4
M. D’ASCENZIO ET AL.
with water and the aqueous phase was extracted with dichlorome- monitored by TLC. After 5 h the reaction was quenched with water
thane (3 ꢂ 30 mL). The organic layers were reunited, dried over and the aqueous phase was extracted with dichloromethane
sodium sulfate, and concentrated in vacuo to give a crude product (3 ꢂ 30 mL). The organic layers were reunited, dried over sodium
which was purified by column chromatography (EtOAc/n-hexane, sulfate, and concentrated in vacuo to give a crude product which
1:3). The title compound was a white solid (71% yield); mp was purified by column chromatography (EtOAc/n-hexane, 1:1).
76–78 ꢀC; IR ꢀmax 3430 (ꢀ O–H), 3278 (ꢀ N–H), 1317 (ꢀas S¼O), The title compound was a white solid (70% yield); mp 75–76 ꢀC; IR
1160 (ꢀs S¼O), 700 (d Csp2–H) cmꢁ1
;
1H-NMR (400 MHz, CDCl3) d ꢀmax 3454 (ꢀ O–H), 3214 (ꢀ N–H), 2955 (ꢀ Csp3–H), 1319 (ꢀas S¼O),
1
1156 (ꢀs S¼O), 694 (d Csp2-H) cmꢁ1; H-NMR (400 MHz, DMSO-d6) d
2.98 (t, 1H, J ¼ 4.8 Hz, OH, D2O exch.), 4.06 (d, 2H, J ¼ 6.4 Hz, CH2),
4.91 (d, 2H, J ¼ 4.0 Hz, CH2), 6.07 (m, 1H, NH, D2O exch.), 7.24–7.37 4.00 (d, 2H, J ¼ 6 Hz, CH2), 4.87 (d, 2H, J ¼ 5.2 Hz, CH2), 5.42 (bs, 1H,
OH, D2O exch.), 7.20 (bs, 2H, CHAr), 7.38 (bs, 3H, CHAr), 7.59–7.63
(m, 6H, CHAr), 7.42–7.46 (m, 1H, CHAr), 7.82 (d, 1H, J ¼ 7.6 Hz, CHAr);
13C-NMR (101 MHz, CDCl3) d 46.9 (CH2), 63.9 (CH2), 123.9 (C-F, JC-
1
(m, 1H, CHAr), 7.75–7.78 (m, 2H, CHAr), 8.23 (bs, 1H, NH, D2O exch.);
13C-NMR (101 MHz, DMSO-d6) d 45.6 (CH2), 59.9 (CH2), 122.0 (Ar),
¼273.4 Hz, CF3), 124.5 (Ar), 124.6 (Ar), 128.6 (Ar), 129.1 (Ar), 129.7
F
127.0 (Ar), 127.2 (Ar), 127.9 (Ar), 128.5 (Ar), 130.4 (Ar), 130.7 (Ar),
130.8 (Ar), 132.9 (Ar), 137.2 (Ar), 141.2 (Ar), 141.5 (Ar).
(Ar), 130.7 (Ar), 131.3 (Ar), 131.7 (Ar), 133.3 (Ar), 137.4 (Ar), 137.8
(Ar), 138.0 (Ar); 19F-NMR (564.7 MHz, CDCl3) d -60.09 (s, CF3).
2-(Hydroxymethyl)-N-(4-methylbenzyl)benzenesulfonamide (10)
(4-Methylbenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 eq.)
was suspended in 20 mL of anhydrous methanol at room tempera-
ture. An excess of NaBH4 was added portionwise and the reaction
monitored by TLC. After 6 h the reaction was quenched with water
and the aqueous phase was extracted with dichloromethane
(3 ꢂ 30 mL). The organic layers were reunited, dried over sodium
sulfate, and concentrated in vacuo to give a crude product which
was purified by column chromatography (EtOAc/n-hexane, 1:4).
The title compound was a white solid (56% yield); mp 100–102 ꢀC;
IR ꢀmax 3437 (ꢀ O–H), 3130 (ꢀ N–H), 2930 (ꢀ Csp3–H), 1310 (ꢀas
2-(Hydroxymethyl)-N-(3-nitrobenzyl)benzenesulfonamide (7)
(3-Nitrobenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 eq.)
was suspended in 20 mL of anhydrous methanol at room tempera-
ture. Excess of NaBH4 was added portionwise and the reaction
monitored by TLC. After 6 h the reaction was quenched with water
and the aqueous phase was extracted with dichloromethane
(3 ꢂ 30 mL). The organic layers were reunited, dried over sodium
sulfate, and concentrated in vacuo to give a crude product that
was purified by column chromatography (EtOAc/n-hexane, 2:1).
The title compound was a white solid (37% yield); mp 109–111 ꢀC;
IR ꢀmax 3491 (ꢀ O–H), 3164 (ꢀ N–H), 2958 (ꢀ Csp3–H), 1536 (ꢀ N–O),
S¼O), 1151 (ꢀs S¼O), 701 (d Csp2-H) cmꢁ1
;
1H-NMR (400 MHz,
1326 (ꢀas S¼O), 1162 (ꢀs S¼O), 695 (d Csp2–H) cmꢁ1
;
1H-NMR
CDCl3) d 2.31 (s, 3H, CH3), 2.80 (bs, 1H, OH, D2O exch.), 4.07 (d, 2H,
J ¼ 5.2 Hz, CH2), 4.99 (s, 2H, CH2), 5.60 (bs, 1H, NH, D2O exch.), 7.06
(bs, 4H, CHAr), 7.44–7.50 (m, 2H, CHAr), 7.55–7.60 (m, 1H, CHAr),
8.00 (d, 1H, 7.6 Hz, CHAr); 13C-NMR (101 MHz, CDCl3) d 21.1 (CH3),
47.3 (CH2), 63.8 (CH2), 127.9 (Ar), 128.5 (Ar), 129.3 (Ar), 129.9 (Ar),
131.6 (Ar), 133.1 (Ar), 133.2 (Ar), 137.6 (Ar), 138.1 (Ar), 138.2 (Ar).
(400 MHz, DMSO-d6) d 4.16 (s, 2H, CH2), 4.87 (s, 2H, CH2), 5.47 (bs,
1H, OH, D2O exch.), 7.33–7.37 (m, 1H, CHAr), 7.51–7.60 (m, 2H,
CHAr), 7.64 (d, 1H, J ¼ 7.6 Hz, CHAr), 7.73–7.75 (m, 2H, CHAr), 8.04 (s,
1H, CHAr), 8.06 (s, 1H, CHAr), 8.35 (bs, 1H, NH, D2O exch.); 13C-NMR
(101 MHz, DMSO-d6) d 45.4 (CH2), 59.9 (CH2), 122.5 (Ar), 122.6 (Ar),
127.1 (Ar), 127.9 (Ar), 128.5 (Ar), 130.2 (Ar), 132.9 (Ar), 134.6 (Ar),
137.2 (Ar), 140.8 (Ar), 141.5 (Ar), 148.1 (Ar).
2-(Hydroxymethyl)-N-(4-(trifluoromethyl)benzyl)benzenesulfona-
mide (11)
N-(3-fluorobenzyl)-2-(hydroxymethyl)benzenesulfonamide (8)
(3-Fluorobenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 eq.)
was suspended in 20 mL of anhydrous methanol at room tempera-
ture. An excess of NaBH4 was added portionwise and the reaction
monitored by TLC. After 5 h the reaction was quenched with water
and the aqueous phase was extracted with dichloromethane
(3 ꢂ 30 mL). The organic layers were reunited, dried over sodium
sulfate, and concentrated in vacuo to give a crude product which
was purified by column chromatography (EtOAc/n-hexane, 1:1).
The title compound was a light yellow oil (67% yield); IR ꢀmax
3492 (ꢀ O–H), 3283 (ꢀ N–H), 2895 (ꢀ Csp3–H), 1318 (ꢀas S¼O), 1252
(4-Trifluoromethylbenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide
(1.0 eq.) was suspended in 20 mL of anhydrous methanol at room
temperature. An excess of NaBH4 was added portionwise and the
reaction monitored by TLC. After 8 h the reaction was quenched
with water and the aqueous phase was extracted with dichlorome-
thane (3 ꢂ 30 mL). The organic layers were reunited, dried over
sodium sulfate, and concentrated in vacuo to give a crude product
which was purified by column chromatography (EtOAc/n-hexane,
1:3). The title compound was a white solid (79% yield); mp
78–80 ꢀC; IR ꢀmax 3417 (ꢀ O–H), 3161 (ꢀ N-H), 3065 (ꢀ Csp2–H), 1321
1
(ꢀ Csp2–F), 1175 (ꢀs S¼O), 689 (d Csp2–H) cmꢁ1; H-NMR (400 MHz,
(ꢀas S¼O), 1157 (ꢀs S¼O), 688 (d Csp2–H) cmꢁ1
;
1H-NMR (400 MHz,
CDCl3) d 2.84 (bs, 1H, OH, D2O exch.), 4.05 (s, 2H, CH2), 4.97 (s, 2H,
CH2), 6.04 (bs, 1H, NH, D2O exch.), 6.85–6.94 (m, 3H, CHAr),
7.17–7.20 (m, 1H, CHAr), 7.39–7.55 (m, 3H, CHAr), 7.92 (d, 1H,
CDCl3) d 3.03 (bs, 1H, OH, D2O exch.), 4.15 (d, 2H, J ¼ 6.4 Hz, CH2),
5.02 (d, 2H, J ¼ 5.2 Hz CH2), 6.14 (t, 1H, J ¼ 6.4 Hz, NH, D2O exch.),
7.32 (d, 2H, J ¼ 8.0 Hz, CHAr), 7.40–7.49 (m, 4H, CHAr), 7.54–7.58 (m,
J ¼ 7.6 Hz, CHAr); 13C-NMR (101 MHz, CDCl3) d 46.6 (CH2), 63.6 1H, CHAr), 7.91 (s, 1H, CHAr); 13C-NMR (101 MHz, CDCl3) d 46.9 (CH2),
2
2
1
(CH2), 114.6 (Ar-F, JC-F ¼ 21.1 Hz), 114.8 (Ar-F, JC-F ¼ 22.0 Hz), 123.4 63.9 (CH2), 124.0 (C-F, JC-F¼ 273.1 Hz, CF3), 125.4 (Ar), 125.5 (Ar),
long-range
(Ar-F,
J
¼ 2.7 Hz), 128.5 (Ar), 129.7 (Ar), 130.1 (Ar-F, 128.1 (Ar), 128.6 (Ar), 129.7 (Ar), 129.8 (Ar), 130.1 (Ar), 131.7 (Ar),
C-F
3JC-F ¼ 8.2 Hz), 131.6 (Ar), 133.2 (Ar), 137.9 (Ar), 138.1 (Ar), 139.0 133.3 (Ar), 137.8 (Ar), 138.0 (Ar), 140.4 (Ar); 19F-NMR (564.7 MHz,
3
1
(Ar-F, JC-F ¼ 7.3 Hz), 162.7 (Ar-F, JC-F ¼ 247.45 Hz); 19F-NMR CDCl3) d -60.08 (s, CF3).
(564.7 MHz, CDCl3) d -110.03 (ddd, JF-H ¼ 9.5 Hz, 8.6 Hz, 5.2 Hz, CF).
N-(4-cyanobenzyl)-2-(hydroxymethyl)benzenesulfonamide (12)
(4-Cyanobenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 eq.)
N-(3-bromobenzyl)-2-(hydroxymethyl)-benzenesulfonamide (9)
(3-Bromobenzyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 eq.) was suspended in 20 mL of anhydrous methanol at room tempera-
was suspended in 20 mL of anhydrous methanol at room tempera- ture. An excess of NaBH4 was added portionwise and the reaction
ture. An excess of NaBH4 was added portionwise and the reaction monitored by TLC. After 8 h the reaction was quenched with water