J.R. Fulton et al. / Tetrahedron 65 (2009) 9134–9141
9139
2-oxide 11 to give 12m as an oil (8.04 g, 73%); [
a
]
D ꢀ7.3 (c 1, CHCl3);
solution and extracted with EtOAc. The combined organic phases
were washed with brine, dried (Na2SO4), and concentrated to afford
the crude sulfinamide, which was purified by chromatography
(eluent 1:1 EtOAc/hexane to 100% EtOAc gradient) to afford the
product.
ymax (thin film/cmꢀ1) 3234, 3064, 2976, 2935, 1599, 1496, 1453,
1380, 1334, 1185, 1164, 1107, 1000, 944, 816, 738, 703, 666; dH
(300 MHz, CDCl3) 7.80 (2H, d, J¼8.3 Hz, H-20, H-60), 7.21–7.19 (5H,
m, ArH), 7.00 (2H, d, J¼7.2 Hz, H-200, H-600-Ph), 5.94 (1H, d, J¼8.5 Hz,
H-1), 3.94 (2H, septet, J¼6.9 Hz, H-2%, H-5%), 3.45–3.39 (1H, m, H-
2), 2.37 (3H, s, CH3-Tol), 1.26–1.05 (12H, m, 4ꢂCH3 of i-Pr), 0.90 (3H,
d, J¼6.8 Hz, CH3); dC (CDCl3, 75 MHz) 143.6, 138.9, 138.6, 130.1,
128.7, 128.2, 127.7, 126.0, 79.2, 54.8, 44.0, 23.6, 22.0, 14.6; HRMS (EI)
found: [MþNa]þ 475.1669. C22H32N2O4S2Na requires [MþNa]þ
475.1696.
4.4.1. (R)-4-(Phenylsulfinyl)morpholine 10d29,30. General procedure
C was performed on a 2.65 mmol scale of morpholinesulfinamic acid
(12d) using phenylmagnesium bromide to give (R)-4-(phenyl-
sulfinyl)morpholine (10d) as a crystalline solid (208 mg, 37%);
mp¼84–86 ꢁC; [
a
]
ꢀ75.8 (c 1, CHCl3); ymax (thin film/cmꢀ1) 3055,
D
2859, 1445, 1266, 1113, 922, 738; dH (300 MHz, CDCl3) 7.54–7.44 (2H,
M, H-2, H-6), 7.32–7.21 (3H, m, H-3, H-4, H-5), 3.58–3.37 (4H, m, 2ꢂH-
20, 2ꢂH-30), 3.01–2.84 (2H, m, 2ꢂH-10), 2.77–2.64 (2H, m, 2ꢂH-40); dC
(CDCl3, 75 MHz) 142.7, 131.7, 129.3, 67.3, 46.2; HRMS (EI) found:
[MþNa]þ 234.0559. C10H13NO2SNa requires [MþNa]þ 234.0547.
4.3. General procedure B: synthesis of sulfinamides from
Andersen’s sulfinate
nBuLi (2.5 M in hexane; 1.05 equiv) was added dropwise to
a solution of amine (1.05 equiv) in THF (0.5 M) at 0 ꢁC. The mixture
was stirred for 1 h and was added slowly to a solution of (1R,2S,5R)-
(þ)-menthyl (S)-p-toluenesulfinate 8 (1.0 equiv) in THF (1.1 M) at
ꢀ78 ꢁC. The mixture was stirred for 3 h and was warmed to rt
overnight. The reaction was poured into saturated aqueous NaHCO3
solution and extracted with EtOAc. The combined organic phases
were washed with brine, dried (Na2SO4) and concentrated to afford
the crude product, which was purified by chromatography (eluent
1:3 EtOAc/hexane) to afford the desired compound.
4.4.2. (R)-4-(Ethylsulfinyl)morpholine 10e31. General procedure C
was performed on a 3.79 mmol scale of sulfinamic acid derivative 12d
using ethylmagnesium chloride to give (R)-4-(ethylsulfinyl)morpho-
line(10e)asanoil(0.24 g, 38%);[
a
]D ꢀ12.5 (c1, CHCl3);ymax (thin film/
cmꢀ1) 2923, 2856, 2762, 2498, 1955, 1721, 1646, 1455, 1379, 1290,
1259, 1156, 1025, 920, 846, 753, 697; dH (300 MHz, CDCl3) 3.78–3.71
(4H, m, 2ꢂH-20, 2ꢂH-30), 3.19–3.01 (4H, m, 2ꢂH-10, 2ꢂH-40), 2.77 (2H,
q, J¼7.6 Hz, 2ꢂH-1), 1.18 (3H, t, J¼7.6 Hz, CH3); dC (CDCl3, 75 MHz)
67.2, 46.0, 45.1, 8.3; LRMS: m/z 163 [M]þ, 134, 86, 77.
4.3.1. (S)-N,N-Diethyl-p-toluenesulfinamide 10a26,27. General pro-
cedure B was performed on a 17.05 mmol scale of sulfinate 8 using
diethylamine to give (S)-N,N-diethyl-p-toluenesulfinamide (10a) as
4.4.3. (R)-4-(Isopropylsulfinyl)morpholine 10f32. General procedure
C was performed on a 2.40 mmol scale of sulfinamic acid derivative
12d using isopropylmagnesium chloride to give (R)-4-(iso-
an oil (2.76 g, 77%); [
a
]
þ77.3 (c 1, CHCl3); ymax (thin film/cmꢀ1
)
D
3052, 2974, 2872, 1596, 1490, 1381, 1175, 1087, 1009, 898, 814, 734;
dH (300 MHz, CDCl3) 7.31 (2H, d, J¼8.1 Hz, H-2, H-6), 7.07 (2H, d,
J¼7.9 Hz, H-3, H-5), 2.90 (4H, q, J¼7.2 Hz, 2ꢂH-10, 2ꢂH-30), 2.20 (3H,
s, CH3-Tol), 0.91 (6H, t, J¼7.2 Hz, 2ꢂCH3); dC (CDCl3, 75 MHz) 141.5,
141.2, 129.8, 126.6, 42.3, 21.7, 14.8; LRMS: m/z 211 [M]þ, 139, 72.
propylsulfinyl)morpholine (10f) as an oil (0.34 g, 81%); [
a
]
D ꢀ80.1 (c
1, CHCl3); ymax (thin film/cmꢀ1) 3053, 2971, 2504, 1645, 1368, 1266,
1162, 1113, 1045, 924, 738, 703; dH (300 MHz, CDCl3) 3.71 (4H, t,
J¼4.3 Hz, 2ꢂH-20, 2ꢂH-60), 3.15–3.02 (4H, m, 2ꢂH-30, 2ꢂH-50), 2.88
(1H, septet, J¼7.0 Hz, H-2), 1.25 (3H, d, J¼7.0 Hz, CH3), 1.09 (3H, d,
J¼7.0 Hz, CH3); dC (CDCl3, 75 MHz) 67.3, 51.2, 46.5, 17.3; LRMS: m/z
177 [M]þ, 134, 43.
4.3.2. (S)-4-N,N-Diisopropyl-p-toluenesulfinamide 10b26. General
procedure B was performed on a 2.82 mmol scale of sulfinate 8
using diisopropylamine to give (S)-4-N,N-diisopropyl-p-toluene-
4.4.4. (R)-4-(tert-Butylsulfinyl)morpholine 10g29. General pro-
cedure C was performed on a 3.15 mmol scale of sulfinamic acid
derivative 12d using tert-butylmagnesium chloride to give (R)-4-
(tert-butylsulfinyl)morpholine (10g) as a white crystalline solid
sulfinamide (10b) as an oil (647 mg, 96%); [
a]
þ77.6 (c 1, CHCl3);
D
ymax (thin film/cmꢀ1) 2855, 1595, 1491, 1459, 1365, 1304, 1176, 1122,
1057, 1018, 949, 868, 817, 666; dH (300 MHz, CDCl3) 7.44 (2H, d,
J¼8.1 Hz, H-2, H-6), 7.21 (2H, d, J¼7.9 Hz, H-3, H-5), 3.48 (2H, septet,
J¼6.8 Hz, H-20, H-50), 2.33 (3H, s, CH3-Tol), 1.34 (6H, d, J¼6.8 Hz,
2ꢂCH3), 1.03 (6H, d, J¼6.8 Hz, 2ꢂCH3); dC (CDCl3, 75 MHz) 141.9
(CAr), 140.7 (CAr), 129.3 (CHAr), 126.9 (CHAr), 46.9 (CH), 24.3 (CH3),
21.7 (CH3); LRMS: m/z 239 [M]þ, 148, 91.
(0.43 g, 72%); mp¼78–80 ꢁC; [
D ꢀ14.5 (c 1, CHCl3); ymax (thin film/
a
]
cmꢀ1) 3055, 2986, 2306, 1422, 1267, 1112, 1071, 913, 896, 739; dH
(300 MHz, CDCl3) 3.68–3.56 (4H, m, 2ꢂH-20, 2ꢂH-30), 3.15–3.00
(4H, m, 2ꢂH-10, 2ꢂH-40), 1.13 (9H, s, t-Bu); dC (CDCl3, 75 MHz) 67.1,
58.6, 47.3, 23.0; HRMS (EI) found: [MþNa]þ 214.0872. C8H17NO2SNa
requires [MþNa]þ 214.0864.
4.3.3. (S)-4-(p-Toluenesulfinyl)morpholine 10c28. General procedure
B was performed on a 13.58 mmol scale of sulfinate 8 using mor-
pholine to give (S)-4-(p-toluenesulfinyl)morpholine (10c) as an oil
4.4.5. (R)-N,N-Diethylbenzenesulfinamide 10h29,33. General pro-
cedure C was performed on a 1.75 mmol scale of sulfinamic acid
derivative 12h using phenylmagnesium chloride to give (R)-N,N-
(730 mg, 24%); mp 108–110 ꢁC; [
a
]D ꢀ2.6 (c 1, CHCl3); ymax (thin film/
cmꢀ1) 2955, 2853, 1592, 1451, 1377, 1285, 1259, 1110, 1088, 1068,
1019, 905, 819, 709, 695; dH (300 MHz, CDCl3) 7.43 (2H, d, J¼8.1 Hz,
H-2, H-6), 7.23 (2H, d, J¼8.1 Hz, H-3, H-5), 3.67–3.56 (4H, m, 2ꢂH-20,
2ꢂH-6), 3.08–3.00 (2H, m, 2ꢂH-5), 2.99–2.75 (2H, m, 2ꢂH-3), 2.31
(3H, s, CH3-Tol); dC (CDCl3, 75 MHz) 141.9, 139.5, 130.0, 126.5, 67.3,
46.1, 21.8; LRMS: m/z 255 [M]þ, 139, 86.
diethylbenzenesulfinamide (10h) as an oil (0.32 g, 94%); [
a
]
D ꢀ88.1
(c 1, CHCl3); ymax (thin film/cmꢀ1) 3163, 3061, 2931, 2872, 1599,
1445, 1380, 1289, 1167, 1060, 1009, 900, 690, 665; dH (300 MHz,
CDCl3) 7.58 (2H, d, J¼6.2 Hz, CHAr), 7.41 (3H, d, J¼7.2 Hz, CHAr), 3.16
(4H, q, J¼7.2 Hz, 2ꢂCH2), 1.05 (6H, t, J¼7.2 Hz, 2ꢂCH3); dC (CDCl3,
75 MHz) 130.9, 128.8, 126.7, 42.4, 14.8; LRMS: m/z 197 [M]þ, 72, 125.
4.4. General procedure C: synthesis of sulfinamides from
sulfinamic acid derivatives
4.4.6. (R)-N,N-Diethylisopropylsulfinamide 10i32. General procedure
C was performed on a 3.89 mmol scale of sulfinamic acid derivative
12h using isopropylmagnesium chloride to give (R)-N,N-diethyl-
Grignard reagent (3.0 M in Et2O; 2.1 equiv) was added dropwise
to a solution of sulfinamic acid (12) (1.0 equiv) in Et2O (0.1 M) at
0 ꢁC. The mixture was stirred for 1 h and was warmed to rt over-
night. The reaction was poured into saturated aqueous NaHCO3
isopropylsulfinamide (10i) as an oil (0.59 g, 93%); [
a
]
ꢀ29.6 (c 1,
D
CHCl3); ymax (thin film/cmꢀ1) 2967, 2870, 1605, 1464, 1381, 1289,
1241, 1175, 1072, 1010, 895, 782, 665; dH (300 MHz, CDCl3) 3.23 (2H,
dq, J¼14.5, 7.3 Hz, 2ꢂH-10), 3.03 (2H, dq, J¼14.2, 7.1 Hz, 2ꢂH-30), 2.80