Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008 – S1 – Lee et al. Supplementary Information Phase-Transfer Catalytic Aza-Michael Addition of tert-Butyl benzyloxycarbamate to Electron-Deficient Olefins Jihoon Lee, a Mi-hyun Kim, a Sang-sup Jew, a Hyeung-geun Park* ,a and Byeong-Seon Jeong* ,b a Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea b Institute for Drug Research and College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea [email protected][email protected]I. General methods Infrared (IR) spectra were recorded on a JASCO FT/IR-300E and Perkin-Elmer 1710 FT spectrometer. Nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) spectra were measured on a JEOL JNM-LA 300 [300 MHz ( 1 H), 75 MHz ( 13 C)] spectrometer, JEOL JNM-GSX 400 [400 MHz ( 1 H), 100 MHz ( 13 C)] spectrometer, and Bruker AMX 500 [500 MHz ( 1 H), 125 MHz ( 13 C)] spectrometer, using DMSO-d 6 or CHCl 3 -d as a solvent, and were reported in ppm relative to DMSO (δ 2.50) or CHCl 3 (δ 7.24) for 1 H-NMR and relative to the central DMSO-d 6 (δ 39.51) or CHCl 3 -d (δ 77.23) resonance for 13 C- NMR. Coupling constants (J) in 1 H-NMR are in Hz. Low-resolution mass spectra (MS) were recorded on a VG Trio-2 GC-MS spectrometer, and high-resolution mass spectra (HRMS) were measured on a JEOL JMS-AX 505wA, JEOL JMS-HX 110A spectrometer. For thin-layer chromatography (TLC) analysis, Merck precoated TLC plate (silica gel 60 GF 254 , 0.25 mm) were used. For flash column chromatography, E. Merck Kieselgel 60 (70~230 mesh) was used. All solvents and commercially available chemicals were used without additional purification.
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Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
– S1 –
Lee et al. Supplementary Information
Phase-Transfer Catalytic Aza-Michael Addition of tert-Butyl benzyloxycarbamate to Electron-Deficient Olefins
I. General methods Infrared (IR) spectra were recorded on a JASCO FT/IR-300E and Perkin-Elmer 1710 FT spectrometer. Nuclear magnetic resonance (1H-NMR and 13C-NMR) spectra were measured on a JEOL JNM-LA 300 [300 MHz (1H), 75 MHz (13C)] spectrometer, JEOL JNM-GSX 400 [400 MHz (1H), 100 MHz (13C)] spectrometer, and Bruker AMX 500 [500 MHz (1H), 125 MHz (13C)] spectrometer, using DMSO-d6 or CHCl3-d as a solvent, and were reported in ppm relative to DMSO (δ 2.50) or CHCl3 (δ 7.24) for 1H-NMR and relative to the central DMSO-d6 (δ 39.51) or CHCl3-d (δ 77.23) resonance for 13C-NMR. Coupling constants (J) in 1H-NMR are in Hz. Low-resolution mass spectra (MS) were recorded on a VG Trio-2 GC-MS spectrometer, and high-resolution mass spectra (HRMS) were measured on a JEOL JMS-AX 505wA, JEOL JMS-HX 110A spectrometer. For thin-layer chromatography (TLC) analysis, Merck precoated TLC plate (silica gel 60 GF254, 0.25 mm) were used. For flash column chromatography, E. Merck Kieselgel 60 (70~230 mesh) was used. All solvents and commercially available chemicals were used without additional purification.
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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II. Synthetic procedure and Characterization of new compounds II-1. Preparation of New Substrates tert-Butyl 2-(diphenylmethylene)hydrazinecarboxylate (2).
OPh
Ph
NH
Ot-Bu
OH2N+ N
HOt-Bu
ONPh
Ph
AcOH, CH2Cl2rt, 20 h, 80%
2
To a solution of tert-butyl carbazate (1.00 g, 7.57 mmol) in CH2Cl2 were added benzopheone (1.65 g, 9.08 mmol) and acetic acid (0.52 mL, 9.08 mmol) under argon atmosphere, and the resulting solution was stirred at room temperature. After 20 h, the mixture was neutralized by the addition of a solution of NaHCO3. The organic later was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer and extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 2 (1.80 g, 80% yield) as a white solid. m.p. 148 °C; 1H-NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.60–7.51 (m, 3H), 7.42–7.34 (m, 5H), 7.27–7.24 (m, 2H), 1.41 (s, 9H) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 152.1, 150.0, 129.5, 128.4, 128.3, 126.8, 80.0, 27.9 ppm; IR (neat): ν 3357, 2977, 1746, 1480, 1367, 1321, 1229, 1156, 1065, 869, 766, 699 cm–1; MS (FAB+): m/z 297 [M+H]+; HRMS (FAB+): calcd for C18H21N2O2 [M+H]+
To a stirred solution of 4-chlorobenzaldehyde (2.00 g, 14.23 mmol) in THF was added a solution of tert-butyl carbazate (2.26 g, 17.07 mmol) in THF at room temperature. After stirring for 48 h, EtOAc and water were added, and the organic later was separated. The aqueous layer was extracted with EtOAc, and the combined organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc = 10:1) to give 3 (2.99 g, 82% yield) as a white solid. m.p. 171 °C; 1H-NMR (300 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.97 (s, 1H), 7.62–7.59 (m, 2H), 7.46–7.44 (m, 2H), 1.45 (s, 9H) ppm; 13C-NMR (100 MHz, DMSO-d6): δ
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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152.3, 141.8, 133.7, 133.5, 128.8, 128.1, 79.5, 28.0 ppm; IR (neat,): ν 3222, 2979, 1705, 1538, 1489, 1367, 1252, 1163, 1090, 1057, 869, 825, 759 cm–1; MS (FAB+): m/z 255 [M+H]+; HRMS (FAB+): calcd for C12H16ClN2O2 [M+H]+ 255.0900, found 255.0896. II-2. Aza-Michael Reaction General Procedure To a solution of tert-butyl benzyloxycarbamate (5, 2.0 equiv.) and tetra-n-butylammonium bromide (0.1 equiv.) was added 50% KOH (1.2 equiv.) and enone (6, 1.0 equiv.) successively. The resulting mixture was stirred at room temperature until the starting enone disappeared on TLC. After the reaction was completed, EtOAc and brine were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic solution was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to afford the aza-Michael adduct 7. tert-Butyl benzyloxy(3-oxocyclohexyl)carbamate (7a)
7c 8c To a solution of 7c (64 mg, 0.218 mmol) in EtOAc (1 mL) was added a catalytic amount of acetone-washed (5×1 mL) Raney-Ni (4200; slurry in water; active catalyst; Aldrich). The reaction mixture was stirred under hydrogen atmosphere at room temperature. After stirring for 1 h, the mixture was filtered through Celite pad, and washed with EtOAc. The filtrate and washings were combined and concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc = 3:1) to afford 8c (37 mg, 90% yield) as colorless oil. 1H-NMR (300 MHz, CDCl3): δ 4.95 (br s, 1H), 3.31 (m, 2H), 2.63 (t, J=5.85 Hz, 2H), 2.12 (s, 3H), 1.39 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3): δ 208.13, 155.84, 79.27, 43.49, 35.17, 30.14, 28.35 ppm; IR (neat): ν 3365, 2976, 2931, 1712, 1518, 1455, 1366, 1275, 1251, 1168, 866 cm–1; MS (FAB+): m/z 210 [M+Na]+; HRMS (FAB+): calcd for C9H17NO3Na [M+Na]+ 210.1106, found: 210.1109.
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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tert-Butyl hydroxyl(3-oxobutyl)carbamate (9c)
N
OO
OHO
NO
OO
O
N
OO
O
OH
H2, Pd/C, EtOH
rt, 20 min, 72%
7c 9c 9c' To a solution of 7c (52 mg, 0.177 mmol) in EtOH was added a catalytic amount of Pd/C (10% on activated carbon) The reaction mixture was stirred under hydrogen atmosphere at room temperature. After stirring for 20 min, the reaction mixture was filtered through Celite pad, and washed with EtOH. The filtrate and washings were combined and concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc = 3:1) to afford 9c (25 mg, 72% yield) as colorless oil. 1H-NMR (300 MHz, C6D6): δ 8.06 (br s, 1H), 3.83 (t, J=6.78 Hz, 2H), 2.43 (t, J=6.78 Hz, 2H), 1.63 (s, 3H), 1.42 (s, 9H) ppm, [Minor Lactol (9c’) δ 5.0 (br, 1H), 3.92−4.02 (m, 1H), 3.25−3.31 (m, 1H), 1.97−2.03 (m, 1H), 1.58 (s, 3H), 1.53−1.58 (m, 1H), 1.42 (s, 9H) ppm]; 13C-NMR (75 MHz, C6D6): δ 205.6, 157.2, 81.3, 47.7, 40.6, 29.5, 28.2 ppm, [Minor Lactol (9c’) δ 159.9, 105.1, 81.3, 45.9, 39.3, 27.9, 23.1 ppm]; MS (FAB+): m/z 226 [M+Na]+; HRMS (FAB+): calcd for C9H18NO4 [M+H]+ 204.1236, found: 204.1243. 4-(Benzyloxyamino)butan-2-one (10c)
NH
ON
O
OO
O
CF3CO2H, CH2Cl2rt, 1 h, 92%
7c10c
O
To a solution of 7c (64 mg, 0.218 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.5 mL) in water bath. After stirring for 1 h at room temperature, the reaction mixture was diluted with CH2Cl2 (10 mL), washed with saturated aqueous NaHCO3
solution (2×1 mL) and then back-extracted with CH2Cl2 (2×5 mL). The combined organic layer was dried and concentrated to afford 9c (39 mg, 92% yield) as colorless oil. 1H-NMR (300 MHz, C6D6): δ 7.36−7.11(m, 5H), 4.65 (s, 2H), 2.99 (t, J=6.15, 2H), 2.11 (t, J=6.15, 2 H), 1.58 (s, 3H) 13C-NMR (75 MHz, C6D6): δ 206.0, 138.9, 130.0, 128.7, 128.5, 128.4, 76.2, 47.0, 40.7, 29.4 ppm; MS (FAB+): m/z 194 [M+H]+; HRMS (CI+): calcd for C11H16NO2 [M+H]+ 194.1181, found: 194.1183.
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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III. 1H and 13C-NMR spectra of the new compounds
NNH
Ot-Bu
O
2
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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NNH
Ot-Bu
OCl
3
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O7a
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O
7b
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O7c
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O7d
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
Ph O7e
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
Ph O7f
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O O7g
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
O O7h
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
H2N O7i
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
CN7j
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
SOPh
7k
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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ON Ot-Bu
O
SO2Ph
7l
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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HN Ot-Bu
O
O8c
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008
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N Ot-Bu
O
O9c
HO
Supplementary Material (ESI) for Chemical Communications This journal is (c) The Royal Society of Chemistry 2008