LETTER
1579
Palladium Catalyzed Bispyrimidine Thioether Synthesis
Molly S. Harr, Alice L. Presley, Atli Thorarensen*
Medicinal Chemistry I, Pharmacia and Upjohn, 301 Henrietta Street, Kalamazoo, MI 49001, USA
Fax (616)-833-2232; E-mail: atli.thorarensen@am.pnu.com
Received 18 July 1999
along with 0.1 equivalents of palladium (Pd(PPh ) ), pro-
ducing a comparable 48% yield of the desired thioether. In
a related sequence, 4-hydroxy-5,6-dimethylpyrimidine-2-
3
4
Abstract: The synthesis of sulfur-bridged bispyrimidines via cou-
pling of a halopyrimidine and pyrimidine thiolate anion has been
explored utilizing a palladium catalyzed cross coupling reaction.
Several reaction parameters including stoichiometry and choice of thiol was reacted with 2-bromopyrimidine and base in the
solvent have been optimized. These reaction conditions have al- presence and absence of palladium catalysis. In this case,
lowed for the preparation of a wide range of functionalized bispyri-
midines.
only the palladium catalyzed reaction afforded any of the
desired bispyrimidine thioether. In addition when t-BuOK
Key words: catalysis, palladium, pyrimidines, thioethers
was replaced with K CO and the reaction was performed
2 3
in the presence of palladium the desired product could not
be detected. Therefore, it appears that with very unreac-
tive thiol nucleophiles, such as the 2-thiopyrimidine,
strong base and palladium catalysis is essential. In con-
trast, there are limited benefits to the addition of palladi-
um in the case of a thiol with sufficient nucleophilicity,
such as thiophenol.
Palladium catalyzed carbon-sulfur bond formation is of
synthetic interest, but relatively unexplored in the litera-
ture. The reactivity of thiols is in most instances suffi-
1
cient to achieve the direct replacement of a halide or a
triflate without catalysis, resulting in formation of an aryl-
sulfur bond. Recently we had the need to prepare several
unsymmetrical bispyrimidine thioethers to evaluate the
effect on antibacterial activity when a nitrogen linker was
2
replaced with a sulfur linkage. The synthesis of bispyri-
midine thioethers has been accomplished previously
through direct nucleophilic attack of a thiolate anion on a
3
,4,5
pyrimidine halide, though in low yield.
In our case, the
direct displacement reaction failed to afford any of the de-
sired product. Alternatively the synthesis of unsymmetri-
cal bispyrimidine thioethers could involve the
intermediate of a substituted thioamidate, followed by cy-
clization with a ketoester. The lability of thioamidates to-
wards hydrolysis encouraged us to pursue an alternative
6
,7
strategy. Reports describing palladium catalyzed bisaryl
thioether synthesis from less activated thiols utilizing
8
,9
Pd(PPh3)4 or prepared palladium aryl halide complexes,
1
0,11
attracted our attention.
However, the analogous bispy-
rimidine thioether synthesis has not been investigated and
poses a synthetic challenge due to the unreactivity of the
reaction partners and the potential multiple coordination
of either the substrate or the product to the catalytic metal
resulting in inhibition of catalysis. This report details our
successful synthesis of unsymmetrical bispyrimidine thio-
ethers utilizing a variation of the Migita palladium cata-
lyzed thioether preparation. In addition, we report our
subsequent efforts to explore the scope and utility of this
reaction.
Since the reaction conditions can have a dramatic effect
on reaction efficiency, we decided to explore the effect of
different solvent systems in an attempt to improve the sol-
ubility of both coupling partners. The more readily avail-
able 6-hydroxy-4-methoxymethyl-pyrimidine-2-thiol was
utilized as the model nucleophile in the coupling reaction
In an attempt to understand the need for palladium cataly-
sis as well as the required degree of reactivity of each re-
action partner in the coupling reaction, 2-
bromopyrimidine was reacted with thiophenol in the pres-
ence of potassium t-butoxide (Table 1). After workup, a
(
Table 2). Although polar solvents such as DMSO and
4
4% yield of the desired thioether was isolated. Next, the
ethanol afforded homogeneous mixtures and were the sol-
bromopyrimidine was reacted with thiophenol and base
Synlett 1999, No. 10, 1579–1581 ISSN 0936-5214 © Thieme Stuttgart · New York