A. Ivachtchenko et al. / Bioorg. Med. Chem. 21 (2013) 4614–4627
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of 200 mg (0.73 mmol) of compound 15 in 5 mL of THF, and the
mixture was stirred at ambient temperature for 12 h under Ar.
The solution was quenched with a saturated NaHCO3 solution
and extracted with DCM. The extract was dried over Na2SO4 and
roto-evaporated. The crude product was purified by HPLC to afford
70 mg (37%) of 10b. LS MC m/z 262 (M+1). 1H NMR (DMSO-d6,
column chromatography (eluent – hexane/AcOEt 4:1) to afford
270 mg (71%) of 3-(3-nitro-4-(phenylsulfonyl)phenyl)pyridine 19.
Iron powder (222 mg, 3.97 mmol) was added to a suspension of
270 mg (0.79 mmol) of compound 19 in 2.5 mL of AcOH. The mix-
ture was stirred at 70 °C for 3 h and then cooled down and filtered.
The precipitate was washed with AcOEt. The filtrate was diluted
with water and extracted with AcOEt. The extract was washed with
saturated NaHCO3 solution, dried over Na2SO4 and roto-evaporated
to afford 145 mg (59%) of 2-(phenylsulfonyl)-5-(pyridin-3-yl)ani-
line 21. A solution of 120 mg (0.39 mmol) of compound 21 in
2 mL formic acid was refluxed for 3 h. The solvent was stripped
in vacuo and the residue was treated with saturated NaHCO3
solution, filtered, washed with water and dried in vacuo to
afford 115 mg (87%) of N-(2-(phenylsulfonyl)-5-(pyridin-3-yl)
phenyl)formamide 23. A solution of borane dimethyl sulfide
complex (2 M in THF, 0.49 mL, 0.98 mmol) was added to a solution
of 110 mg (0.33 mmol) of compound 23 in 2 mL of THF and the
mixture was stirred at ambient temperature for 12 h under Ar.
The solution was quenched with saturated NaHCO3 solution and
extracted with DCM. The extract was dried over Na2SO4 and
roto-evaporated. The crude product was purified by column chro-
matography (eluent–hexane/AcOEt 4:1) to afford 52 mg (49%) of
compound 10h. LS MC m/z 325 (M+1). 1H NMR (DMSO-d6,
400 MHz) d 8.90 (s, 1H), 8.60 (s, 1H), 8.01 (m, 4H), 7.60 (m, 4H),
7.06 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.50 (s, 1H), 2.89 (s, 3H).
N-Methyl-4-(phenylsulfonyl)biphenyl-3-amine 10i. This com-
pound was synthesized according to the procedure for compound
10h from 4-iodo-2-nitro-1-(phenylsulfonyl)benzene 17 and phen-
ylboronic acid. LS MC m/z 324 (M+1). 1H NMR (DMSO-d6, 400 MHz)
d 7.94 (m, 3H), 7.58 (m, 3H), 7.46 (m, 5H), 6.96 (dd, J1 = 8.4 Hz,
J2 = 1.6 Hz, 1H), 6.83 (s, 1H), 6.45 (m, 1H), 2.93 (d, J = 4.8 Hz, 3H).
1-(4-(Phenylsulfonyl)phenyl)piperazine) 10j.23 A mixture of
5.64 g (40 mmol) of 1-fluoro-4-nitrobenzene 25 and 6.5 g
(40 mmol) of sodium phenylsulfinate in 100 mL of DMF was stirred
for 12 h at 120 °C. After cooling, the mixture was poured into
300 mL of water. The formed precipitate was filtered, washed with
water and dried in vacuo. Yield was 9 g (86%) of compound 26. 1H
NMR (DMSO-d6, 400 MHz) d 8.39 (d, J = 8.8 Hz, 2H), 8.23 (d,
J = 8.8 Hz, 2H), 8.02 (d, J = 7.6 Hz, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.66
(t, J = 7.6 Hz, 2H). A mixture of 1 g (3.8 mmol) of compound 26
and 0.1 g of 10% Pd/C in 100 mL of methanol was stirred for 12 h
under hydrogen. The solution was filtered through celite and
roto-evaporated. The residue was dissolved in 50 mL of EtOAc
and precipitated with 50 mL of hexane, filtered and dried in vacuo.
Yield was 0.68 g (77%) of compound 27. LS MC m/z 234 (M+1). 1H
NMR (DMSO-d6, 400 MHz) d 7.82 (d, J = 7.2 Hz, 2H), 7.55 (m, 5H),
6.61 (d, J = 8.4 Hz, 2H), 6.16 (s, 2H). A solution of 0.68 g (3 mmol)
of 4-(phenylsulfonyl)aniline 27 in 4.2 mL of water and 0.42 mL of
H2SO4 was cooled to 0 °C with stirring and a solution of 0.21 g
(3.04 mmol) of NaNO2 in 1 mL of water was added dropwise. The
temperature was kept below 5 °C. After 30 min of stirring, a solu-
tion of 0.9 g (5.4 mmol) of Ki in 3.6 mL of water was added, and
the stirring continued for 3 h. The mixture was extracted with
ether. The extract was washed with 10% HCl, then with saturated
NaHCO3 solution and, finally, with a Na2S2O3 solution and then
dried over Na2SO4 and roto-evaporated. The crude product was
purified by column chromatography (eluent–hexane/AcOEt 2:1)
to afford 0.4 g (40%) of compound 28. 1H NMR (DMSO-d6,
400 MHz) d 8.01 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.71
(m, 3H), 7.63 (t, J = 7.6 Hz, 2H). A mixture of 0.4 g (1 mmol) of 1-
iodo-4-(phenylsulfonyl)benzene 28, 0.4 g (4.7 mmol) of piperazine,
0.19 g (17 mmol) of sodium tert-butoxide and 28 mg (0.036 mmol)
of dichlorobis(tri-o-tolylphoCPhine)palladium (II) in 9 mL of dry
toluene was refluxed under Ar for 12 h. The cooled mixture was fil-
tered through celite and roto-evaporated. The product was isolated
by HPLC. The yield was 23 mg (6%) of 10j. LS MC m/z 303 (M+1).
400 MHz)
d 8.10 (dd, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.79 (d,
J = 7.6 Hz, 2H), 7.69 (m, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.55 (t,
J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H),
2.31 (s, 6H).
1-Methoxy-2-(phenylsulfonyl)benzene 10c.
A
mixture of
144 mL (1 mmol) of 85% N,N0-dimethylethylenediamine and
96 mg (0.5 mmol) of CuI in 7 mL of DMSO was stirred for 5 min
to dissolve CuI. Then, 2.7 mL of water, 0.87 mL (5 mmol) of DIPEA,
1.64 g (10 mmol) of sodium phenylsulfinate and 1.17 g (5 mmol) of
1-iodo-2-methoxybenzene 16 (obtained according to29) were suc-
cessively added. The mixture was stirred under argon at 100 °C for
12 h and then cooled down and stirred at ambient temperature for
5 h. The mixture was filtered, treated with water and extracted
with DCM. The extract was washed with water, dried over Na2SO4
and roto-evaporated. The crude product was purified by column
chromatography (eluent-hexane/AcOEt 4:1) to afford 1.26 g (50%)
of 10c. LS MC m/z 249 (M+1). 1H NMR (DMSO-d6, 400 MHz) d
8.00 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.67 (m, 2H), 7.59
(t, J = 6.8 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8 Hz, 1H),
3.72 (s, 3H).
2-(Phenylsulfonyl)aniline 10f. A 5.22 g (0.09315 mol) aliquot of
iron (powder) was added gradually to a suspension of 4.9 g
(0.01863 mol) of 2-nitrodiphenylsulfone 11, obtained according
to previous results,26,27 in 60 mL of acetic acid. The mixture was
stirred for 3 h at 70 °C, cooled and filtered from inorganic impuri-
ties. A 100 mL aliquot of water was added to the obtained solution.
The formed precipitate was filtered, washed with water and dried
in vacuum. The yield of 10f was 4 g (92%). LS MC m/z 234 (M+1). 1H
NMR (DMSO-d6, 400 MHz) d 7.91 (d, J = 8 Hz, 2H), 7.67 (t, J = 9.6 Hz,
2H), 7.58 (t, J = 7,6 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.77 (d,
J = 8.4 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.12 (s, 2H).
N-Methyl-2-(phenylsulfonyl)aniline 10g. A solution of borane
dimethyl sulfide complex (2 M in THF, 2.65 mL, 5.28 mmol) was
added to a solution of 460 mg (1.76 mmol) of N-formyl-2-(phenyl-
sulfonyl)aniline 14 in 11 mL of THF. The mixture was stirred at
ambient temperature for 12 h under Ar. The solution was
quenched with saturated NaHCO3, extracted with DCM, and then
the extract was dried over Na2SO4 and roto-evaporated. The crude
product was purified by column chromatography (eluent-hexane/
AcOEt 4:1) and recrystallized from AcOEt to afford 264 mg (61%)
of 10g. LS MS m/z 248 (M+1). 1H NMR (DMSO-d6, 400 MHz) d
7.95 (d, J = 7.2 Hz, 2H), 7.78 (dd, J1 = 9.6 Hz, J2 = 1.2 Hz, 1H), 7.66
(t, J = 7,6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 8 Hz, 1H),
6.75 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H).
N-Methyl-2-(phenylsulfonyl)-5-(pyridin-3-yl)aniline 10h.
A
mixture of 4.9 g (17.4 mmol) of 1-chloro-4-iodo-2-nitrobenzene
17 and 2.85 g (17.4 mmol) of sodium phenylsulfinate in 70 mL of
DMF was stirred at 120 °C for 12 h. The mixture was cooled down,
diluted with water and extracted with AcOEt. The extract was
dried over Na2SO4 and roto-evaporated. Purification by column
chromatography (eluent – hexane/AcOEt 4:1) afforded 2.07 g
(31%) of 4-iodo-2-nitro-1-(phenylsulfonyl)benzene 31. A mixture
of 110 mg (0.9 mmol) of pyridin-3-ylboronic acid and 240 mg
(2.26 mmol) of Na2CO3 in 8.8 mL of ethanol and 2.2 mL of water
was stirred at 90 °C under Ar for 40 min and then cooled down.
To this mixture, 432 mg (1.12 mmol) of compound 18 was added,
followed by 20 mg of Pd(PPh3)2Cl2. The mixture was stirred at
85 °C under Ar for 2 h and then cooled, diluted with water and ex-
tracted with DCM. The extract was washed with water, dried over
Na2SO4 and roto-evaporated. The crude product was purified by