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C. W. Downey et al. / Tetrahedron Letters 55 (2014) 5213–5215
Nonetheless, the intriguing ability of PMBME to act as an alkylating
agent led us to examine other nucleophiles that are compatible
with TMSOTf. The use of silylated thiol nucleophiles in thioketal-
ization reactions,9 heteroconjugate additions,10 and epoxide open-
ings11 is well established. Very recently, Baba et al. reported the
indium-catalyzed alkylation of silylated thiols with alkyl ace-
tates.12 Accordingly, in situ generation of a silylated thiol in the
presence of a benzyl cation appeared to be a prime opportunity
to observe alkylation.
Optimization studies suggested that the use of iPr2NEt and
CH2Cl2 was optimal for efficient alkylation in the presence of
TMSOTf (Table 1). The reaction performed well even when PMBME
was the last reactant added to the mixture, which suggests that
silylated thiols formed in situ are quite reactive with the putative
cationic electrophile. The reaction was somewhat sensitive to the
stoichiometry of PMBME. To wit, when greater than 1.1 equiv
PMBME was present, byproduct generation often resulted from
either over alkylation at sulfur (preferred) or Friedel–Crafts
alkylation of the aryl rings on the product.
A brief survey of the reaction scope revealed that aryl thiols are
excellent substrates (entries 1–3). In the case of 4-bromothiophe-
nol (entry 3), a larger excess of PMBME could be used without
competing byproduct formation, which resulted in very high yield.
Aliphatic thiols were more challenging. Although benzyl thiol
underwent alkylation with moderate yield (entry 4), octanethiol
did not provide any thioether product under our reaction condi-
tions (entry 5). Previous experience with aliphatic thiols in our
group suggested that a stronger base might be necessary to
activate octanethiol,13 but the replacement of trialkylamines with
KOt-Bu under a variety of conditions did not result in an increase
in yield.
When 2-mercaptothiazoline was subjected to the reaction
conditions, it provided the S-alkylation adduct with no observed
reactivity at the nitrogen center (entry 6), a result in accord with
literature precedent14 and in striking contrast to the highly regio-
selective N-acylation reactions of this substrate.15 When TMSOTf,
iPr2NEt, and 2-mercaptothiazoline were mixed in CD2Cl2, 13C
NMR spectroscopy showed the presence of a peak at 206 ppm. This
resonance is consistent with the presence of a thiocarbonyl, which
suggests that silylation of 2-mercaptothiazoline occurs primarily at
nitrogen (Eq. 3). This S-silylation may prevent competitive N-alkyl-
ation when PMBME is included in the reaction mixture.
ð3Þ
Encouraged by the ability of PMBME to act as an efficient alkyl-
ating agent for thiols, we moved on to aryl ketone pronucleophiles.
These alkylation reactions require the in situ generation of enol
silane nucleophiles through the action of trialkylamine base and
TMSOTf, such that the silylating agent must play a role in the acti-
vation of both the nucleophile and the electrophile if alkylation is
to occur.16 Previous work from our group suggested that enol
silane generation would not be problematic,5a,17 and we were grat-
ified to observe high yields of the alkylation product for a variety of
aryl ketones (Table 2). Again, the use of larger excesses of PMBME
(e.g., 1.5 equiv) consistently generated byproducts derived from
Friedel–Crafts alkylation of the desired product with excess
PMBME.
A range of electron-rich and electron-poor acetophenone deriv-
atives reacted smoothly, as did the more sterically encumbered
acetonaphthones (Table 2, entries 1–6). Propiophenone and alkyl
(two alkyls are necessary to describe the substitution pattern to
either side of the carbonyl) alkyl ketones appeared to be unreac-
tive, but modest success was achieved with the thioester substrate
S-phenyl thioacetate. The yield for thioester 4g was reduced
because of significant byproduct formation. Analysis of the byprod-
uct showed that it was thiophenol alkylation adduct 3a, presum-
ably generated through deacylation of the thioester and
subsequent attack of the thiolate-derived nucleophile upon the
PMB cation.
Despite the successes presented here, nucleophile scope for this
reaction is somewhat narrow. Most notably, alcohol- and amine-
based nucleophiles failed to produce appreciable yields of
Table 2
Table 1
Alkylation of aryl ketones with PMBME
Alkylation of thiols with PMBME
Entrya
RCOMe
Product
Yieldb (%)
Entrya
1
RSH
Product
Yieldb (%)
75
1
2
4a
4b
82
67
3a
3
4
4c
88
92
2
3
3b
3c
89
4d
96c
5
4e
82
4
5
6
3d
3e
3f
58
6
7
4f
75
NDd
70e
4g
47c
a
b
c
All reactions performed on 1.00 mmol scale in 5 mL CH2Cl2.
Isolated yield after chromatography.
Reaction performed with 1.5 equiv PMBME.
ND = not determined.
a
b
c
All reactions performed on 1.00 mmol scale in 5 mL CH2Cl2.
Isolated yield after chromatography.
Reaction was performed with Et3N instead iPr2NEt, and was stirred for 1 h
d
e
Reaction performed with 1.3 equiv TMSOTf and 1.2 equiv iPr2NEt.
instead of 16 h. Major byproduct was thioether 3a.
Downey, C. Wade
