SYNTHESIS
Short Papers
1102
1H NMR (200 MHz, acetone-d6): δ = 7.97 (t, 1 H, J = 8.0 Hz), 7.65
(m, 6 H), 7.45 (m, 9 H), 7.32 (dd, 1 H, J = 11.1, 10.0 Hz), 2.81 (m, 4
H).
The chemical shift of the NH in 2 (δ = 8.84) was similar
to that of the NH in flosulide (δ = 8.78), suggesting that
the indanone and the 1,1-dioxo-2,3-dihydrobenzothio-
phene had similar electronic character. However, on test-
ing against COX-2 in both whole cell8 and whole blood9
assays, sulfonyl flosulide 2 showed no activity (>5 µM
and >33 µM, respectively). This result suggests that the
acidifying effect of the carbonyl on the sulfonamide NH
is by itself not sufficient to retain the activity. The ketone
must interact with the enzyme in a way that the sulfone is
unable to duplicate with its non-coplanar oxygens. Thus
the synthesis of 2 has helped to clarify the nature of the
flosulide pharmacophore.
13C NMR (75 MHz, CDCl3): δ = 163.2 (dd, J = 258.4, 11.0 Hz), 165.1
(dd, J = 264.8, 12.8 Hz), 135.6, 132.7, 130.3, 128.7, 128.6, 128.2,
124.4 (dd, J = 17.8, 4.1 Hz), 106.1 (dd, J = 26.9, 24.2 Hz), 30.9 (d, J
= 28.1 Hz), 26.8 (d, J = 3.5 Hz).
MS (CI): m/z = 478, 400, 259, 199.
Anal. C26H21F2NO2SSi (477.6): Calcd C, 65.38; H, 4.43; N, 2.94.
Found C, 65.61; H, 4.49; N, 3.09.
6-Fluoro-2,3-dihydro-5-nitrobenzo[b]thiophene (7):
A solution of 6 (1.23 g, 2.57 mmol) in EtOH (45 mL) and THF
(90 mL) was cooled in an ice bath and treated with 8 N aq KOH
(0.48 mL , 3.84 mmol). The resulting mixture was stirred for 10 min,
then quenched with 6 N HCl (0.48 mL, 2.88 mmol) and concentrated.
The residue was partitioned between 1 M HCl and Et2O. The aqueous
layer was washed with Et2O and the combined organics were washed
with brine, dried (MgSO4) and concentrated. Purification by flash
chromatography (35 % CH2Cl2/hexanes) provided 435 mg (85 %) of
7.
5-Bromo-2,4-difluoronitrobenzene (4):
To a suspension of 3 (12.0 mL, 106 mmol) in concd H2SO4 (77 mL)
at 0°C was added dropwise concd HNO3 (68.0 mL) maintaining an
internal temperature below 20°C. The resulting mixture was stirred
for 10 min at 0°C, then poured into a mixture of Et2O and ice water
with vigorous stirring. The aqueous phase was separated and extract-
ed with Et2O. The combined organic phases were washed with aq
NaHCO3 solution (3 × 200 mL) and brine, dried (MgSO4) and con-
centrated. Purification by flash chromatography (15% acetone/hex-
anes) provided 25.2 g (99%) of the title compound as a yellow oil.
IR (film): ν = 3050, 1595, 1480, 1340, 1285, 1157, 1012, 845, 750,
683 cm–1.
IR (KBr): ν = 3040, 2940, 1600, 1580, 1510, 1340, 1330, 1235, 990,
960, 750 cm–1.
1H NMR (200 MHz, acetone- d6): δ = 7.96 (d, 1 H, J = 7.3 Hz), 7.34
(d, 1 H, J = 11.4 Hz), 3.56 (m, 2 H), 3.42 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 155.7 (d, J = 263.5 Hz), 153.5, 153.4 ,
136.5 (d, J = 3.2 Hz), 120.8 (d, J = 2.1 Hz), 110.9 (d, J = 23.6 Hz),
34.6, 34.3.
MS (CI): m/z = 200, 183, 169.
Anal. C8H6FNO2S (199.2): Calcd C, 48.22; H, 3.03; N, 7.06. Found:
C, 48.21; H, 3.12; N, 6.99.
1H NMR (200 MHz, acetone d ): δ = 8.54 (t, 1 H, J = 7.5 Hz), 7.65
6
(dd, 1 H, J = 11.0, 8.6 Hz).
13C NMR (75 MHz, CDCl ): δ = 161.8 (dd, J = 260, 11.6 Hz), 155.4
3
(dd, J = 266.7, 11.5 Hz), 134.1, 130.7 (t, J = 2.6 Hz), 107.4 (dd, J =
25.1, 1.6 Hz), 104.5 (dd, J = 18.7, 4.4 Hz).
MS (CI): m/z = 240, 238, 223, 221, 112.
6-(2,4-Difluorophenoxy)-2,3-dihydro-5-nitrobenzo[b]thiophene(8):
A mixture of 7 (400 mg, 2.0 mmol) and 2,4-difluorophenol (0.25 mL,
2.6 mmol) was heated to 100ºC. To this solution was added dropwise
a solution of KOH (173 mg, 2.6 mmol) in H2O (0.2 mL). The result-
ing mixture was heated for 1 h at 100ºC, then cooled and partitioned
between EtOAc and H2O. The aqueous phase was extracted with
EtOAc and the combined organic phases were washed with brine,
dried (MgSO4) and concentrated. Purification by flash chromatogra-
phy (10% acetone/hexanes) provided 495 mg (80%) of 8 as yellow
crystals.
2,4-Difluoro-5-vinylnitrobenzene (5):
A mixture of Pd (dba) (200 mg, 0.21 mmol) and Ph3P (220 mg,
2
3
0.84 mmol) was dissolved in toluene (20 mL), degassed and stirred 10
min at r.t. A solution of 4 (1.0 g, 4.2 mmol) in toluene (20 mL) was
then added, followed by vinyltributyltin (1.84 mL, 6.3 mmol). The
mixture was refluxed for 2 h, then poured into a mixture of aq NaF
and Et2O. The aqueous phase was separated and extracted with Et2O.
The combined organic phases were washed with brine, dried
(MgSO4) and concentrated. Purification by flash chromatography
(7% acetone/hexanes) provided 700 mg (90%) of the title compound
as pale yellow crystals.
IR (KBr): ν = 1680, 1580, 1500, 1460, 1340, 1245, 1190, 1070, 955,
850, 800 cm–1.
1H NMR (200 MHz, acetone-d6): δ = 7.91 (s, 1 H), 7.29 (m, 2 H), 7.10
(m, 1 H), 6.96 (s, 1 H), 3.52 (m, 2 H), 3.39 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 159.4 (dd, J = 245.8, 10.4 Hz), 153.8
(dd, J = 251.0, 12.4 Hz), 152.3, 151.8, 138.5 (dd, J = 11.6, 5.6 Hz),
136.2, 135.3, 122.7 (dd, J = 9.9, 1.6 Hz), 121.3, 111.7 (dd, J = 22.7,
3.8 Hz), 110.8, 105.7 (dd, J = 26.6, 21.4 Hz), 34.7, 34.2.
MS (CI): m/z = 310, 293, 180, 93.
IR (film): ν = 3085, 1630, 1585, 1490, 1345, 1290, 1045, 850,
775 cm–1.
1H NMR (200 MHz, acetone-d6): δ = 8.41 (t, 1 H, J = 8.0 Hz), 7.45
(t, 1 H, J = 10.7 Hz), 6.87 (dd, 1 H, J = 17.6, 11.3 Hz), 6.10 (d, 1 H,
J = 17.6 Hz), 5.60 (d, 1 H, J = 11.3 Hz).
13C NMR (75 MHz, CDCl3): δ = 163.3 (dd, J = 258.6, 11.0 Hz), 156.1
(dd, J = 263.5, 13.6 Hz), 127.4, 126.0 (m), 123.7 (dd, J = 14.7, 5.3
Hz), 120.3 (dd, J = 2.4, 1.9 Hz), 107.7 (dd, J = 28.1, 24.9 Hz).
MS (CI): m/z = 185, 169, 156.
Anal. C14H9F2NO3S (277.2): Calcd C, 54.36; H, 2.93; N, 4.55.
Found: C, 54.61; H, 3.16; N, 4.53.
5-Amino-6-(2,4-difluorophenoxy)-2,3-dihydrobenzo[b]thio-
phene (8a):
Anal. C8H5F2NO2 (185.1): Calcd C, 51.89; H, 2.72; N, 7.60; Found
C, 51.24; H, 2.76; N, 7.65.
To a solution of 8 (495 mg, 1.6 mmol) in EtOH (24 mL), THF
(12 mL), aq NH4Cl (6 mL ) and H2O (6 mL) was added iron powder
(575 mg, 10.2 mmol). The mixture was refluxed for 1 h, then filtered
hot through Celite. The filter pad was washed with hot EtOAc (3 ×
50 mL). The filtrate was concentrated and the residue was partitioned
between EtOAc and brine. The organic phase was dried (MgSO4) and
concentrated to provide 453 mg (100 %) of 8a.
2,4-Difluoro-5-[2-(triphenylsilylsulfanyl)ethyl]nitrobenzene (6):
To a solution of 5 (2.0 g, 10.8 mmol) and triphenylsilanethiol (4.74 g,
16.2 mmol) in benzene (36 mL) was added AIBN (532 mg,
3.24 mmol). The mixture was refluxed for 45 min, then cooled to r.t.
and concentrated. Purification by flash chromatography (10 % ace-
tone/hexanes) provided 2.65 g (52%) of the title compound as a white
solid.
IR (KBr): ν = 3450, 3350, 2930, 1610, 1500, 1475, 1240, 1195, 1133,
1090, 955, 845 cm–1.
1H NMR (200 MHz, acetone-d6): δ = 7.17 (m, 1 H), 6.99 (m, 2 H ), 6.81
(s, 1 H), 6.60 (s, 1 H), 4.49 (br s , 2 H), 3.28 (m, 2 H), 3.13 (m, 2 H).
IR (KBr): ν = 3062, 1625, 1587, 1530, 1425, 1342, 1285, 1105, 705,
695 cm–1.