Several methods are known for the reductive scission of
heterocyclic thioethers and follow two general routes
(Figure 1). One route involves the single-step reductive
scission to directly afford the parent heterocycle. Raney
nickel has become the most common reagent for the single-
step reduction.6 Less common reagents include Raney
copper,7 NiCl2/NaBH4,8 NiCRA/NiCRAL,9 Zn/HCl,10
Zn/AcOH/Ac2O,11 Red-Al,12 Al/HgCl213 and hydrazine-
Pd/C.14 These methods can sufferfrom low yields and poor
chemoselectivity. In addition, the use of stoichiometric
quantities of metal can complicate purification and presents
waste disposal and safety issues. A second common route
involves a two-step process: oxidation to the sulfoxide or
sulfone followed by reduction.15 Chemoselectivity can be a
major issue in the presence of functional groups which are
readily oxidized, and the oxidationÀreduction route also
suffers from inferior redox16 and step economy.17
systems was considered (Figure 2). The reduction of thio-
esters using triethylsilane and palladium on carbon was first
introduced by Fukuyama and later modified by others.5,18
The mild reaction conditions and chemoselectivity of the
Fukuyama reduction have been demonstrated on complex
and chemically sensitive systems.19 For the present study,
the principal insight was the recognition that heterocyclic
compounds often retain the reactivity of the carbonyl
compounds from which they are often derived.20 An addi-
tional precedent was the work of Castle and co-workers
which demonstrated the use of triethylsilane and Lindlar
catalyst to reductively cleave 4-(methylthio)pyridones.21
A tangential precedent was the reductive scission of a thio-
methylborondipyrromethene with triethylsilane, Pd2(dba)3,
tri(furan-2-yl)phosphine, and copper 2-thienylcarboxylate
(CuTC) in THF at 55 °C; however, an alternative mechan-
ism was suggested because the standard Fukuyama condi-
tions were not effective and CuTC was required.22 Based on
these prior works, a general method was developed for the
mild and selective removal of thioether substituents from
heterocycles.
Initial studies focused on 2-(alkylthio)pyrimidines be-
cause of the frequent occurrence of this motif and because
of the requirements of the current medicinal chemistry
campaign. The scope of the method was evaluated with a
variety of 2-(alkylthio)pyrimidines (Table 1). Methyl (1a),
ethyl (1b), and benzyl (1c) thioethers were removed in
89À93% yields. Similarly substituted aminopyrimidine 1d
and hydroxypyrimidine 1e afforded the corresponding
products in 86% and 73% yields, respectively. A variety
of phenyl substitutions (1fÀi) as well as trifluoromethyl
substitution (1j) also afforded products. N-Benzyl-substi-
tuted pyrimidines (1iÀm) were tolerated by the reductive
reaction conditions and provided the corresponding pro-
ducts in 67À96% yields. Substrates 1aÀd and 1iÀl, with
exchangeable protons, were readily N-silylated under the
reaction conditions and thus required a mild acid or
fluoride-mediated workup. For substrates 1aÀc, the sta-
bility of the N-triethylsilyl adduct (R2 = NHSiEt3) al-
lowed for purification by chromatography on silica gel.
The N-methyl-N-benzylaminopyrimidine 1m afforded a
lower yield compared to 1l; however, this appears to be a
consequence of both the substitution on the pyrimidine ring
(1p vs 1n, 1o) and the substitution on the exocyclic nitrogen
(1m, 1p vs 1l, 1t, 1u). Functional groups which are suscep-
tible to hydrogenation or hydrogenolysis were also evalu-
ated. A trisubstituted olefin (1q) gave a 7:1 mixture of the
desired tetrahydropyridine (2q) to the saturated piper-
idine in a combined 89% yield. A benzyloxycarbonyl-
protected amine (1r) was stable to the reaction condi-
tions. A variety of sulfur-containing functional groups,
Figure 2. Analogy between thioesters and heterocyclic thioethers.
While designing an efficient method for the reductive
scission of heterocyclic thioethers, the analogy with acyclic
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