The Journal of Organic Chemistry
ARTICLE
J1 = 12.0 Hz, J2 = 4.5 Hz, 1H), 2.43 (s, 3H), 2.37ꢀ2.35
(m, 1H), 2.21 (s, 6H), 2.05 (app. d, J = 12.0 Hz, 1H), 1.70 (app. d,
J = 10.0 Hz, 2H), 1.59 (app. d, J = 13.5 Hz, 1H), 1.41ꢀ1.32 (m, 2H),
1.20ꢀ1.09 (m, 2H), 1.07ꢀ0.98 (m, 1H). 13C NMR (125 MHz, CDCl3):
δ 142.9, 137.4, 129.6, 127.2, 68.3, 43.6, 43.5, 32.8, 29.6, 25.8, 24.4, 21.7,
2H), 3.18 (dd, J1 = J2 = 11.5 Hz, 1H), 2.91 (dd, J1 = 12.0 Hz, J2 = 3.5 Hz,
1H), 2.50 (br s, 4H), 2.43 (s, 3H), 2.35ꢀ2.33 (m, 1H), 2.22 (ddd, J1 =
12.5 Hz, J2 = J3 = 3.5 Hz, 1H), 1.72ꢀ1.54 (m, 7H), 1,46 (br s, 2H),
1.42ꢀ1.29 (m, 2H), 1.18ꢀ1.07 (m, 2H), 1.06ꢀ0.96 (m, 1H). 13C NMR
(125 MHz, CDCl3): δ 142.8, 137.6, 129.6, 127.1, 66.7, 51.5, 43.9, 32.5,
30.1, 26.5, 26.1, 24.6, 23.6, 21.7, 20.6. IR (KBr): νmax 3446, 2936, 2919,
2859, 1328, 1315, 1161, 1145, 1096, 661, 567, 550 cmꢀ1. HRMS
(ESIþ): m/z calcd for [C19H30N2O2S þ H]þ: 351.2101, found
351.2104.
Typical Procedure for the Synthesis of Diamides 10bꢀd.
To a solution of (ꢀ)-1 (495 mg, 2.00 mmol) and TEA (310 μL,
2.23 mmol) in CHCl3 (5 mL), ethyl chloroformate (190 μL, 2.00 mmol)
was added dropwise at 0 °C. After completion of addition, the reaction
mixture was allowed to warm to room temperature and stirred for 1 h.
To the reaction mixture, Et2NH (420 μL, 4.06 mmol) was added under
stirring, and stirring was continued for 15 h at room temperature. The
solvents were removed under reduced pressure, and the residue was
diluted by EtOAc (10 mL), and the organic solution was washed with 1 M
HCl aq (10 mL ꢁ 2) and 1 M NaOH aq (10 mL ꢁ 2) and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure,
and the residue was dried in vacuo to give the diamide 10b (339 mg,
1.12 mmol, 56% yield) as a white powder. The diamide was directly used
in the next reaction without further purification.
20.1. IR (KBr): νmax 3445, 2925, 1328, 1163, 1096, 664, 572, 553 cmꢀ1
.
HRMS (ESIþ): m/z calcd for [C16H26N2O2S þ H]þ: 311.1788, found
311.1794.
N-{[(1S,2S)-2-(Diethylamino)cyclohexyl]methyl}-4-methyl-
benzenesulfonamide (3e). The 1,3-sulfonamide 3e (39.8 mg, 0.118
mmol, 24% yield) was obtained as a white powder according to the
typical procedure using 3a (141 mg, 0.500 mmol), K2CO3 (180 mg,
1.30 mmol) and EtI (4.02 mL, 50.0 mmol) under reflux. Mp:
104ꢀ105 °C. [R]2D3 = þ28.3 (c 0.11, CHCl3). 1H NMR (500 MHz,
CDCl3):δ8.66 (br s, 1H), 7.73 (d, J= 7.5 Hz, 2H), 7.29 (d, J= 7.5 Hz, 2H),
3.20 (dd, J1 = J2 = 11.5 Hz, 1H), 2.92 (dd, J1 = 11.5 Hz, J2 = 3.5 Hz,
1H), 2.69 (dq, J1 = 14.0 Hz, 7.0 Hz, 2H), 2.58 (dq, J1 = 13.5 Hz, J2 =
7.0 Hz, 2H), 2.51 (app. d, J = 11.5 Hz, 1H), 2.43 (s, 3H), 2.33ꢀ2.31
(m, 1H), 1.71ꢀ1.66 (m, 2H), 1.55 (app. d, J = 14.0 Hz, 1H),
1.42ꢀ1.33 (m, 2H), 1.21ꢀ1.08 (m, 3H), 0.97 (dd, J1 = J2 = 7.0 Hz,
6H). 13C NMR (125 MHz, CDCl3): δ 142.8, 137.5, 129.6, 127.2,
63.0, 43.7, 41.4, 32.9, 30.0, 26.2, 24.2, 21.7, 20.6, 10.4. IR (KBr): νmax
3444, 2976, 2927, 2867, 1327, 1160, 1092, 823, 661, 563, 553 cmꢀ1
.
HRMS (ESIþ): m/z calcd for [C18H30N2O2S þ H]þ: 339.2101,
N-[(1S,2R)-2-(Diethylcarbamoyl)cyclohexyl]benzamide
(10b). The analytical sample was prepared by purification of the
product on silica gel PTLC (EtOAc/hexane = 1:1). Mp: 117ꢀ118 °C.
[R]2D0 = þ54.0 (c 0.60, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.79
(d, J = 7.6 Hz, 2H), 7.47 (t, J = 6.8 Hz, 1H), 7.42 (dd, J1 = J2 = 7.6 Hz,
2H), 7.24 (br d, J = 4.8 Hz, 1H), 4.24ꢀ4.21 (m, 1H), 3.41ꢀ3.24
(m, 4H), 3.02ꢀ2.99 (m, 1H), 2.52ꢀ2.48 (m, 1H), 1.94 (app. q, J = 9.3
Hz, 1H), 1.68ꢀ1.62 (m, 3H), 1,59ꢀ1.41 (m, 3H), 1.18 (t, J = 6.8 Hz,
3H), 1.05 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.5,
167.3, 135.1, 131.4, 128.7, 127.1, 48.1, 42.3, 40.9, 40.5, 29.4, 26.3,
23.5, 22.1, 15.1, 13.3. IR (KBr): νmax 3377, 2979, 2933, 2874, 1655,
1620, 1489, 1463, 1073, 710, 691 cmꢀ1. HRMS (ESIþ): m/z calcd for
[C18H26N2O2 þ Na]þ 325.1888, found 325.1884.
found 339.2103.
N-{[(1S,2S)-2-(Dipropylamino)cyclohexyl]methyl}-4-me-
thylbenzenesulfonamide (3g). The 1,3-sulfonamide 3g (81.4 mg,
0.222 mmol, 44% yield) was obtained as a white powder according to the
typical procedure using 3a (141 mg, 0.500 mmol), K2CO3 (180 mg,
1.30 mmol) and nPrI (4.86 mL, 50.0 mmol) under reflux. Mp:
74ꢀ75 °C. [R]2D3 = þ11.0 (c 0.17, CHCl3). 1H NMR (500 MHz,
CDCl3):δ8.50 (br s, 1H), 7.73 (d, J= 8.0 Hz, 2H), 7.29 (d, J= 8.0 Hz, 2H),
3.20 (dd, J1 = J2 = 11.3 Hz, 1H), 2.93 (dd, J1 = 11.5 Hz, J2 = 4.5 Hz, 1H),
2.52ꢀ2.44 (m, 4H), 2.43 (s, 3H), 2.32 (ddd, J1 = 7.0 Hz, J2 = J3 = 3.5 Hz,
1H), 1.73ꢀ1.70 (m, 1H), 1.64 (app. d, J = 10.5 Hz, 1H), 1.55 (app. d, J =
13.5 Hz, 1H), 1.49ꢀ1.32 (m, 7H), 1.19ꢀ1.10 (m, 3H), 0.86 (t, J =
7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 142.8, 137.5, 129.6, 127.2,
64.0, 51.4, 43.6, 33.1, 29.9, 26.2, 24.4, 21.6, 20.6, 18.9, 12.0. IR (KBr):
νmax 3279, 2951, 2930, 2869, 2851, 1456, 1426, 1329, 1157, 1092, 1059,
816, 670, 550 cmꢀ1. HRMS (ESIþ): m/z calcd for [C20H34N2O2S þ
H]þ: 367.2414, found 367.2416.
N-[(1S,2R)-2-(Pyrrolidine-1-carbonyl)cyclohexyl]benza-
mide (10c). The diamide 10c (541 mg, 1.80 mmol, 90% yield) was
obtained as a white powder according to the typical procedure using
(ꢀ)-1 (495 mg, 2.00 mmol), TEA (310 μL, 2.23 mmol), ethyl chloro-
formate (190 μL, 2.00 mmol) and pyrrolidine (330 μL, 4.11 mmol).
The analytical sample was prepared by purification of the product on
4-Methyl-N-{[(1S,2S)-2-(pyrrolidin-1-yl)cyclohexyl]me-
thyl}benzenesulfonamide (3h). The 1,3-sulfonamide 3h (150 mg,
0.446 mmol, 89% yield) was obtained as a white powder according to the
typical procedure using 3a (141 mg, 0.500 mmol), K2CO3 (180 mg, 1.30
mmol) and 1,4-diiodobutane (75.5 μL, 0.577 mmol) under reflux. Mp:
silica gel PTLC (EtOAc/hexane = 1:1). Mp: 94ꢀ95 °C. [R]D18
=
þ54.6 (c 0.50, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J =
7.6 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.42 (dd, J1 = J2 = 7.6 Hz, 2H),
7.28 (d, J = 7.2 Hz, 1H), 4.25ꢀ4.20 (m, 1H), 3.54ꢀ3.37 (m, 4H),
2.92ꢀ2.89 (m, 1H), 2.51ꢀ2.48 (m, 1H), 1.98ꢀ1.89 (m, 3H),
1.88ꢀ1.81 (m, 2H), 1.69ꢀ1.53 (m, 4H), 1.49ꢀ1.40 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 172.7, 167.2, 135.0, 131.4, 128.6, 127.1,
47.7, 46.7, 45.9, 43.1, 29.4, 26.3, 25.6, 24.3, 23.4, 22.2. IR (KBr): νmax
3419, 2932, 1646, 1620, 1523, 1486, 1448, 754, 714 cmꢀ1. HRMS
(ESIþ): m/z calcd for [C18H24N2O2 þ Na]þ 323.1730, found
323.1737.
1
118ꢀ119 °C. [R]2D3 = þ16.0 (c 0.38, CHCl3). H NMR (500 MHz,
CDCl3): δ 7.72 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.23 (dd,
J1 = J2 = 11.5 Hz, 1H), 2.97 (dd, J1 = 12.0 Hz, J2 = 5.0 Hz, 1H),
2.62ꢀ2.61 (m, 2H), 2.43 (s, 3H), 2.41ꢀ2.40 (m, 2H), 2.31 (ddd, J1 =
8.0 Hz, J2 = J3 = 4.0 Hz, 1H), 2.24ꢀ2.21 (m, 1H), 1.82ꢀ1.72 (m, 4H),
1.68ꢀ1.66 (m, 2H), 1.56 (app. d, J = 14.0 Hz, 1H), 1.40 (dddd, J1 = J2 =
13.5 Hz, J3 = J4 = 3.0 Hz, 1H), 1.36ꢀ1.33 (m, 1H), 1.25ꢀ1.09 (m, 3H).
13C NMR (125 MHz, CDCl3): δ 142.9, 137.5, 129.6, 127.1, 67.7, 52.0,
43.4, 34.3, 29.2, 25.7, 25.6, 23.1, 21.6, 20.3. IR (KBr): νmax 3445, 2938,
2867, 1320, 1161, 1144, 1092, 822, 661, 568, 553 cmꢀ1. HRMS (ESIþ):
m/z calcd for [C18H28N2O2S þ H]þ: 337.1944, found 337.1945.
4-Methyl-N-{[(1S,2S)-2-(piperidin-1-yl)cyclohexyl]meth-
yl}benzenesulfonamide (3i). The 1,3-sulfonamide 3i (99.1 mg,
0.283 mmol, 57% yield) was obtained as a white powder according to the
typical procedure using 3a (141 mg, 0.500 mmol), K2CO3 (180 mg,
1.30 mmol) and 1,5-diiodopentane (85.5 μL, 0.575 mmol) under reflux.
Mp: 123ꢀ124 °C. [R]2D3 = þ21.1 (c 0.38, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 8.96 (br s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz,
N-[(1S,2R)-2-(Piperidine-1-carbonyl)cyclohexyl]benzamide
(10d). The diamide 10d (610 mg, 1.94 mmol, 97% yield) was obtained as
a white powder according to the typical procedure using (ꢀ)-1 (495 mg,
2.00 mmol), TEA (310 μL, 2.23 mmol), ethyl chloroformate (190 μL,
2.00 mmol) and piperidine (590 μL, 5.97 mmol). The analytical sample
was prepared by purification of the product on silica gel PTLC (EtOAc/
hexane = 1:1). Mp: 76ꢀ77 °C. [R]2D3 = þ42.7 (c 0.11, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.78 (d, J = 7.0 Hz, 2H), 7.48 (tt, J1 = 7.3 Hz, J2 =
1.7 Hz, 1H), 7.43ꢀ7.40 (m, 2H), 7.08 (br d, J = 7.0 Hz, 1H), 4.28ꢀ4.25
(m, 1H), 3.57ꢀ3.46 (m, 2H), 3.43ꢀ3.38 (m, 2H), 3.08 (ddd, J1 = 7.5 Hz,
J2 = J3 = 4.5 Hz, 1H), 2.42ꢀ2.40 (m, 1H), 1.95ꢀ1.91 (m, 1H), 1.71ꢀ1.62
5422
dx.doi.org/10.1021/jo200834n |J. Org. Chem. 2011, 76, 5413–5428