equiv), 2-propanol (100 mL), and potassium hydroxide (13.8
g, 0.245 mol, 3.26 equiv) were boiled at reflux under a nitrogen
atmosphere at ∼83 °C for 5 h. After reaction was completed,
it was cooled to room temperature. The resulting suspension
was added to water (100 mL) with stirring. The product was
isolated by filtration, washed with H2O (30 mL), and vaccuum
dried (40 °C). Yield 19.05 g (89%): mp 245-247 °C; m/z 284;
C12H14BrNO2 requires: C, 50.7; H, 4.97; N,4.93. Found: C, 50.5;
oxybenzenethiol (2.0 mL, 16.26 mmol, 1.0 equiv) were added
to a reaction flask set for boiling at reflux under a nitrogen
atmosphere. The mixture was refluxed for 16 h. After the
reaction was completed, it was cooled (<30 °C) and quenched
with water (30 mL) which resulted in formation of a precipitate.
The resultant slurry was granulated for 1 h at room temperature
(10-15 °C). The product was isolated by vacuum filtration and
washed with a 1:1 mixture of 2-propanol and water (20 mL).
The product was dried overnight in a vacuum oven at 40-45
°C. Yield 5.31 g, 95% Recrystallization from 2-propanol gave
analytically pure material: m/z 343; C19H21NO3S requires: C,
66.45; H, 6.16; N, 4.08; S, 9.34. Found: C, 66.35; H, 5.84; N,
3.97; S, 9.65. 1H NMR (300 MHz, DMSO-d6) δ 7.44 (d, 2H),
7.22 (m, 2H), 7.08 (m, 2H), 6.92 (d, 2H), 3.8 (s, 3H), 3.72 (d,
1
H, 5.09; N, 4.92%; H NMR (300 MHz, DMSO-d6) δ 7.54
(s,1H), 7.50 (d, 1H), 7.38 (m, 2H), 3.77 (m, 2H), 3.50 (m, 2H),
2.43 (m, 2H), 1.80 (m, 2H); IR (cm-1) νmax; 3363, 3174, 1631,
1102, 943, 694.
Tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2H-pyran-4-
carbonitrile (8). Tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-
2H-pyran-4-carboxamide 6 (2.10 g, 6.34 mmol, 1 equiv) and
thionyl chloride (5 mL, 68.5 mmol, 10.8 equiv) were refluxed
under a nitrogen atmosphere for 1 h (∼80 °C). After the reaction
was completed it was concentrated to form a yellow oil. The
oil crystallized upon standing for 3 days at room temperature.
The solids were triturated with hexanes (10 mL) and dichlo-
romethane (1 mL). The solids dissolved and then reformed as
the vessel was stirred, open to the atmosphere. The product was
isolated, rinsed with hexanes, and vaccuum dried (∼40 °C).
Yield 1.42 g (72%); mp 56-58 °C; m/z 313; C18H16FNOS
requires: C, 69.0; H, 5.15; N, 4.47; S, 10.2. Found: C, 68.8; H,
2H), 3.45 (t, 2H), 2.51 (d, 2H), 1.7 (t, 2H); IR (cm-1) Vmax
;
3377, 3178, 2934, 1682.
This compound can also be made in the same way using
tetrahydro-4-(3-bromophenyl)-2-H-pyran-4-carboxamide, 7, in
place of the nitrile 1. Yield 88%.
Plant Procedures. Manufacture of Tetrahydro-4-[3-(4-
fluorophenyl)thio]phenyl-2H-pyran-4-carboxamide (6). 2-Pro-
panol (270 L), potassium hydroxide (21.8 kg), tetrahydro-4-
(3-bromophenyl)-2H-pyran-4-nitrile 1 (45.0 kg), tetrakis-
(triphenylphosphine)palladium (1.0 kg), and (S)-BINAP (1.05
kg) were charged into a nitrogen-purged glass-lined jacketed
reaction vessel fitted with a reflux condenser and agitator.
Charged liquid 4-fluorothiophenol (21.7 kg) and 2-propanol
(8 L) into a nitrogen purged ancillary jacketed glass lined vessel
by using isolated vacuum application, when the charge was
complete the nitrogen blanket was reestablished and agitation
was commenced. Using isolated vacuum on the reactor slowly
suck the contents of the ancillary vessel into the main reactor
and reestablish the nitrogen blanket when the transfer process
is complete. A 10 °C exotherm was observed during the addition
process as the potassium thiolate salt was formed. Heated the
reactor contents to 80-85 °C and established steady reflux
under gentle agitation at ∼83 °C and maintained for 18 h. The
reactor contents were cooled to ∼25 °C and reaction completion
was confirmed on a representative sample of the reaction
mixture. Added city water (270 L) to the agitated reactor over
1.5 h to precipitate product. The vessel contents were then
warmed to 50-55 °C for 2 h. then cooled to ∼20 °C. The
resultant slurry was transferred onto a horizontal plate pressure
filter and the crude product isolated. While on the pressure filter
the isolate was washed with 50: 50 2-propanol/water mixture
(220 L) via the reactor, and the isolate pulled as dry as
practicable. The nitrogen purged reactor was charged with filter
aid (3.0 kg), activated charcoal (2.25 kg), glacial acetic acid
(360 L) and damp crude product isolate (∼132 kg). The reactor
contents were heated to 95-100 °C and held for 0.5 h and then
cooled to ∼65 °C. The carbon/filter aid residue was removed
by filtration on a horizontal plate pressure filter at ∼60 °C and
the warm product solution transferred into a clean crystallizer
ensuring the transfer was free of extraneous material. The
crystallizer vessel was heated to 70-75 °C and city water (285
L) added over 0.75 h. to initiate product crystallization. The
crystallizer contents were cooled to ∼20 °C and granulated for
5 h.to form a solid-liquid slurry, this was filtered on a
1
5.20; N, 4.55; S, 10.3%; H NMR (300 MHz, DMSO-d6) δ
7.50 (m, 5H), 7.38 (m, 2H), 7.20 (m, 1H), 4.00 (m, 2H), 3.65
(m, 2H), 2.07 (m, 4H), IR (cm-1) νmax; 1904, 1590, 1491, 1390,
1301, 1225, 1124, 835, 692.
Tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2H-pyran-4-
carboxylic acid (9). Tetrahydro-4-[3-(4-fluorophenyl)thio]phe-
nyl-2H-pyran-4-carboxamide 6 (10.20 g, 30.8 mmol, 1 equiv),
potassium hydroxide14 (7.70 g, 119 mmol, 3.9 equiv), and
n-butanol (75 mL) were added to a reaction flask set for reflux
under a nitrogen atmosphere. The mixture was heated at 100
°C for 7 h. The resulting slurry was cooled to 20 °C and filtered.
The retained solids were suspended in a mixture of dichlo-
romethane (60 mL) and water (60 mL). The suspension was
filtered, and the filtrate layers were settled and separated.
Dichloromethane (60 mL) was added to the aqueous phase of
the filtrate, and the pH of the stirred mixture was adjusted to
3.0 using concd HCl. The dichloromethane layer was concen-
trated to an oil (2.99 g). The oil was dissolved in isopropyl
ether (12 mL) at ∼55 °C. Upon cooling to 20 °C the product
crystallized. The solids were collected by filtration and dried
to give product, 1.33 g, (13.0%); m/z 332; C18H17FO3S requires
C, 65.0; H, 5.16; S, 9.65. Found: C, 65.2; H, 5.19; S, 9.83%;
1H NMR (300 MHz, DMSO-d6) δ 12.8 (s, 1H), 7.47 (m, 2H),
7.30 (m, 5H), 7.13 (m, 1H), 3.80 (m, 2H), 3.43 (m, 2H) 2.32
(m, 2H), 1.77 (m, 2H), IR (cm-1) νmax; 2882, 2596, 1716, 1490,
1304, 1208, 1132, 940, 828, 816.
Example of Synthesis of Model Compound. Tetrahydro-
4-[3-(4-methoxyphenyl)thio]phenyl-2H-pyran-4-carboxamide (10).
Tetrahydro-4-(3-bromophenyl)-2H-pyran-4-nitrile, 1 (4.33 g,
16.26 mmol, 1.0 equiv), 2-propanol (26 mL), potassium
hydroxide (2.11 g, 32.52 mmol, 2.0 equiv), tetrakis(triph-
enylphosphine)palladium(0) (188 mg, 0.163 mmol, 0.01 equiv),
(S)-BINAP (101 mg, 0.163 mmol, 0.01 equiv), and 4-meth-
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