C.-C. Han, R. Balakumar / Tetrahedron Letters 47 (2006) 8255–8258
8257
Table 3. Reaction conditions and products for the conversion of
benzyl thioacetate to thiol at 20 ꢁC under nitrogen atmosphere
Table 4. Reaction conditions and products for a single step conversion
of benzylic bromides to thiols in 1 h at 20 ꢁC using K2CO3 as base
under nitrogen atmosphere
Base (1.2 equiv.), Solvent
BzSAc
BzSH
20 °C
Method A
Method B
(i) HSAc (1.2 equiv.)
K2CO3 (2.2 equiv.)
THF / 0.5 h / N2
(i) HSAc (1.2 equiv.)
K2CO3 (1.2 equiv.)
MeOH / 0.5 h / N2
Entry
Base
Solvent
Time (h)
Yield (%)
BzSAc/BzSH/
BzSSBz
BzBr
BzSH
BzSH
1
2
3
4
5
6
7
8
9
10
11
12
13
K2CO3
NaHCO3
NaHCO3
Et3N
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
Acetone
CH3NO2
CHCl3
CH2Cl2
Et2O
0.5
1
—
96
28
83
—
69
—
59
—
—
—
—
—
—
—
(ii) K2CO3 (1.2 equiv.)
0.5 h / N2
(ii) MeOH / 0.5 h / N2
65
5
16
—
8
—
11
—
—
—
—
—
—
15
0.5
15
0.5
15
15
15
15
15
15
15
—
100
23
100
21
100
100
100
100
100
100
Entrya,b Substrate
Solvent Yield (%)
BzSH
Et3N
Pyridine
Pyridine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1
2
3
4
5
6
7
8
Benzyl bromide
MeOH
MeOH
MeOH
96
98
99
97
94
99
97
94
2-(Bromomethyl)biphenyl
4-Bromobenzyl bromide
1,4-Bis(bromomethyl)benzene MeOH
Benzyl bromide
THF
THF
THF
2-(Bromomethyl)biphenyl
4-Bromobenzyl bromide
1,4-Bis(bromomethyl)benzene THF
a Entries 1–4 used method A and entries 5–8 used method B. In method
A, the base was added in two portions within the first 0.5 h; while in
method B, after the base was added as one portion and stirred for
0.5 h, an equal volume of MeOH was added to the reaction solution.
b In entries 4 and 8, the base equiv is proportional to the number of
bromo groups and the product is a dithiol.
search for the suitable base/solvent combination for the
second step. Accordingly, with benzyl thioacetate as the
substrate, the different combinations of bases and sol-
vents were tried out. The results are presented in Table 3.
The results in Table 3 indicate that in MeOH, K2CO3
(1.2 equiv) can rapidly convert thioester to thiols with
high yield (96%) in as short as 0.5 h (entry 1). Weaker
bases such as NaHCO3 (entry 3), Et3N (entry 5), and
pyridine (entry 7) can also give good or fair yields of
thiol, but they require much longer reaction time
(15 h). With regard to the solvent, it is interesting to
note that the reaction is facilitated only in methanol;
whereas in all other solvents (entries 8–13) only the
starting material was recovered.
sults in entries 5–8 of Table 4 show that similar high
yields of thiols can also be obtained using this approach.
When this reaction strategy (method B) was applied to
other solvent like acetone, the reactions also worked
well except that longer reaction times were required.
The fact that the reaction proceeded slowly in acetone
than in THF is probably due to polarity differences in
their corresponding resultant co-solvent systems.
Based on our systematic studies, we felt that K2CO3/
methanol is the most ideal combination of reaction con-
dition to achieve a single step conversion of benzylic
bromides to thiols. To avoid the formation of sulfide
(as we have encountered in entry 1 of Table 1), we
decided to add the base in a portionwise fashion as illus-
trated in method A of Table 4 (entries 1–4) for a variety
of bromide substrates. Sure enough, we are able to syn-
thesize thiols directly from benzylic bromides with very
high yields (94–99%) at rt within 1 h.
In conclusion, efficient and very mild reaction methods,
for the synthesis of benzylic thiols directly from benzylic
bromide using rather mild bases at rt within 1 h with
very high yields, have been successfully established.
Our results indicate that a polar solvent like methanol
and THF, and a milder base like K2CO3 have been
proved to be the ideal solvent/base combination to
achieve a high yield of thiols from benzylic bromides
in a single step. The two proposed methods can be used,
depending on the reactivity natures of the employed
substrates. For example, if the first step (i.e., formation
of thioester) is fast enough than the second step (i.e.,
deacetylation), then method A (K2CO3/methanol) can
be used. Alternatively, when the first step is relatively
slower, then method B should be used. In method B,
the use of an organic solvent other than MeOH is served
as an effective strategy to suppress the deacetylation at
the initial stage to prevent the premature formation of
the thiols, which would otherwise be converted into
the corresponding sulfides in the presence of a large ex-
cess amount of base and unreacted benzylic bromides.
Certainly, method B is particularly suitable for those
benzylic halides having relatively poorer solubility in
MeOH. A detailed study is under progress to apply
these reaction methods to other alkyl halides.
In addition, we envisaged that method B may also work
well for a single step conversion of the benzylic bromides
to thiols (entries 5–8). We felt the fact that the solvents
other than methanol do not interfere in the deacetyl-
ation process can be used to our advantage. For example,
since polar solvent like THF works quite well for the
first step, it can be used as the solvent for the formation
of thioester by adding all the required base K2CO3
(2.2 equiv) in one portion at the very beginning. After
the reaction mixture was stirred for a sufficient time
(ꢀ0.5 h for entries 5–8), an equal volume of methanol
can then be added as a cosolvent (or as a promoter) to
initiate the deacetylation step. In this way, we felt we
can avoid the formation of sulfide byproduct. The re-