Enantioselective One-Pot Conjugate Addition of Grignard Reagents
OMe (3.75 mL), and the resulting solution was stirred at room tem-
perature for 30 min. The reaction mixture was then cooled to
HPLC (OD-H; hexane/iPrOH, 90:10; 0.6 mLmin–1): tR(minor) =
19.6, t (major) = 27.2 min. IR (neat): ν = 3205 (m, N–H), 1700 (s,
˜
R
–60 °C. Cyclohex-2-enone (36 mg, 0.375 mmol) was added to this C=O), 1328 (s), 1159 (s, SO2) cm–1.
solution, and the resulting mixture was stirred at –60 °C for an
(R,R,R)-N-[(2-Ethyl-6-oxocyclohexyl)(phenyl)methyl]-4-methyl-
additional 10 min. MeMgBr (3 in Et2O, 188 µL, 0.563 mmol) was
added over 5 min, and the resulting mixture was stirred at –60 °C
for an additional 2 h. Finally, imine 2 (65 mg, 0.25 mmol), dis-
solved in mTHF (2.5 mL), was added, and the reaction mixture
was slowly allowed to reach room temperature overnight. The reac-
tion was then quenched with aq. NH4Cl and extracted with Et2O.
The combined organic extracts were concentrated. The crude prod-
uct was purified by column chromatography.
benzenesulfonamide [(R,R,R)-5]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2, 83:14:3) afforded pure (R,R,R)-5 (17 mg,
18%). M.p. 111–113 °C (hexane). [α]D = +30.4 (c = 0.75 in CHCl3,
1
94% ee). H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.2 Hz, 2
H, Ar), 7.22–6.90 (m, 7 H, Ar), 6.33 (d, J = 10.1 Hz, 1 H, CH),
4.67 (dd, J = 10.0, 6.0 Hz, 1 H, CH), 2.62 (dd, J = 8.7, 6.2 Hz, 1
H, CH), 2.42–2.23 (m, 1 H), 2.31 (s, 3 H, CH3), 2.22–2.07 (m, 1 H),
1.98–1.78 (m, 2 H, CH2), 1.70–1.20 (m, 5 H), 0.88 (t, J = 7.2 Hz, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 213.2 (CO), 142.7
(qC-SO2), 138.0 (qC-Ph), 137.4 (qC-CH3), 129.1 (CH), 128.5
(CH),128.2 (CH) 127.4 (CH), 126.8 (CH), 59.6 (CH), 57.0 (CH),
41.8 (CH2), 40.1 (CH), 27.9 (CH2), 25.6 (CH2), 23.4 (CH2), 21.4
(CH3),10.3 (CH3) ppm. C22H27NO3S (385.52): calcd. C 68.54, H
7.06, N 3.63; found C 68.02, H 7.02, N 3.48. HPLC (OD-H; hex-
ane/iPrOH, 90:10; 0.6 mLmin–1): tR(major) = 15.9, tR(minor) =
(S,R,R)-4-Methyl-N-[(2-methyl-6-oxocyclohexyl)(phenyl)methyl]-
benzenesulfonamide [(S,R,R)-3]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2, 83:14:3) afforded pure (S,R,R)-3 (34 mg,
36%). M.p. 117–119 °C (heptane). [α]D = +23.7 (c = 0.75 in CHCl3,
1
94% ee). H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 8.3 Hz, 2
H, Ar), 7.04–6.97 (m, 7 H, Ar), 6.28 (d, J = 10.5 Hz, 1 H, NH),
4.78 (dd, J = 3.1, 10.5 Hz, 1 H, CH), 2.46 (dd, J = 3.0, 7.5 Hz, 1
H, CH), 2.29 (s, 3 H, CH3), 2.21–1.90 (m, 5 H), 1.77–1.40 (m, 2
H, CH2), 1.25 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 212.9 (CO), 142.6 (qC-SO2), 139.7 (qC-Ph), 138.1 (qC-
CH3), 129.0 (CH), 127.8 (CH), 126.9 (CH), 126.8 (CH), 126.5
(CH), 64.1 (CH), 55.7 (CH), 42.7 (CH2), 37.2 (CH), 33.6 (CH2),
26.4 (CH2), 21.3 (CH3),20.3 (CH3) ppm. C21H25NO3S (371.49):
calcd. C 67.89, H 6.78, N 3.77; found C 67.53, H 7.03, N 3.72.
HPLC (OD-H; hexane/iPrOH = 90:10; 0.55 mLmin–1): tR(minor)
20.3 min. IR (neat): ν = 3267 (m, N–H), 1708 (s, C=O), 1320 (s),
˜
1152 (s, SO2) cm–1.
(S,R,R)-N-[(2-Butyl-6-oxocyclohexyl)(phenyl)methyl]-4-methyl-
benzenesulfonamide [(S,R,R)-6]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2; 83:14:3 and CH2Cl2 with 5% MeOH) af-
forded pure (S,R,R)-6 (11 mg, 11%). M.p. 126–128 °C (EtOAc/hex-
ane). [α]D = +21.4 (c = 0.35 in CHCl3, 73 % ee). 1H NMR
(300 MHz, CDCl3): δ = 7.45 (d, J = 8.3 Hz, 2 H, Ar), 7.09–6.96
(m, 7 H, Ar), 6.12 (d, J = 10.0 Hz, 1 H, NH), 4.77 (dd, J = 4.9,
10.0 Hz, 1 H, CH), 2.55 (dd, J = 4.7, 8.3 Hz, 1 H, CH), 2.29 (s, 3
H, CH3), 2.32–2.13 (m, 2 H, CH2), 2.08–1.84 (m, 3 H), 1.79–1.55
(m, 2 H, CH2), 1.54–1.35 (m, 2 H, CH2), 1.35–1.13 (m, 4 H, CH2),
0.91 (t, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 213.4 (CO), 142.6 (qC-SO2), 139.6 (qC-Ph), 138.1 (qC-CH3),
129.0 (CH), 128.0 (CH), 126.9 (CH), 126.86 (CH), 126.7 (CH), 61.9
(CH), 55.9 (CH), 42.1 (CH2), 40.6 (CH) 32.5 (CH2), 28.8 (CH2),
28.1 (CH2),25.6 (CH2), 22.8 (CH2),21.3 (CH3), 14.1 (CH3) ppm.
C24H31NO3S (413.57): calcd. C 69.70, H 7.56, N 3.39; found C
69.97, H 8.03, N 3.30. HPLC (OD-H; hexane/iPrOH, 90:10;
0.6 mLmin–1): tR(minor) = 14.2, tR(major) = 23.2 min. IR (neat):
= 20.3, t (major) = 24.7 min. IR (neat): ν = 3172 (m, N–H), 1697
˜
R
(s, C=O), 1325 (s), 1163 (s, SO2) cm–1.
(R,R,R)-4-Methyl-N-[(2-methyl-6-oxocyclohexyl)(phenyl)methyl]-
benzenesulfonamide [(R,R,R)-3]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2, 83:14:3) afforded pure (R,R,R)-3 (28 mg,
30%). M.p. 127–129 °C (hexane/CHCl3). [α]D = +35.2 (c = 0.75 in
CHCl3, 94% ee). 1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J =
8.3 Hz, 2 H, Ar), 7.10–7.01 (m, 7 H, Ar), 6.49 (d, J = 10.3 Hz, 1
H, NH), 4.78 (dd, J = 5.3, 10.3 Hz, 1 H, CH), 2.50 (ddd, J = 1.1,
5.3, 10.6 Hz, 1 H, CH), 2.31 (s, 3 H, CH3), 2.25–2.10 (m, 1 H, CH),
1.94–1.70 (m, 2 H, CH2), 1.65–1.20 (m, 4 H, CH2), 1.25 (d, J =
6.3 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 212.9
(CO), 142.6 (qC-SO2), 138.1 (qC-Ph), 137.4 (qC-CH3), 129.1 (CH),
128.8 (CH), 128.2 (CH), 127.4 (CH), 126.8 (CH), 61.6 (CH), 57.2
(CH), 42.0 (CH2), 34.7 (CH), 33.0 (CH2), 23.8 (CH2), 21.4 (CH3),
20.3 (CH3) ppm. C21H25NO3S (371.49): calcd. C 67.89, H 6.78, N
3.77; found C 68.09, H 7.10, N 3.70. HPLC (OD-H; hexane/iPrOH,
90:10; 0.55 mL min–1): tR(major) 28.2, tR(minor) 23.0 min. IR
ν = 3193 (m, N–H), 1699 (s, C=O), 1333 (s), 1160 (s, SO ) cm–1.
˜
2
(R,R,R)-N-[(2-Butyl-6-oxocyclohexyl)(phenyl)methyl]-4-methyl-
benzenesulfonamide [(R,R,R)-6]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2; 83:14:3 and CH2Cl2 with 5% MeOH) af-
1
forded pure (R,R,R)-6 (6 mg, 6%). M.p. 133–136 °C (hexane). H
NMR (300 MHz, CDCl3): δ = 7.50–7.43 (m, 2 H, Ar), 7.15–7.00
(m, 7 H, Ar), 6.25 (d, J = 10.1 Hz, 1 H), 4.67 (dd, J = 6.1, 10.1 Hz,
1 H), 2.59 (ddd, J = 1.0, 6.1, 9.4 Hz, 1 H), 2.32 (s, 3 H, CH3), 2.30–
2.23 (m, 1 H), 2.23–2.08 (m, 1 H), 1.96–1.80 (m, 2 H, CH2), 1.70–
1.40 (m, 3 H), 1.39–1.19 (m, 5 H), 1.19–1.05 (m, 1 H), 0.89 (t, J =
7.0 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 213.2
(CO), 142.8 (qC-SO2), 138.1 (qC-Ph), 137.5 (qC-CH3), 129.2 (CH),
128.5 (CH), 128.2 (CH), 127.5 (CH), 126.9 (CH), 60.0 (CH), 57.1
(CH), 41.8 (CH2), 38.9 (CH) 32.8 (CH2), 28.4 (CH2), 28.3
(CH2),23.4 (CH2), 22.8 (CH2), 21.4 (CH3), 14.0 (CH3) ppm.
C24H31NO3S (413.57): calcd. C 69.70, H 7.56, N 3.39; found C
69.22, H 7.59, N 3.26. HPLC (OD-H; hexane/iPrOH, 90:10;
0.6 mLmin–1): tR(minor) = 12.4, tR(major) = 16.5 min. IR (neat):
(neat): ν = 3265 (m, N–H), 1710 (s, C=O), 1321 (s), 1153 (s, SO )
˜
2
cm–1.
(S,R,R)-N-[(2-Ethyl-6-oxocyclohexyl)(phenyl)methyl]-4-methyl-
benzenesulfonamide [(S,R,R)-5]: Column chromatography (SiO2;
hexane/EtOAc/CH2Cl2, 83:14:3) afforded pure (S,R,R)-5 (30 mg,
32%). M.p. 118–120 °C (hexane). [α]D = +29.5 (c = 0.75 in CHCl3,
90% ee). 1H NMR (300 MHz, CDCl3): δ = 7.81–7.41 (m, 2 H, Ar),
7.10–6.95 (m, 7 H, Ar), 6.18 (d, J = 10.2 Hz, 1 H, CH), 4.77 (dd,
J = 10.2, 4.4 Hz, 1 H, CH), 2.58 (dd, J = 8.6, 4.3 Hz, 1 H, CH),
2.34–2.13 (m, 2 H, CH2), 2.28 (s, 3 H, CH3), 2.08–1.85 (m, 3 H,
CH + CH2), 1.78–1.62 (m, 2 H, CH2), 1.61–1.43 (m, 2 H, CH2),
0.91 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 213.4 (CO), 142.6 (qC-SO2), 139.6 (qC-Ph), 138.1 (qC-CH3),
ν = 3249 (m, N–H), 1704 (s, C=O), 1333 (s), 1184 (s, SO ) cm–1.
˜
2
129.0 (CH), 128.0 (CH), 126.9 (CH), 126.8 (CH), 126.7 (CH), 61.4 (S,R,R)-N-[(2-Isobutyl-6-oxocyclohexyl)(phenyl)methyl]-4-methyl-
(CH), 55.7 (CH), 42.3 (CH2), 42.0 (CH), 28.5 (CH2), 25.7 (CH2), benzenesulfonamide [(S,R,S)-7]: Column chromatography (SiO2;
25.3 (CH2), 21.3 (CH3),10.0 (CH3) ppm. C22H27NO3S (385.52):
calcd. C 68.54, H 7.06, N 3.63; found C 68.52, H 7.30, N 3.53.
hexane/EtOAc/CH2Cl2, 83:14:3 and CH2Cl2 with 5% MeOH) af-
forded pure (S,R,R)-7 (14 mg, 14%). M.p. 163–165 °C (heptane).
Eur. J. Org. Chem. 2010, 5666–5671
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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