Improved 3-hydroxythiophenol synthesis

Article abstract of DOI:10.1080/00397911.2011.611921

Hydroxythiophenols have provided access to a number of unique heterocycles. Historically, access to 3-hydroxythiophenol has been challenging because of inefficiencies and prohibitive cost. A straightforward and efficient route to 3-hydroxythiphenol has been devised.

Full text of DOI:10.1080/00397911.2011.611921

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Improved 3-Hydroxythiophenol Synthesis
a
a
a
a
Tim Biggs , Tom Volek , Gary Jesionowski & Vaughn Romell
a
INDSPEC Chemical Corporation, Pittsburgh, Pennsylvania, USA
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 21 Dec 2012.
To cite this article: Tim Biggs , Tom Volek , Gary Jesionowski & Vaughn Romell (2013): Improved
3-Hydroxythiophenol Synthesis, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:6, 877-881
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1
Synthetic Communications , 43: 877–881, 2013
Copyright # INDSPEC Chemical Corporation
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.611921
IMPROVED 3-HYDROXYTHIOPHENOL SYNTHESIS
Tim Biggs, Tom Volek, Gary Jesionowski, and Vaughn Romell
INDSPEC Chemical Corporation, Pittsburgh, Pennsylvania, USA
GRAPHICAL ABSTRACT
Abstract Hydroxythiophenols have provided access to a number of unique heterocycles.
Historically, access to 3-hydroxythiophenol has been challenging because of inefficiencies
and prohibitive cost. A straightforward and efficient route to 3-hydroxythiphenol has been
devised.
Keywords Cost-effective; 3-hydroxybenzenesulfonic acid sodium salt; 3-hydroxybenze-
nesulfonic chloride; 3-hydroxythiophenol; red phosphorus reduction
INTRODUCTION
-Hydroxythiophenol has provided access to
3
heterocycles. As an example, coupling 3-hydroxythiophenol with bis(benzylbro-
a
number of unique
[
1]
[
2]
mide) affords a strained novel heterocyclic meta-cyclophane (Scheme 1).
Immunosuppressant KRP-203 and benzothiophene PPAR agonist incorporate
[
3]
3
-hydroxythiophenol as a central feature (Fig 1).
Additionally, Eli Lilly’s raloxifene, an osteoporosis medicine, uses 3-hydro-
[
1a]
xythiophenol as a key starting material (Fig. 2).
Various methods have been designed to produce 3-hydroxythiophenol. One of
the original syntheses was a three-step conversion of 3-hydroxybenzene sulfonic acid
sodium salt to monothioresorcinol-O-carboxylic acid ethyl ether followed by
[4]
hydrolysis to 3-hydroxythiophenol. Sourcing the sodium sulfonate was problem-
atic, thereby limiting the usefulness of this procedure. Another group reacted
3
-hydroxybenezene sulfonic acid sodium salt with phosphorus pentachloride to pro-
vide 3-hydroxybenzenesulfonyl chloride, which was then reductively coupled to give
[5]
bis-(3-hydroxybenzene)disulfide. Independently, Haitinger and Leuckart described
[
reducing this disulfide to 3-hydroxythiophenol by two different routes. Again,
6]
Received July 20, 2011.
Address correspondence to Tim Biggs, INDSPEC Chemical Corporation, 1010 William Pitt Way,
Pittsburgh, PA 15238, USA. E-mail: tim_biggs@oxy.com
8
77

878
T. BIGGS ET AL.
Scheme 1. Strained novel heterocyclic meta-cyclophane.
sourcing the raw material was an issue. Also reported in the literature was the
reaction of aqueous potassium ethylxanthate with the diazonium salt of 3-
[7]
aminophenol. High temperatures and high pressures when using diazonium
[
8]
xanthates have been well documented and limit their use. These undesirable char-
acteristics are also shared by the gaseous hydrogen sulfide reaction with 3-chlorophe-
ꢀ
[9]
nol at 500–600 C to provide 3-hydroxythiophenol.
A later procedure
demonstrated reaction of 3-methoxyphenyl methyl sulfide with sodium diethylamide
and hexamethylphosphoric triamide in refluxing xylene to give 3-hydroxythiophe-
[
10]
nol. This method is labor intensive and expensive. A 2003 publication disclosed
two synthetic approaches. First, 3-nitrobenzene-sulfonyl chloride was reductively
[11]
Figure 1. Immunosuppressant KRP-203 and benzothiophene PPAR agonist.

IMPROVED 3-HYDROXYTHIOPHENOL SYNTHESIS
879
Figure 2. Eli Lilly’s raloxifene.
converted to a disulfide, followed by a second reduction to 3-hydroxythiophenol.
The next approach consisted of silylating 3-bromophenol with trimethylsilylchloride,
then reacting it with magnesium to form the Grignard. The Grignard was then
coupled with elemental sulfur, followed by hydrolysis to remove the protecting silyl
group to afford 3-hydroxythiophenol. While both approaches are reasonably
straightforward, sourcing 3-nitrobenzenesulfonylchloride and 3-bromophenol is
not. The raw materials are expensive and certainly not available in ton quantities.
As a resorcinol producer, INDSPEC recently has recognized its unique pos-
ition as a bulk supplier of 3-hydroxybenzene sulfonic acid sodium salt, the precursor
to 3-hydroxythiophenol. Resorcinol can be converted quite easily to 3-hydroxyben-
zenesulfonic acid sodium salt, overcoming the sourcing hurdle disclosed earlier. A
simple, two-step route to 3-hydroxythiophenol from 3-hydroxybenzene sulfonic acid
sodium salt was developed that eliminates the need to form the disulfide in the earlier
process. Reaction of 3-hydroxybenzene sulfonic acid sodium salt with thionyl chlor-
ide yields 3-hydroxybenzene-sulfonyl chloride. This sulfonyl chloride is then treated
with iodine and red phosphorus in acetic acid, providing good yields (>80%) of
3-hydroxythiophenol (Scheme 2). Additionally, red phosphorus can be recycled sim-
ply by washing with water and then drying.
In summary, a straightforward and inexpensive route to 3-hydroxythiophenol
from readily available 3-hydroxybenzene sulfonic acid sodium salt has been developed.
Scheme 2. 3-Hydroxythiophenol from 3-hydroxybenzene-sulfonyl chloride.

880
T. BIGGS ET AL.
The two-step process is efficient and yields high-purity 3-hydroxythiophenol without
the need to form a disulfide intermediate.
EXPERIMENTAL
Proton NMR spectra were acquired using a Bruker AC300 NMR spectrometer,
equipped with a 5 mm multinuclear probe. The solution concentration is 0.6 M in
methanol-d4 (Cambridge Isotope Laboratories DLM-24). The chemical shifts are
in parts per million (ppm) and the coupling constants are in hertz (Hz). The Fourier
transform–infrared (FT-IR) spectra were obtained using a Perkin-Elmer System 2000
FT-IR spectrometer as a thin liquid film between sodium chloride plates.
3-Hydroxybenzene Sulfonyl Chloride
3-Hydroxybenzene sulfonic acid sodium salt (91 g, 0.46 mols) and dimethylfor-
mamide (DMF) (4 g) were added to a dry 1-L, three-necked flask equipped with a mag-
netic stirrer, thermometer=thermowell, and tap water–cooled condenser. Thionyl
ꢀ
chloride (400 g, 3.3 mol) was slowly added with offgas and exotherm to 80 C. After
0% of the thionyl chloride was added, the pot was cooled to ambient temperature
2
and external heating to 70–80 C was necessary. After addition of the thionyl chloride,
ꢀ
ꢀ
the reaction was stirred for 1 h at 70–80 C. At this point, the temperature was lowered
ꢀ
to 20–25 C. The reaction vessel contents were slowly added to a beaker containing ice
ꢀ
(
600 g). The mixture exothermed with the temperature, never rising above 30 C. The
mixture was added to a separatory funnel containing methylene chloride (800 mL).
The organic layer (lower) was dropped out and washed with water (2 ꢁ 200 mL) and
then with saline (1 ꢁ 100 mL), and dried with sodium sulfate (30 g). Concentration
in vacuo (rotary evaporator) yielded a tan solid (80 g, 91% yield) characterized as
1
-hydroxybenzene sulfonyl chloride by H NMR and suitable for the next step.
3
3-Hydroxythiophenol
3-Hydroxybenzene sulfonyl chloride (80 g, 0.42 mols), acetic acid (250 g) and
red phosphorus (50 g) were added to a dry, 500-mL three-necked flask equipped with
a magnetic stirrer, thermometer=thermowell, and tap water–cooled condenser. The
ꢀ
mixture was agitated and heated to 110 C, whereupon 0.1 g iodine in 5 mL acetic
acid was added slowly. The reaction exothermed several degrees, and then stabilized.
ꢀ
Stirring was continued at 110 C for 1 h. The reaction temperature was decreased to
ꢀ
ꢀ
1
00 C, and water (50 g) was added. The reaction mass was stirred at reflux (110 C)
ꢀ
for 1 h. At this point, the temperature was dropped to 25–30 C and the reaction was
filtered to remove red phosphorus. The filtrate was added to a separatory funnel with
diethyl ether (500 mL). The organic layer was removed, washed with water
(
2 ꢁ 100 mL) and then saline (1 ꢁ 50 mL), then dried with sodium sulfate (30 g).
Concentration in vacuo (zero plate distillation column) yielded colorless
ꢀ
3
8
-hydroxythiophenol (42 g, 81% yield, 97% pure); bp 105-108 C at 0.5 mm Hg.
IR (neat): 3378 (br, OH), 2563 (SH), 1582, 1474, 1440, 1302, 1245, 1102, 997,
ꢂ1 1
81, 772, 680 cm . H NMR (300 MHz, CDCl ); d ¼ 3.47 (s, 1H), 4.9 (s, very broad,
3

IMPROVED 3-HYDROXYTHIOPHENOL SYNTHESIS
881
1
H), 6.63–6.65 (dd, J ¼ 7.9, J ¼ 2.1 Hz, 1H), 6.78 (t, J ¼ 1.8 Hz, 1H), 6.85 (d,
1
2
J ¼ 7.6 Hz, 1H), 7.11 (t, J ¼ 7.9 Hz, 1H).
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