Directed Ortho Metalation-Cross Coupling Strategies
1
1170, 572 cm-1; H NMR (200 MHz, acetone-d6) δ 9.06 (s, 1H),
20.5, 17.3 ppm; EIMS (m/z (%)) 261 [M+] (1), 244 (93), 180 (41),
165 (100); HRMS (EI) calcd for C14H15NO2S [M+] 261.0828, found
261.0824.
8.27 (d, 1H, J ) 7.5 Hz), 8.01 (d, 1H, J ) 7.7 Hz), 7.65-7.57
(m, 1H) ppm; 13C NMR (50 MHz, acetone-d6) δ 206.7, 164.4,
145.0, 143.7, 136.8, 134.2, 128.1, 87.8 ppm; EIMS (m/z (%)) 293
[M+] (75), 245 (51), 202 (11), 176 (5), 166 (10), 149 (5), 138 (8),
127 (21), 118 (22), 107 (21), 102 (100); HRMS (EI) calcd for C7H4-
NO3S [M+] 292.9008, found 292.8996.
2-(N,N-Diethylcarboxamido)-6-phenyl-N-(2-phenylpropan-2-
yl)benzenesulfonamide (20a). This compound was prepared ac-
cording to General Procedure 1 with the following materials: 18a
(1.16 g, 3.30 mmol), TMEDA (1.1 mL, 7.27 mmol), n-BuLi
(2.9 mL. 2.5 M, 7.27 mmol), THF (30 mL), and N,N-diethylcar-
bamoyl chloride (0.84 mL, 6.6 mmol), with the following
changes: lithiation was carried out at 0 °C for 1 h. Column
chromatography (4:1 hexanes:EtOAc) yielded 20a (1.5 g, 99%) as
a colorless solid: mp 109-110 °C (hexanes); IR (KBr) υmax 3225,
7-Iodo-3-isopropoxy-2-(2-phenylpropan-2-yl)-2,3-dihydroben-
zo[d]isothiazole 1,1-Dioxide (16). A solution of 13c (51 mg,
0.11 mmol) in i-PrOH (1 mL) was heated at reflux for 48 h and
cooled. Concentration in vacuo and column chromatography (3:2
hexanes:EtOAc) yielded 16 (36 mg, 75%) as a colorless solid: mp
91-93 °C; IR (KBr) υmax 2991, 2950, 1298, 1189, 1144, 1016,
1
2979, 1617, 1438, 1355, 1157, 767 cm-1; H NMR (400 MHz,
556 cm-1; H NMR (400 MHz, CDCl3) δ 7.96-7.95 (m, 1H),
1
CDCl3) δ 7.51 (t, 1H, J ) 7.6 Hz), 7.33-7.16 (m, 10H), 6.87
(br s, 1H), 5.70 (s, 1H), 3.74 (sx, 1H, J ) 7.0 Hz), 3.45 (sx, 1H,
J ) 7.0 Hz), 3.18 (q, 2H, J ) 7.1 Hz), 1.61 (s, 3H), 1.46 (s, 3H),
1.30 (t, 3H, J ) 7.1 Hz), 1.13 (t, 3H, J ) 7.1 Hz) ppm; 13C NMR
(101 MHz, CDCl3) δ 170.9, 146.1, 141.7, 139.5, 138.3, 136.8,
133.1, 130.9, 128.0, 127.7, 126.8, 126.7, 125.4, 59.6, 43.2, 39.1,
31.4, 29.0, 13.3, 12.0 ppm; EIMS (m/z (%)) M+ not found, 435
[M - Me]+ (4), 316 (82), 152 (61), 119 (100), 91 (95), 72 (65);
HRMS (EI) calcd for C16H14NO2S [M+] 450.1975, found 450.1977.
Synthesis of Substituded Saccharins: General Procedure 5.
7-Phenylbenzo[d]isothiazol-3(2H)-one 1,1-Dioxide (23a). This
compound was prepared according to General Procedure 2 with
the following materials: 20a (190 mg, 0.42 mmol) and TFA
(2 mL). Column chromatography (4:1-1:1 hexanes:EtOAc) af-
forded an oil that was dissolved in AcOH (10 mL) and the resulting
solution was heated at reflux for 12 h. The cooled mixture was
concentrated in vacuo to afford a solid residue that was dissolved
in water (10 mL) and acidified (1M HCl) to pH 1, forming a
precipitate that was collected by vacuum filtration yielding 23a
(98 mg, 90%) as colorless crystals: mp 222-223 °C (water); IR
7.53-7.50 (m, 2H), 7.47-7.45 (m, 1H), 7.36-7.33 (m, 2H), 7.30-
7.25 (m, 2H), 5.79 (s, 1H), 3.78 (h, 1H, J ) 6.1 Hz), 2.01 (s, 3H),
1.96 (s, 3H), 1.23 (d, 3H, J ) 6.1 Hz), 0.75 (d, 3H, J ) 6.1 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 144.4, 141.1, 140.1, 137.3,
133.4, 128.3, 127.4, 126.3, 125.0, 84.7, 83.1, 67.0, 63.3, 30.8, 27.6,
23.9, 23.3 ppm; EIMS (m/z (%)) M+ not found, 456 [M - Me]+
(1), 414 (4), 352 (3), 295 (16), 293 (15), 245 (12), 119 (100); HRMS
(EI) calcd for C16H15INO2S [M+] 411.9868, found 411.9867.
Suzuki-Cross Coupling of 2-Iodo N-Cumyl Arylsulfona-
mides: General Procedure 4. A round-bottom flask fitted with a
reflux condenser containing the appropriate iodide 5f,g,i (1 mmol),
boronic acid 17a-g (1.1 - 2 mmol), and Pd(PPh3)4 (5 mmol %)
was flushed thoroughly with argon before the addition of the
following degassed solvent (5 mL) and base: Procedure 4A, DMF
and K3PO4 (3 mmol) at 100 °C; Procedure 4B, THF and 2 M Na2-
CO3 (8-10 mmol) at 70 °C; Procedure 4C, THF and 0.35-2 M
Cs2CO3 (2-8 mmol) at 70 °C; Procedure 4D, DME and 2 M Na2-
CO3 (10 mmol) at 90 °C. The reaction mixtures were heated under
argon for 24 h, cooled, and processed as follows. Procedure A:
The mixture was diluted with water (25 mL) and the whole was
transferred to an extraction funnel with Et2O, the organic phase
was separated, and the aqueous phase was extracted with Et2O
(2 × 20 mL). The combined organic extracts were washed with
water (2 × 20 mL), washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. Procedures 4B-D: After addition of
water (10 mL), the whole was extracted with EtOAc (2 × 10 mL),
and the organic extracts were combined, dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by column
chromatography (hexanes:EtOAc).
1
(KBr) υmax 3082, 2954, 2712, 1714, 1456, 1340, 1161 cm-1; H
NMR (400 MHz, DMSO-d6) δ 8.03-7.95 (m, 3H), 7.73 (d, 2H, J
) 7.67 Hz), 7.57-7.52 (m, 3H) ppm; 13C NMR (101 MHz, DMSO-
d6) δ 161.2, 137.9, 137.4, 137.1, 136.0, 135.6, 129.7, 129.3, 129.2,
124.3 ppm; EIMS (m/z (%)) 259 [M]+ (100). Anal. Calcd for C13H9-
NO3S: C, 60.22; H, 3.50; N, 5.40; O, 18.51; S, 12.37. Found: C,
59.99; H, 3.48; N, 5.45; O, 18.98; S, 12.66.
2-(N,N-Diethylcarboxamido)-3-iodo-6-phenyl-N-(2-phenyl-
propan-2-yl)benzenesulfonamide (21a). This compound was
prepared according to General Procedure 1 with the following
materials: 20a (1.20 g 2.65 mmol), TMEDA (0.88 mL, 5.83 mmol),
n-BuLi (4.8 mL, 1.21 M, 5.83 mmol), THF (30 mL), and I2
(1.35 g, 5.30 mmol, in 10 mL of THF), allowing only 1 h for
metalation. Column chromatography (4:1 hexanes:EtOAc) and
recrystallization yielded 21a (800 mg, 53%) as colorless crystals:
mp 91-92 °C (hexanes); IR (KBr) υmax 3290, 2972, 1645, 1418,
2-Phenyl-N-(2-phenylpropan-2-yl)benzenesulfonamide (18a).
This compound was prepared according to General Procedure 4A
with the following materials: 5f (0.500 g, 1.25 mmol), 17a
(0.300 g, 2.5 mmol), Pd(PPh3)4 (0.073 g, 0.063 mmol), K3PO4
(0.795 g, 3.75 mmol), and DMF (10 mL). Column chromatography
(9:1 hexanes:EtOAc) yielded 18a (0.334 g, 76%) as an oil: IR
1335, 1150, 1028 cm-1 1H NMR (400 MHz, CDCl3) δ 7.93
;
(neat) υmax 3370, 2935, 1322, 1247, 1159 cm-1 1H NMR
;
(d, 1H, J ) 8.1 Hz), 7.29-7.25 (m, 9H), 6.75 (d, 2H, J ) 8.1 Hz),
5.87 (s, 1H), 3.71 (sx, 1H, J ) 7.1 Hz), 3.58 (sx, 1H, J ) 7.1 Hz),
3.19 (h, 2H, J ) 7.4 Hz), 1.59 (s, 3H), 1.45 (s, 3H), 1.36 (t, 3H, J
) 7.1 Hz), 1.25 (t, 3H, J ) 7.2 Hz) ppm; 13C NMR (101 MHz,
CDCl3) δ 170.0, 145.3, 141.8, 141.5, 140.1, 139.7, 139.0, 133.9,
130.6, 128.0, 127.8, 127.5, 127.1, 126.7, 125.5, 94.5, 59.5, 43.5,
39.3, 31.8, 28.5, 12.7, 11.9 ppm; EIMS (m/z (%)) M+ not found,
561 [M - Me]+ (4), 487 (5), 386 (7), 152 (25), 119 (100), 91
(50), 72 (95); HRMS (EI) calcd for C26H29IN2O3S [M+] 576.0955,
found 576.0944.
(300 MHz, CDCl3) δ 7.98 (dd, 1H, J ) 1.1, 8.0 Hz), 7.59-7.18
(m, 13H), 3.94 (s, 1H), 1.40 (s, 6H) ppm; 13C NMR (75 MHz,
CDCl3) δ 146.3, 142.6, 140.4, 139.9, 132.9, 132.4, 130.5, 130.3,
129.0, 128.8, 128.7, 128.4, 127.7, 125.9, 116.0, 59.4, 30.2 ppm;
EIMS (m/z (%)) M+ not found, 336 [M - Me]+ (100), 153 (9),
120 (23), 119 (21); HRMS (EI) calcd for C21H21NO2S [M - Me]+
336.1072, found 336.1058.
2-(2,3-Dimethylphenyl)benzenesulfonamide (19a). This com-
pound was prepared according to General Procedure 2 with the
following materials: 18b (190 mg, 0.50 mmol) and TFA (2 mL).
Column chromatography (4:1 hexanes:EtOAc) yielded 19a
(120 mg, 92%) as colorless crystals: mp 176 °C (hexanes); IR
(KBr) υmax 3373, 3247, 1332, 1446, 1333, 1158 774 cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.13 (d, 1H, J ) 8.0 Hz), 7.62 (t, 1H J )
7.5 Hz), 7.51 (t, 1H J ) 7.6 Hz), 7.27 (t, 2H, J ) 7.6 Hz), 7.18 (t,
1H, J ) 7.5 Hz), 7.10 (d, 1H, J ) 7.5 Hz), 4.37 (s, 2H), 2.36 (s,
3H), 1.99 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 140.6, 140.4,
138.2, 137.7, 135.9, 132.3, 131.9, 130.3, 127.7, 127.5, 127.2, 125.0,
2-(N,N-Diethylcarboxamido)-3,6-diphenyl-N-(2-phenylpropan-
2-yl)benzenesulfonamide (22a). This compound was prepared
according to General Procedure 4D with the following materials:
21a (0.720 g, 1.25 mmol), 17a (0.170 g, 1.38 mmol), Pd(PPh3)4
(0.070 g, 0.063 mmol), in DME (10 mL) and Na2CO3 (2 M,
5 mL). Column chromatography (4:1 hexanes:EtOAc) yielded 22a
(0.500 g, 76%) as colorless crystals: mp 175-176 °C (hexanes);
IR (KBr) υmax 3026, 2976, 1602, 1434, 1341, 1148, 981 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.57 (d, 2H, J ) 7.1 Hz), 7.46-7.44
J. Org. Chem, Vol. 72, No. 9, 2007 3205