General flow procedure for 3a,3c–m
145.33, 148.38; IR: n 2938.9(w), 1542.3(s), 1455.3(w), 1369.3(m),
1344.6(s), 1280.3(w), 1163.6(s), 1129.5(m), 1099.8(w), 1059.6(m),
934.5(s), 869.2, 856.8(w), 823.8(m), 804.9, 751.7, 720(s), 671.5(w).
HRMS (ESI) m/z calculated for C12H17N2O4S: 285.0909, found:
285.0907.
Solution A, containing 1a, 1c–m (1 mmol), SO2–MeCN (1.2 mL,
7.9 M, 9.5 equiv.) and BTEAC (1 mmol) in MeCN (4.8 mL) was
flowed at 0.3 mL min-1 and mixed in a T-piece with Solution
C, containing CuCl2 (0.25 mmol), ethylene glycol (2 mmol) in
MeCN (2.0 mL) (solution previously sonicated) at 0.1 mL min-1.
Shortly after, Solution B was flowed at 0.3 ml min-1, containing the
tBuONO (3 mmol) in MeCN (6.0 mL) and mixed in a 2nd T-piece
with the main stream. The combined mixture was flowed into a
10 mL coil reactor submerged in an ice/water bath, followed by
a 5 mL coil reactor at room temperature. The two T-pieces were
also submerged in an ice/water bath and the system was fitted
with a 100 psi back pressure regulator. The collected stream was
concentrated under reduced pressure and the residue partitioned
between H2O (3 mL) and DCM (8 mL). Piperidine or morpholine
(3 mmol) was added to the organic layer and stirred at room
temperature for 20 min. Excess of quadrapure-DMA resin was
added, stirred and filtrated. The resin was washed with 90 : 10
DCM–MeOH to completely elute the product. Combined filtrates
were concentrated under reduced pressure to yield a solid. It was
purified with 12 g silica biotage cartridge and an appropriate
EtOAc–Hexane gradient.
1-(3,5-Bis-trifluoromethyl-benzenesulfonyl)-piperidine
(3f).
1
Yield: 71%. H NMR (400 MHz, CDCl3): d ppm 1.48 (m, 2H),
1.67 (m, 4H), 3.06 (m, 4H), 8.08 (s, 1H), 8.18 (s, 2H); 13C NMR
(400 MHz, CDCl3): d ppm 23.29, 25.12, 46.87, 122.53 (q, J =
34.35, CF3), 126.07, 127.62, 132.93 (q, J = 273.62, C-CF3),
140.04; IR: n 2949.1, 1626.1, 1474.8 (w), 1363.8, 1347.6 (m),
1320.2(w), 1280.0(s), 1215.0(w), 1169.7, 1152.6, 1130, 1105.1(s),
1055.6(m), 1027.2(w), 936.8, 902.4(s), 862.6(w), 843.6(m), 730.8,
704.7, 696.4(m), 681.8(s). HRMS (ESI) m/z calculated for
C13H14NO2F6S: 362.0649, found: 362.0638.
1
1-(3-Ethynyl-benzenesulfonyl)-piperidine (3g). Yield: 42%. H
NMR (400 MHz, CDCl3): d ppm 1.41 (m, 2H), 1.62 (m, 4H),
2.98 (m, 4H), 3.18(s, 1H), 7.48 (m, 1H), 7.68 (m, 1H), 7.84(s,
1H); 13C NMR (400 MHz, CDCl3): d ppm 23.46, 25.17, 46.96,
79.48, 81.86, 123.44, 127.67, 129.05, 130.99, 135.90, 137.00; IR: n
3276.6(m), 3068.3(w), 2933.1(m), 2868.2(w), 2111.7, 1717.0(w),
1471.0(m), 1440.0, 1410.0(m), 1388.8, 1366.6(w), 1352.8(m),
1338.3 (s), 1325.9, 1307.0, 1287.1(m), 1262.2(w), 1206.2(m),
1158.5, 1146.8(s), 1090.1, 1050.7(s), 1027.2(m), 996.0, 964.5(w),
725.0(s), 856.4(m), 833.5(w), 800.1(s), 727.9, 687.5, 668.2(s).
HRMS (ESI) m/z calculated for C13H16NO2S: 250.0902, found:
251.0892.
4-(Piperidine-1-sulfonyl)-benzonitrile (3a¢). See general flow
procedure. Yield: 83%; 1H NMR (400 MHz, CDCl3): d 1.41
(m, 2H), 1.60 (m, 4H), 2.99 (m, 4H), 7.82 (m, 4H); 13C NMR
(400 MHz, CDCl3): d 23.36, 25.14, 46.91, 116.29, 117.38, 128.17,
132.87, 141.08; IR: n 3091.1, 29.34.2, 2868.3, 2237.85(w), 1491.0,
1471.4, 1441.4, 1389.1, 1366.9, 1352.8(w), 1338.2 (s), 1325.9,
1313.2(m), 1280.9, 1209.0(w), 1185.8(m), 1165.0 (s), 1092.1 (m),
1051.7, 1027.2, 1019.2, 964.9(w), 928.0(s), 856.85(m), 842.8(s),
804.8, 785.2(w), 728.4, 715.0(m). HRMS (ESI) m/z calculated
for C10H15N2O2S: 251.0854, found: 251.0842.
5-Chloro-2-(piperidine-1-sulfonyl)-benzoic acid methyl ester (3h).
Yield: 69%. 1H NMR (400 MHz, CDCl3): d ppm 1.47 (m,
2H), 1.60 (m, 4H), 3.13 (m, 4H), 3.91 (s, 3H), 7.43 (d, J =
1.83 Hz, 1H), 7.50 (m, J = 1.83, 8.42, 1H), 7.72 (d, J = 8.42,
1H); 13C NMR (400 MHz, CDCl3): d ppm 23.57, 25.37, 46.78,
53.28, 128.40, 130.15, 130.57, 134.11, 135.06, 138.60, 167.10;
IR: n 3666.0(w), 2984.9(m), 2856.8, 2207.7(w), 1731.8(s), 1586.2,
1557.7(w), 1452.3(w), 1433.9(m), 1383.7(w), 1360.8(m), 1342.2,
1291.2, 1258.8(s), 1218.5(w), 1165.9(s), 1144.4(m), 1120.0, 1104.7,
1055.6, 1045.77(s), 1024.2, 966.9(m), 934.5(s), 891.5, 854.3(w),
827.7, 765.0(s), 731.9(m), 705.1(s), 668.1(w). HRMS (ESI) m/z
calculated for C13H16NO4NaSCl: 340.0386, found: 340.0388.
1-(5-Fluoro-2-methyl-benzenesulfonyl)-piperidine (3c). Yield:
77%; 1H NMR (400 MHz, CDCl3): d ppm 1.51 (m, 2H), 1.59 (m,
4H), 2.55 (s, 3H), 3.13 (m, 4H), 7.12 (m, 1H), 7.25 (m, 1H), 7.57
(m, 1H); 13C NMR (400 MHz, CDCl3): d ppm 19.82, 23.71, 25.41,
46.15, 116.93, 119.33, 133.49, 134.20, 138.01, 159.04, 161.50; IR:
n 2940.8, 2856.7, 1605.1(w), 1484.3(m), 1453.1, 1390.9, 1357.7(s),
1321.9, 1269.4, 1226.6(m), 1183.3(w), 1162.9, 1145.6(s), 1105.6(w),
1056.6 (m), 1026.2 (w), 930.1(s), 900.7, 885.6(m), 857.5(w),
822.9(m), 747.9(w), 720(s), 698.7(m), 683.5(s). HRMS (ESI) m/z
calculated for C12H17NO2FS: 258.0964, found: 258.0952.
2-Methyl-6-(piperidine-1-sulfonyl)-benzonitrile
(3i). Yield:
80%. 1H NMR (400 MHz, CDCl3): d ppm 1.46 (m, 2H), 1.59 (m,
4H), 2.60 (s, 3H), 3.17 (m, 4H), 7.56 (m, 2H), 7.79 (d, J = 7.69,
1H); 13C NMR (400 MHz, CDCl3): d ppm 21.13, 23.54, 25.26,
46.76, 110.58, 115.17, 127.81, 132.22, 134.10, 140.80, 145.37;
IR: n 2948.3(m), 2853.2, 2226.4, 1657.4, 1589.0, 1466.1(w),
1445.1(m), 1361.8, 1344.2(s), 1326.6, 1310.6, 1276.1, 1199.0(m),
1181.1, 1167.0, 1133.1(s), 1097.1, 1068.7(w), 1053.8(s), 1029.1(m),
930.0(s), 911.8, 864.2(m), 841.5(w), 791.5, 783.1 (m), 731.2,
715.0(s), 668.2. HRMS (ESI) m/z calculated for C13H17N2O2S:
265.1011, found: 265.1018.
3-(Morpholine-4-sulfonyl)-benzonitrile (3d). Yield: 72%; 1H
NMR (400 MHz, CDCl3): d ppm 3.20 (m, 4H), 3.72 (m, 4H), 7.75
(m, 1 H), 7.88 (m, 1 H), 7.99 (m, 1H); 13C NMR (400 MHz, CDCl3):
d ppm 45.90, 66.13, 111.06, 116.27, 130.51, 133.12, 133.14,
135.76, 139.38; IR: n 2971.5, 2233.9, 1473.8, 1447.9, 1434.9(w),
1353.0(s), 1297.6(m), 1263.2(s), 1176.3, 1163.4(s), 1133.6(m),
1150.0(s), 1078.8(m), 946.2(s), 924.6, 851.8(w), 784.5(s), 732.2,
720.3(s), 668.3(w). HRMS (ESI) m/z calculated for C11H13N2O3S:
253.0647, found: 253.0636.
2-Methyl-5-(piperidine-1-sulfonyl)-benzonitrile
(3j). Yield:
1-(4-Methyl-2-nitro-benzenesulfonyl)-piperidine (3e). Yield:
90%. 1H NMR (400 MHz, CDCl3): d ppm 1.47 (m, 2 H), 1.58 (m,
4 H), 2.43 (s, 3H), 3.17 (m, 4 H), 7.33 (s, 1H), 7.43 (d, J = 8.42 Hz,
1H), 7.75 (d, J = 8.42 Hz, 1H); 13C NMR (400 MHz, CDCl3):
d ppm 21.20, 23.54, 25.40, 46.76, 124.23, 128.32, 130.65, 132.02,
61%. 1H NMR (400 MHz, CDCl3): d ppm 1.40 (m, 2H), 1.60 (m,
4H), 2.59 (s, 3H), 2.66 (m, 4H), 7.48 (d, J = 8.42, 1H), 7.79 (d,
J = 8.42, 1H), 7.92 (s, 1H); 13C NMR (400 MHz, CDCl3): d ppm
20.66, 23.37, 25.11, 46.92, 113.90, 116.56, 131.17, 131.33, 131.49,
135.43, 146.72; IR: n 2933.3(s), 2867.6, 2229.0(w), 1654.5(m),
5330 | Org. Biomol. Chem., 2010, 8, 5324–5332
This journal is
The Royal Society of Chemistry 2010
©