P. Li et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
4.5. 1-(3-Methoxyphenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-
3. Conclusion
1-one 3da
Herein we have developed an organocatalytic aza-Michael addi-
tion of pyrazole to chalcone to afford products in 40–98% yields
with 68–88% ee. Compared with the reported results,5e,g higher
ee values and yields were obtained with this methodology. A wide
range of chalcones reacted smoothly with pyrazole to afford good
yields and ee values. These results represent the first systematic
and general report on the organocatalytic enantioselective
aza-Michael addition of pyrazole to chalcone. The development
of a new type of organocatalyst and further applications of these
reactions are currently under investigation.
1H NMR (400 MHz, CDCl3): d (ppm) 7.96 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 9.6, Hz, 2H), 7.33–7.24 (m, 5H), 6.91 (d, J = 8.8 Hz, 2H), 6.22
(s, 1H), 6.11 (dd, J = 5.4, 8.6 Hz, 1H), 4.42 (dd, J = 8.4, 17.2 Hz, 1H),
3.84 (s, 3H), 3.60 (dd, J = 5.2, 17.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 195.2, 163.8, 141.0, 139.4, 130.7, 129.9, 129.8,
128.9, 128.0, 126.8, 113.9, 105.6, 61.1, 55.6, 43.9. ½a D20
¼ þ66:5 (c
ꢀ
1.00, CHCl3) 77% ee. IR mmax: 3063, 3031, 2930, 1675, 1600, 1510,
1455, 1259, 1212, 1170, 1028, 835, 754, 694 cmꢁ1. HRMS: exact
mass calculated for [M+Na]+ (C19H18N2O2Na) requires m/z
329.1266, found m/z 329.1257.
4. Experimental
4.6. 3-(4-Fluorophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ea
4.1. General procedure for aza-Michael addition
1H NMR (400 MHz, CDCl3): d (ppm) 7.98-7.96 (m, 2H), 7.56
(t, J = 7.4 Hz, 1H), 7.52–7.48 (m, 2H), 7.44 (d, J = 7.8 Hz, 2H),
7.35–7.32 (m, 2H), 7.01 (t, J = 8.8 Hz, 2H), 6.23 (t, J = 2.0 Hz, 1H),
6.09 (dd, J = 5.6, 8.0 Hz, 1H), 4.43 (dd, J = 8.0, 17.6 Hz, 1H), 3.65
(dd, J = 5.6, 17.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm)
Unless noted otherwise, the reaction was carried out as
follows: to a solution of Et2O or 1,4-dioxane (0.3 mL) were added
chalcone 1 (0.1 mmol) and pyrazole 2 (0.2 mmol) in the presence
of catalyst Ib (10 mol %) combined with A3 (20 mol %). The reac-
tion mixture was stirred at room temperature for the time given.
Then the solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel to yield the
desired Michael adducts 3.
1
4
196.6, 162.5 (d, JCꢁF = 245.4 Hz), 139.6, 136.6 (d, JC–F = 3.3 Hz),
3
136.58, 133.6, 129.8, 128.8, 128.6 (d, JC–F = 8.1 Hz), 128.3, 115.8
(d, JC–F = 21.4 Hz), 105.8, 60.3, 44.4. ½a D20
ꢀ
¼ þ58:2 (c 1.00, CHCl3)
2
72% ee. IR mmax: 3117, 3063, 2914, 1685, 1597, 1510, 1449, 1396,
1224, 1045, 752, 689 cmꢁ1. HRMS: exact mass calculated for
[M+Na]+ (C18H15N2OFNa) requires m/z 317.1066, found m/z
317.1065.
4.2. 1,3-Diphenyl-3-(1H-pyrazol-1-yl)propan-1-one 3aa
1H NMR (400 MHz, CDCl3): d (ppm) 7.98 (d, J = 7.2 Hz, 2H),
7.58–7.50 (m, 3H), 7.46–7.43 (m, 2H), 7.34–7.26 (m, 5H), 6.24 (t,
J = 1.8 Hz, 1H), 6.12 (dd, J = 5.2, 8.4 Hz, 1H), 4.50 (dd, J = 4.6,
17.8 Hz, 1H), 3.64 (dd, J = 5.2, 18.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.7, 140.9, 139.4, 136.7, 133.5, 129.9, 128.9,
4.7. 3-(4-(Trifluoromethyl)phenyl)-1-phenyl-3-(1H-pyrazol-1-
yl) propan-1-one 3fa
1H NMR (400 MHz, CDCl3): d (ppm) 7.97 (d, J = 7.2 Hz, 2H),
7.60–7.51 (m, 5H), 7.47–7.43 (m, 4H), 6.26 (t, J = 2.0 Hz, 1H),
6.19–6.16 (m, 1H), 4.48 (dd, J = 8.0, 17.6 Hz, 1H), 3.68 (dd, J = 5.4,
17.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 196.3, 144.9,
128.7, 128.3, 128.1, 126.8, 105.7, 60.9, 44.3. ½a D20
¼ þ64:3 (c 1.00,
ꢀ
CHCl3) 76% ee. IR
mmax: 3063, 3031, 2914, 1684, 1556, 1508,
1449, 1261, 1207, 1043, 751, 689 cmꢁ1. HRMS: exact mass calcu-
lated for [M+Na]+ (C18H16N2ONa) requires m/z 299.1160, found
m/z 299.1161.
139.9, 136.5, 133.7, 130.0, 128.8, 128.3, 127.3, 125.9 (q, JC–F
=
3.6 Hz), 106.1, 60.5, 44.3. ½a D20
¼ þ60:2 (c 1.00, in CHCl3) 84% ee. IR
ꢀ
m
max: 3060, 2917, 1686, 1621, 1505, 1449, 1326, 1167, 1124,
4.3. 1-Phenyl-3-(1H-pyrazol-1-yl)-3-p-tolylpropan-1-one 3ba
1069, 753, 688 cmꢁ1. HRMS: exact mass calculated for [M+H]+
1H NMR (400 MHz, CDCl3): d (ppm) 7.98 (d, J = 7.2 Hz, 2H), 7.55
(t, J = 7.4 Hz, 1H), 7.50 (s, 1H), 7.47–7.42 (m, 3H), 7.24 (d, J = 8.0 Hz,
2H), 7.13 (d, J = 8.0 Hz, 2H), 6.22 (t, J = 2.0 Hz, 1H), 6.10–6.06 (m,
1H), 4.46 (dd, J = 8.4, 17.6 Hz, 1H), 3.64 (dd, J = 5.2, 17.6 Hz, 1H),
2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): d (ppm) 196.8, 139.3,
137.9, 137.8, 136.8, 133.4, 129.7, 129.6, 128.7, 128.3, 126.8,
(C19H16N2OF3) requires m/z 345.1215, found m/z 345.1199.
4.8. 3-(4-Bromophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ga
1H NMR (400 MHz, CDCl3): d (ppm) 7.96 (d, J = 7.2 Hz, 2H), 7.56
(t, J = 7.4 Hz, 1H), 7.51–7.48 (m, 2H), 7.46–7.44 (m, 4H), 7.22 (d,
J = 8.4 Hz, 2H), 6.24 (t, J = 2.0 Hz, 1H), 6.08–6.05 (m, 1H), 4.43
(dd, J = 8.0, 17.6 Hz, 1H), 3.64 (dd, J = 5.4, 17.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d (ppm) 196.4, 139.9, 139.7, 136.5, 133.6,
132.0, 129.9, 128.8, 128.6, 128.3, 122.1, 105.9, 60.4, 44.2.
105.6, 60.8, 44.3, 21.2. ½a D20
ꢀ
¼ þ34:2 (c 1.00, CHCl3) 68% ee. IR mmax
:
3060, 3022, 2920, 1686, 1596, 1513, 1448, 1283, 1204, 1043, 749,
688 cmꢁ1. HRMS: exact mass calculated for [M+H]+ (C19H19N2O)
requires m/z 291.1497, found m/z 291.1499.
½
a 2D0
ꢀ
¼ þ36:0 (c 1.00, CHCl3) 83% ee. IR
mmax: 3060, 2920, 1685,
4.4. 3-(3-Bromophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ca
1596, 1488, 1448, 1396, 1207, 1011, 754, 689 cmꢁ1. HRMS: exact
mass calculated for [M+H]+ (C18H16N2OBr) requires m/z 355.0446,
found m/z 355.0445.
1H NMR (400 MHz, CDCl3): d (ppm) 7.98–7.96 (m, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.52–7.50 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H), 7.41 (d,
J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.25
(t, J = 2.0 Hz, 1H), 6.07 (dd, J = 5.2, 8.4 Hz, 1H), 4.47 (dd, J = 8.4,
17.6 Hz, 1H), 3.61 (dd, J = 5.2, 17.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.3, 143.1, 139.7, 136.5, 133.6, 131.3, 130.5,
4.9. 3-(3-Nitrophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-one
3ha
1H NMR (400 MHz, CDCl3): d (ppm) 8.25 (s, 1H), 8.14 (d,
J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H),
7.59–7.55 (m, 3H), 7.51 (t, J = 8.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H),
6.27 (t, J = 2.0 Hz, 1H), 6.23-6.19 (m, 1H), 4.47 (dd, J = 7.8,
17.8 Hz, 1H), 3.74 (dd, J = 5.6, 18.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.0, 142.9, 140.2, 136.3, 133.8, 133.2, 130.1,
130.0, 128.8, 128.3, 125.5, 123.0, 106.0, 60.3, 44.2. ½a D20
¼ þ56:9
ꢀ
(c 1.00, CHCl3) 82% ee. IR
mmax: 3110, 3059, 2914, 1685, 1596,
1509, 1448, 1395, 1207, 1090, 756, 690 cmꢁ1. HRMS: exact mass
calculated for [M+H]+ (C18H16N2OBr) requires m/z 355.0446, found
m/z 355.0445.