examples have been achieved in a regioselective manner.7
Generally, 2-blocked thiazoles were used to ensure the
selective 5-arylatedthioazoles,4o and conversely, the 5-sub-
stituted thiazoles were adopted to facilitate the formation
of 2-arylated thiazole derivatives.8 Notably, for all the
successful examples, either the air- and moisture-sensitive
Pd(PPh3)4 or an additional ligand set was used to promote
both efficacy and selectivity.9 Therefore, the development
of sustainable processes for direct functionalization of the
thiazole moiety in a regioselective fashion is still highly
desirable for practical synthetic application. Herein we
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Figure 1. Representatives of thiazole-containing compounds.
demonstrated a new development in the regioselective
arylation of thiazole derivatives via Pd catalysis under
ligand-free conditions.
It is known that the C-5 position of the thiazole moiety
possesses high electron density. Therefore, electrophilic
palladation usually occurred at this site. Subsequent re-
ductive elimination based on this prediction would deliver
the 5-selective functionalization of the thiazole scaffold.
Based on this concept, Pd(OAc)2 was initially examined as
a catalyst for the reaction of 4-methylthiazole (2a) with
phenyl iodide (1a) in the presence of 1.0 equiv of Cs2CO3 in
DMF (2.0 mL) at 140 °C. To our delight, in the presence of
10 mol % of Pd(OAc)2, the reaction proceeded smoothly
to afford the desired 5-phenylated 4-methylthiazole (3aa)
in 54% yield, together with a detectable 2,5-diphenylated
4-methylthiazole as a byproduct (Table 1, entry 1).
Encouraged by this preliminary result, a variety of Pd-
(II) species were evaluated (see Supporting Information,
Table S1). We found that Pd(OPiv)2 was the optimal
catalyst, providing the desired product in 80% yield. Using
other inorganic bases led to no improvement in the reac-
tion performance. It is noteworthy that, in the absence
of the base, the reaction did work while delivering the
5-phenylated product with a negligible yield (only 5%).
Obviously, no reaction took place in the absence of Pd species
(Table 1, entries 7 and 14). Solvent screening indicated that
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Advance Article, DOI: 10.1039/C3SC52199K.
Org. Lett., Vol. 15, No. 22, 2013
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