Scheme 1
Table 1. Suzuki and Stille Couplings of Scaffold 4
to thioether 2 by reaction with sodium hydroxide and methyl
iodide followed by bromination afforded the known com-
pound 5-bromo-2-methylthiouracil (3).8 Synthesis of 4 was
accomplished by regioselective N-alkylation with tert-butyl
bromoacetate as described in Scheme 1. It is important to
emphasize the simplicity of this rapid large scale assembly
of a heterocyclic scaffold with three orthogonal points of
reactivity.
Table 1 depicts the isolated and purified yields9 of standard
Suzuki-Miyaura and Stille couplings at the bromide position
of 4. In all cases, the principal product observed by analysis
of the crude LCMS was formed via the desired bromide
cross-coupling reaction. No lone cross-coupling at the
thiomethyl center was detected, and only traces of double
coupling products were observed. In some cases (entries 1
and 2), anhydrous conditions with Cs2CO3 afforded accept-
able results. In reactions for which conversions were under
75% using Cs2CO3 as base (entries 3-7), aqueous carbonate
conditions proved very effective for acceleration of the
transmetalation step. The Stille variants (entries 8-10) were
somewhat sluggish compared to the Suzuki cases and
required higher temperatures and additional catalyst to
proceed to completion. Still, under these more stringent
conditions, good conversions and excellent selectivities were
observed.
Table 2 depicts the isolated and purified yields9 of selective
cross-couplings at the thiomethyl position of 4 in the presence
of the Suzuki- and Stille-active bromide. This unique
selectivity is effected by the use of a Cu(I) carboxylate as a
metal cofactor of higher thiophilicity than the Pd catalyst.7
In addition to facilitating transmetalation from boron or tin
a 10% catalyst. b 3%catalyst. c 105 °C.
to the -Pd-SMe bond,7 the results reported herein suggest
that interaction of the soft sulfur atom with the soft Cu(I)
metal facilitates selective oxidative addition at the thiomethyl
center through direct polarization of the C-S bond and/or
through coordination of the adjacent pyrimidine nitrogen.10
An elegant study reported by Jacobi, which supports this
hypothesis, details the activation of a methylthioimidate C-S
bond for oxidative addition to Pd(0) by Lewis acid coordina-
tion of the imidate nitrogen. The study also found that direct
(7) (a) Heteroarylthioethers: Liebeskind, L. S.; Srogl, J. S. Org. Lett.
2002, 4, 979. Egi, M. Liebeskind, L. S. Org. Lett. 2003, 5, 801. Alphonse,
F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett.
2003, 5, 803. For other thioorganic cross-couplings, see: Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2001, 3 (1), 91. Savarin, C.; Liebeskind, L.
S. Org. Lett. 2001, 3 (14), 2149. Srogl, J.; Liebeskind, L. S. Org. Lett.
2002, 4 (6), 979. Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L. Org.
Lett. 2002, 4 (6), 983. Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C.
Pure Appl. Chem. 2002, 74 (1), 115. Egi, M.; Wittenberg, R.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2003, in press.
(10) An alternative explanation of the unique selectivity requires rapid
and reversible oxidative addition to both the C-Br and C-SMe bonds
followed by highly selective Cu(I) carboxylate activation of transmetalation
at the C-Pd-SMe center under these nonbasic conditions.
(8) Barrett, H. W.; Goodman, I. Dittmer, K. J. Am. Chem. Soc. 1948,
70, 1753.
(9) Unoptimized.
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Org. Lett., Vol. 5, No. 23, 2003