M. A. Saputra et al. / Tetrahedron Letters 56 (2015) 1392–1396
1393
for the production of alkyl bromide 9. The typical protocol in these
studies involved treatment of alcohol 7 with 1.1 equiv of CDI for
one hour at room temperature, followed by the addition of
pyridinium bromide. The reaction was then brought to reflux for
R
OH
R
X
CO
H
2
+ imid.
X
CDI;
Py•HX
CO2 + py
X
2
4 h. Upon aqueous workup, the crude mixtures were subjected
to GC–MS analyses.
O
N
O
We began by screening various solvents for the reaction. As
indicated in entries 1–5, commonly used polar and non-polar
solvents, such as tetrahydrofuran, dichloromethane, toluene and
dimethylformamide, only yielded imidazole carbamate adduct 8.
In fact, alkyl bromide 9 was not (or barely) detected in the crude
reaction mixtures with these solvents. Interestingly, when the
reaction was performed in acetonitrile, GC–MS analyses of the
crude reaction revealed formation of alkyl bromide 9 in 28%
conversion. These findings were quite unexpected, considering
the fact that our previously reported chlorination reactions, which
were proposed to have involved participation of analogous reactive
intermediates as shown in Scheme 1, were most efficient when
py
R
O
R
O
N
N
imid.
5
6
Scheme 2. Alkyl halides formation via imidazolium carbamate intermediates.
The propensity of triethylammonium carbamate ion 2 and
pyridinium carbamate ion 4 to undergo decarboxylative nucleo-
philic substitution with chloride ions led us to investigate analo-
gous electrophilic systems that can be specifically harnessed
towards nucleophilic attack by other halide ions. Naturally, such
reactive intermediates must be generated under chloride ion-free
conditions, which essentially rules out the use of triphosgene to
activate the starting alcohols. These considerations led us to for-
mulate a hypothesis as depicted in Scheme 2. We envisioned that
aliphatic alcohols could be reacted with carbonyl diimidazole
5
,6
performed in dichloromethane.
Our study then continued with the investigation on the effect of
reaction concentration. The above preliminary reactions were per-
formed in 100 mM concentration with respect to starting alcohol 7.
As shown in entries 5–8, changing the reaction concentration did
not improve the production of alkyl bromide 9. However, we
observed that the formation of symmetrical carbonate 10 appeared
to become more prominent at higher reaction concentrations.
Interestingly, this carbonate formation did not appear to originate
from the initial step when alcohol 7 was treated with CDI. Further
reaction optimization then involved varying the amount of
pyridinium bromide salts. As shown in entries 9–12, increasing
the molar equivalence of pyridinium bromide directly correlates
to the increasing production of the alkyl bromide. In fact, the use
of 10 equiv of pyridinium bromide readily generated product 9 in
(
CDI) to give imidazole carbamate adduct, that would be further
activated in situ with pyridinium halides, prompting proton
transfer that should generate imidazolium carbamate ion 5. This
reactive intermediate would subsequently undergo nucleophilic
substitution with halide ions at the carboxyl position to produce
the target alkyl halides, while releasing carbon dioxide and
imidazole as byproducts. It is also conceivable that imidazolium
carbamate ion 5 participated in a reversible nucleophilic acyl
substitution with free pyridine, which would be liberated during
1
3,14
proton transfer, to form pyridinium carbamate ion 6.
ensuing nucleophilic attack of this reactive species by halide ions
should also readily produce the intended alkyl halides.
The
7
3% conversion yield as determined by GC–MS analyses.
Although we were able to considerably improve the conversion
yield of alkyl bromide 9, the use of 10 equiv of pyridinium bromide
was not ideal due to the challenge in removing excess pyridine
from crude reaction mixtures during aqueous workup. Further-
more, limited commercial availability of other pyridinium halide
salts would simply restrict this chemistry to bromination. These
concerns led us to explore analogous reaction conditions. As shown
in Table 2, we proposed the use of a Brønsted acid to activate
imidazole carbamate adduct 8 in the presence of potassium bro-
mide, which supplied the bromide ions. A typical protocol for these
new activation conditions is as follows: starting alcohol 7 was
initially treated with 1.1 equiv of CDI in anhydrous acetonitrile
for one hour at room temperature. Then, potassium bromide,
Brønsted acid and other additives were sequentially added. The
reaction was then stirred at reflux for 24 h, followed by aqueous
workup and GC–MS analyses of the crude mixtures.
Results and discussion
Table 1 depicts the results of our initial experiments, in which
we employed 3-phenyl-1-propanol 7 as a model substrate to aim
Table 1
Initial investigation
As indicated in Table 2, entries 1 and 2, we initially employed
.0 equiv of Brønsted acid, such as pyridinium triflate and pyridini-
Entry
Solvent
PyÁHBr (equiv)
Conc. (mM)a
% 7:8:9:10b
2
1
2
3
4
5
6
7
8
9
THF
DCM
Toluene
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.0
5.0
7.0
10.0
100
100
100
100
100
50
250
500
100
100
100
100
0
0
0
0
0
10
0
3
0
6
95
100
100
100
72
79
86
72
69
5
0
0
0
0
0
0
0
0
3
18
0
0
um tosylate. These conditions were found to be ineffective to acti-
vate imidazole carbamate intermediate 8, as the crude reaction
mixture only contained a negligible amount of alkyl bromide 9.
Increasing the molar concentration of these pyridinium salts to
0
28
11
11
7
31
35
56
73
4
.0 equiv also failed to improve the product output. Interestingly,
formation of carbonate byproduct 10 became more competitive
under these conditions. We also explored the compatibility of
pyridinium sulfate in this reaction. Interestingly, the use of
10
11
12
59
44
11
2
.0 equiv of this acid, that is, 4.0 molar equivalents of the pyridini-
um ions, readily afforded alkyl bromide 9 in 71% conversion (entry
). A further increase in the product formation to 81% yield was
observed when both 4 Å molecular sieves and catalytic
dibenzo-18-crown-6 were introduced to the reaction mixture
0
8
0
8
6
The best reaction conditions were highlighted in bold texts.
a
a
Reaction concentration was based on 3-phenyl-1-propanol.
Ratios were determined by GC–MS analysis of the crude mixtures assuming
that these compounds elicited identical GC responses.
b
1
5–17
(entry 7).