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Cl
OCH
3
S
S
CH
3
O
S
S
HO
N
NH
O
N
HN
NO
2
O
(H
3
C)
2
N
thiazesim
gemmacin
F15845
Figure 6.3 Examples of bioactive molecules containing thioether structures.
formation is likely the lesser importance of such bonds relative to carbon-
oxygen bonds in natural products and pharmaceuticals. However, there are
numerous reports of thioethers within the structure of bioactive molecules
(Figure 6.3). For example, thiazesim acts as an antidepressant,
66
gemmacin
is a highly active antibacterial,
67
and F15845 is an antianginal agent.
68
6.4.1 Palladium-Catalyzed Cross-Coupling Reactions of Aryl
Halides With Aryl or Aliphatic Thiols
The most general catalysts developed for metal-catalyzed reactions of aryl
halides with alkyl or aryl thiols are shown in Scheme 6.13 (40,
69
41,
70
42
71,72
),
reacting equally well with both aliphatic and aryl thiols and aryl bromides or
chlorides. Owing to the nucleophilicity of the thiolate group, most of the
general catalysts bear strongly coordinating ligands. This strong coordin-
ation prevents the thiolate anion from attacking the palladium center and
displacing the ligand from the metal. If the thiolate is allowed to interact
unfavorably with the palladium center, precipitation of the catalyst as pal-
ladium black can occur, which would destroy the catalytic activity of the
metal center. Therefore, most catalysts for carbon-sulfur bond formation
work better with aryl thiols, which are less nucleophilic than alkyl thiols. If
the ligand is not strong, bulky and bidentate, zinc and/or lithium additives
can be used to attenuate the reactivity of the nucleophilic thiolate and
protect the palladium center.
69
This latter strategy was used in the devel-
opment of the palladium(I) dimer complex 40, one of the most general
catalysts for carbon-sulfur bond formation of aryl bromides. The other two
palladium catalysts shown in Scheme 6.13 have tight chelation to the metal
center.
6.4.2 Palladium-Catalyzed Intramolecular Cyclization
Reactions to Form Carbon-Sulfur Bonds
The intramolecular coupling reactions of aryl halides with thioketones have
been reported.
73
In the presence of a palladium complex formed from
Pd
2
dba
3
and DPEphos, benzothiophenes are formed from the coupling of
aryl bromides or aryl chlorides and thioketones in good yields.
73
Aryl
bromides are more reactive than aryl chlorides in this chemistry as the
formation of benzothiophene in Scheme 6.14 occurs in 30% greater yield
with the aryl bromide than with the aryl chloride starting material.
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