Umpolung reactions in an ionic liquid catalyzed by electrogenerated N-heterocyclic carbenes. Synthesis of saturated esters from activated α,β-unsaturated aldehydes

Article abstract of DOI:10.1039/c2cc30371j

The umpolung reaction of α,β-unsaturated aldehydes to saturated esters has been carried out in an ionic liquid by organocatalysis of electrogenerated NHC. The roles of solvent, precatalyst and proton donor of the ionic liquid have been verified and good to high yields of esters have been obtained using a "green" and mild methodology.

Full text of DOI:10.1039/c2cc30371j

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COMMUNICATION
Umpolung reactions in an ionic liquid catalyzed by electrogenerated
N-heterocyclic carbenes. Synthesis of saturated esters from activated
a,b-unsaturated aldehydesw
Marta Feroci,*a Isabella Chiarotto,a Monica Orsini,b Romina Pelagallia and Achille Inesiz*a
Received 16th January 2012, Accepted 3rd April 2012
DOI: 10.1039/c2cc30371j
The umpolung reaction of a,b-unsaturated aldehydes to saturated
esters has been carried out in an ionic liquid by organocatalysis of
electrogenerated NHC. The roles of solvent, precatalyst and proton
donor of the ionic liquid have been verified and good to high yields
of esters have been obtained using a ‘‘green’’ and mild methodology.
use of imidazolium salts in the double role of solvent and
precatalyst,7 we have investigated the possibility to obtain
esters from a,b-unsaturated aldehydes and alcohols, by internal redox
reaction catalyzed by electrogenerated NHC. The advantages of this
methodology reside in the use of a ‘‘green’’ deprotonating reagent, the
electron (cheap, easy to dose, and without byproducts), in a
very polar solvent, the ionic liquid, which should stabilize the
charged intermediates and lead to good yields in products.
Moreover, the use of a solvent with virtually null vapour
pressure allows us to reuse the solvent, limiting the costs for
waste disposal and avoiding air pollution.8
The remarkable versatility of esters as building blocks and as
protecting groups in organic synthesis and their significant
importance for industrial applications have spurred an extensive
investigation aimed to improve the methods for their preparation
as well as to develop new strategies for synthesis.1
The monoelectronic galvanostatic reduction of an imidazolium
salt (at a Pt cathode, in a divided cell) leads to the formation of the
corresponding NHC and H2 (Scheme 1, eqn (1)).7,9 The addition
of cinnamaldehyde 1a to the catholyte, followed by benzyl alcohol
2a, gives the corresponding saturated ester 3aa (Scheme 1, eqn (2)).
In addition, if the NHC–aldehyde adduct reacts with a molecule of
aldehyde, g-butyrolactone 4aa is obtained as a byproduct. In the
absence of current, no ester was isolated from the reaction between
1-butyl-3-methylimidazolium tetrafluoroborate (Bmim-BF4),
aldehyde 1a and alcohol 2a, and the starting material was
recovered (Table 1, entry 1).
The classical procedures for the synthesis of esters involve
the reaction of activated carboxylates with suitable nucleophiles
(esterification) or the exchange of an alkoxy moiety between an
ester and an alcohol (transesterification).2 Recently, the oxidative
esterification of aldehydes, catalyzed by N-heterocyclic carbenes
(NHCs),3 has been proposed as an alternative strategy.4 In this
reaction, the inversion of the normal polarity of the aldehyde
moiety (umpolung) is achieved by addition of an NHC to the
carbonyl group, followed by the H+ shift to yield the ‘‘Breslow
intermediate’’.5 After reaction with the nucleophile (an alcohol),
the corresponding ester is obtained. The organocatalyst
(an NHC) is usually produced by chemical deprotonation of a
suitable imidazolium or thiazolium salt (using DIPEA, DBU,
KOtBu, etc. as bases) in an organic solvent (THF, toluene, etc.).
The oxidation of the aldehyde to ester is accomplished by the
reduction of an external oxidant (O2, MnO2, quinone, azobenzene)4
or by the reduction of a functional group present in the aldehyde
itself (double or triple bond, carbon–halogen bond).6 So, when an
a,b-unsaturated aldehyde is used, after an internal redox reaction a
saturated ester is obtained.
The yield of ester 3aa is affected by many factors (IL,
Faradays per mole of aldehyde, mole ratio alcohol/aldehyde),
as reported in Table 1. When cinnamaldehyde 1a and benzyl
alcohol 2a (in equimolar amounts) were added to previously
electrolyzed (0.5 F molꢀ1 1a) Bmim-BF4, saturated ester 3aa
was isolated in 54% yield (Table 1, entry 2), along with a
significant amount of g-butyrolactone 4aa, a byproduct
obtained due to the reaction of the NHC–aldehyde adduct
with another molecule of aldehyde.7d In order to suppress this
side reaction, an excess of alcohol must be used (Table 1,
entries 3 and 4). A crucial role in this reaction is played by the
As part of efforts focused on the development of ecofriendly
electrochemical methodologies in ionic liquids, based on the
a Dept. SBAI, Sapienza University of Rome, via Castro Laurenziano,
7, I-00161 Rome, Italy. E-mail: marta.feroci@uniroma1.it;
Fax: +39 06 49766749; Tel: +39 06 49766563
b Dept. Elettronica Applicata, University of Roma Tre,
via Vasca Navale, 84, I-00146 Rome, Italy
w Electronic supplementary information (ESI) available: Complete experi-
mental details and spectral data of all products. See DOI: 10.1039/
c2cc30371j
Scheme 1 Scheme for the electrogenerated NHC-catalysed reaction
z Present address: via Antelao, 9, I-00141 Rome, Italy. E-mail:
achille.inesi@uniroma1.it
between cinnamaldehyde and benzyl alcohol.
c
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Chem. Commun., 2012, 48, 5361–5363 5361

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Table 1 Umpolung reaction in electrolyzed ILs.a Reactivity of
cinnamaldehyde 1a vs. benzyl alcohol 2a (Scheme 1)
Productsd (yields %)
Qb/ F molꢀ1 2a/1ac t/h
3aa
4aa
Rec. 1a
Entry IL, R
1
2
3
4
5
6
7
8
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Butyl
Ethyl
Ethyl
—
3
1
2
3
3
3
3
3
3
3
3
3
3
3
2
2
2
2
4
4
2
1
1
1
1
1
1
1
—
54
64
67
6
62
69
91
85
72
63
85
82
84
—
38
28
21
—
6
96
—
—
—
71
28
—
—
—
—
—
—
—
—
0.5
0.5
0.5
0.2
0.4
0.5
0.7
1.0
0.7
1.0
4
Tr.
—
—
20
—
—
—
9
10
11
12
13
14e
Methyl 0.7
Hexyl
Butyl
0.7
0.7
a
Electrolyses of ILs were carried out in a divided cell (Pt electrodes)
under galvanostatic conditions (I = 20 mA cmꢀ2; T = 60 1C).
Number of Faradays per mole of 1a supplied to the electrodes.
b
c
Mole ratio 2a/1a, 1a and 2a were added to the catholyte at the end of
the electrolysis; then the catholyte was stirred for aꢀtime t at 60 1C.
Scheme 2 Proposed mechanism for a,b-unsaturated aldehydes umpolung
d
e
Isolated yields with respect to starting 1a. PF6 was used as a
to esters.6a
counterion of IL.
activated a,b-unsaturated aldehydes 1a–c and alcohols 2a–h
(Table 2), under the optimized experimental conditions
(Table 1, entry 7). Starting from cinnamaldehyde, hydrocinnamic
esters have been obtained in very good yields using benzyl alcohols
with donor groups, while the use of benzyl alcohols with EWG
leads to lower yields. Aliphatic alcohols work well, but the
secondary one (cyclohexanol) is less reactive, while a,b-unsaturated
aldehydes with donor groups work as cinnamaldehyde with benzyl
alcohol, yielding good amounts of esters. When a non-activated
a,b-unsaturated aldehyde is used, i.e. trans 2-hexenal 1d, the
corresponding saturated ester 3da was isolated in very poor
yield (10%). This result seems to be consistent with the
inferences of our previous investigations.7a In fact, in the case
of saturated aliphatic aldehydes the formation of the Breslow
intermediate in cathodically reduced Bmim-BF4 is not efficient
enough: either aldol condensation products or NHC–aldehyde
stable adducts have been isolated in high yields.
amount of catalyst (Table 1, entries 5–9), 0.7 F molꢀ1 being the
optimum (91% yield). The nature of the imidazolium salt is less
influential, and good yields in ester were obtained using ILs with
aliphatic chains on the nitrogen atom (Table 1, entries 10–14).
The best experimental conditions seem to be Bmim-BF4 as IL,
0.7 F molꢀ1 of catalyst and a mole ratio 2a/1a of 3/1, in order to
suppress the side reaction (Table 1, entry 8).
The proposed mechanism6a for this reaction is reported in
Scheme 2. The competition between the formation of expected
ester and g-butyrolactone lies in the extent of the protonation of
homoenolate II, the more the protonation, the less the byproduct.
Scheidt and Chan6a reported the necessity to add to the reaction
mixture an external proton donor in order to efficiently protonate
intermediate II; the addition of a phenol of suitable acidity and
steric hinderance gives high yields of expected ester, suppressing
the formation of any byproduct. In contrast, Bode and Sohn6b
reported the necessity of the presence of weak amine bases (NEt3,
DIPEA) as proton shuttles to have excellent conversions.
It should be noted that this electrochemical reaction does
not need the use of an external proton donor or of a proton
shuttle; therefore it can be inferred that the ionic liquid acts as
a proton donor towards homoenolate II (Scheme 2),10 its acidity
being suitable for this reaction (its pKa has been evaluated in the
range of 21–24 in DMSO and water).11 This possibility was also
suggested by Bode in reference to a triazolium salt.6b
Nevertheless, spurred by the suggestions of a referee, we
have tried to carry out this redox esterification of 2-hexenal in
the presence of a different NHC precursor, i.e. 1,3-dimesityl
imidazolium chloride (IMes-Cl)6b or 1,3-dimethyl benzimidazolium
iodide (BI-I),6a probably more efficiently. These salts are solid
(m.p. 4 300 1C), but more acidic than the Bmim cation, so we
have added to reduced Bmim-BF4 1 mmol of IMes-Cl or BI-I,
in view to obtain a more reactive NHC. After the addition of
2-hexenal 1d and benzyl alcohol 2a to this solution, the
corresponding saturated ester 3da was isolated in 28% yield
with IMes-Cl (Table 2, last entry) and 13% with BI-I. There-
fore, in Bmim-BF4 as solvent the formation of the Breslow
intermediate from not activated aldehydes is not efficient
enough also using more suitable NHCs. Any attempt to isolate
an adduct between NHC and 2-hexenal from the cathodic
solution failed.
To raise the efficiency of the overall procedure, the possible
reuse of the ionic liquid has been studied. After ethereal
extraction of the catholyte and isolation of the products, the
catholyte itself was kept under vacuum (to eliminate Et2O
traces) and reused in subsequent electrolyses (up to five times).
Using Bmim-BF4, after supplying 1.0 F molꢀ1 each time, ester
3aa was isolated as the only product (85, 76, 70, 72, 73%) with
no significant decrease in the yield.12
Last, we have tested the reactivity of a nucleophile different
from an alcohol, in order to broaden these reaction applications;
the use of benzylamine instead of benzyl alcohol led to the
In order to test the generality of this electrochemical
methodology in ionic liquids, we have subjected to reaction
c
5362 Chem. Commun., 2012, 48, 5361–5363
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Table 2 Umpolung reaction in electrolyzed Bmim-BF4. Reactivity of
aldehydes 1a–c vs. alcohols 2a–ha
The manifold role of the cheap ionic liquid Bmim-BF4
(solvent, precatalyst and proton donor) has been established
and no additive was needed to obtain good to high yields in
esters. Moreover, the use of the electron as base and of an ionic
liquid (not air-pollutant and recyclable) renders this synthesis in
agreement with the principles of ‘‘green chemistry’’.
Aldehyde
Alcohol
Esterb (yield)
Notes and references
1 K. Ishihara, Tetrahedron, 2009, 65, 1085 and references therein.
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T. Rovis, Top. Curr. Chem., 2010, 291, 77; (d) P.-C. Chiang and
J. W. Bode, RSC Catal. Ser., 2011, 6, 399.
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Org. Chem., 2011, (32), 6527; (b) B. Maji, S. Vedachalan, X. Ge, S. Cai
and X.-W. Liu, J. Org. Chem., 2011, 76, 3016; (c) S. De Sarkar,
S. Grimme and A. Studer, J. Am. Chem. Soc., 2010, 132, 11–90;
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5 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
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¨
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a
Tetrahedron Lett., 2008, 49, 4316) reported a strong hydrogen
bond between the C-2 position of an NHC and the O–H proton of
an alcohol. This interaction weakens the O–H bond. It cannot be
excluded that this electrochemical reaction part of NHC acts as an
enhancer of the acidity of the alcohol, favouring the protonation of
homoenolate II.
The syntheses were carried out following the experimental condition
b
reported in Table 1, entry 7. Isolated yields with respect to starting
c
aldehyde. 1 mmol of 1,3-dimesitylimidazolium chloride was added to
the catholyte at the end of the electrolysis and 10 min before the
addition of 2-hexenal and benzyl alcohol.
11 (a) R. W. Alder, P. R. Allen and S. J. Williams, J. Chem. Soc., Chem.
Commun., 1995, (12), 1267; (b) T. L. Amyes, S. T. Diver, J. P. Richard,
F. M. Rivas and K. Toth, J. Am. Chem. Soc., 2004, 126, 4366.
12 The use of N-mesityl triazolium chloride in the redox esterification
of cinnamaldehyde to methyl cinnamate in the absence of base
has been reported. It is suggested that the NHC catalyst could
be generated by deprotonation of the triazolium cation carried
out by its counterion Clꢀ (i.e. a weak base). The use of this
salt (solid at rt) requires the presence of organic solvents; in
contrast, the use of Bmim-BF4 avoids their use, according to a
greener methodology (a) J. Kaeobamrung, J. Manhatthananchai,
P. Zheng and J. W. Bode, J. Am. Chem. Soc., 2010, 132, 8810;
(b) J. Manhatthananchai and J. W. Bode, Chem. Sci., 2012, 3, 192;
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Catal., 2012, 2, 494.
formation of 47% yield of hydrocinnamic benzylamide after
supplying 1.0 F molꢀ1, with 20% of imine (deriving from
the reaction between cinnamaldehyde and benzylamine, not
involving NHC). Work on this reaction is at present in progress
in order to suppress imine formation and to increase the yield
of amide.
In conclusion, we have reported the first example (to the
best of our knowledge) of synthesis of saturated esters from
a,b-unsaturated aldehydes and alcohols in ionic liquids, via
umpolung reaction catalyzed by electrogenerated N-hetero-
cyclic carbene.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5361–5363 5363