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J. Ko et al. / Tetrahedron Letters 47 (2006) 7101–7106
steps, resulted in a low yield, and was achieved under
drastic conditions. Later the Kozikowski group reported
a more efficient method for the synthesis of GW501516.6
They synthesized the key intermediate, 4-mercapto-
2-methylphenol, from o-cresol through two steps,
performed the coupling reaction with thiazole chloride
and obtained the corresponding aryl alkyl sulfide.
Recently, Hartwig and co-workers reported palladium-
catalyzed coupling of aryl chlorides with thiols using
CyPF-t-Bu ligand.7 Yet it is still inconvenient because
of the involvement of unstable thiols. Therefore, a much
simpler method, of greater efficiency, for the synthesis of
aryl alkyl sulfides containing a hydroxy functionality
has been required in organic and medicinal chemistry.
Recently, we reported the general synthesis of aryl alkyl
sulfides from aryl bromides and applied the method-
ology for the synthesis of an antiobestic drug,
GW501516.8 We then further extended our one-pot pro-
cedure to prepare hydroxylated and carboxylated aryl
alkyl sulfides. In this letter, we want to report an efficient
one-pot synthesis of aryl alkyl sulfides containing a hy-
droxy functionality such as hydroxy, hydroxymethyl,
hydroxyethyl, and carboxylic acid group via in situ pro-
tection of the group by reaction with the Grignard re-
agent, isopropyl magnesium chloride. We obtained the
corresponding sulfides in high yields (75–97%). The
method overcame many problems encountered in other
reports: being very quick, catalyst-free, and involving no
unstable thiols.
viable. In the case of entry 4 condition, 1 equiv of t-
butyllithium was used for lithium-halogen exchange
reaction and the rest of t-butyllithium (1 equiv) for the
removal of t-butyl bromide formed during the lithium-
halogen exchange.
The general procedure for these reactions is as follows.
To a solution of aryl bromide at 0 °C, a solution of
Grignard reagent (1.0 equiv) was added for the protec-
tion of the hydroxy group and then tert-butyllithium
(2.0 equiv) was added to the reaction solution at
À78 °C under nitrogen atmosphere. Through lithium-
halogen exchange of bromide by t-butyllithium, an aryl-
lithium salt was formed. Sulfur powder (1.0 equiv) was
then added to the reaction mixture, thus forming lithium
aryl thiolate. Because the generated lithium thiolate is a
good nucleophile, after adding an electrophile, the cor-
responding aryl alkyl sulfide was obtained in a good
yield.
We set up many reactions to explore the scope of this
methodology with respect to various hydroxylated and
carboxylated aryl bromides as substrates. The reaction
was unaffected by the electronic factor of aryl bromides
but moderately affected by the electrophilic affinity of
alkyl halides reacting with various lithium aryl thiolates
(see below). This one-pot procedure required very short
reaction times (1–1.5 h) and gave the products in high
yields (75–97%).
We screened suitable bases and reagent equivalence for
optimization of the reaction by using 4-bromophenol
and benzyl bromide (Table 1).
In the first part of this study, we applied this reaction to
the coupling of hydroxylated aryl bromides and various
electrophiles (Table 2). Phenols, having a bromide at -o,
-m, or -p position, readily reacted with benzyl bromide
to give the corresponding sulfides in high yields of
92%, 96%, and 92%, respectively, without regard to
the electronic factor caused by the hydroxy functionality
(entries 1–3). An electron withdrawing group such as a
fluoride on aryl bromides did not affect the reactivity
(entries 4–7, and entry 10). It was found that activated
alkyl bromides gave the corresponding sulfides in
slightly better yields than alkyl bromides did (entries 4,
6, and 7). Epoxide readily reacted with lithium thiolate,
which was formed from bromophenol, to give the corre-
sponding sulfide at a high yield (entry 10). In the case of
bromo-resorcinol having two hydroxy functionalities,
When n-butyllithium (2.0 equiv) or t-butyllithium
(3.0 equiv) was used, as a base to protect the phenolic
hydroxy group and lithium-halogen exchange reagent,
the reaction gave a low yield and resulted in many impu-
rities (entries 1 and 2). However, in the case of a Grig-
nard reagent, such as isopropyl magnesium chloride,
being used as a base, the yield was high and the level
of impurities decreased (entries 3 and 4). In entry 3,
n-butyl bromide, which is formed by lithium-halogen
exchange reaction, competed with benzyl bromide in
nucleophilic substitution reaction, thus forming 4-butyl-
sulfanylphenol as a side product. Therefore, the use of n-
butyllithium as a lithium-halogen exchanger was not
Table 1. Optimization of reaction conditions for one-pot synthesis of sulfidea
Br
conditions
S
HO
HO
Entry
Conditions
% Yieldb
1
2
3c
4
n-BuLi (2.0 equiv), sulfur, benzyl bromide, THF
31
39
52
92
t-BuLi (3.0 equiv), sulfur, benzyl bromide, THF
iPrMgCl (1.0 equiv), n-BuLi (1.0 equiv), sulfur, benzyl bromide, THF
iPrMgCl (1.0 equiv), t-BuLi (2.0 equiv), sulfur, benzyl bromide, THF
a All reactions were performed with 4-bromophenol (0.5 mmol), sulfur (1.0 equiv), and benzyl bromide (1.0 equiv).
b Yields refer to the average isolated yield of two runs.
c 4-Butylsulfanylphenol was isolated as a side product at 35% yield.
Ko, Jaeyoung
