JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
995
3.44 (s, 2H), 2.40 (m, 4H) ppm. 13C NMR (CDCl3): d 152.6, 148.7, HRMS (ESI) m/z calculated for C24H33N2O5S [(M þ H)þ] 461.2110,
found 461.2095.
139.2, 135.0, 130.2, 129.2, 129.0, 128.8, 128.4, 127.8, 127.5, 121.4,
110.4, 110.4, 66.9, 63.0, 56.2, 56.01, 54.4, 53.5 ppm. HRMS (ESI) m/z
calculated for C26H31N2O5S [(M þ H)þ] 483.1954, found 483.1956.
N-Cyclobutyl-3,4-dimethoxy-N-(4-morpholinobenzyl)benzenesulfo-
namide (4d). Yield: 70%. 1H NMR (CDCl3): d 7.41 (dd, J ¼ 8, 2 Hz,
1H), 7.25–7.21 (m, 3H), 6.92 (d, J ¼ 9 Hz, 1H), 6.86 (d, J ¼ 9, 2H),
4.32 (s, 2H), 4.20 (quintet, J ¼ 8 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H),
3.86–3.46 (m, 4H), 3.15–3.12 (m, 4H), 2.02–1.90 (m, 4H), 1.54–1.45
(m, 2H) ppm. 13C NMR (CDCl3): d 152.4, 150.4, 149.0 132.2, 129.8,
128.2, 120.9, 115.6, 110.6, 109.7, 66.9, 56.2, 56.1, 52.9, 49.4, 48.0,
29.7, 29.3, 15.1 ppm. HRMS (ESI) m/z calculated for C23H31O5N2S
[(M þ H)þ]: 446.1948, found 447.1949.
3,4-Dimethoxy-N-(3-(morpholinomethyl)benzyl)-N-phenylbenzene-
sulfonamide (3b). Yield: 64%. H NMR (CDCl3): d 7.36–7.31 (m, 2H),
1
7.17–7.09 (m, 7H), 6.98–6.91 (m, 4H), 4.69 (s, 2H), 3.95 (s, 3H), 3.73
(s, 3H), 3.63 (t, J ¼ 4 Hz, 4H), 3.39–3.37 (m, 2H), 2.27 (m, 4H) ppm.
13C NMR (CDCl3): d 152.7, 148.8, 139.1, 137.8, 135.9, 130.1, 129.6,
129.1, 128.8, 128.6, 128.4, 127.8, 127.6, 121.5, 110.5, 67.0, 63.2,
56.3, 56.2, 54.5, 53.5, 48.5 ppm. HRMS (ESI) m/z calculated for
C26H31N2O5S [(M þ H)þ] 483.1948, found 483.1928.
N-((2,2-Dimethyl-2H-chromen-6-yl)methyl)-3,4-dimethoxy-N-(2-mor-
pholinoethyl)benzenesulfonamide (5a). Yield: 49%. 1H NMR
(CDCl3): d 7.45 (d, J ¼ 8 Hz, 1H), 6.93 (t, J ¼ 9 Hz, 2H), 6.88–6.85 (m,
1H), 6.67 (d, J ¼ 8 Hz, 1H), 6.22 (d, J ¼ 10 Hz, 1H), 5.59 (d, J ¼ 7 Hz,
1H), 4.23 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.59–3.56 (m, 4H), 3.19 (t,
J ¼ 7 Hz, 2H), 2.30 (t, J ¼ 7 Hz, 2H), 2.25 (s, 4H), 1.23 (s, 6H) ppm.
13C NMR (CDCl3): d 152.7, 152.5, 149.1, 131.8, 131.3, 129.1, 128.3,
126.5, 122.0, 121.4, 121.0, 116.3, 110.6, 109.8, 66.8, 57.3, 57.3, 56.3,
56.2, 53.6, 52.2, 44.4, 27.9 ppm. HRMS (ESI) m/z calculated for
C26H35N2O6S [(M þ H)þ] 503.2210, found 503.2204.
3,4-Dimethoxy-N-(2-(morpholinomethyl)benzyl)-N-phenylbenzene-
sulfonamide (3c). Yield: 47%. 1H NMR (CDCl3): d 7.36 (d, J ¼ 8 Hz,
1H), 7.21–7.18 (m, 4H), 7.10–7.09 (m, 3H), 7.03–7.01 (m, 2H),
6.95–6.93 (m, 2H), 4.97 (s, 2H), 3.97 (s, 3H), 3.75 (s, 3H), 3.62 (m,
4H), 3.48 (s, 2H), 2.35 (m, 4H) ppm. 13C NMR (CDCl3): d 152.7,
148.8, 139.5, 136.1, 135.2, 130.8, 130.2, 129.7, 128.9, 128.8, 127.8,
127.4, 127.3, 121.7, 110.7, 110.5, 67.2, 61.1, 56.3, 56.2, 53.6, 51.3,
31.0, 30.8, 13.6 ppm. HRMS (ESI) m/z calculated for C26H31N2O5S
[(M þ H)þ] 483.1948, found 483.1941.
N-((2,2-Dimethyl-2H-chromen-6-yl)methyl)-3,4-dimethoxy-N-(3-mor-
pholinopropyl)benzenesulfonamide (5b). Yield: 15%. 1H NMR
(CDCl3): d 7.43 (d, J ¼ 8 Hz, 1H) 6.97 (d, J ¼ 8 Hz, 1H), 6.94 (d,
J ¼ 8 Hz, 1H), 6.87 (s, 1H), 6.68 (d, J ¼ 8 Hz, 1H), 6.23 (d, J ¼ 10 Hz,
1H), 4.19 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.60 (s, 4H), 3.12 (t, J ¼ 8,
2H), 2.22 (s, 4H), 2.18 (t, J ¼ 7, 2H), 1.59–1.52 (m, 2H), 1.40 (s, 6H)
ppm. 13C NMR (CDCl3): d 152.7, 152.4, 149.1, 131.6, 131.3, 129.3,
128.4, 126.5, 121.9, 121.3, 121.0, 116.3, 110.6, 109.8, 66.9, 56.3,
56.2, 55.9, 53.4, 52.0, 46.2, 28.0, 25.4 ppm. HRMS (ESI) m/z calcu-
lated for C27H37N2O6S [(M þ H)þ] 517. 2367, found 517.2366.
3,4-Dimethoxy-N-(4-morpholinobenzyl)-N-phenylbenzenesulfona-
1
mide (3d). Yield: 40%. H NMR (CDCl3): d 7.35 (d, J ¼ 8 Hz, 1H), 7.21
(m, 3H), 7.12 (d, J ¼ 7 Hz, 2H), 7.01–6.93 (m, 4H), 6.76 (d, J ¼ 7 Hz,
2H), 4.65 (s, 2H), 3.97 (s, 3H), 3.84–3.83 (m, 4H), 3.77 (s, 3H),
3.11–3.10 (m, 4H) ppm. 13C NMR (CDCl3): d 152.5, 150.5, 148.7,
139.2, 130.3, 129.6, 129.1, 128.7, 127.7, 127.1, 121.4, 115.3, 110.4,
66.8, 56.2, 56.1, 54.1, 49.1 ppm. HRMS (ESI) m/z calculated for
C25H29N2O5S [(M þ H)þ] 469.1797, found 469.1796.
N-Cyclobutyl-3,4-dimethoxy-N-(4-(morpholinomethyl)benzyl)benze-
nesulfonamide (4a). Yield: 46%. 1H NMR (CDCl3): d 7.43 (dd, J ¼ 8,
2 Hz, 1H), 7.34–7.25 (m, 5H), 6.94 (d, J ¼ 9 Hz, 1H), 4.39 (s, 2H), 4.27
(quintet, J ¼ 9 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.75–3.72 (m, 4H),
3.51 (s, 2H), 2.46 (s, 4H), 1.99–1.94 (m, 4H), 1.57–1.52 (m, 2H) ppm.
13C NMR (CDCl3): d 152.4, 149.0, 137.8, 132.0, 129.4, 127.0, 120.9,
110.6, 109.8, 66.9, 63.0, 56.2, 56.2, 53.5, 52.9, 48.2, 29.2, 15.0 ppm.
HRMS (ESI) m/z calculated for C24H33N2O5S [(M þ H)þ] 461.2110,
found 461.2102.
Typical procedure for sulfonylation with 4-morpholinosulfonyl
chloride (6a–b)
Amine (1 equivalent) was dissolved in dichloroethane. Pyridine (3
equivalents) and 4-morpholinosulfonyl chloride (1.3 equivalents)
were added. The reaction was refluxed for 2 days, then concen-
trated, taken up in ethyl acetate, washed with saturated NH4Cl
and brine, then dried over MgSO4, and concentrated. The residue
was then purified by column chromatography in 4:1 hexane/ethyl
acetate.
N-Cyclobutyl-3,4-dimethoxy-N-(3-(morpholinomethyl)benzyl)benze-
1
nesulfonamide (4 b). Yield: 81%. H NMR (CDCl3): d 7.43 (dd, J ¼ 8,
2 Hz, 1H), 7.30–7.21 (m, 5H), 6.95–6.93 (d, J ¼ 8 Hz, 1H), 4.39 (s, 2H),
4.28 (quintet, J ¼ 8 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.71 (t,
J ¼ 4 Hz, 4H), 3.49 (s, 2H), 2.43 (s, 4H), 1.99–1.92 (m, 4H), 1.55–1.48
(m, 2H) ppm. 13C NMR (CDCl3): d 152.4, 149.0, 138.7, 137.9, 131.9,
128.4, 128.1, 127.8, 126.0, 120.9, 110.5, 109.7, 67.0, 63.3, 56.2, 56.2,
53.6, 52.9, 48.3, 29.2, 15.0 ppm. HRMS (ESI) m/z calculated for
C24H33N2O5S [(M þ H)þ] 461.2110, found 461.2112.
N-((2,2-Dimethyl-2H-chromen-6-yl)methyl)-N-phenylmorpholine-4-
1
sulfonamide (6a). Yield: 17%. H NMR (CDCl3): d 7.32–7.25 (m, 5H),
6.90 (d, J ¼ 8 Hz, 1H), 6.83 (s, 1H), 6.65 (d, J ¼8 Hz, 1H), 6.25 (d,
J ¼ 10 Hz, 1H), 5.60 (d, J ¼ 10 Hz, 1H), 4.70 (s, 2H), 3.63–3.62 (m,
4H), 3.17 (m, 4H), 1.42 (s, 6H) ppm. 13C NMR (CDCl3): d 131.0,
129.6, 129.2, 129.1, 127.9, 126.9, 122.1, 116.2, 66.3, 56.3, 46.5,
28.0 ppm. HRMS (ESI) m/z calculated for C22H27N2O4S [(M þ H)þ]
415.1692, found 415.1695.
N-Cyclobutyl-3,4-dimethoxy-N-(2-(morpholinomethyl)benzyl)benze-
1
N-Cyclobutyl-N-((2,2-dimethyl-2H-chromen-6-yl)methyl)morpholine-
4-sulfonamide (6b). Yield: 16%. 1H NMR (CDCl3): d 7.04 (dd, J ¼ 8,
2 Hz, 1H), 6.95 (s, 1H), 6.72 (d, J ¼ 8 Hz, 1H), 6.30 (d, J ¼ 10 Hz, 1H),
5.61 (d, J ¼ 10 Hz, 1H), 4.35 (s, 2H), 4.19 (quintet, J ¼ 8 Hz, 1H), 3.63
(t, J ¼ 5 Hz, 4H), 3.09 (t, J ¼ 5 Hz, 4H), 2.13 – 2.06 (m, 4H), 1.60 (m,
nesulfonamide (4c). Yield: 63%. H NMR (CDCl3): d 7.56 (d, J ¼ 8 Hz,
1H), 7.47 (dd, J ¼ 8, 2 Hz, 1H), 7.31–7.27 (m, 2H), 7.17 (d, J ¼ 7 Hz,
1H), 6.95 (d, J ¼ 8 Hz, 1H), 4.68 (s, 2H), 4.45 (quintet, J ¼ 8 Hz, 1H),
3.96 (s, 3H), 3.92 (s, 3H), 3.65 (m, 4H), 3.50 (bs, 2H), 2.42 (bs, 4H),
1.93–1.90 (m, 4H), 1.56–1.50 (m, 2H) ppm. 13C NMR (CDCl3): d
152.4, 149.0, 138.4, 133.4, 132.1, 130.6, 128.0, 127.4, 126.4, 121.0, 2H), 1.41 (s, 6H) ppm. 13C NMR (CDCl3): d 152.4, 131.2, 130.6,
110.5, 109.7, 67.1, 61.6, 56.3, 56.2, 53.5, 52.7, 44.5, 29.0, 15.1 ppm. 128.2, 125.5, 122.4, 121.4, 116.4, 76.4, 66.4, 53.0, 48.8, 46.2, 29.6,