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A. Bunrit et al. / Tetrahedron Letters 52 (2011) 3124–3127
efficiency to provide bromoalkenes 6 in excellent ratios and high
LiBr, TMSCl,
TEAB
CH3CN, MW
yields in most cases. In stark contrast to conventional heating (vide
supra), homopropargyl alcohol (5a) was smoothly hydrobrominat-
ed under microwave irradiation to give 6a and 7a (93:7 ratio) in
90% combined yield as determined by 1H NMR spectroscopy (entry
1). These results clearly confirmed the importance of microwave
irradiation in this protocol. Functional groups such as aromatic
rings, ester, carbonate, carbamate, and carboxylic acid were well-
tolerated under the reaction conditions (entries 5–6, and 8–11).
Limitations were observed with some substrates. Alkyne 5b (entry
2), for example, was hydrobrominated in only 48% yield at 54%
conversion, possibly due to the intramolecular participation from
the hydroxy group which hindered the desired reaction or gave
other side products.12 Hydrobromination of 1-hexyne (5d; entry
4) proceeded in 93% conversion. However, the yield as determined
by 1H NMR spectroscopy was modest which may be due to the vol-
atility of the products. Also, for alkynes 5c and 5g (entries 3 and 7)
we observed partial desilylation and saponification, respectively,
leading to incomplete reactions.
2-Bromo-1-alkenes obtained by the current procedure are free
of the ammonium salt and are sufficiently clean to be used directly
in subsequent transformations. For example, upon hydrobromina-
tion of 5a under the optimized conditions, the resulting crude mix-
ture of 6a and 7a was subjected to Sonogashira cross-coupling with
phenyl acetylene to give enynes 8 and 9 in 83% overall yield as an
inseparable mixture (Scheme 3).
In conclusion, the combination of LiBr, TMSCl, and TEAB in ace-
tonitrile under microwave irradiation presents an efficient and
selective reagent system for the hydrobromination of many 1-al-
kynes. The procedure is simple to conduct and the conditions are
well-tolerated by many functional groups. The current protocol
also allows for the convenient generation of HBr of known and ex-
act stoichiometry from known amounts of reagents. Sufficiently
clean 2-bromo-1-alkene products can be isolated conveniently by
filtration to remove solid by-products and can be used directly in
subsequent synthetic transformations. The current hydrobromina-
tion of terminal alkynes to give 2-bromo-1-alkenes should provide
an efficient, safe, and convenient access to this important and use-
ful synthetic building block.
OH
Br
Br
HO
+
6a
7a
40 °C, 60 min
5a
HO
Crude; 6a:7a = 93:7
PdCl2(PPh3)2, Et3N
CuI, THF, reflux
HO
+
8
Ph
HO
Ph
9
83% over 2 steps
8:9 = 93:7
Scheme 3. Sonogashira cross-coupling performed on the crude products from
hydrobromination of homopropargyl alcohol.
at reflux, resulted in the formation of HBr which added to the
homopropargyl alcohol. Although the reaction proceeded in only
58% conversion after 3 h, we found that the desired 6a was ob-
tained as the major isomer (6a:7a = 87:13) in a combined yield
of ca. 46% as determined by 1H NMR spectroscopy using toluene
as the internal standard. We then attempted this reaction again
by adding water to the acetonitrile while keeping all the other con-
ditions identical and found that the reaction still could not be dri-
ven to completion.
In an attempt to further optimize the reaction, propargyl alco-
hol (2) was chosen as the representative 1-alkyne substrate as it
is less expensive than homopropargyl alcohol. In contrast to con-
ventional heating, we found that microwave irradiation8 could
accelerate hydrobromination of 2 to completion within one hour
using acetonitrile without the need of added water. Microwave
irradiation was therefore used in our subsequent studies. Other
reaction variables, including reagent equivalents, concentration ef-
fect, temperature and solvent, were investigated, the results of
which are summarized in Table 1.
Acknowledgements
When using commercial grade MeCN, we found that with
microwave irradiation at 80 °C for 60 min, higher reagent equiva-
lents led to high conversion, a good 3:4 ratio and modest combined
yield (entries 1 and 2). By increasing the concentration of alcohol 2
from 0.57 to 0.86 M using the same equivalents of LiBr and TMSCl,
the yields could be improved significantly (compare entries 1 and
3, and 2 and 4). We also found that when the concentration of 2
was increased to 1.72 M, the number of equivalents of the reagents
could be lowered to 1.5 to achieve 100% conversion with an accept-
able 3:4 ratio and excellent combined yield (entry 6). Finally, addi-
tion of 0.2 equiv of tetraethylammonium bromide (TEAB) as an
HBr-transferring agent9 allowed the reaction to proceed at a much
lower temperature (40 °C) yielding the products in an excellent
90:10 ratio and quantitative combined yield (entry 7). As a result,
we used TEAB in our standard protocol for the hydrobromination
reaction of terminal alkynes. TEAB can be easily removed by simple
filtration of the crude reaction mixture after treatment with water
and sodium sulfate (Na2SO4).10,11 Interestingly, under the current
conditions the reaction performed in CH2Cl2, a typical solvent used
in the hydrobromination reaction, did not provide a satisfactory re-
sult compared to the reaction performed in MeCN (compare entries
5 and 8).
This work was supported by Thailand Research Fund grant
MRG5380094, and in part by Chulabhorn Research Institute and
Chulabhorn Graduate Institute, for which we are grateful.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
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These optimized conditions were then applied to various termi-
nal alkynes and the results are summarized in Table 2. The current
protocol could be utilized to hydrobrominate 1-alkynes with high
9. According to reference
6 above (and references 7–10 cited therein), the
insoluble tetraalkylammonium bromide salt (R4NBr) absorbs gaseous HBr to