Chapter I Overview
4.6 Experimental section
4.6.2 General procedure for the synthesis of trans-γ-hydroxyenones and unsaturated pyrazolones
Trans-γ-hydroxyenones were prepared according to reported procedure.14 Unsaturated pyrazolones were prepared according to reported procedures.15 4.6.3 General procedure for the synthesis of catalyst
The catalysts I, II, III and VII were prepared according to reported procedures.16 The catalyst IV was prepared according to reported procedure.17 The catalysts V and VI were prepared according to reported procedures.18The catalyst VIII was prepared according to reported procedure.19
4.6.4 General procedure for the synthesis of compound 3a-3z8
In an oven dried round bottom flask, 1 (0.2 mmol), 2 (0.24 mmol), 10 mol% of catalyst V or VI were taken, then 0.8 mL of toluene was added to the reaction mixture and stirred at rt for 5 days. Completion of the reaction was checked by TLC. After the completion of the reaction, solvent was concentrated and the reaction mixture was directly purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10-15%) to afford the desired products 3a-3z6.
4.6.5 General procedure for the preparation of derivatives 420
In an oven dried round bottom flask, compound 3d (45.2 mg, 0.1 mmol) in CH2Cl2 (3.3 mL) was taken. Then m-CPBA (56.0 mg, 0.25 mmol) and Na2HPO4 (36.0 mg, 0.25 mmol) were added and the solution was stirred at room temperature overnight. The mixture was poured into water (2 mL) and saturated aq. NaHCO3 (2 mL), the organic layer was separated and the aqueous phase was extracted with CH2Cl2 (3 × 2 mL). The combined organic layer was washed with water (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography using EtOAc-Hexane (15-20%) as eluent to afford compound 4.
4.6.6 General procedure for the preparation of derivatives 521
To a solution of compound 4 (47.0 mg, 0.1 mmol) in THF (1 mL) was added benzylamine (23 μL, 0.2 mmol) and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (3 mL), the organic layer was washed with 1 N HCl (2 × 2 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using EtOAc-Hexane (30-50%) as eluent to afford amide 5.
Chapter 4
168 4.6.7 Crystal structure of compound 3s22
ORTEP crystal structure
Table 2. Crystal data and structure refinement for compound 3s
Parameters 3s
CCDC No. 1824042
Empirical formula C27H23N2O3Cl
Formula weight 458.92
Crystal habit, colour block/colourless
Crystal size, mm3 0.36× 0.33 × 0.33
Temperature, T 293 K
Wavelength, λ (Å) 0.71073
Crystal system Triclinic
Space group 'P -1'
Unit cell dimensions
a = 10.0751(6) Å b = 10.5272(5) Å c = 12.2309(9) Å
α = 107.851(5)°, β = 98.524(5)°, γ = 103.443(5)°
Volume, V (Å3) 1166.70(12)
Z 2
Calculated density, Mg/m3 1.306
Absorption coefficient, µ (mm1) 0.195
F(000) 480
range for data collection 3.4170 to 27.5150
Limiting indices –13 ≤ h ≤ 13, –14 ≤ k ≤ 13, –
16 ≤ l ≤ 16
Reflection collected/unique 4107/3047[R(int) = 0.0195]
Completeness to 99.83% ( = 26.320°)
Max. and min. transmission 0.943/ 0.932
Refinement method 'SHELXL-97 (Sheldrick,
1997)'
Data/restraints/parameters 4100/0/299
Goodness of fit on F2 1.054
Final R indices [I > 2σ(I)] R1 = 0.0460, wR2 = 0.1055 R indices (all data) R1 = 0.0646, wR2 = 0.1212
Ellipsoid contour % probability 40%
Chapter 4
170 4.7 Characterization data of products
(5R,6R,9S)-4-methyl-9-(2-oxo-2-phenylethyl)-2,6-diphenyl-7- oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3a): Purified by silica-gel column chromatography using 15% ethyl acetate/hexane; light yellow sticky solid; 70% yield (59.4 mg).
1H NMR (400 MHz, CDCl3) δ 7.90-7.84 (m, 4H), 7.55 (t, J = 7.4 Hz, 1H), 7.44-7.40 (m, 4H), 7.26-7.21 (m, 6H), 5.41 (s, 1H), 4.88 (t, J = 9.2 Hz, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.85-3.74 (m, 1H), 3.17 (dd, J = 17.7, 4.8 Hz, 1H), 3.01 (dd, J = 17.7, 10.0 Hz, 1H), 2.03 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 196.7, 171.8, 159.2, 137.9, 136.0, 135.9, 133.7, 129.0, 128.9, 128.6, 128.2, 128.1, 125.5, 124.4, 119.2, 86.3, 72.6, 68.1, 45.1, 38.2, 17.6. FT-IR (thin film) 3057, 2910, 1704, 1678, 1596, 1496, 792 cm-1. HPLC Analysis: 96% ee; Determined using a Daicel Chiralpak IA Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 254 nm (tmajor = 21.2 min, tminor = 18.2 min). [α]D24 = -60.0 (c 0.35, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C27H25N2O3 [M+H]+ 425.1865, found 425.1861.
(5R,6R,9S)-4-methyl-9-(2-oxo-2-(p-tolyl)ethyl)-2,6-
diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3b):
Purified by silica-gel column chromatography using 15%
ethyl acetate/hexane; off white solid; 71% yield (62.3 mg).
m.p. = 135-138 oC. 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.26-7.20 (m, 8H), 5.39 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.82-3.72 (m, 1H), 3.14 (dd, J = 17.5, 4.7 Hz, 1H), 2.96 (dd, J = 17.5, 10.1 Hz, 1H), 2.39 (s, 3H), 2.02 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 196.4, 171.9, 159.3, 144.7, 138.0, 136.0, 133.6, 129.6, 129.1, 128.6, 128.3, 128.2, 125.5, 124.4, 119.2, 86.3, 72.7, 68.1, 45.2, 38.1, 21.8, 17.7. FT-IR (thin film) 3060, 2954, 1706, 1685, 1597, 1492, 789 cm-1. HPLC Analysis: 94% ee; Determined using a Daicel Chiralpak IA Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 220 nm (tmajor = 29.9 min,
tminor = 20.1 min). [α]D26 = -36.9 (c 0.13, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C28H27N2O3 [M+H]+ 439.2022, found 439.2023.
(5R,6R,9S)-9-(2-(4-(tert-butyl)phenyl)-2-oxoethyl)-4- methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3- en-1-one (3c): Purified by silica-gel column chromatography using 10% ethyl acetate/hexane; brown sticky solid; 72% yield (69.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.47-7.38 (m, 4H), 7.23 (d, J = 7.3 Hz, 6H), 5.40 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.84-3.73 (m, 1H), 3.15 (dd, J = 17.5, 4.8 Hz, 1H), 2.97 (dd, J = 17.5, 10.1 Hz, 1H), 2.02 (s, 3H), 1.31 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 196.4, 171.9, 157.7, 138.0, 136.1, 133.5, 129.2, 129.0, 128.2, 128.0, 126.0, 125.7, 124.6, 119.4, 119.2, 86.5, 86.3, 68.2, 45.4, 45.1, 35.3, 31.3, 31.1, 17.8. FT-IR (thin film) 3055, 2915, 1708, 1672, 1590, 1493, 790 cm-1. HPLC Analysis: 88% ee; Determined using a Daicel Chiralpak IA Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 254 nm (tmajor = 18.4 min, tminor = 13.6 min). [α]D25 = -60.0 (c 0.170, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C31H33N2O3 [M+H]+ 481.2491, found 481.2487.
(5R,6R,9S)-9-(2-(4-methoxyphenyl)-2-oxoethyl)-4- methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3- en-1-one (3d): Purified by silica-gel column chromatography using 15% ethyl acetate/hexane; brown sticky solid; 69% yield (62.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.26-7.18 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 5.39 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.78 (dd, J = 9.3, 4.8 Hz, 1H), 3.12 (dd, J = 17.3, 4.7 Hz, 1H), 2.93 (dd, J = 17.1, 10.1 Hz, 1H), 2.02 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 195.2, 171.9, 164.0, 159.4, 138.0, 136.0, 130.5, 129.1,
Chapter 4
172
129.0, 128.6, 128.2, 125.5, 124.4, 119.2, 114.0, 86.3, 72.7, 68.2, 55.6, 45.3, 37.8, 17.7.
FT-IR (thin film) 3063, 2962, 1700, 1668, 1595, 1491, 757 cm-1. HPLC Analysis: 90%
ee; Determined using a Daicel Chiralpak IA Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 220 nm (tmajor = 38.5 min, tminor = 31.8 min). [α]D25 = -48.8 (c 0.40, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C28H27N2O4 [M+H]+ 455.1971, found 455.1969.
(5R,6R,9S)-9-(2-(4-bromophenyl)-2-oxoethyl)-4-methyl- 2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3e): Purified by silica-gel column chromatography using 15% ethyl acetate/hexane; brown sticky solid; 66% yield (66.3 mg). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.26-7.20 (m, 6H), 5.39 (s, 1H), 4.85 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.77 (qd, J = 9.3, 5.0 Hz, 1H), 3.12 (dd, J = 17.7, 4.9 Hz, 1H), 2.96 (dd, J = 17.7, 9.9 Hz, 1H), 2.01 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 195.8, 171.8, 159.2, 138.0, 135.9, 134.8, 132.3, 129.7, 129.1, 128.6, 128.3, 125.6, 124.5, 119.2, 86.5, 72.6, 68.1, 45.1, 38.2, 17.7. FT-IR (thin film) 3060, 2965, 1703, 1680, 1595, 1490, 765 cm-1. HPLC Analysis: 92% ee; Determined using a Daicel Chiralpak IA Column (hexane/2- propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 254 nm (tmajor = 26.6 min, tminor = 24.1 min). [α]D23 = -34.6 (c 0.455, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C27H24BrN2O3 [M+H]+ 503.0970, found 503.0972.
(5R,6R,9S)-4-methyl-9-(2-oxo-2-(m-tolyl)ethyl)-2,6-
diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3f):
Purified by silica-gel column chromatography using 15%
ethyl acetate/hexane; brown sticky solid; 62% yield (54.4 mg). 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.29-7.23 (m, 6H), 5.42 (s, 1H), 4.90 (t, J = 9.2 Hz, 1H), 4.04 (t, J = 9.0 Hz, 1H), 3.87-3.77 (m, 1H), 3.17 (dd, J =
17.6, 4.8 Hz, 1H), 3.01 (dd, J = 17.6, 10.1 Hz, 1H), 2.40 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.0, 171.8, 159.3, 138.8, 138.0, 136.1, 136.0, 134.5, 129.1, 128.8, 128.6, 128.2, 125.5, 125.4, 124.4, 119.2, 86.4, 72.7, 68.1, 45.2, 38.3, 21.4, 17.7.
FT-IR (thin film) 3061, 2925, 1702, 1678, 1596, 1495, 791 cm-1. HPLC Analysis: 94%
ee; Determined using a Daicel Chiralpak IA Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 220 nm (tmajor = 16.0 min, tminor = 15.1 min). [α]D28 = -72.8 (c 0.390, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C28H27N2O3 [M+H]+ 439.2022, found 439.2022.
(5R,6R,9S)-9-(2-(3-methoxyphenyl)-2-oxoethyl)-4-methyl- 2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3g):
Purified by silica-gel column chromatography using 15%
ethyl acetate/hexane; light yellow sticky solid; 68% yield (62.0 mg). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.9 Hz, 2H), 7.41 (t, J = 7.9 Hz, 3H), 7.37 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.26-7.21 (m, 6H), 7.12-7.10 (m, 1H), 5.40 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.78 (dd, J = 9.7, 4.2 Hz, 1H), 3.14 (dd, J = 17.6, 4.9 Hz, 1H), 2.99 (dd, J = 17.6, 9.9 Hz, 1H), 2.02 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 196.7, 171.9, 160.1, 159.2, 138.1, 137.5, 136.0, 129.9, 129.1, 128.9, 128.6, 128.3, 125.5, 124.5, 120.8, 120.2, 119.6, 119.3, 112.5, 86.5, 72.7, 68.1, 55.6, 45.3, 38.4, 17.7.
FT-IR (thin film) 3063, 2923, 1710, 1685, 1589, 1496, 792 cm-1. HPLC Analysis: 92%
ee; Determined using a Daicel Chiralpak IB Column (hexane/2-propanol = 90:10), flow rate 1.0 mL/min, 25 oC, λ = 254 nm (tmajor = 15.7 min, tminor = 12.2 min). [α]D24 = -42.4 (c 0.50, CHCl3). HRMS (+ESI-TOF) m/z: calcd. For C28H27N2O4 [M+H]+ 455.1971, found 455.1962.