L-isoleucine in a choline chloride/ethylene glycol deep eutectic solvent: A reusable reaction kit for the asymmetric cross-aldol carboligation

Article abstract of DOI:10.1021/acs.orglett.6b01989

l-Isoleucine is able to catalyze the cross-aldol reaction between cyclohexanone and aromatic aldehydes in a deep eutectic solvent consisting in choline chloride and ethylene glycol, rendering products with high diatereo- and enantioselectivity. This proto

Full text of DOI:10.1021/acs.orglett.6b01989

Letter
pubs.acs.org/OrgLett
L‑Isoleucine in a Choline Chloride/Ethylene Glycol Deep Eutectic
Solvent: A Reusable Reaction Kit for the Asymmetric Cross-Aldol
Carboligation
Noe Fanjul-Mosteirín, Carmen Concellon,* and Vicente del Amo*
́
́
Departamento de Química Organ
́
ica e Inorgan
́
ica, Universidad de Oviedo, C/Julian
́
Clavería 8, 33006 Oviedo, Spain
S
* Supporting Information
ABSTRACT: L-Isoleucine is able to catalyze the cross-aldol
reaction between cyclohexanone and aromatic aldehydes in a
deep eutectic solvent consisting in choline chloride and
ethylene glycol, rendering products with high diatereo- and
enantioselectivity. This protocol is straightforward and green:
the organocatalyst and the reaction medium can be recycled up
to five times, allowing the preparation of different substrates
with a single load of solvent and catalyst.
he independent discoveries of List, Lerner, and Barbas1 and
at a specific molar ratio of salt to HBD,6 affording DESs with
melting points lower than either of their individual components;
(b) low vapor pressure, therefore avoiding vapor emissions to the
atmosphere; (c) an easily tunable nature; and (d) compatibility
with water. Furthermore, both the ammonium salt (commonly
choline chloride) and the HBD units (mainly ethylene glycol,
glycerol, urea, lactic acid) required to form the DESs are costless,
readily available, biodegradable, and noncytotoxic.7
Considering the advantages listed above, DESs are starting to
encounter extensive applications in metal-catalyzed organic
transformations,8 as well as in enzymatic processes.9 In contrast,
to the best of our knowledge, only few examples have been
recently reported dealing with organocatalytic transformations
operating in a DES-based reaction media.10 Following our
interest in environmentally friendly organocatalysis,11 herein we
report an exhaustive study on the asymmetric cross-aldol
reaction catalyzed by a natural primary amino acid, L-isoleucine,
carried out in a benign deep-eutectic solvent consisting of choline
chloride and ethylene glycol.
2
TMacMillan,
in 2000, put forward how small organic
molecules are able to catalyze organic transformations with
optimum levels of selectivity. Since then, the interest of the
scientific community in the so-termed field of asymmetric
organocatalysis has increased rapidly, new catalysts and organo-
catalyzed reactions being discovered at a breathtaking pace.
Research dealing with organocatalysis is particularly attractive
for the industry, as it is considered a green technology. The
concept of Green Chemistry refers to actions aimed to improve
the efficiency in the use of natural resources, comprising the
design and implementation of new chemical processes and
transformations operating in a more efficient, safer, and more
environmentally friendly way. In order to evaluate the “greenness”
of a certain process, Green Chemistry has been formulated
according to 12 universal principles.3 Organocatalytic trans-
formations satisfy several of them: high atomic efficiency, low
generation of residues, and use of reagents in catalytic amounts,
among others. However, as a drawback, most of these practices
imply the use of organic solvents.
The aldol reaction is one of the most renowned trans-
formations in organic synthesis, privileged as a carboligation
process for assembling the backbone of complex organic
molecules.12 This C−C bond forming reaction is receiving
particular attention since the advent of organocatalysis,13 being
nowadays considered as a standard playground for testing the
chemical behavior of novel chiral organocatalysts and their
methodologies. In this sense, in order to study the feasibility of
DESs as reaction media in organocatalyzed processes, we
adopted the reaction of Scheme 1 as a case of study.
With the intention of developing yet more sustainable
processes, deep-eutectic solvents (DESs) have been recently
introduced as environmentally benign reaction media, capable of
pushing aside hazardous volatile organic solvents. First reported
in 2001 by Abbot and co-workers,4 DESs typically consist in a
combination of an electron neutral hydrogen-bond donor unit
(HBD) and an ammonium- or phosphonium-based salt. The
HBD partner is able to establish a complex network of strong
hydrogen-bonding interactions with the anion (commonly a
halide anion) of the salt. Such interactions organize DESs
according to a layered sandwich-like structure,5 which is
ultimately responsible of the unique physicochemical properties
of this kind of fluids, mainly (a) low glass transition temperature
Received: July 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
competitive selectivities (SI, Table S1, entry 1), in agreement
Scheme 1. Case of Study for the Asymmetric Cross-Aldol
Reaction in [ChCl/2 EG]
with the work of Guillena and Ramon
́
and their study of this
catalyst in ChCl-based DESs.10c
To our delight, picking out L-isoleucine as the organocatalyst
of choice for the cross-aldol reaction in ChCl/EG, an exhaustive
screening of reaction parameters (catalyst loading, concen-
tration, reaction temperature, and reaction time; see SI, Tables
S2−S8) revealed an ideal setup: when a solution of 4-
nitrobenzaldehyde 1a (1.0 equiv), L-isoleucine (20 mol %),
cyclohexanone (10.0 equiv), and distilled water15 (10.0 equiv), in
ChCl/EG (1:2, c = 0.25 M), was vigorously stirred for 90 h16 at
20 °C (controlled by a thermostatic bath), the corresponding
aldol adduct 2a was rendered in full conversion, with good anti-
diastereoselectivity (90:10 anti/syn) and excellent enantioselec-
tivity (98% ee, for (2S,3R)-anti-2a) (Table 1, entry 1). The
reaction is carried out in a closed-cap test tube, under air, with no
special care against moisture. In spite of its substantial polarity,
the aldol adduct 2a could be fully extracted from the eutectic
solvent with portions of ethyl acetate (EtOAc), being purified
afterward by flash chromatography. Interestingly, when the
reaction between cyclohexanone and aldehyde 1a was run under
analogous conditions, but using pure EG as the solvent, the
corresponding aldol product 2a was produced in very low
conversion, featuring modest diastereo- and enantioselectivity
(Table 1, entry 2), hence manifesting the positive cooperative
A deep eutectic solvent consisting of a 1:2 molar mixture of
choline chloride (ChCl) and ethylene glycol (EG) was chosen as
reaction medium, considering that this specific composition of
DES had not been previously explored in other works dealing
with organocatalysis.10 ChCl and EG are both rather inexpensive,
and they are meant to present very low toxicity. Looking for
developing a green methodology amenable of being adopted by a
broad audience readily accessible off-the-bench, proteinogenic
amino acids were thought as potential chiral catalysts
(Supporting Information (SI), Table S1). The effectiveness of
the organocatalysts was evaluated in terms of conversion,
diastereoselectivity, and enantiomeric excess of product 2a.
Interestingly, L-isoleucine provided the best results, with an ee
peaking at 96%, favoring the (2S,3R)-enantiomer of adduct 2a. It
is worth noting that the isoleucine-catalyzed cross-aldol reaction
between cyclic ketones and aromatic aldehydes has received little
attention in classical methodologies that employ organic
solvents.14 In this protocol, L-proline fails in providing
a
Table 1. Scope of the Cross-Aldol Reaction Catalyzed by L-Isoleucine in [ChCl/2 EG]
a
General reaction conditions: aldehyde (0.2 mmol), cyclohexanone (2.0 mmol), distilled water (2.0 mmol), and L-isoleucine (0.04 mmol) were
added to the [ChCl/2 EG] DES (0.8 mL), at 20 °C. The reaction mixtures were stirred for 90 h, and the reaction products were extracted with
b
c
EtOAc. Isolated yield of analytically pure products 2. In entries 1, 2, and 4, reaction conversion is given in brackets. Diastereisomeric ratio (dr)
d
determined by 1H NMR spectroscopy from crude reaction mixtures. Enantiomeric excess of major diastereoisomer (anti), as determined by chiral
HPLC on analytically pure products. Control reaction carried out under analogous experimental conditions using pure EG as reaction medium.
Blank experiment with no participation of isoleucine. Water was not added. Isobutyraldehyde (2-methylpropanal) was used instead of
e
f
g
h
cyclohexanone, affording product 3a.
B
DOI: 10.1021/acs.orglett.6b01989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
effect of the DES and the chiral catalyst. Another blank
experiment confirmed that the DES itself, without isoleucine,
does not suffice to catalyze the reaction (Table 1, entry 3).
With ideal conditions in hand, to establish the scope of our
aldol protocol a selection of aldehydes 1b−k bearing diverse
functional groups and substitution patterns were reacted with
cyclohexanone. All the reactions shown in Table 1 proceeded
smoothly: aldols 2b−i, decorated with nitro, nitrile, amide, or
halide substituents were isolated in good yield, and with high
diastereo- and enantioselectivity (Table 1, entries 4−11). 4-
Carboxymethyl benzaldehyde 1j was conveniently converted
into the corresponding β-hydroxyketone 2j with no hydrolysis or
transesterification of the ester function (Table 1, entry 12).
Interestingly, aldol 2k, derived from pyridine 2-carboxaldehyde, a
challenging substrate in the aldol reaction, was isolated in fair
yield (Table 1, entry 13). Moreover, isobutyraldehyde also
proved to be an acceptable substrate for the cross-aldol reaction
with 4-nitrobenzaldehyde 1a, giving rise to the aldol adduct 3a in
good yield, although with modest enantioselectivity (Table 1,
entry 14). In either case, such an ee value for 3a is comparable to
the one previously reported in the literature for the same
product, prepared by a cross-aldol methodology that employs 50
mol % of L-isoleucine in DMSO.17
At this stage, the recyclability of the DES containing L-
isoleucine was assessed. To this end, a reaction between
cyclohexanone and 4-nitrobenzaldehyde, 1a, was set up as in
Table 1, entry 1. With the completion of the reaction (full
conversion), the crude mixture was treated with several portions
of EtOAc (3 × 1 mL), being decanted each time. The organic
phases were collected together and evaporated under reduced
pressure to afford product 2a quantitatively. L-Isoleucine,
presumably as its zwitterionic form, remained solubilized in the
ChCl/EG DES and was not transferred into the organic solvent.
The DES medium was further subjected to vacuum to remove
the rest of EtOAc, cyclohexanone, or water, before it was reused
in subsequent reactions. By these means, the DES could be
reused up to 5 times, upon addition of fresh reagents (aldehyde
1a, ketone, and water), without jeopardizing the conversion or
the enantioselectivity of β-hydroxy ketone 2a, but with a slight
decrease of its diastereoselectivity from the fifth catalytic cycle,
probably due to some coextraction of L-isoleucine and the
concomitant decrease of catalyst loading (Table 2). After the fifth
run L-isoleucine displays a catalytic turn over number (TON) of
over 24 units, which is a convenient figure for an organocatalyzed
transformation.
Challenging our system further, we next decided to carry out
recycling experiments in which the aldehyde used as substrate
would be changed after each catalytic run. Thus, after setting up a
reaction between cyclohexanone and 4-nitrobenzaldehyde 1a
(Table 3, cycle 1), the DES and L-isoleucine were recovered as
stated in the previous paragraph. The so-recycled material was
then treated with cyclohexanone (2 mmol) and 2-nitro-
benzaldehyde 1c (0.2 mmol), being the mixture vigorously
stirred for 90 h, to render adduct 2c in quantitative conversion
and excellent diastereo- and enantioselectivity (Table 3, cycle 2),
with no traces of any product 2a coming from the previous run. It
is worth noting that product 2c obtained by this way shows the
same selectivity values as those reported in Table 1, entry 5, when
it is prepared using fresh organocatalyst and DES. Finally, after
recycling DES plus catalyst from the second cycle, a third
reaction could be run within the same medium employing 4-
nitrobenzaldehyde 1a (Table 3, cycle 3). Gratifyingly, the desired
β-hydroxy ketone 2a was produced with comparable selectivities
Table 2. Recyclability of DES and L-Isoleucine in the
Asymmetric Cross-Aldol Reaction between Cyclohexanone
a
and 4-Nitrobenzaldehyde 1a
b
c
d
e
cycle
conv (%)
dr (anti/syn)
ee (%)
TON
1
2
3
4
5
99
99
99
99
98
90:10
90:10
89:11
88:12
82:18
98
98
98
97
97
4.9
9.8
14.7
19.6
24.4
a
Reaction conditions: aldehyde 1a (0.2 mmol), cyclohexanone (2.0
mmol), distilled water (2.0 mmol), and L-isoleucine (0.04 mmol) were
added to [ChCl/2 EG] (0.8 mL), at 20 °C. The reaction mixture was
stirred for 90 h. Recycling was performed as stated in the main text.
b
1
Conversion of aldehyde 1a to anti- and syn-2a, as determined by H
NMR spectroscopy of crude reaction mixtures. Resonances of 2a were
integrated and quantified against CHBr3 (9 μL, 0.103 mmol) used as
c
analytical internal standard. Diastereisomeric ratio (dr) determined by
d
1H NMR spectroscopy from crude reaction mixtures. Enantiomeric
excess of major diastereoisomer (anti), as determined by chiral HPLC
e
on crude reaction mixtures. Accumulative turn over number (TON)
values (TON = mol product/mol catalyst).
Table 3. Recyclability of DES and L-Isoleucine in the
Asymmetric Cross-Aldol Reaction between Cyclohexanone
and 4-Nitrobenzaldehyde 1a or 2-Nitrobenzaldehyde 1c
a
b
c
d
cycle
1
ArCHO
2
conv (%)
dr (anti/syn)
ee (%)
1a
1c
1a
2a
2c
2a
99
99
99
90:10
90:10
88:12
98
99
98
e
2
3
a
Reaction conditions: aldehyde (0.2 mmol), cyclohexanone (2.0
mmol), distilled water (2.0 mmol), and L-isoleucine (0.04 mmol) were
added to [ChCl/2 EG] (0.8 mL), at 20 °C. The reaction mixture was
stirred for 90 h. Recycling was performed as stated in the main text.
b
Conversion of aldehydes 1a or 1c to anti/syn-2a or anti/syn-2c, as
determined by 1H NMR spectroscopy of crude reaction mixtures.
Resonances of aldol adducts were integrated and quantified against
CHBr3 (9 μL, 0.103 mmol) used as analytical internal standard.
c
Diastereisomeric ratio (dr) determined by 1H NMR spectroscopy
d
from crude reaction mixtures. Enantiomeric excess of major
diastereoisomer (anti), as determined by chiral HPLC on crude
e
reaction mixtures. No water was used.
as those of Table 2, entry 3, and Table 1, entry 1, which refer to
the same product. The aldol adduct 2c was not detected as a
contaminant.
To the light of the experiments presented in Table 3, the
reaction system DES−isoleucine keeps no memory when it is
recycled and reused in further transformations. Therefore, the
combination of L-isoleucine + [ChCl/2 EG] can be foreseen as a
reaction kit for the asymmetric cross-aldol reaction between
cyclohexanone and aromatic aldehydes, being reusable a
minimum of three times with different substrates. Furthermore,
the simplicity of the experimental setup and the low cost of
naturally occurring L-isoleucine and DES make this methodology
C
DOI: 10.1021/acs.orglett.6b01989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chinchilla, R.; Guillena, G.; Pastor, I. M.; Ramon
́
, D. J. Eur. J. Org. Chem.
amenable of being adopted by any nonspecialized group
interested in getting access to compounds of the likes of 2a−k.
To conclude, we have developed and implemented a novel L-
isoleucine-based organocatalytic system for the cross-aldol
reaction between cyclohexanone and aromatic aldehydes that
operates in a ChCl/EG DES. This protocol is green and
straightforward. The reaction products can be isolated in high
yield and with good levels of diastereo- and enantioselectivity,
comparable to those obtained by classical organocatalytic
methodologies employing organic solvents. The amino acid
catalyst and the reaction medium (DES) can be recycled a
minimum of five times without altering the reaction outcome.
This recycling process retains no memory about the substrate
used, thus permitting the consecutive preparation of different
aldol adducts with a single L-isoleucine-DES reaction kit. The
development of other environmentally friendly recyclable
systems able to catalyze multiple organic transformations is
currently underway in our laboratory and will be reported in due
course.
́
2016, 2016, 612−621. (c) García-Alvarez, J. Eur. J. Inorg. Chem. 2015,
31, 5147−5157. (d) Liu, P.; Hao, J.- W.; Mo, L.- P.; Zhang, Z.- H. RSC
Adv. 2015, 5, 48675−48704. (e) Tang, B.; Row, K. H. Monatsh. Chem.
2013, 144, 1427−1454. (f) Ruß, C.; Konig, B. Green Chem. 2012, 14,
̈
2969−2982. (g) Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jer
Chem. Soc. Rev. 2012, 41, 7108−7146.
́
(8) (a) Marset, X.; Perez, J. M.; Ramon, D. J. Green Chem. 2016, 18,
́ ̂
ome, F.
́
́
826−833. (b) Vidal, C.; Merz, L.; García-Alvarez, J. Green Chem. 2015,
́
17, 3870−3878. (c) Rodríguez-Alvarez, M. J.; Vidal, C.; Díez, J.; García-
́
Alvarez, J. Chem. Commun. 2014, 50, 12927−12929. (d) Vidal, C.;
́
Suarez, F. J.; García-Alvarez, J. Catal. Commun. 2014, 44, 76−79.
(9) For a recent review, see: Potdar, M. K.; Kelso, G. F.; Schwarz, L.;
Zhang, C.; Hearn, M. T. W. Molecules 2015, 20, 16788−16816.
(10) (a) Massolo, E.; Palmieri, S.; Benaglia, M.; Capriati, V.; Perna, F.
M. Green Chem. 2016, 18, 792−797. (b) Martínez, R.; Berbegal, L.;
Guillena, G.; Ramon
́
, D. J. Green Chem. 2016, 18, 1724−1730.
(c) Muller, C. R.; Meiners, I.; Domínguez de María, P. RSC Adv.
̈
2014, 4, 46097−46101.
(11) (a) Martínez-Castaneda, A.; Poladura, B.; Rodríguez-Solla, H.;
̃
Concello
́
n, C.; del Amo, V. Org. Lett. 2011, 13, 3032−3035.
(b) Martínez-Castaneda, A.; Poladura, B.; Rodríguez-Solla, H.;
̃
Concellon
́
, C.; del Amo, V. Chem. - Eur. J. 2012, 18, 5188−5190.
, C.; del
Amo, V. J. Org. Chem. 2012, 77, 10375−10381. (d) Martínez-Castaneda,
ASSOCIATED CONTENT
* Supporting Information
■
(c) Martínez-Castaneda, A.; Rodríguez-Solla, H.; Concellon
́
̃
S
̃
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01989.
A.; Kędziora, K.; Lavandera, I.; Rodríguez-Solla, H.; Concellon
́
, C.; del
Amo, V. Chem. Commun. 2014, 50, 2598−2560.
(12) For some recent monographs and reviews, see: (a) Mahrwald, R.,
Ed. Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
(b) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506−
7525. (c) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20,
131−173.
General procedures, spectroscopic data, copies of 1H and
13C NMR spectra, and chromatographic data for
compounds 2a−k and 3a (PDF)
(13) (a) Mase, N.; Hayashi, Y. Compr. Org. Synth. 2014, 273−339.
AUTHOR INFORMATION
Corresponding Authors
■
(b) Guilena, G.; Naj
18, 2249−2293.
(14) (a) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.;
Liao, W. W. Chem. Commun. 2005, 3586−3588. (b) Cordova, A.; Zou,
́ ́
era, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007,
́
*E-mail: vdelamo@uniovi.es. Phone: + 34 985 10 3450. Fax: +34
985 10 3446.
*E-mail: ccf@uniovi.es. Phone: +34 985 10 3075.
́
W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. - Eur. J. 2006, 12,
5383−5397. (c) Hayashi, Y.; Itoh, T.; Nagae, N.; Ohkubo, M.; Ishikawa,
H. Synlett 2008, 2008, 1565−1570. (d) Ma, G.; Bartoszewicz, A.;
Notes
́
Ibrahem, I.; Cordova, A. Adv. Synth. Catal. 2011, 353, 3114−3122.
The authors declare no competing financial interest.
(15) Jimeno, C. Org. Biomol. Chem. 2016, 14, 6147−6164.
(16) Reaction time was set to 90 h to guarantee full conversion of
aldehyde 1a into product 2a. Conversion rises up under long reaction
times at the expense of diastereoselectivity of aldol products 2
(Supporting Information, Table S8).
ACKNOWLEDGMENTS
■
We thank MINECO (CTQ2014-55015-P) for financial support.
C.C. expresses her gratitude to MINECO for the award of a
“Ramon y Cajal” contract (RYC-2014-16021). The authors
(17) Rohr, K.; Mahrwald, R. Org. Lett. 2012, 14, 2180−2183.
́
́
́
extend thanks to Dr. Joaquin Garcia-Alvarez (Universidad de
Oviedo) for his useful advices along the preparation of the
manuscript.
REFERENCES
■
(1) List, B.; Lerner, A. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395−2397.
(2) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243−4244.
(3) (a) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998. (b) Tang, S. L. Y.;
Smith, R. L.; Poliakoff, M. Green Chem. 2005, 7, 761−762.
(4) Abbott, A. P.; Capper, G.; Davies, D. L.; Munro, H. L.; Rasheed, R.
K.; Tambyrajah, V. Chem. Commun. 2001, 2010−2011.
(5) Hammond, O. S.; Bowron, D. T.; Edler, K. J. Green Chem. 2016, 18,
2736−2744.
(6) Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.;
Tambyrajah, V. Chem. Commun. 2003, 70−71.
(7) For some recent reviews on the use of DESs, with particular
emphasis on their uses in organic transformations, see: (a) Guajardo, N.;
Mueller, C. R.; Schrebler, R.; Carlesi, C.; Domínguez de María, P.
ChemCatChem 2016, 8, 1020−1027. (b) Alonso, D. A.; Baeza, A.;
D
DOI: 10.1021/acs.orglett.6b01989
Org. Lett. XXXX, XXX, XXX−XXX