914 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
J ones et al.
mp 217 °C); NMR (Me2SO-d6) δ 2.77 (t, 4H, J ) 4.6 Hz), 3.62
(t, 4H, J ) 4.6 Hz), 6.15 (s, 2H), 6.67 (d, 2H, J ) 8.7 Hz), 7.35
(d, 2H, J ) 8.7 Hz). Anal. (C10H14N2O3S) C,H,N,S.
4-((4-(N-((3,4-Dih yd r o-2-m eth yl-4-oxo-6-qu in a zolin yl)-
m eth yl)-N-p r op -2-yn yla m in o)p h en yl)su lfon yl)-1-(ter t-bu -
tyloxyca r bon yl)p ip er a zin e (29). A solution of 28 (0.678 g,
1.79 mmol), 6 (0.452 g, 1.79 mmol), and 2,6-lutidine (0.31 mL,
2.66 mmol) in DMF (10 mL) was heated at 100 °C. At 1 h,
further 6 (0.452 g, 1.79 mmol) and lutidine (0.21 mL, 1.80
mmol) were added. At 2 h, further 6 (0.226 g, 0.89 mmol) and
lutidine (0.1 mL, 0.90 mmol) were added. At 4 h, the reaction
mixture was poured into 0.5 N HCl (75 mL); extractive workup
(EtOAc) followed by flash chromatography with benzene-
EtOAc (1:2) gave the desired product as an off-white solid (330
mg, 33%): mp 193-195 °C; IR (KBr, cm-1) 1680, 1590, 1160;
NMR (CDCl3) δ 1.4 (s, 9H), 2.31 (t, 1H, J ) 2.3 Hz), 2.55 (s,
3H), 2.95 (m, 4H), 3.49 (t, 4H, J ) 4.8 Hz), 4.18 (d, 2H, J )
2.3 Hz), 4.77 (s, 2H), 6.88 (d, 2H, J ) 9.0 Hz), 7.58 (d, 2H, J
) 9.0 Hz), 7.68 (s, 2H), 8.15 (s, 1H), 10.72 (s, 1H). Anal.
(C28H33N5O5S) C,H,N,S.
N-((4-(N-((3,4-Dih yd r o-2-m eth yl-4-oxo-6-qu in a zolin yl)-
m et h yl)-N-p r op -2-yn yla m in o)p h en yl)su lfon yl)p ip er a -
zin e (30). CF3COOH (0.50 mL, 6.49 mmol) was added to a
stirred solution of 29 (0.200 g, 0.363 mmol) in CH2Cl2 (4 mL).
After 1 h, volatile components were removed under reduced
pressure and the resulting residue was dissolved in EtOAc (25
mL) and washed with 2 N NaOH (10 mL). Exhaustive
extractive workup (EtOAc) followed by flash chromatography
with 10% CH3OH in CH2Cl2 gave the product as a white,
hygroscopic solid (150 mg, 92%): mp indeterminate; NMR
(CDCl3) δ 2.30 (t, 1H, J ) 2.3 Hz), 2.52 (s, 3H), 3.02 (br s, 8H),
4.13 (d, 2H, J ) 2.3 Hz), 4.82 (s, 2H), 6.93 (d, 2H, J ) 9.0 Hz),
7.62 (d, 2H, J ) 9.0 Hz), 7.66 (m, 2H), 7.88 (m, 1H), NH’s not
discernable; HRMS (C23H25N5O3S)+ calcd 451.1688, found
451.1678. HCl salt: mp 225-227 °C.
4-((4-(N-((3,4-Dih yd r o-2-m eth yl-4-oxo-6-qu in a zolin yl)-
m et h yl)-N-p r op -2-yn yla m in o)p h en yl)su lfon yl)-1-m et h -
ylp ip er a zin e (31). Iodomethane (0.017 mL, 0.273 mmol) was
added to a stirred solution of 30 (123 mg, 0.272 mmol) and
N,N-diisopropylethylamine (0.048 mL, 0.276 mmol) in DMF
(5 mL). After 18 h at 25 °C, the mixture was poured into H2O
(20 mL); extractive workup (CH2Cl2) followed by chromatog-
raphy with CH2Cl2-CH3OH (10:1) gave the product as a white
solid (75 mg, 59%): mp 139-141 °C; NMR (CDCl3) δ 2.26 (s,
3H), 2.31 (t, 1H, J ) 2.3 Hz), 2.47 (br t, 4H), 2.99 (br t, 4H),
4.18 (d, 2H, J ) 2.3 Hz), 4.77 (s, 2H), 6.88 (d, 2H, J ) 7.2 Hz),
7.61 (d, 2H, J ) 7.2 Hz), 7.68 (d, 2H, J ) 1.2 Hz), 8.19 (s, 1H),
11.09 (br s, 1H); HRMS (C24H27N5O3S)+ calcd 465.1835, found
465.1830. Anal. (C24H27N5O3S) C,H,N,S.
N-((4-(N-P r op -2-yn yla m in o)p h en yl)su lfon yl)m or p h o-
lin e (24). A solution of 23 (1.001 g, 4.14 mmol), N,N-
diisopropylethylamine (0.86 mL, 4.93 mmol), and propargyl
bromide (80% (w/w) in toluene, 0.46 mL, 4.14 mmol) in DMF
(10 mL) was heated at 75 °C. At 5 h, additional diisopropy-
lethylamine (0.36 mL, 2.5 mmol) and propargyl bromide (0.23
mL, 2.07 mmol) were added, and the mixture was heated for
3 h more. It was poured into 0.5 N HCl (200 mL), and
extractive workup (EtOAc) followed by flash chromatography
with CH2Cl2-EtOAc (20:1) gave the desired product as a pale
yellow solid (0.47 g, 41%): mp 117-120 °C; NMR (CDCl3) δ
2.27 (t, 1H, J ) 2.5 Hz), 2.97 (m, 4H), 3.73 (m, 4H), 4.00 (dd,
2H, J ) 2.5, 6.0 Hz), 4.47 (m, 1H), 6.71 (d, 2H, J ) 8.8 Hz),
7.58 (d, 2H, J ) 8.8 Hz). Anal. (C13H16N2O3S) C,H,N,S.
N-((4-(N-((3,4-Dih yd r o-2-m eth yl-4-oxo-6-qu in a zolin yl)-
m et h yl)-N-p r op -2-yn yla m in o)p h en yl)su lfon yl)m or p h o-
lin e (25). A solution of 24 (1.314 g, 4.69 mmol), 6 (1.185 g,
4.69 mmol), and 2,6-lutidine (0.85 mL, 7.3 mmol) in DMF (15
mL) was heated at 100 °C. At 1.5 h, further 6 (0.885 g, 3.52
mmol) and 2,6-lutidine (0.41 mL, 3.52 mmol) were added. At
4.5 h, the reaction mixture was poured into 0.5 N HCl (150
mL), and extractive workup (EtOAc) followed by flash chro-
matography with 50% EtOAc in CH2Cl2 gave the desired
product as an off-white solid (0.630 g, 30%): mp 222-225 °C
slight dec; NMR (Me2SO-d6) δ 2.31 (s, 3H), 2.77 (m, 4H), 3.26
(t, 1H, J ) 1.9 Hz), 3.59 (m, 4H), 4.37 (d, 2H, J ) 1.7 Hz),
4.81 (s, 2H), 6.95 (d, 2H, J ) 9.0 Hz), 7.52 (m, 3H), 7.68 (dd,
1H, J ) 1.9, 8.3 Hz), 7.96 (d, 1H, J ) 1.5 Hz), 12.18 (s, 1H);
HRMS (C23H24N4O4S)+ calcd 452.1518, found 452.1497. Anal.
(C23H24N4O4S).
4-((4-Nitr op h en yl)su lfon yl)-1-(ter t-bu tyloxyca r bon yl)-
p ip er a zin e (26). To a stirred solution of tert-butyl 1-pipera-
zinecarboxylate (3.069 g, 16.48 mmol) and diisopropylethy-
lamine (3.16 mL, 18.13 mmol) in CH2Cl2 (80 mL) at 0 °C was
slowly added a solution of 4-nitrobenzenesulfonyl chloride
(3.652 g, 16.48 mmol) in CH2Cl2 (50 mL). When the addition
was complete, the reaction mixture was allowed to warm to
room temperature, and then it was poured into 0.5 N HCl (75
mL); extractive workup (CH2Cl2) gave the desired sulfonamide
as a tan solid (5.78 g, 94%): mp 169-171 °C; NMR (CDCl3) δ
1.40 (s, 9H), 3.03 (t, 4H, J ) 5.0 Hz), 3.53 (t, 4H, J ) 5.1 Hz),
7.94 (d, 2H, J ) 8.8 Hz), 8.39 (d, 2H, J ) 8.8 Hz). Anal.
(C15H21N3O6S) C,H,N,S.
N-((3,4-Dih ydr o-2-m eth yl-4-oxo-6-qu in azolin yl)m eth yl)-
4-(p h en ylsu lfon yl)a n ilin e (32). A mixture of 4-aminophenyl
phenyl sulfone (4n ; 7.0 g, 30 mmol), 6 (technical grade, 7.91
g, 25 mmol), 2,6-lutidine (2.95 g, 28 mmol), and DMA (50 mL)
was stirred under argon at 60 °C for 17 h. The solvent was
evaporated (90 °C/2 mmHg) to leave a yellow solid which was
flash chromatographed on SiO2 (1 kg) with 6% MeOH in EtOAc
to give the pure product as a tan powder (4.33 g, 43%): mp
4-((4-Am in oph en yl)su lfon yl)-1-(ter t-bu tyloxycar bon yl)-
p ip er a zin e (27). A solution of 26 (5.00 g, 13.46 mmol) in
EtOAc (50 mL) with 5% Pd on activated carbon (1.0 g) in
suspension, in a Parr apparatus, was shaken under 44 psi of
hydrogen gas for 18 h. At this time further catalyst (0.60 g)
was added, and the mixture was hydrogenated at 44 psi for a
further 4 h. The reaction mixture was filtered through Celite,
the catalyst washed with EtOAc (1 L), and the solvent removed
under reduced pressure to give the desired aniline as a white
solid (4.58 g, ∼100%): mp 194-197 °C; NMR (CDCl3) δ 1.40
(s, 9H), 2.92 (t, 4H, J ) 5.0 Hz), 3.49 (t, 4H, J ) 5.1 Hz), 4.15
(s, 2H), 6.69 (d, 2H, J ) 8.7 Hz), 7.50 (d, 2H, J ) 8.7 Hz);
HRMS (C15H23N3O4S)+ calcd 341.1409, found 341.1419. This
material was used without further purification.
4-((4-(P r op -2-yn yla m in o)p h en yl)su lfon yl)-1-(ter t-b u -
tyloxyca r bon yl)p ip er a zin e (28). A solution of the aniline
27 (1.50 g, 4.39 mmol), propargyl bromide (80% (w/w) in
toluene, 0.49 mL, 4.39 mmol), and N,N-diisopropylethylamine
(0.80 mL, 4.61 mmol) in DMF (20 mL) was heated at 75 °C.
At 4 h, additional propargyl bromide (0.49 mL, 4.39 mmol)
and diisopropylethylamine (0.80 mL, 4.61 mmol) were added,
and the mixture was heated for 4 h more. It was poured into
0.5 N HCl (100 mL); extractive workup (EtOAc) followed by
flash chromatography with CH2Cl2-EtOAc (20:1) gave the
desired propargylamine as a pale yellow solid (0.923 g, 55%):
mp 142-143 °C; IR (KBr, cm-1) 3390, 1680, 1595, 1325, 1160;
NMR (CDCl3) δ 1.41 (s, 9H), 2.27 (t, 1H, J ) 2.5 Hz), 2.94 (t,
4H, J ) 5.0 Hz), 3.49 (t, 4H, J ) 5.0 Hz), 4.00 (dd, 2H, J )
2.3, 5.6 Hz), 4.45 (t, 1H, J ) 5.7 Hz), 6.71 (d, 2H, J ) 8.8 Hz),
7.57 (d, 2H, J ) 8.8 Hz). Anal. (C18H25N3O4S) C,H,N,S.
300-301 °C; NMR (Me2SO-d6) satisfactory.
(C22H19N3O3S) C,H,N,S.
Anal.
4-(P h en ylsu lfon yl)-N-eth yla n ilin e (33). Meth od A. A
mixture of 4-aminophenyl phenyl sulfone (4n ; 5.83 g, 25 mmol),
iodoethane (7.80 g, 50 mmol), K2CO3 (3.45 g, 25 mmol), and
DMA (125 mL) was stirred at 110 °C for 3.5 h. The DMA was
removed in vacuo at 80 °C leaving a white residue; extractive
workup (EtOAc/H2O) (500 mL) gave an oil that was flash
chromatographed using 10% MeOH in toluene to give the pure
product as a white solid (3.17 g, 48.5%): mp 134.5-136 °C;
NMR satisfactory. Anal. (C14H15NO2S) C,H,N,S.
Meth od B. A stirred solution of 4-(phenylsulfonyl)fluo-
robenzene (25.00 g, 0.106 mol) and C2H5NH2 (20.8 mL, 0.318
mol, 3 equiv) in DMSO (125 mL) in a flask fitted with a dry
ice condenser was heated at 130 °C for 3 h under argon. The
resulting amber solution was allowed to cool, poured into H2O
(1.3 L), and extracted with CH2Cl2 (2 × 200 mL) and finally
with EtOAc (2 × 200 mL). The organic layers were combined,
dried, and evaporated in vacuo to give the crude beige-colored
product. Recrystallization from ethanol gave off-white crystals
(23.03 g, 83.1%) identical by TLC with the product prepared
as above.