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Published on the web December 2, 2010
Sequential One-pot Reactions of Thioformates with Lithium Silylacetylides,
Arylmagnesium Halides, and Electrophiles Leading to Formation of Propargyl Sulfides
Toshiaki Murai,* Takayuki Ohashi, and Fumitoshi Shibahara
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193
(Received October 12, 2010; CL-100873; E-mail: mtoshi@gifu-u.ac.jp)
One-pot reactions of thioformates with lithium silylacety-
PhMgBr
3
TMSC CLi
SPh
S
lides, arylmagnesium halides, and electrophiles that produce
propargyl (2-propynyl) sulfides are described. The pathway for
this process begins with addition of lithium (trimethylsilyl)ace-
tylide to the thioformate C=S carbon. This step is followed
by addition of the arylmagnesium halide to the sulfur atom of
the C=S group in the in situ generated propynethial. The
intermediacy of the propynethial in this process was confirmed
by trapping through a Diels-Alder reaction with cyclopenta-
diene.
2
Et2O
–78 °C– –18 °C
H
OR
4
TMS
1
2.5–3.5 h
1a R = C8H17-n
59%
66%
1b
R = CH(CH3)(CH2)3CH3
Scheme 1.
SLi
OR
SPh
S
-ROLi
TMS
3
2
1
MgBr
H
H
5
TMS
6
TMS
7
Addition reactions of organolithium and Grignard reagents
to carbonyl compounds are among the most traditional, well-
established processes in synthetic organic chemistry.1 Studies
using thiocarbonyl compounds as substrates in these addition
reactions2 have uncovered the striking feature that organolithium
and Grignard reagents add to these reagents at both carbon
and sulfur of the C=S moiety, depending on the substitution
patterns. For example, phenyllithium undergoes thiophilic
addition to thiobenzophenone3 and (2,4,6-tri-t-butyl)thiobenzal-
dehyde,4 whereas addition of Grignard reagents to thioaldehydes
takes place at both carbon and sulfur in the C=S group.4 In
recent studies that were guided by the aim to develop sequential
one-pot reactions,5 we uncovered an addition reaction in which
two different organometallic reagents add successively to
thioiminium salts derived from thioamides6 and to thioform-
amides directly.7 In these transformations, the organometallic
reagents selectively add to the carbon atom of the thiocarbonyl
group. In more recent investigations aimed at applying this
process to thioformate substrates, we observed that both the
thiocarbonyl carbon and sulfur serve as electrophilic centers
when two different organometallic reagents are used. Below, we
describe the results of this effort, which have led to the
development of a novel sequential reaction between thiofor-
mates, lithium silylacetylide, arylmagnesium halides, and
electrophiles that leads to the production of propargyl sulfides.
In initial studies, thioformates 18 were subjected to
sequential addition reactions with lithium (trimethylsilyl)acety-
lide (2) and phenylmagnesium bromide (3) since these combi-
nations have led to better results in the reaction of thioamides.6
Aqueous workup of the reaction mixtures gave rise to the
propargyl sulfide 49 (Scheme 1) in yields that were only slightly
influenced by the alkoxy group in 1. The highest yield of 4 was
obtained when 1b was used as the substrate.10 Inspection of the
product of these reactions shows that lithium acetylide 2 was
introduced at the C=S carbon in 1 whereas the Grignard reagent
added to the sulfur atom. Among the lithium acetylides tested,
only the one derived from (trimethylsilyl)acetylene led to
efficient formation of products. Since the silyl group at the
terminal position of the products can be used to affect carbon-
Scheme 2.
S
TMSC CLi
S
8
2
Et2O
OR
9
rt, 2 h
H
TMS
1b
–78 °C then –18 °C, 3 h
65% 61:39 dr
Scheme 3.
carbon bond forming reactions, the process described above
is potentially applicable to the preparation of a variety of
derivatives of the sulfide 4.
A plausible mechanistic pathway for this process, given in
Scheme 2, involves initial nucleophilic addition of 2 to the C=S
carbon in 1 to form lithium hemithioacetals 5. Elimination of
ROLi from 5 then generates the propynethial 6, which reacts
with phenylmagnesium bromide at sulfur to form propargyl-
magnesium bromide 7. Finally, aqueous workup produces the
propargyl sulfide 4. Evidence for the existence of intermediate
thioaldehyde 6 in this pathway was gained by addition of excess
cyclopentadiene 8 to the mixture formed by reaction of 1b and 2.
This process leads to formation of adduct 9, derived by the
Diels-Alder reaction between 6 and 8, in a manner similar to
known cycloaddition reactions of thioaldehydes11 (Scheme 3).
We envisioned that the in situ generated propargylic
Grignard reagent 7 could be used as a novel nucleophile in
reactions with a variety of electrophilic reagents. The results of
studies probing reactions of 7 with alkyl halides, trimethylsilyl
chloride, and carbonyl compounds are shown in Table 1. In all
cases, sequential reactions took place to yield the corresponding
propargyl sulfides. For example, addition of methyl (10a) and
propyl iodide (10b) to mixtures containing 7, formed by reaction
of 1b, 2, and 3, at ¹18 °C leads to formation of the respective
alkylation products 11a and 11b (Entries 1 and 2). Trimethylsilyl
chloride also participates in a reaction that affords 11c (Entry 3).
Allylation of in situ generated 7 also occurs upon treatment with
the allylic halide 10d to give 4-phenylsulfanyl-1,5-enyne 11d
(Entry 4). Also, reactions of aldehydes 10e-10g with in situ
Chem. Lett. 2011, 40, 70-71
© 2011 The Chemical Society of Japan
Murai, Toshiaki
