.406 (1H, s), 7.354 (2H, d, J=8.0 Hz), 3.663 (3H, s), 3.272 (1H, septet, J=6.8 Hz), 2.710-2.575 (2H, m), 2.448 (3H, s), 2.234 (1H, d, d, J=12.0, 6.4 Hz), 1.195 (1H, brd, J=13.2 Hz), 1.746-1.616 (5H, m), 1.329 (3H, s), 1.241 (3H, d, J=6.8 Hz), 1.178 (3H, d, J=6.8 Hz), 1.051 (3H, s). 13C NMR (CDCl3) δ: 177.64, 161.65, 151.22, 145.22, 145.12, 132.61, 129.43, 129.20, 128.31, 127.78, 126.09, 123.59, 52.27, 46.13, 41.24, 37.13, 36.76, 36.48, 32.47, 24.80, 22.90, 22.66, 22.49, 21.65, 17.81, 16.46. Anal. Calcd. for C28H34BrNO5S: C, 58.33; H, 5.94; N, 2.43. Found: C, 58.05; H, 5.83; N, 2.46. HRMS (ESI+, [M + Na]+): Calcd. for C28H34BrNO5SNa: 598.12333. Found: 598.12226.
-
S18
CO2MeH
N
O
Br
CO2MeNOTs
Br
H
12
14
12
H
TFA20°C, 6 hr
87 %2f 3f
To weighted 2f (58.1 mg, 0.10 mmol), TFA (3.0 mL) was added at 0°C (in an ice-water bath). The reaction mixture was stirred at 20 °C (in a water bath) for 6 hrs. At 3°C, ice-water (5 mL) was added, the whole was diluted with water (20 mL), and extracted with CH2Cl2 (100 mL), and the organic layer was washed with brine (30 mL), dried over MgSO4. The solvent was evaporated to give a crude product (42.2 mg), which was flash-column chromatographed (ethyl acetate: n-hexane = 2 : 3) to give 3f (37.2 mg, 87 % yield) as a white powder. 3f: Mp. 236.0-236.5 °C (colorless rods, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.521 (1H, s), 7.228 (1H, brs), 6.714 (1H, s), 3.651 (3H. s), 3.271 (1H, septet, J=6.8 Hz), 2.763 (1H, d, d, J=8.2, 3.6 Hz), 2.540 (1H, d, d, J=14.8, 8.4 Hz), 2.158 (1H, d, d, J=14.8, 2.8 Hz), 1.924-1.734 (4H, m), 1.694-1.655 (2H, m), 1.450 (3H, s), 1.416 (3H, s,), 1.226 (3H, d, J=6.8 Hz), 1.209 (3H, d, J=6.8 Hz). 13C NMR (CDCl3) δ: 177.98, 174.90, 146.40, 141.68, 135.32, 130.89, 120.79, 120.06, 52.21, 49.77, 48.02, 40.62, 39.50, 36.56, 36.21, 32.45, 22.69, 22.56, 21.87, 18.13, 16.92. Anal. Calcd. for C21H28BrNO3: C, 59.72; H, 6.68; N, 3.32. Found: C, 59.42; H, 6.56; N, 3.33. HRMS (ESI+, [M + Na]+): Calcd. for C21H28BrNO3Na: 444.11448. Found: 444.11206.
N OHONH2OH/HCl
pyridineEtOH
N OTs1) NaH, THF
2) TsCl, THF
2g-2 2g2g-1 N OHO
NH2OH/HCl
pyridineEtOH
2g-22g-1 A mixture of 1-tetralone 2g-1 (293.5 mg, 2.0 mmol), NH2OH·HCl (211 mg, 3.0 mmol, 1.5 eq), pyridine (0.2 mL) in EtOH (4 mL) was heated at 100 °C for 60 min under microwave irradiation with stirring, then the whole was cooled to rt., and the solvent was evaporated. The residue was acidified with 2 M aqueous HCl and the whole was extracted with CH2Cl2. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuum. The residue was column chromatographed (n-hexane：AcOEt = 3：1) to afford 2g-2 (309.3 mg, 1.9mmol, 96% yield) as a white powder. 2g-2: Mp. 99.2-102.1 °C (in a sealed test tube). 1H NMR (CDCl3) δ: 8.16 (1H, brs), 7.89 (1H, d, d, J = 7.6, 1.2 Hz), 7.29-7.14 (3H, m), 2.83 (2H, t, J = 6.6 Hz), 2.77 (2H, t, J = 6.0 Hz), 1.91-1.85 (2H, m). 13C NMR (CDCl3) δ: 155.5, 139.8, 130.5, 129.2, 128.7, 126.5, 124.1, 29.8, 23.7,21.3. Anal. Calcd. for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.59; H, 6.82; N, 8.59. HRMS (ESI+): Calcd. for C10H11NNaO ([M + Na]+): 184.0738. Found: 184.0755.
-
S19
N OH NOTs
1) NaH, THF
2) TsCl, THF
2g-2 2g TO a Solution of 2g-2 (151.1 mg, 0.94 mmol) in dry THF (6 mL), NaH (60% in oil, 86.8 mg, 2.2 mmol, 2.3 equiv.) was added at 0 °C. Then the whole was stirred at 0 °C for 45 min and added TsCl (214.0 mg, 1.1 mmol, 1.2 eq). The mixture was stirred at 0 °C for 60 min and was poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4. The solvent was evaporated and the residue was purified by recrystallization from CH2Cl2-n-hexane to give 2g (259.0 mg, 0.82 mmol, yield 79%) as a white powder. 2g: Mp. 96.2-98.6 °C. 1H NMR (CDCl3) δ: 7.94 (2H, d, d, J = 8.4, 2.0 Hz), 7.86 (1H, d, d, J = 8.0, 1.2 Hz), 7.37-7.29 (3H, m), 7.21-7.13 (2H, m), 2.83 (2H, t, J = 6.4 Hz), 2.74 (2H, t, J = 6.0 Hz), 2.44 (3H, s), 1.87-1.80 (2H, m). 13C NMR (CDCl3) δ: 162.2, 144.9, 141.1, 132.8, 131.0, 129.6, 129.0, 128.8, 128.1, 126.5, 125.3, 29.4, 25.3, 21.7, 21.0. Anal. Calcd. for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44. Found: C, 64.70; H, 5.48; N, 4.35. HRMS (ESI+, [M + Na]+): Calcd. for C17H17NNaO3S: 338.0827. Found: 338.0802.
NH OH
OTsN TFA
20°C, 1hr 91 %2g
H
3g
2g (47.4 mg, 0.15 mmol) was dissolved in TFA (2.4 ml) at water temperature (17 °C). The reaction mixture was stirred at 17 °C for 60 min and was poured into water, and the whole was extracted with CHCl3. The organic layer was washed with saturated aqueous NaHCO3., brine, dried over MgSO4. The organic solvent was evaporated. The residue was column chromatographed (n-hexane：AcOEt = 1：1) to give 3g (22.0 mg, 0.14 mmol, yield 91 %) as a off-white powder. 3g: Mp. 137.2-138.8 °C. 1H NMR (CDCl3) δ: 7.51 (1H, brs), 7.23 (2H, d, J = 7.2 Hz), 7.16-7.12 (1H, m), 6.97 (1H, d, J = 8.0 Hz), 2.81 (2H, t, J = 7.2 Hz), 2.36 (2H, t, J = 7.2 Hz), 2.28-2.20 (2H, m). 13C NMR (CDCl3) δ: 174.9, 137.7, 134.4, 129.9, 127.5, 125.8, 121.8, 32.7, 30.3, 28.4. Anal. Calcd. for C10H11NO + 0.1 H2O: C, 73.68; H, 6.93; N, 8.59. Found: C, 73.58; H, 6.69; N, 8.55. HRMS (ESI+, [M + Na]+): Calcd. for C10H11NNaO: 184.0738. Found: 184.0738.
Br
F
NF OH
CH3
1) Mg, Et2O
2) CdCl23)Cl OCH3
O
O
F
CH3
CO2CH3
OH2O-MeOH (1:3)
LiOH
F
CH3
CO2H
O
OFCF3SO3H
CH2Cl20°C
NH2OH/HCl
pyridine
NF OTs1) NaH, THF
2) TsCl, THF
2h-1 2h-2 2h-3
2h-5
2h-OH 2h
NH2NH2•H2O
diethylen glycol205 °C
KOH
F
CH3
CO2H
2h-4 CH3
CH3 CH3
-
S20
Br
F
CH3
1) Mg, Et2O
2) CdCl23)Cl OCH3
O
O
F
CH3
CO2CH3
O
2h-1 2h-2 2h was synthesized with the method previously reported with some modification. 2h-2: 2h-2 was synthesized from 2h-1 as described previously. The detail of the general procedure was described previously (182,31) 2h-2: Colrless oil: 1H NMR (CDCl3) δ: 7.387 (1H, d, d, J=9.2, 2.8 Hz), 7.210 (1H, d, d, J=8.4, 5.6 Hz), 7.008 (1H, d, t, J=2.8, 8.2Hz), 3.711 (3H, s), 3.176 (2H, t, J=6.4Hz), 2.754 (2H, t, J=6.4 Hz), 2.441 (3H, s). 13C NMR (CDCl3) δ: 200.86 (d, 4JCF=3 Hz), 173.12, 160.57 (d, 1JCF=243Hz), 138.63 (d, 3JCF=6Hz), 133.61 (d, 4JCF=4 Hz), 133.32 (d, 3JCF=7Hz), 118.20 (d, 2JCF=21Hz), 115.14 (d, 2JCF=22Hz), 51.84, 36.04, 28.10, 20.37. HRMS (ESI-TOF, [M+Na]+): Calcd. for C12H13FO3+Na+: 247.07409. Found: 247.07074. Anal. Calcd. for C12H13FO3+0.2H2O: C, 63.26; H, 5.93; N, 0.00. Found: C, 63.63; H, 5.73; N, 0.00.
F
CH3
CO2CH3
OH2O-MeOH (1:3)
LiOH
F
CH3
CO2H
O
2h-2 2h-3 To a suspension of 2h-2 (2.8405 g) in 10 mL of water and 20 mL of methanol, LiOH•H2O (749.5 mg, 1.4 equiv.) was added in several portions at rt. Gradually a clear solution was formed. After stirring at rt for 4 hrs, methanol was evaporated and the residue was acidified with 2M HCl aqueous solution at 0 °C (ice-water bath). The resultant white precipitate was extracted with CH2Cl2 (250 mL), the organic layer was washed with brine (100mL), and dried over MgSO4. Evaporation of the solvent, and the residual white solide was washed with n-hexane to give 2h-3 (2.4838 g) in 93 % yield. 2h-3: White powder. Mp. 84-86 °C. 1H NMR (CDCl3) δ: 7.362 (1H, d, d, J=9.2, 2.8 Hz), 7.203 (1H, d, d, J=5.6, 8.4 Hz), 7.078 (1H, t, d, J=8.2, 2.8 Hz), 3.164 (2H, t, J=6.4Hz), 2.792 (2H, t, J=6.4Hz), 2.431 (3H, s). 13C NMR (CDCl3) δ: 200.45 (d, J=2Hz), 178.37, 160.55 (d, J=244Hz), 138.38 (d, J=5Hz), 133.75 (d, J=3Hz), 133.37 (d, J=7Hz), 118.29 (d, J=20Hz), 115.14 (d, J=22Hz), 35.73, 28.05, 20.38. HRMS (ESI, [M-H]-): Calcd. for C11H10FO3-: 209.06195. Found: 209.6275. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H11FO3+Na+: 233.05844. Found: 233.05548. Anal. Calcd. for C11H11FO3: C, 62.57; H, 5.22; N, 0.00. Found: C, 62.85; H, 5.27; N, 0.00.
F
CH3
CO2H
O 2h-3
NH2NH2•H2O
diethylen glycol205 °C
KOH
F
CH3
CO2H
2h-4 Wolff-Kishner reduction of the keto acid 2h-3 yielded the acid 2h-4: A mixture of the keto acid 2h-3 (1.9773 g), hydrazine hydrate (1.6 mL), and KOH (1.9950 g, 3 equiv.) in dimethyl glycol (12 mL) was heated at 100 °C for 30 min, at 145 °C for 25 min, and at 205 °C (at vigorous reflux) for 25 hrs. After cooling to rt, 150 mL of 2M aqueous HCl solution was added, and the whole was extracted with CH2Cl2 (250 mL), and the organic layer was washed with brine (70 mL), and dried over MgSO4. The solvent was evaporated to give the colorless solid, which was flash-column
-
S21
chromatographed (ethyl acetate: n-hexane=2:3) to give the acid 2h-4 (1.5164 g, 82 % yield) as white powder. 2h-4:Mp.65-66°C. 1H NMR (CDCl3): δ 7.066 (1H, d, d, J=8.4, 6Hz), 7.835 (1H, d, d, J=8.4, 6.0 Hz), 6.789 (1H, t, d, J=8.6, 2.8 Hz), 2.627 (2H, t, J=8.0 Hz), 2.423 (2H, t, J=7.2 Hz), 2.249 (3H, s), 1.910 (2H, quintet, J=7.6 Hz). 13C NMR (CDCl3): δ 179.62, 161.26 (d, J=242Hz), 141.39 (d, J=8Hz), 131.37 (d, J=2 Hz), 131.32 (d, J=8Hz), 115.36 (d, J=15Hz), 112.66 (d, J=21Hz), 33.43, 32.38 (d, J=1Hz), 24.65, 18.43. HRMS (ESI-TOF, [M-H]-): Calcd. for C11H12FO2-: 195.08268. Found: 195.08668. Anal. Calcd. for C11H13FO2: C, 67.33; H, 6.68; N, 0.00. Found: C, 67.21; H, 6.62; N, 0.00.
TMSCHN2
CH2Cl2-MeOHrt 2h-4-Me
F
CH3
CO2H
2h-4
F
CH3
CO2CH3
The acid 2h-4 was converted to the methyl ester 2h-4-Me by the action of an ethereal solution of TMSCHN2 in CH2Cl2 and methanol at rt. Purification was carried out by flash column chromatography (CH2Cl2: n-hexane 1:2). 2h-4-Me: Colorless oil. 1H NMR (CDCl3): δ 7.067 (1H, d, d, J=8.0, 6.0 Hz), 6.832 (1H, d, d, J=10.0, 2.8 Hz), 6.789 (1H, t, d, J=8.4, 2.8 Hz), 3.678 (3H, s), 2.607 (2H, t, J=8.0 Hz), 2.375 (2H, t, J=7.6 Hz), 2.253 (3H, s), 1.902 (2H, quintet, J=8.0Hz). 13C NMR (CDCl3): δ 173.67, 161.23 (d, J=241Hz), 141.57 (d, J=7Hz), 131.36 (d, J=3Hz), 131.26 (d, J=7Hz), 115.34 (d, J=24 Hz), 112.54 (d, J=21Hz), 51.48 (d, J=8 Hz), 33.45, 32.47, 24.93, 18.40. HRMS (ESI-TOF, [M+Na]+): Calcd. for C12H15FO2+Na+: 233.09483. Found: 233.09342. Anal. Calcd. for C12H15FO2: C, 68.55; H, 7.19; N, 0.00. Found: C, 68.30; H, 7.48; N, 0.00.
OFCF3SO3H
CH2Cl20°C
2h-5
F
CH3
CO2H
2h-4 CH3 To a stirred solution of CF3SO3H (6.2 mL, 10 equiv.) and CH2Cl2 (14 mL) at 0°C, the carboxylic acid 2h-4 (1.2042 g, 6 mmol) and was added by portions over 5 min. The resultant yellow-colored mixture was stirred at 2°C for 6 hrs. Ice-water (150 mL) was added and the whole was extracted with CH2Cl2 (300 mL), and the organic layer was washed with brine (60 mL) and dried over MgSO4. The solvent was evaporated to give a pale yellow solid which was flash-column chromatographed (ethyl acetate: n-hexane =1:7) to give the tetralone derivative 2h-5 (1.0518 g, 96 % yield) as a white powder. 2h-5: Mp. 57-57.5 °C (white powder). 1H NMR (CDCl3): δ 7.283 (1H, d, d, J=8.4, 4.8Hz), 6.889 (1H, d, d, J=11.2, 8.4 Hz), 2.833 (2H, t, J=6.4 Hz), 2.633 (2H, t, J=6.4 Hz), 2.261 (3H, s), 2.130 (2H, quintet, J=6.8 Hz). 13C NMR (CDCl3): δ 196.71, 160.64 (d, J=261Hz), 144.37, 135.48 (d, J=10Hz), 131.63 (d, J=4Hz), 121.49 (d, J=5Hz), 114.21 (d, J=22Hz), 39.96, 27.14 (d, J=2Hz), 22.23, 19.28. HRMS (ESI-TOF, [M+Na]+): Calcd. for C11H11FO+Na+: 201.06861. Found: 201.07032. Anal. Calcd. for C11H11FO: C, 74.14; H, 6.22; N, 0.00. Found: C, 74.07; H, 6.39; N, 0.00.
-
S22
NF OH
2h-OHCH3
OFNH2OH/HCl
pyridine2h-5CH3
A mixture of 2h-5 (215.2 mg, 1.2 mmol), NH2OH·HCl (129.8 mg, 1.8 mmol, 1.5 equiv.), dry pyridine (1 mL) in dry EtOH (5 mL) was heated at 100 °C for 90 min under microwave irradiation with stirring, then the whole was cooled, and the solvent was evaporated. The residue was diluted with CH2Cl2 (70 mL), and the solution was washed with 5 % aqueous KHSO4 (30 mL), and brine (40 mL), and dried over MgSO4. Evaporation of the solvent gave the residue, which was flash-column chromatographed (ethyl acetate: n-hexane=1:4), followed by recrystallization from n-hexane/CH2Cl2 to give 2h-OH (221.7 mg, 95 % yield) as colorless rods. 2h-OH: Mp. 199-200 °C. 1H NMR (CDCl3) δ: 10.46 (1H, s, OH), 7.071 (1H, d, d, J=8.2, 5.6Hz), 6.888 (1H, d, d, J=11.6, 8.2 Hz), 2.885 (2H, t, J=6.8 Hz), 2.666 (2H, t, J=5.6 Hz), 2.240 (3H, s), 1.853 (2H, quintet, J=6.4 Hz). 13C NMR (CDCl3) δ: 159.04 (d, J=232 Hz), 153.29 (d, J=7Hz), 140.66 (d, J=1 Hz), 131.11 (d, J=4 Hz), 130.83 (d, J=9 Hz), 118.56 (d, J=9 Hz), 113.75 (d, J=23 Hz), 26.83 (d, J=2 Hz), 23.78, 20.66, 19.37. Anal. Calcd. for C11H12FNO: C, 68.38; H, 6.26; N, 7.25. Found: C, 68.33; H, 6.23; N, 7.19. HRMS (ESI+, [M + Na]+): Calcd. for C11H12FNONa+: 216.07951. Found: 216.07811.
NF OH NFOTs
1) NaH, THF
2) TsCl, THF
2h-OH 2hCH3 CH3 TO a suspension of NaH (60% in oil, 96.5 mg, 2.4 mmol, 3 equiv.) in dry THF (4 mL), 2h-OH (154.5 mg, 0.8 mmol) was added in one portion at 0 °C (in an ice-water). Then the whole was stirred at 0 °C for 1hr and 45 min and TsCl (172.2 mg, 0.9 mmol, 1.1 equiv.) was added. The whole was stirred at 0 °C for 1.5 hr, and 10 mL of ice-water was added. The whole was extracted with CH2Cl2 (110 mL) and the organic layer was washed with brine (20 mL) and dried over MgSO4. The solvent was evaporated in vacuum. The residue was washed with n-hexane to give 2h (267.6 mg, 96% yield) as a white powder. 2h: Mp. 98-100 °C (colorless cubes, recrystallized from n-hexane-CH2Cl2). 1H NMR (CDCl3) δ: 7.967 (2H, d, J = 8.4 Hz), 7.340 (2H, d, J=8.4 Hz), 7.131 (1H, d, d, J=8.2, 4.8 Hz), 6.848 (1H, d, d, J=10.8, 8.4 Hz), 2.846 (2H, t, J=6.8 Hz), 2,630 (2H, t, J=6.0 Hz), 2.433 (3H, s), 2.212 (3H, s), 1.800 (2H, quintet, J =6.0 Hz). 13C NMR (CDCl3) δ: 161.01 (d, J=6Hz), 159.15 (d, J=257Hz), 144.86, 141.68, 132.90 (d, J=9Hz), 132.59, 131.22 (d, J=4Hz), 129.32, 129.29, 116.57 (d, J=9 Hz), 114.01 (d, J=22 Hz), 26.49 (d, J=2 Hz), 25.34, 21.67, 20.33, 19.28. Anal. Calcd. for C18H18FNO3S: C, 62.23; H, 5.22; N, 4.03. Found: C, 62.38; H, 5.21; N, 4.13. HRMS (ESI+, [M + Na]+): Calcd. for C18H18FNO3S+Na+: 370.08836. Found: 370.08730.
NF OF N
OTsTFA
20°C, 2.5 hr 87 %2hCH3 CH3
H
3h
-
S23
To weighted 2h (140.9 mg, 0.4 mmol) TFA (3 mL) was added at 0 °C (in an ice-water bath). After 10 min, the cooling bath was changed to water bath (20 °C). The whole was stirred at 20 °C for 2.5 hr. At 0°C (in an ice-water bath), 20 mL of ice-water was added. The whole was extracted with CH2Cl2 (120 mL), and the organic layer was washed with brine (20 mL), and dried over MgSO4. The organic solvent was evaporated. The residue was flash-column chromatographed (ethyl acetate: n-hexane= 1：3) to give 3h (68.2mg, 87 % yield) as a pale brown solid. 3h: Mp. 154-155.5 °C (pale brown plates, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.129 (1H, brs), 6.970 (1H, d, d, J=8.6, 5.6 Hz), 6.891 (1H, d, d, J=8.8, 9.0 Hz), 2.825 (2H, t, J=7.2 Hz), 2.363 (2H, t, J=7.2 Hz), 2.313 (3H, s), 2.212 (2H, quintet, J=7.2 Hz). 13C NMR (CDCl3) δ: 174.31, 152.36 (d, J=243Hz), 134,60, 131.64 (d, J=4Hz), 127.47 (d, J=7Hz), 125.89 (d, J=12 Hz), 112.95 (d, J=19 Hz), 32.98, 27.50, 26.13 (d, J=1Hz), 19.22. HRMS (ESI+, [M + Na]+): Calcd. for C11H12FNONa+: 216.07951. Found: 216.07970. Anal. Calcd. for C11H12FNO: C, 68.38; H, 6.26; N, 7.25. Found: C, 68.32; H, 6.23; N, 7.13.
CH3
NCH3OH
CH3
CH3
CH3
CO2HOCH3
CF3SO3H
CH2Cl20°C
NH2OH/HCl
pyridine
NCH3OTs
1) NaH, THF
2) TsCl, THF
2i-1 2i-2 2i-3
2i-4 2i
Cl OH
O
AlCl3CH3
CH3 CH3
CH3
CH3
CH3
CH3
CO2H
2i-1 2i-2
Cl OH
O
AlCl3
To a mixture of AlCl3 (2.06 g, 15 mmol, 1.5equiv.) in p-xylene (2i-1) (5 mL) was added a solution of 4-chlorobutyric acid (1.2319 g, 10 mmol) in p-xylene (3 mL) at water temperature (14 °C) under argon atmosphere over 2 min. After stirring at this temperature for 20 min, the red-colored reaction mixture was cooled to 10 °C (ice-water) and the whole was stirred for 3 hrs (23). Then the reaction mixture was poured into aqueous HCl (100mL water containing 10 mL concentrated aqueous HCl) and the whole was extracted with CH2Cl2 (150 mL). The organic phase was extracted with 5% aqueous NaOH (100 mL) and the aqueous layer was acidified with concentrated aqueous HCl. The whole was extracted with CH2Cl2 (150 mL). The organic layer was washed with brine, and dried over MgSO4. The solvent was evaporated to give crude 2i-2 (1.3936 g, 72% yield) as a colorless solid. 2i-2: Mp. 60-61 °C. 1H NMR (CDCl3) δ: 7.05-6.90 (3H, m), 2.62 (2H, t, J = 8.0 Hz), 2.43 (2H, t, J = 7.6 Hz), 2.26 (3H, s), 2.29 (3H, s), 1.95-1.87 (2H, m). 13C NMR (CDCl3) δ: 179.9, 139.2, 135.4, 132.7, 130.2, 129.7, 126.8, 33.7, 32.4, 25.1, 20.9, 18.7. Anal. Calcd. for C12H16O2 (+ 0.05 H2O): C, 74.62; H, 8.40; N, 0.00. Found: C, 74.59; H, 8.26; N, 0.00. HRMS (ESI-): Calcd. for C12H15O2 ([M - H]-): 191.1072. Found: 191.1078.
-
S24
CH3
CH3
CO2HOCH3
CF3SO3H
CH2Cl20°C
2i-2 2i-3CH3
To a stirred mixture of CF3SO3H (5.3 ml, 10 equiv.) and CH2Cl2 (30 ml), the carboxylic acid 2i-2 (1.1687 g) was added by portions over 2 min at 0°C (in an ice-water bath). The resultant lemon yellow colored mixture was stirred at 0°C for 2.5 hr, then the whole was pored into 200 mL of ice-water The whole was extracted with CH2Cl2 and the organic phase was washed with brine, dried over MgSO4. The solvent was evaporated, and the residue was column chromatographed (CH2Cl2/n-hexane 2:3) to give 2i-3 (709.7 mg, 67% yield) as a colorless solid (mp. < 30 °C). 2i-3: Mp. < 30 °C. 1H NMR (CDCl3) δ: 7.10 (1H, d, J = 8.0 Hz), 7.10 (1H, d, J = 8.4 Hz), 2.85 (2H, d, d, J = 6.1 Hz, 6.1 Hz), 2.64 (2H, dd, J = 6.3 Hz, 13.4 Hz), 2.60 (3H, s), 2.27 (3H, s). 2.08-2.14 (1H, m). 13C NMR (CDCl3) δ: 143.60, 138.73, 133.75, 133.70, 131.43, 129.79, 127.12, 40.64, 27.43, 23.25, 22.37, 19.71. HRMS (ESI+, [M + Na]+): Calcd. for C12H14NaO: 197.0942. Found: 198.0947.
OCH3
2i-3CH3
NCH3OH
NH2OH/HCl
pyridine
2i-4CH3 A mixture of 2i-3, NH2OH·HCl (1.5 equiv.), pyridine (0.2 mL) in EtOH (4.0 mL) was heated at 145°C for 3.5 hr under microwave irradiation with stirring, then the whole was cooled, and the solvent was evaporated in vacuum. The resultant was extracted with CHCl3 (10 ml x 3). The combined organic phase was washed with brine (20 ml), dried over Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was purified by flash chromatography (ethyl acetate: n-hexane = 1: 7) to afford 2i-4 as a colorless solid. 2i-4: Mp. 147.0-147.5 °C. 1H NMR (CDCl3) δ: 8.11 (1H, brs), 7.03 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 2.82 (2H, t, J = 7.2 Hz), 2.62 (2H, t, J = 6.0 Hz), 2.51 (3H, s), 2.26 (3H, s), 1.82-1.75 (2H, m). 13C NMR (CDCl3) δ: 157.6, 140.1, 134.5, 132.4, 130.0, 129.8, 129.3, 26.7, 24.6, 23.1, 21.0, 19.7. Anal. Calcd. for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.15; H, 7.92; N, 7.54. HRMS (ESI+, [M + Na]+): Calcd. for C12H15NNaO: 212.1051. Found: 212.1049.
NCH3OH NCH3
OTs1) NaH, THF
2) TsCl, THF
2i-4 2iCH3 CH3 To a solution of 2i-4 (95.0 mg, 0.5 mmol) in THF (3 ml), NaH (60% in oil) (1.1 eq.) was added at 0 °C. Then the whole was stirred at 0°C for 30 min and added TsCl (114.4 mg, 0.6 mmol, 1.1 equiv.). The mixture was stirred at 0°C for 30 min and was poured into water, and extracted with CHCl3 (30 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the solvent was evaporated in vacuum. The residue was washed with n-hexane to afford 2i (133.2 mg, 0.42 mmol, yield 84%) as a colorless powder. 2i: Mp. 94.0-95.2 °C. 1H-NMR (CDCl3): δ = 7.89 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.00 (1H, d, J = 8.0 Hz), 7.00 (1H, d, d, J = 7.6, 7.6 Hz), 7.06 (1H, d, J =
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8.4 Hz), 2.88 (2H, d, d, J = 6.8, 6.8 Hz), 2.61 (1H, d, d, J = 6.0, 6.0 Hz), 2.43 (3H, s), 2.29 (3H, s), 2.23 (3H, s), 1.72-1.80 (2H, m). 13C NMR (CDCl3, 0 °C) δ: 164.2, 144.9, 141.0, 135.7, 133.0, 132.6, 131.4, 129.5, 129.4, 128.9, 127.2, 26.4, 26.3, 23.7, 21.7, 20.3, 19.8. Anal. Calcd. for C19H21NO3S: C, 66.45; H, 6.16; N, 4.08. Found: C, 66.16; H, 6.05; N, 4.04. HRMS (ESI+, [M + Na]+): Calcd. for C19H21NNaO3S: 366.1140. Found: 366.1141.
NCH3 OCH3
OTsNTFA
20°C, 1 hrCH3 CH3
2i
H
3i 98%
To weighted 2i (28.2 mg) TFA (3.0 mL) was added at 0°C (in an ice-water bath). The reaction mixture was stirred at 0°C for 5 min, then the whole was stirred at 18 °C (water-temperature) for 60 min. At 0 °C, 10 mL of ice-water was added, the whole was extracted with CH2Cl2 (60 mL), and the organic layer was washed with brine (30 mL), dried over MgSO4. The solvent was evaporated to give a crude product (15.5 mg) , which was flash-column chromatographed (n-hexane : AcOEt = 1 : 2) to give 3i (15.3 mg (98 % yield) as a colorless solid. 3i: Mp. 162.0-162.0 (colorless cubes, recrystallized from n-hexane/CH2Cl2). 1H NMR (CDCl3) δ: 7.155 (1H, brs), 6.985 (1H, d, J = 8.0 Hz), 6.946 (1H, d, J = 7.6 Hz), 2.800 (2H, t, J = 7.2 Hz), 2.317 (3H, s), 2.293 (2H, t, J = 7.2 Hz), 2.222 (3H, s), 2.170 (2H, quintet, J=7.2 Hz). 13C NMR (CDCl3) δ: 174.7, 136.4, 134.2, 132.9, 128.1, 127.5, 32.7, 27.7, 25.9, 19.6, 17.8. Anal. Calcd for C12H15NO: C, 76.05; H, 7.98; N, 7.36. Found: C, 76.16; H, 7.99; N, 7.40. HRMS (ESI+, [M + Na]+): Calcd. for C12H15NNaO: 212.1051. Found: 212.1049.
N OMeONH2OMe/HCl
pyridine
N OMeNCS
2g-3 2j-12g-1
Cl
HCldioxane-H2O
O
2j-2
Cl NOH
NH2OH/HCl
pyridine
N OTs
1) NaH, THF
2) TsCl, THF2j-3 2j
Cl Cl
Pd(OAc)2 AcOH
N OMeO
NH2OMe/HCl
2g-32g-1
pyridineEtOH
A mixture of α-tetralone 2g-1 (1463.7 mg, 10 mmol), NH2OMe·HCl (1254.0 mg, 15 mmol, 1.5 eq.), pyridine (1 mL) in EtOH (20 mL) was stirred at 100 °C for 60 min under microwave irradiation, then the whole was cooled, and the solvent was evaporated in vacuum. The resultant was diluted with 2 M aqueous HCl. and extracted with CH2Cl2. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuum. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1：4) to afford 2g-3 (1593.1 mg, 9.1mmol, yield 91%) as a orange oil. 2g-3: 1H NMR (CDCl3) δ: 7.97 (1H, d, d, J = 6.4, 1.2 Hz), 7.24-7.17 (2H, m), 7.11 (1H, d, d, J = 7.6, 0.8 Hz), 3.98 (3H, s), 2.74-2.70 (4H, m), 1.87-1.83 (2H, m). 13C NMR (CDCl3) δ: 154.0, 139.5, 130.7, 128.9, 128.5, 126.3, 124.2, 61.9, 29.8, 24.2, 21.5. HRMS (ESI+, [M + H]+): Calcd. for C11H14NO: 176.1075. Found: 176.1062.
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N OMe NOMe
NCS
2g-3 2j-1
Cl
Pd(OAc)2 AcOH
A mixture of 2g-3 (701.9 mg, 4.0 mmol), Pd(OAc)2 (47.9 mg, 0.21 mmol, 5 mol%), NCS (564.9 mg, 4.2 mmol, 1.05 eq.) in AcOH (28 mL) was stirred at 90 °C for 30 min under microwave irradiation, then the whole was cooled to rt, and poured into 2 M aqueous NaOH The aqueous layer was extracted with CH2Cl2 (27). The organic layer was washed with brine, dried over MgSO4. The solvent was evaporated to give the residue, which was column chromatographed (n-hexane：AcOEt = 12：1) to afford 2j-1 (563.5 mg, 2.7 mmol, yield 67%) as a colorless oil. 2j-1: 1H NMR (CDCl3) δ: 7.30 (1H, dd, J = 7.6, 0.8 Hz), 7.12 (1H, t, J = 7.6 Hz), 7.04 (1H, d, d, J = 7.6, 0.8 Hz), 4.03 (3H, s), 2.77 (2H, t, J = 6.8 Hz), 2.63 (2H, t, J = 5.6 Hz), 1.79-1.71 (2H, m). 13C NMR (CDCl3) δ: 152.8, 143.8, 131.8, 129.7, 129.1, 128.7, 126.4, 62.2, 30.9, 25.0, 21.1. HRMS (ESI+, [M + Na]+): Calcd. for C11H12ClNNaO: 232.0505. Found: 232.0502.
HCldioxane-H2O
O
2j-2
ClNOMe
2j-1
Cl
A solution of 2j-1 (419.6 mg, 2.0 mmol), in 1,4-dioxane (10 mL) and 6 M aqueous HCl (15 mL) was heated at 120 °C for 90 min under microwave irradiation with stirring. Then, the whole was cooled, and the solvent was evaporated. The residue was diluted with water and the whole was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4.The solvent was evaporated to give the residue, which was flash chromatographed (ethyl acetate: n-hexane = 1：15) to afford 2j-2 (278.7 mg, 1.5 mmol, yield 77%) as a yellow oil. 2j-2: 1H NMR (CDCl3) δ: 7.32 (2H, d, J = 4.8 Hz), 7.19-7.14 (1H, m), 2.97 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.8 Hz), 2.14-2.07 (2H, m). 13C NMR (CDCl3) δ: 196.6, 147.1, 134.2, 132.7, 130.3, 129.9, 127.6, 40.4, 30.8, 22.6. HRMS (ESI+, [M + Na]+): Calcd. for C10H9ClNaO: 203.0240. Found: 203.0222.
O
2j-2
Cl NOH
NH2OH/HCl
pyridine2j-3
Cl
A mixture of 2j-2 (147.9 mg, 0.82 mmol), NH2OH·HCl (85.7 mg, 1.2 mmol, 1.5 equiv.), pyridine (0.8 mL) in EtOH (4 mL) was heated at 100 °C for 30 min under microwave irradiation with stirring. Then the whole was cooled, and the solvent was evaporated. The residue was diluted with 2 M aqueous HCl and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4. The solvent was evaporated. Recrystallization of the residue from CH2Cl2-n-hexane gave 2j-3 (131.3 mg, 0.67 mmol, yield 82%) as a white powder. 2j-3: Dec. 186.5-188.7 °C (sealed tube). 1H NMR (CDCl3) δ: 9.26 (1H, brs), 7.32 (1H, d, d, J = 8.0, 1.2 Hz), 7.15 (1H, t, J = 8.0 Hz), 7.07 (1H, d, d, J = 8.0, 1.2 Hz), 2.88 (2H, t, J = 6.4 Hz), 2.66 (2H, t, J = 6.0 Hz), 1.83-1.76 (2H, m). 13C NMR (CDCl3) δ: 154.0, 143.9, 131.5, 129.7, 129.0, 129.0, 126.6, 31.0, 24.7, 21.0. Anal. Calcd. for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.11; H, 5.18; N, 7.06. HRMS (ESI+, [M + Na]+): Calcd. for C10H10ClNNaO: 218.0349. Found: 218.0337.
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N OH NOTs
1) NaH, THF
2) TsCl, THF2j-3 2j
Cl Cl
To a solution of 2j-3 (100.0 mg, 0.51 mmol) in THF (5 mL), NaH (60% in oil, 47.1 mg, 1.2 mmol, 2.3 eq) was added at 0 °C. Then the whole was stirred at 0 °C for 75 min and TsCl (118.1 mg, 0.62 mmol, 1.2 eq) was added. The mixture was stirred at 0 °C for 60 min and was poured into water, and the whole was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4. The solvent was evaporated. The residue was washed with n-hexane and dried in vacuum to afford 2j (159.9 mg, 0.82 mmol, yield 89%) as colorless cubes. 2j: Mp. 117.2-118.2 °C.1H NMR (CDCl3) δ: 7.97 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.27 (1H, d, J = 7.6 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.06 (1H, d, J = 7.6 Hz), 2.91 (2H, t, J = 6.8 Hz), 2.66 (2H, t, J = 6.0 Hz), 2.44 (3H, s), 1.79-1.72 (2H, m). 13C NMR (CDCl3) δ: 160.8, 145.0, 144.7, 132.8, 132.7, 130.5, 129.9 (Cx2), 129.4, 129.4, 126.8, 30.6, 26.3, 21.7, 20.4. Anal. Calcd. for C17H16ClNO3S: C, 58.37; H, 4.61; N, 4.00. Found: C, 58.21; H, 4.71; N, 3.94. HRMS (ESI+, [M + Na]+): Calcd. for C17H16ClNNaO3S: 372.0437. Found: 372.0417.
NCl O
NCl OCl N OTs
TFA
20°C, 1hr+
29% 57%2j
HH
3j 4j 2j (52.3 mg, 0.15 mmol) was dissolved in TFA (2.4 ml) at water temperature (20 °C). The reaction mixture was stirred for 60min at 20 °C and was poured into water (60 mL), and the whole was extracted with CHCl3. The organic layer was washed with saturated aqueous NaHCO3 solution, brine, and dried over MgSO4. The solvent was evaporated to give a residue (3j: 4j =40:60 from the integration of the 1H NMR spectra). Column chromatography (ethyl acetate : n-hexane = 1：3) gave 4j (16.6 mg, yield 57 %) and 3j (8.5 mg, yield 29 %), respectively. 3j: Colorless cubes. Mp. 166.0-166.5 °C. 1H NMR (CDCl3) δ: 7.32 (1H, d, d, J = 8.0, 1.6 Hz), 7.19 (1H, brs), 7.14 (1H, d, J = 7.6, 1.2 Hz), 7.07 (1H, t, J = 8.0 Hz), 2.83 (2H, t, J = 7.2 Hz), 2.38 (2H, t, J = 7.2 Hz), 2.29-2.21 (2H, m). 13C NMR (CDCl3) δ: 173.9, 136.1, 134.9, 128.3, 127.9, 126.2, 125.9, 32.8, 30.8, 28.4. Anal. Calcd. for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.34; H, 5.21; N, 7.16. HRMS (ESI+, [M + Na]+): Calcd. for C10H10ClNNaO: 218.0349. Found: 218.0362. 4j: Colorless cubes. Mp. 194-195 °C. 1H NMR (CDCl3, 50 °C) δ: 7.35 (1H, d, d, J = 8.0, 1.2 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.07 (1H, d, d, J = 8.0, 1.2 Hz), 6.38 (1H, brs), 3.09 (2H, q, J = 8.0 Hz), 2.83 (2H, t, J = 7.2 Hz), 2.02-1.90 (2H, m). 13C NMR (CDCl3) δ: 169.7, 139.5, 133.0, 132.5, 131.1, 128.9, 126.8, 39.0, 30.2, 30.1. Anal. Calcd. for C10H10ClNO + 1/3 H2O: C, 59.56; H, 5.33; N, 6.95. Found: C, 59.30; H, 5.08; N, 7.06. HRMS (ESI+, [M + Na]+): Calcd. for C10H10ClNNaO: 218.0349. Found: 218.0340.
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N OMeONH2OMe/HCl
pyridine
N OMe
NBS
2g-3 2k-12g-1
Br
HCldioxane-H2O
O
2k-2
Br NOH
NH2OH/HCl
pyridine
N OTs
1) NaH, THF
2) TsCl, THF2k-3 2k
Br Br
Pd(OAc)2 AcOH
N OMe N
OMe
NBS
2g-3 2k-1
Br
Pd(OAc)2 AcOH
A mixture of 2g-3 (50.9 mg, 0.3 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol, 5 mol%), NBS (53.4 mg, 0.3 mmol, 1 equiv.) in AcOH (2 mL) was stirred at 90 °C for 30 min under microwave irradiation (27), then the whole was cooled to rt., and poured into 2 M aqueous NaOH. The aqueous layer was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated. The residue was column chromatographed (ethyl acetate: n-hexane = 1：4) to afford 2k-1 (67.2 mg, 0.26 mmol, yield 91%) as a yellow oil. 2k-1:1H NMR (CDCl3) δ: 7.52 (1H, d, d, J = 7.6, 1.6 Hz), 7.10-7.01 (2H, m), 4.04 (3H, s), 2.76 (2H, t, J = 6.8 Hz), 2.63 (2H, t, J = 6.0 Hz), 1.79-1.72 (2H, m). 13C NMR (CDCl3) δ: 153.1, 143.9, 133.3, 130.9, 129.0, 127.0, 120.4, 62.2, 31.0, 24.9, 21.1. Anal. Calcd. for C11H12BrNO: C, 51.99; H, 4.76; N, 5.51. Found: C, 52.11; H, 5.00; N, 5.54. HRMS (ESI+, [M + Na]+): Calcd. for C11H12BrNNaO: 276.0000. Found: 275.9988.
HCldioxane-H2O
O
2k-2
BrNOMe
2k-1
Br
A solution of 2k-1 (51.8 mg, 0.20 mmol), in 1,4-dioxane (1 mL) and 6 M aqueous HCl (1.5 mL) was stirred at 120 °C for 90 min under microwave irradiation (28), then the whole was cooled, and the solvent was evaporated. The residue was diluted with water and the whole was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuum. The residue was flash column chromatographed (n-hexane：AcOEt = 6：1) to afford 2k-2 (41.1 mg, 0.18 mmol, 90% yield) as a pale orange solid. 2: Mp. 53.0-54.5 °C. 1H NMR (CDCl3) δ: 7.60-7.54 (1H, m), 7.25-7.19 (2H, m), 2.98 (2H, t, J = 6.4 Hz), 2.71 (2H, t, J = 6.4 Hz), 2.14-2.07 (2H, m). 13C NMR (CDCl3) δ: 196.7, 147.2, 134.0, 132.8, 131.1, 128.2, 122.0, 40.0, 30.9, 22.5. Anal. Calcd for C10H9BrO: C, 53.36; H, 4.03; N, 0.00. Found: C, 53.35; H, 4.06; N, 0.00. HRMS (ESI+, [M + Na]+): Calcd. for C10H9BrNaO: 246.9734. Found: 246.9718.
O
2k-2
Br NOH
NH2OH/HCl
2k-3
Br
pyridineEtOH
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S29
A mixture of 2k-2 (44.9 mg, 0.20 mmol), NH2OH·HCl (21.7 mg, 0.31 mmol, 1.5 eq), pyridine (0.2 mL) in EtOH (1 mL) was heated at 100 °C for 60 min under microwave irradiation with stirring. Then, the whole was cooled, and the solvent was evaporated. The residue was diluted with 2 M aqueous HCl and the whole was extracted with CH2Cl2. The organic phase was washed with brine, dried over MgSO4. The solvent was evaporated to give the residue, which was column chromatographed (n-hexane：DCM = 4：1) to afford 2k-3 (40.5 mg, 0.19 mmol, 85% yield) as a off-white powder. 2k-3: Dec. 178.0-182.5 °C (sealed tube). 1H NMR (CDCl3) δ: 8.02 (1H, brs), 7.53 (1H, d, d, J = 7.6, 1.6 Hz), 7.13-7.04 (2H, m), 2.86 (2H, t, J = 6.8 Hz), 2.65 (2H, t, J = 6.0 Hz), 1.83-1.75 (2H, m). 13C NMR (CDCl3) δ: 154.7, 144.1, 133.1, 130.9, 129.3, 127.1, 120.1, 31.0, 24.5, 21.0. Anal. Calcd. for C10H10BrNO: C, 50.02; H, 4.20; N, 5.83. Found: C, 50.14; H, 4.24; N, 5.85. HRMS (ESI+, [M + Na]+): Calcd. for C10H10BrNNaO: 261.9843. Found: 261.9864.
N OH NOTs
1) NaH, THF
2) TsCl, THF2k-3 2k
Br Br
To a solution of compound 2k-3 (70.2 mg, 0.29 mmol) in THF (3 mL), NaH (60% in oil) (1.1 equiv.) was added at 0 °C. Then the whole was stirred at 0 °C for 30 min and TsCl (78 mg, 0.35 mmol, 1.1 equiv.) was added. The mixture was stirred at 0 °C for 30 min and was poured into water, and the whole was extracted with CHCl3 (30 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4. The solvent was evaporated to give the residue, which was washed with n-hexane and dried in vacuum to afford 2k (81.1 mg, 0.21 mmol, yield 71%) as a brown powder. 2k: Dec. 99.2-101.0 °C. 1H NMR (CDCl3) δ: 7.98 (2H, d, J = 8.4 Hz), 7.50-7.47 (1H, m), 7.34 (2H, d, J = 8.4 Hz), 7.11-7.09 (2H, m), 2.91 (2H, t, J = 6.8 Hz), 2.65 (2H, t, J = 6.0 Hz), 2.44 (3H, s), 1.79-1.72 (2H, m). 13C NMR (CDCl3) δ: 161.3, 145.0, 144.9, 133.5, 132.8, 130.8, 129.4, 128.6, 127.3, 121.0, 30.6, 26.2, 21.7, 20.4. Anal. Calcd for C17H16BrNO3S: C, 51.79; H, 4.09; N, 3.55. Found: C, 51.63; H, 4.18; N, 3.51. HRMS (ESI+, [M + Na]+): Calcd. for C17H16BrNNaO3S: 415.9932. Found: 415.9902.
NBr O
NBr OBr N OTs
TFA
20°C, 1hr+
88%4%2k
HH
3k 4k 2k (59.4 mg, 0.15 mmol) was added to TFA (2.4 ml) at water temperature (20 °C). The reaction mixture was stirred for 60min and was poured into water, and the whole was extracted with CHCl3. The organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4. The solvent was evaporated to give the residue (3k: 4k=6:94, from proton integrations of the 1H NMR spectra), which was column chlomatographed (n-hexane：AcOEt = 1：1 then 1 : 2) to give 3k (1.6 mg, 0.007 mmol, yield 4 %, 2 conformers) and 4k (31.7 mg, 0.13 mmol, yield 88 %). 3k: Pale yellow solid. Mp. 139.0-142.1 °C. 1H NMR (CDCl3) δ: 7.48 (0.7H, d, d, J = 8.0, 1.2 Hz, conformer A), 7.48 (0.3H, d, d, J = 8.0, 1.6 Hz, conformer B), 7.18 (0.7H, d, d, J = 7.6, 0.8 Hz, conformer A), 7.16 (1H, brs), 7.14 (0.3H, d, d, J = 7.6, 1.2 Hz, conformer B), 7.08 (0.3H, t, J = 8.0 Hz, conformer B), 7.01 (0.7H, t, J = 7.6 Hz, conformer A), 2.86-2.80 (2H, m, conformers A, B), 2.40-2.35 (2H, m, conformers A,
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S30
B), 2.29-2.21 (2H, m, conformers A, B). 13C NMR (CDCl3) δ: 173.8 (conformer B), 173.8 (conformer A), 136.2, 131.1 (conformer A), 129.1 (conformer A), 128.3 (conformer B), 127.9 (conformer B), 126.6 (conformer A), 126.2 (conformer B), 116.2, 32.8 (conformer B), 32.8 (conformer A), 31.0 (conformer A), 30.8 (conformer B), 28.4 (conformer A), 28.4 (conformer B). HRMS (ESI+, [M + Na]+): Calcd. for C10H10BrNNaO: 261.9843. Found: 261.9831. 4k: Off-white solid. Mp. 184.8-187.5 °C. 1H NMR (CDCl3, 50 °C) δ: 7.54 (1H, d, d, J = 8.0, 1.2 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.10 (1H, d, d, J = 7.6, 0.8 Hz), 6.31 (1H, brs), 3.08 (2H, q, J = 6.8 Hz), 2.83 (2H, t, J = 7.2 Hz), 2.00-1.90 (2H, m).13C NMR (CDCl3) δ: 170.2, 139.6, 135.0, 132.2, 131.3, 127.4, 120.9, 39.0, 30.4, 30.1. Anal. Calcd. for C10H10BrNO: C, 50.02; H, 4.20; N, 5.83. Found: C, 50.01; H, 4.18; N, 5.86. HRMS (ESI+, [M + Na]+): Calcd. for C10H10BrNNaO: 261.9843. Found: 261.9850.
2g-Ms
NH OH
OMsN TFA
20°C, 1hr 72%
H
3g
2k-Ms
NBr O
NBr OBr N OMs
TFA
20°C, 1hr+
79 %9 %
HH
3k 4k N OH N
OMs1) NaH, THF
2) MsCl, THF
2g-2 2g-Ms To a solution of the oxime 2g-2 (149.4 mg, 0.93 mmol) in THF (7 mL), NaH (60% in oil, 83.9 mg, 2.1 mmol, 2.3 equiv.) was added at 0 °C. Then the whole was stirred at 0 °C for 60 min and then MsCl (203.2 mg, 1.8 mmol, 1.9 eq) was added. The mixture was allowed to warm to rt. After stirring overnight, the reaction mixture was poured into water, and the whole was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated. The residue was dissolved in n-hexane : AcOEt = 2 : 1, and the solution was filtered through alumina. Evaporation of the filtrate gave O-mesyl oxime 2g-Ms (222.6 mg, 0.93 mmol, yield 100%) as a pale orange solid. 2g-Ms: Mp. 116.0-116.8°C. 1H NMR (CDCl3) δ: 8.03 (1H, d, d, J = 8.0, 0.8 Hz), 7.39 (1H, m), 7.22 (2H, m), 3.24 (3H, s), 2.91 (2H, t, J = 6.8 Hz), 2.81 (2H, t, J = 6.0 Hz), 1.94-1.87 (2H, m). 13C NMR (CDCl3) δ: 163.1, 141.3, 131.4, 129.0, 127.8, 126.7, 125.4, 36.6, 29.4, 25.6, 21.1. Anal. Calcd. for C11H13NO3S: C, 55.21; H, 5.48; N, 5.85. Found: C, 54.95; H, 5.37; N, 5.78. HRMS (ESI+, [M + Na]+): Calcd. for C11H13NNaO3S+: 262.0514. Found: 262.0510.
N OH NOMs
1) NaH, THF
2) MsCl, THF
2k-OH 2k-Ms
Br Br
To a solution of the oxime 2k-OH (148.8 mg, 0.62 mmol) in THF (6 mL), NaH (60% in oil, 56.2 mg, 1.4 mmol, 2.3 equiv.) was added at 0 °C. Then the whole was stirred at 0 °C for 60 min and MsCl (85.9 mg, 0.75 mmol, 1.2 equiv.) was added. The mixture was stirred at 0 °C for 3.5 hrs and was poured into water, and the whole was extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4.
-
S31
The solvent was evaporated. The residue was dissolved in n-hexane : AcOEt = 2 : 1, and the solution was filtered through alumina. Evaporation of the filtrate gave O-mesyl oxime 2k-Ms (202.1 mg, 0.82 mmol, quantitative yield) as a pale orange solid. 2k-Ms: Mp. 124.2-126.2°C. 1H NMR (CDCl3) δ: 7.57 (1H, m), 7.20-7.15 (2H, m), 3.32 (3H, s), 2.96 (2H, t, J = 6.8 Hz), 2.72 (2H, t, J = 6.0 Hz), 1.86-1.80 (2H, m). 13C NMR (CDCl3) δ: 161.9, 145.1, 133.6, 131.1, 128.4, 127.6, 121.0, 37.2, 30.6, 26.3, 20.4. Anal. Calcd for C11H12BrNO3S: C, 41.52; H, 3.80; N, 4.40. Found: C, 41.40; H, 3.70; N, 4.29. HRMS (ESI+, [M + Na]+): Calcd. for C11H12BrNNaO3S+: 339.9619. Found: 339.9602.
HMeO2C
OCH3
14
12
2l-1
4 CrO3Ac2O, AcOH H
MeO2CO
OCH3
14
12
4
HMeO2C
N
OCH3
OH
NH2OMe/HCl
pyridine
HMeO2C
N
OCH3
OTs
1) NaH, THF
2) TsCl, THF
2l-2 2l-4
2l
HMeO2C
OCH3
14
12
2l-1
4 CrO3Ac2O, AcOH H
MeO2CO
OCH3
2l-2 O-methylation (10): To a solution of methyl podocarpate (2.3873 g, 8.28 mmol) in 20 mL of dry THF, NaH (60% in oil, 671.2 mg, 16.78 mmol, 2.03 equiv.) was added at 0°C (in an ice-water bath) by portions. After 15 min, a solution of dimethylsulfonate (2.6335 g, 20.88 mmol, 2.52 equiv.) in 15 mL of dry THF was added at 0 °C to the resultant suspension over 5 min. The whole was stirred at 0 °C for 50 min, and then stirring was continued at rt for 14 hrs. Water (50 mL) was added, and the whole was stirred at rt for 20 min. The organ
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