Rapid and efficient protic ionic liquid-mediated pinacol rearrangements under microwave irradiation

Article abstract of DOI:10.1039/c0gc00916d

Several protic ionic liquids were tested as potential mediators for pinacol rearrangements employing microwave irradiation. Using hydrobenzoin as a model substrate, the optimal conditions were found to be heating at 80°C for 5 min using H₂SO₄:triethylamine as the ionic liquid. A key feature of this reaction was to keep the microwave power low (20 W) to avoid ionic liquid degradation. Application of these conditions to triphenylethylene glycol gave rearrangement products in high yield and purity, while phenylethylene glycol and styrene oxide gave pinacol products that underwent a cascade aldol condensation. These conditions represent an efficient means by which pinacol rearrangements can be carried out while avoiding the use of strong Bronsted acids, high temperatures and extended reaction times. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00916d

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COMMUNICATION
Rapid and efficient protic ionic liquid-mediated pinacol rearrangements
under microwave irradiation†
Luke C. Henderson* and Nolene Byrne*b
a
Received 13th December 2010, Accepted 19th January 2011
DOI: 10.1039/c0gc00916d
Several protic ionic liquids were tested as potential me-
diators for pinacol rearrangements employing microwave
irradiation. Using hydrobenzoin as a model substrate, the
Protic ionic liquids (pILs) are a class of ionic liquids that are
formed by mixing strictly equimolar amounts (1 : 1) of Brønsted
acids and bases. The strength of the acid/base combination
determines the degree to which the acidic proton is transferred—
the proton activity. This tuneable parameter has been used
previously to probe the suitability of pILs to carry out organic
◦
optimal conditions were found to be heating at 80 C for
5
min using H
2
SO :triethylamine as the ionic liquid. A
4
key feature of this reaction was to keep the microwave
power low (20 W) to avoid ionic liquid degradation.
Application of these conditions to triphenylethylene glycol
gave rearrangement products in high yield and purity,
while phenylethylene glycol and styrene oxide gave pinacol
products that underwent a cascade aldol condensation.
These conditions represent an efficient means by which
pinacol rearrangements can be carried out while avoiding
the use of strong Brønsted acids, high temperatures and
extended reaction times.
8
transformations. The pinacol rearrangement is an ideal candi-
date for the application of pILs as several reaction features, such
as the strength of the acid (or in this case the proton activity), the
reaction duration and the temperature, are considered crucial for
3a
a successful transformation. Here, we demonstrate the use of
a pIL as a mediator for pinacol rearrangements to complement
the previously mentioned alternatives to acid catalysis. This
methodology gives products rapidly (5 min) and in high yield
(
> 90%) under microwave irradiation. Additionally, the ionic
liquid can be removed by filtration through silica; a safe and
simple work-up compared to the neutralisation of strong acids.
1
The pinacol–pinacolone (and related) rearrangement has had
2
a major impact on synthetic organic chemistry. This trans-
formation involves the dehydration of vic-diols, resulting in
a carbocation intermediate that is stabilised via an alkyl (or
Results and discussion
We chose hydrobenzoin as our model compound for prelim-
inary studies as it is commercially available, and the pinacol
rearrangement products are both well known and characterized
3
hydride) migration. The pinacol rearrangement has been used
4
to great effect in natural product synthesis, for example D,L-
5
marcfortine C, which possesses antiparasitic activity. Typically,
(
see Scheme 1). Four pILs were investigated for their ability
pinacol rearrangements require the use of very strong Brønsted
to carry out the desired rearrangement. Each of the pILs have
varying degrees of acidity, depending largely on the choice of
anion. This was considered prudent as the strength of acid is
widely regarded as the most important reaction parameter for
pinacol rearrangements.
acids (typically H
2
SO
4
, Cl
3
CCO
2
H, triflic acid), with H
2
SO
4
being the most common. Several alternatives to these acids
6
have been reported, including solid-supported catalysts and
7
antimony-based ionic liquids. Never-the-less, these alternative
catalysts still require the use of harsh reaction conditions,
and an efficient, mild and safe means of carrying out pinacol
rearrangements is desirable.
a
School of Life and Environmental Sciences, Deakin University, Pigdons
Road, Waurn Ponds, Victoria, Australia, 3217.
E-mail: luke.henderson@deakin.edu.au; Fax: +61 3 5227 1040; Tel: +61
9
Scheme 1 Hydrobenzoin pinacol rearrangements.
3
52271416
b
Institute for Research Innovation and Technology, Deakin University,
Pigdons Road, Waurn Ponds, Victoria, Australia, 3217.
Our initial attempts to effect this transformation employed
triethylamine:methane sulfonic acid (TeaMs) (Table 1, entry 1).
We were encouraged to see spots on the TLC corresponding
to the pinacol products but an intense absorbance correlating
E-mail: nolene.byrne@deakin.edu.au; Fax: +61 3 5227 1040; Tel: +61 3
5
22 72609
†
1
Electronic supplementary information (ESI) available. See DOI:
0.1039/c0gc00916d
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Table 1 Preliminary investigations into suitable pILs
◦
Entry pIL
T/ C Time/min Ratio 2 : 3 Conversion (%)
1
2
3
4
5
6
7
TeaMs
TeaMs
TeaTFA
TeaTFA
TeaTFA
120
120
120
120
180
120
20
20
20
40
20
20
20
2 : 1
—
2 : 1
0 : 1
—
2 : 1
—
14
0
9
a
12
b
0
c
Scheme 2 Optimisation of reaction duration, temperature and yield.
TeaH
2
SO
4
100
0
TeaTfOH 120
as 1 min (Table 2, entry 4), pIL degradation was still evident.
Lowering the reaction temperature to 80 C (Table 2, entry 5)
significantly increased the yield to 67%, but unfortunately pIL
degradation seemed to still be occurring, albeit inconsistently
a
b
2
0% v/v water added. Compound and pIL degradation products were
◦
c
observed. Combined isolated yield of 1 and 2 was 31%
to hydrobenzoin 1 suggested a poor conversion. This was
confirmed by H NMR, which showed only a 14% conversion
to desired products 2 and 3.
(
i.e. pIL degradation and subsequently lower yields occurred
1
◦
in 2 out of every 4 repeat reactions at 80 C). Examination of
the reaction temperature/wattage profile for all of the above
examples showed a large temperature spike in the initial stages
of the reaction corresponding to a large pulse of microwave
irradiation (200 W). This large amount of energy elevated
The reaction was repeated in TeaMs using 20% v/v H
2
O
(
Table 1, entry 2) to solubilize 1, but this appeared to inhibit
the reaction. Similarly, using triethylamine trifluoroacetic acid
◦
(
TeaTFA) at 120 C for both 20 (Table 1, entry 4) and 40 (Table
the reaction temperature to well in excess of the set value
◦
1
, entry 5) min gave only traces of the desired products. In an
(typically 30–40 C over the desired temperature), leading to
attempt to encourage reaction conversion, a higher temperature
was employed (Table 1, entry 6), which resulted in only pIL
pIL degradation and low yields. Due to the very high polarity of
pILs they efficiently convert microwave energy to heat. To avoid
this effect, the maximum wattage was decreased from 200 W to
and compound degradation products. Employing TeaH
2
SO ,
4
the pIL with strongest proton activity, we were delighted to see
the complete consumption of the starting material to the desired
products. Diphenyl aldehyde 2 was formed in preference to
ketone 3 in an approximately 2 : 1 ratio (respectively), though in
a moderate yield of 31%. Finally, trifluoromethanesulfonic acid
2
0 W, giving much better control over the reaction temperature
(
see the ESI for a comparison of reaction profiles†).
10
◦
◦
Repeating the reaction at both 120 C and 80 C (Table
2
, entries 6 and 7) utilising the lower microwave power gave
◦
much higher yields, with 80 C being optimal and no pIL
degradation being evident in either case. Microwave irradiation
is also known to increase reaction rates; therefore, to determine
any microwave specific effects, the successful reaction conditions
(
TfOH)Tea (Table 1, entry 7) returned only traces of the desired
11
products. With a suitable pIL in hand, our attention turned
to increasing the yield of this reaction. Though the reaction
proceeded quickly, we considered the 31% yield obtained from
our preliminary investigations not synthetically useful.
(Table 2, entry 7) were repeated using oil bath heating (Table 2,
entry 8). Under thermal heating conditions, the reaction did not
It was noted that after microwave irradiation of TeaH
the reaction mixture was severely discoloured and liberated a
distinct odour (SO ), suggesting degradation of the pIL. It was
2
SO
4
,
proceed at all, showing no trace of either pinacol products 1 or
2.
3
With an optimal set of conditions in hand, our attention
thought that the reaction could be proceeding very rapidly, and
as such the 20 min timescale may be leading to both ionic liquid,
and subsequently product, degradation. In an effort to minimise
this effect, the reaction was repeated under identical conditions
but reducing the duration.
turned to the application of these reaction conditions to another
vic-diol commonly used to evaluate pinacol reaction conditions.
Triphenyldiol 4 was subjected to the optimised reaction condi-
tions, giving 100% conversion to the desired products in a yield
of 91%. Analysis by H NMR of the key resonances showed a
preference for ketone 6 formation over aldehyde 5 in a ratio of
1
◦
Reacting 1 at 120 C for 10 and 5 min (Table 2, entries
1
and 2) increased the yield, supporting the hypothesis of
3
: 1, respectively.
compound degradation. However, even at reaction rates as short
Though it cannot be unequivocally determined, one would
assume that during the reaction, the more stable dibenzylic
cation is formed in preference to the alternative monobenzylic
cation. The two products observed from this intermediate arise
from hydride migration (leading to ketone 6) or phenyl migration
Table 2 Optimisation of the reaction conditions
◦
a
Entry
Time/min
Power/W T/ C
Ratio 2 : 3
Yield (%)
1
2
3
4
5
6
7
10
5
2
1
5
5
5
5
200
200
200
200
200
20
120
120
120
120
80
120
80
74 : 26
67 : 33
46 : 54
31 : 69
82 : 18
84 : 16
83 : 17
nd
47
40
36
21
67
82
91
0
b
b
20
n/a
c
8
80
a
b
Yield taken as the combined yield of 1 and 2. Maximum 20 W
c
of microwave energy. Reaction heated under conventional thermal
conditions (oil bath).
Scheme 3 Pinacol rearrangement of 1,2,2-triphenylethane-1,2-diol (4).
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8
14 | Green Chem., 2011, 13, 813–816

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(
leading to aldehyde 5). Although phenyl groups are reported
3
to migrate in preference to most other alkyl/hydride groups,
in this case, there is a severe steric demand on the aldehyde a-
carbon, and thus the hydride is observed to migrate in preference.
Interestingly, scaling up this reaction (5 fold) while incorporating
the same volume of ionic liquid (0.25 mL) gave a very similar
result under the specified conditions (yield 86%, product ratio
Scheme 5 Attempted rearrangement of pinacol (11).
This result, while not optimal, has been observed in other
pinacol methodology studies, whereby it is presumed that the
present a-hydrogens to the carbocationic species preferentially
undergo elimination reactions. Never-the-less, this has clearly
demonstrated the suitability of ionic liquid-mediated pinacol
rearrangements to either di- or tri-phenyl-bearing glycols, as is
observed with compounds 1 and 4.
1
: 3 5 : 6, respectively), thus demonstrating the suitability of this
methodology for the large scale synthesis of synthetically useful
synthons.
Though pinacol rearrangements are not usually carried out
with monosubstituted glycols due to potential side reactions, we
applied these conditions to phenyl-1,2-ethanediol (7). Complete
consumption of the starting material was observed within the 5
1
min timeframe, but analysis by H NMR of the crude material
Conclusions
showed a mixture of products, within which the desired aldehyde
8
was the minor product (< 10%). The major constituent of
the reaction mixture was found to be unsaturated aldehyde
, isolated in an excellent yield of 85%. The formation of
We have demonstrated the suitability of the protic ionic liquid
TeaH
2
SO as a mediator for pinacol rearrangements employing
4
9
either di- or tri-phenyl glycols. Complete consumption of the
starting materials and high yields can be obtained from this
this product was attributed to a rapid pinacol rearrangement
followed by aldol condensation.
◦
system in 5 min and at a mild temperature of 80 C under
In an attempt to diminish the formation of 9, a semi-pinacol
reaction using epoxide 10 was carried out under identical
reaction conditions. Similarly to the previous reaction, the
crude material was a mixture of products, in which unsaturated
aldehyde 9 was, again, the principle component. Chromato-
graphic separation gave aldehyde 9 in a good 71% isolated yield.
Obtaining unsaturated aldehyde 9 from both 7 and 10, though,
disappointed our attempts to obtain aldehyde 8. Scheme 4 high-
lights the potential application of protic ionic liquids to facilitate
aldol reactions. This area of investigation is currently under
way in our laboratory and the results will be reported in due
course. Finally, to expand the generality of this methodology, we
wished to employ a non-phenyl bearing substrate to account for
carbocation stabilisation. A typical example is 2,3-dimethyl-2,3-
butanediol (11, pinacol), which involves only methyl migration
to effect the successful transformation. Application of our
optimal conditions to pinacol 12 (Scheme 5) resulted in complete
compound degradation with no identifiable compound being
isolated from the reaction work-up.
microwave irradiation. It was found that microwave irradiation
power was important in controlling pIL degradation and for
furnishing products in excellent yield. This reaction system
removes the requirement of highly corrosive and dangerous
acids. In all of the reactions undertaken in this manuscript,
removal of the ionic liquid was carried out by filtration through
a silica plug to give analytically-pure pinacol products.
Acknowledgements
The authors would like to thank the Strategic Research Center
for Biotechnology, Chemistry and Systems Biology for financial
assistance. N. B. acknowledges the Australian Research Council
for an APD.
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SO (0.25 mL). The
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4
(
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This journal is © The Royal Society of Chemistry 2011