Natural deep eutectic solvents as an efficient and reusable active system for the Nazarov cyclization

Article abstract of DOI:10.1039/c9gc03465j

Natural deep eutectic solvents have emerged as alternative non-toxic, non-aqueous solvents for an increasing number of synthetic transformations. Remarkably, in some cases one (or more) components of the NaDES plays an active role in the reaction mechanism and directly participates as either a catalyst or a reagent in the reaction. In this paper, we tested several NaDESs in which one of the components is a carboxylic acid as a medium to perform the Nazarov cyclization of divinyl ketones to obtain cyclopentenones, a widespread motif in natural compounds. The reaction conditions were optimized and the scope was investigated on C-, O- A nd N-derived compounds. To assess the full sustainability of the proposed approach, the recyclability and scalability of the process were investigated, thus proving that multi-gram preparations are possible with complete recycling of the medium.

Full text of DOI:10.1039/c9gc03465j

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Natural deep eutectic solvents as an efficient and
reusable active system for the Nazarov cyclization†
Cite this: Green Chem., 2020, 22,
110
Stefano Nejrotti,
Marco Blangetti
Marta Iannicelli, Salwa Simona Jamil, Davide Arnodo,
and Cristina Prandi
*
Natural deep eutectic solvents have emerged as alternative non-toxic, non-aqueous solvents for an
increasing number of synthetic transformations. Remarkably, in some cases one (or more) components of
the NaDES plays an active role in the reaction mechanism and directly participates as either a catalyst or a
reagent in the reaction. In this paper, we tested several NaDESs in which one of the components is a
carboxylic acid as a medium to perform the Nazarov cyclization of divinyl ketones to obtain cyclopente-
nones, a widespread motif in natural compounds. The reaction conditions were optimized and the scope
was investigated on C-, O- and N-derived compounds. To assess the full sustainability of the proposed
approach, the recyclability and scalability of the process were investigated, thus proving that multi-gram
preparations are possible with complete recycling of the medium.
Received 7th October 2019,
Accepted 19th November 2019
DOI: 10.1039/c9gc03465j
rsc.li/greenchem
Remarkably, organocatalytic versions of the NC were also
reported in which chiral phosphoric acid derivatives,16 dia-
1. Introduction
The Nazarov reaction or Nazarov cyclization (NC) was first mines,17 thioureas,18 and cinchona alkaloids19 were also
reported in 1942 and consists of the 4π conrotatory electrocy- used.20
clization of divinyl ketones to cyclopentenones in the presence
Despite its importance as a synthetic tool for the prepa-
of Brønsted or Lewis acids (Scheme 1).1 The reaction is tolerant ration of natural and pharmaceutically active compounds and
to substituents on the dienone skeleton (Scheme 1, A) and its undeniable potential as a synthetic tool which fulfills green
thus allows for the facile synthesis of functionalized cyclo- chemistry principles in terms of atom economy, the NC still
pentenones B, including relatively simple non-annulated struc- presents some drawbacks related to sustainability. Indeed,
tures as well as complex polynuclear cyclopentenoid skeletons strong Brønsted acids (e.g. TFA, TfOH, and MsOH), which are
annulated with one or more non-aromatic, aromatic or hetero- toxic and corrosive, are usually employed and are often
aromatic rings.
required in a stoichiometric or super-stoichiometric amount.21
Over the years, the Nazarov reaction has found wide appli- On the other hand, the use of Lewis acids is affected by the
cation in synthesis and has become one of the most useful cost and air-sensitivity of the metal catalyst. Furthermore, vola-
tools for the preparation of various cyclopentenone motifs.1b,2 tile organic solvents (VOCs) and in particular chlorinated sol-
The study of the torquoselectivity of the reaction allowed for vents are by far the most common solvent system for the NC.2e
stereochemical control of the substituted cyclopentenones Up to now, only a few references report on more sustainable
obtained,3 and enantioselective versions of the NC were versions of the NC, in which non-toxic and recyclable homo-
reported.4 Modern protocols for the facile generation of the
pentadienyl cation intermediate include a wide number of pre-
cursors beyond the traditional divinyl ketones A,5 including
oxiranes,6 unsaturated carbinols,7 allene ethers8 and pro-
pargylic esters.9 Besides strong Brønsted acids, the NC can be
catalysed by Lewis acids, such as main-group Lewis acids and
transition metals: successful data are for example reported for
BF3·Et2O,10 Pd(0),11 Ag,12 Au(I),13 Au(III)9b,14 and halides.15
Dipartimento di Chimica, Università di Torino, via P. Giuria 7, I-10125 Torino, Italy.
E-mail: cristina.prandi@unito.it
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 (a) The Nazarov reaction. (b) Examples of the occurrence of
c9gc03465j
the cyclopentenone motif in natural compounds.
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geneous22 and heterogeneous23 catalysts were used. A remark- ditions in a renewable active solvent system, which combines
able example in this sense is represented by the cellulose– the lower toxicity and good biodegradability31 with its low cost.
SO3H catalyst reported by Rostami.24 Finally, a Nazarov cycliza- As to our knowledge, this is the first example of a NC pro-
tion performed in water in the presence of surfactants (and moted by weak carboxylic acids. Remarkably, the medium can
Lewis acids) was reported.25
be recycled up to 4 times without considerable loss in its
Deep eutectic solvents (DESs) have emerged as a new prom- activity.
ising class of green solvents, since they are non-flammable,
non-toxic, biodegradable and very easily prepared from cheap
and readily accessible components.26 An appropriate choice of
2. Results and discussion
the constituents paves the way for the design of different
matrices with specific physicochemical properties.27 When the To start our project and investigate the feasibility of the NC in
compounds that constitute the DESs are primary metabolites NaDESs, we chose the symmetric tetra-substituted dienone 1a
and in general natural compounds, namely amino acids, as a model substrate.32 Various choline chloride (ChCl)-
organic acids, sugars or choline derivatives, the DESs are called carboxylic acid based NaDESs were tested on the basis of their
natural deep eutectic solvents (NaDESs). NaDESs totally fulfill ability to convert 1a into the product cyclopentenone 2a
green chemistry principles and are now foreseen as potential (Table 1). First, ChCl/L-(+)-lactic acid in 1 : 2 molar ratio was
contributors to more sustainable industrial processes.28
tested and was ineffective in promoting the reaction at room
Since the first report by Abott,29 DESs have been success- temperature, even after 24 h (Table 1, entry 1). On the other
fully employed in several fields of application,26c,27 including hand, ChCl/oxalic acid 1 : 1 partially converted the substrate at
organic synthesis.30 It has been shown that, apart from consti- the same temperature (entry 2). Raising the temperature up to
tuting a more sustainable alternative to traditional solvents, 60 °C resulted in an improvement of the reaction yield to 91%
DESs often behave as a non-innocent reaction medium and after 16 h (entry 3). NaDESs based on L-(−)-malic acid (entry 4),
can play an active role in promoting organic reactions, by citric acid (entry 5) and L-(+)-tartaric acid (entry 6) were less
improving the reaction rate and the yield and allowing for effective, as lower yields were obtained with these NaDESs
milder conditions. This has been attributed to the supramole- under the same experimental conditions. Conversely, malonic
cular structure of these mixtures, characterized by an extensive acid (entry 7) and maleic acid (entry 8) based NaDESs per-
hydrogen bonding pattern.30c–e
formed well, affording 2a with a yield of 92% and 87% respect-
In this work, we wish to report on our study on the Nazarov ively. ChCl/p-toluenesulfonic acid (TsOH) in 1 : 2 molar ratio
cyclization in deep eutectic solvents, in open-air and under was also tested, and in this case a yield up to 99% was
mild conditions. Naturally occurring carboxylic acids are obtained (entry 9).21,31 NaDESs based on betaine (entry 11)
employed as components of the DES, allowing for mild con- and L-proline (entry 12), instead of ChCl, were found to be
Table 1 Study of the reaction conditions for the Nazarov cyclization of substrate 1a in NaDESs
Entry
Solvent
T (°C)
Time
2aa (%)
cis/transb
1
2
3
4
5
6
7
8
ChCl/L-(+)-lactic acid 1 : 2
ChCl/oxalic acid dihydrate 1 : 1
ChCl/oxalic acid dihydrate 1 : 1
ChCl/L-(−)-malic acid/H2O 1 : 1 : 2
ChCl/citric acid 1 : 1 + 2% H2O
ChCl/L-(+)-tartaric acid 1 : 1 + 2% H2O
ChCl/malonic acid 1 : 1
rt
rt
24 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
Traces
30%
91%
22%
36%
67%
92%
87%
99%
59%
—
—
—
—
33%
Traces
23%
—
57/43
14/86
26/74d
67/33
17/83d
17/83
16/84
15/85
20/80d
—
—
—
—
24/76
—
60
60
60
80c
60
60
60
60
60
60
60
60
60
60
60
ChCl/maleic acid 1 : 1
9
ChCl/TsOH monohydrate 1 : 2
ChCl/R-(−)-mandelic acid 1 : 1
Betaine/malonic acid 1 : 2
L-Proline/oxalic acid dihydrate 1 : 1
ChCl/H2O 1 : 2
10
11
12
13
14
15
16
17
EtOH
EtOH (10 eq. malonic acid)
DCE (10 eq. malonic acid)
H2O (10 eq. malonic acid)
30/70
Reaction conditions: 1a (0.2 mmol), in 1 g of the appropriate DES. a Yield of the isolated product. b Determined by 1H-NMR analysis of purified
compounds. c Higher temperature was required due to the viscosity of the medium. d 0% enantiomeric excess.
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ineffective in promoting the reaction. We then performed
Based on the optimization study, we extended the scope of
some control experiments, which are summarized in Table 1, the reaction to different substrates, choosing ChCl/malonic
entries 13–16. A DES not containing an acid, such as ChCl/ acid, ChCl/oxalic acid or ChCl/TsOH as a possible reaction
H2O 1 : 2 (entry 13), and a polar organic solvent, such as medium (entries 7, 3 and 9 of Table 1). The results reported in
ethanol (entry 14), were ineffective in promoting the reaction, Scheme 2 refer to the best score we obtained for each of the
indicating that an acid-containing DES is required.
substrates.
Symmetrical dienones bearing electron-rich or electron-
The acidic component of the eutectic mixture, malonic
acid, was tested in polar and apolar solvents such as ethanol poor aryl substituents were successfully cyclized to the corres-
(entry 15), 1,2-dichloroethane (entry 16) and water (entry 17), ponding cyclopentenones 2b–e with very good yields
but very low yields were obtained in these cases, suggesting (Scheme 2). Sterically encumbered substrates leading to 2d
that the activity is a peculiar property of the eutectic mixture and 2e afforded the corresponding products with almost com-
and does not derive from its acidic component per se.33 plete diastereoselectivity for the trans isomer.
Considering that in general the acidity of the DES is governed
Since one of the most synthetically useful aspects of the NC
by the acidity of the HBD, we then tried to rationalize these is represented by the possibility to access fused (hetero)poly-
results, taking into consideration the pKa of the acidic com- cyclic molecular scaffolds and due to our own research interest
ponent of the NaDES. The NaDESs containing malic acid (pKa in the synthesis of heterocyclic natural compounds,37 we inves-
3.40), citric acid (2.92, 4.28 and 5.21) and tartaric acid (2.99) tigated the reactivity of several dienones whose structure is
were almost ineffective, while the best results were obtained embedded in an indole or dihydropyran moiety. To our
with oxalic (1.23), malonic (2.83) and maleic acids (1.93),34 delight, for all the substrates the reaction proceeded smoothly
with malonic acid better performing (see entry 7, Table 1) than to afford cyclopentenones 2f–o in 78% to 95% yields. Finally,
maleic acid (entry 8, Table 1). Taken together, these data do we showed that also aryl vinyl ketones, which are less prone to
not account for a direct correlation between performance in undergo the cyclization due to the interruption of the aromatic
the NC and pKa of the acidic component of the DES. According system as a consequence of the cyclization,38 are converted
to a recently published study,35 the acidic properties of DES into the corresponding Nazarov products 2p and 2q in good
mixtures can differ from those of their components alone, and yield with diastereoselectivity.
moreover they can be significantly affected by the temperature.
One of the most attractive features of a catalytic system is
This behaviour suggests the crucial role played by the supra- undoubtedly the recyclability. We tested the possibility to
molecular interactions in the eutectic mixture and is particu- recycle the ChCl/malonic acid eutectic mixture for the cycliza-
larly relevant in the cases of ChCl/oxalic acid 1 : 1 and ChCl/ tion of dienone 1a, at a concentration of 0.2 mmol g−1 (i.e.
malonic acid 1 : 1, where a drop in the pH values is observed mmol of substrate per g of NaDES). The procedure for the
as the temperature increases.36 These observations are in line recovery of the NaDES, shown in Fig. 3, is highly feasible and
with our results, which showed how in ChCl/oxalic acid 1 : 1 involves the addition of water to the reaction mixture upon
and ChCl/malonic acid 1 : 1 (entries 3 and 7 of Table 1) at completion of the reaction, causing the precipitation of the
60 °C 2a was obtained in both cases in 92% yield despite the product, which can be collected by filtration. Water is then
different pKa of the HBD component (1.23 for oxalic acid and evaporated to restore the eutectic mixture, which is used
2.83 for malonic acid). The diastereoselectivity of the reaction without further manipulations for another run. As shown in
was also evaluated in terms of the cis/trans ratio. At room Fig. 1, the activity of the NaDES remains essentially unchanged
temperature (entry 2) the cyclization is not diastereoselective. for the first two cycles and is acceptable up to the fourth one,
At 60 °C the selectivity improves in favour of trans-2a to a 14/86 while in the fifth run a drop in the yield of product 2a is
ratio in the case of ChCl/oxalic acid (entry 3).
observed.
The activity of the NaDES strongly depends on the dynamic
Similar results have been obtained with ChCl/malonic acid
and ChCl/maleic acid (entries 7 and 8) thus proving that the behaviour of its molecules and possibly in this case on the
most efficient NaDESs are also those inducing the best intermolecular interactions in which the COOH of the NaDES
diastereoselectivity. It should be noted that in the case of is involved. It seems then reasonable that the protic nature of
ChCl/citric acid (entry 5) the diastereoselectivity is in favour of the carboxylic acid component becomes stronger or weaker
cis-2a. A proposed mechanism to account for the diastereo- either in a more restricted or more disordered supramolecular
selectivity either in favour of the cis or the trans cyclopente- network. To investigate how the activity of the NaDES changes
none and based on the acidic character of the melt might in each recycling cycle we decided to evaluate the structure of
involve multiple key activation roles of the solvent (Brønsted the NaDES ChCl/malonic acid by 1H and 13C NMR (see the
acid and hydrogen bond formation) as well as a plausible ESI† for full size spectra).39
structure of the eutectic mixture. Further computational and
physicochemical investigations are needed to elucidate these malonic acid is reported. The H NMR signals at 3.1 (9H), 3.4
aspects. Regarding the enantioselectivity of the reaction, when (2H) and 4.1 ppm (2H) are attributable to ChCl (*), while at
In Fig. 2 the 1H NMR spectrum of pure NaDES ChCl/
1
○
we employed NaDESs composed of a chiral carboxylic acid 3.5 ppm the CH2 of malonic acid is detectable ( ). The COOH
(entries 4, 6 and 10) we did not observe any induction of chir- proton of malonic acid is entrapped in the tight network of
ality in the product.
intermolecular H bonds and is detectable in the 1H NMR spec-
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Scheme 2 Scope of the Nazarov cyclization in NaDESs. All reactions were performed at 60 °C for 16 h and extracted with cyclopentyl methyl ether
(CPME), as described in the ESI.†
trum as a very broad signal between 10 and 11 ppm. In Fig. 2b,
the 1H NMR spectrum of ChCl/malonic acid in which a 10% of
water has been added on purpose is reported. A signal at
around 7 ppm is detectable and assigned to water entrapped
in the NaDES, while free water is detectable at 4.7 ppm. In
1
Fig. 2c, the H NMR spectra of the NaDES recovered after each
cycle are reported. It is evident that the structure of the NaDES
Fig. 2 1H NMR spectra of NaDES ChCl/malonic acid after recycling. (a)
○
Fig. 1 Recyclability of the ChCl/malonic acid DES for the Nazarov cycli-
zation of 1a. Yields were determined by quantitative 1H NMR analysis
using CH3NO2 as the internal standard.
ChCl/malonic acid (* ChCl; malonic acid). (b) ChCl/malonic acid with
10% water w/w. (c) ChCl/malonic acid after the first (1), second (2), third
(3), fourth (4) and fifth (5) cycles.
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remains substantially unchanged after the first cycle (Fig. 2c,
1), compared to the freshly prepared one (Fig. 2c, 0). In these
3. Conclusions
cases yields of 2a of 94% and 97% respectively were obtained In this paper, for the first time we have disclosed a concep-
(see Fig. 1). Starting from the NaDES recovered from the second tually new, flexible, versatile, and high-yielding Nazarov cycli-
cycle, a broad signal around 8 ppm starts to appear and zation of divinyl ketones performed in deep eutectic solvents,
becomes progressively more evident after the fourth and fifth in which the reaction medium plays a dual role both as a
cycles, shifting towards 7 ppm. The presence of some other solvent and as a promoter of the cyclization. The combination
minor peaks might indicate that the structure of the DES is par- of divinyl ketones and NaDESs composed of carboxylic acids
tially decomposed.40 To rationalize these results, it should be as an environmentally benign reaction medium enables access
worthwhile to recall that the activity of the NaDES ChCl/ to the targeted compounds with excellent yields and good
malonic acid is higher than that of malonic acid alone (see stereocontrol, at moderate temperature. The scope of the reac-
entries 13–15 in Table 1), as the supramolecular structure of the tion is wide and several substituents on the divinyl ketone
DES might enhance the polarizability of COOH groups and framework are well tolerated.
facilitate the reactivity. The increase in the amount of water con-
Furthermore, the potential of this reaction in terms of
tained in the DES (and not removable by simple evaporation) is coherence with green chemistry principles was addressed and
apparently correlated with the observed drop in yield. Further several sustainable features of this transformation have been
investigations are needed to assess how the supramolecular developed. In particular, we demonstrated that the process is
structure of the NaDES is modified in each cycle.41
scalable and multi-gram preparations are possible. A practical
The successful recycling procedure prompted us to further and easy work-up allows for the recovery of both the NaDES
increase the efficiency of the process, with a view to improving and water. We demonstrated that 4 cycles of reaction is toler-
its scalability. To this aim, we tested various substrate concen- ated with an overall acceptable yield. The beneficial effect of
trations in NaDESs, in order to find the highest concentration the DES is further showcased by its ability to obtain, in some
at which the product yield remains unaltered, which was found cases, pure compounds, thus avoiding purification by column
to be 1 mmol g−1, provided that the substrate was well dispersed chromatography.
in the medium and the stirring of the mixture was effective.
Therefore, we set up a gram-scale reaction starting from 1.05 g
(4.0 mmol) of substrate 1a and 4.0 g of ChCl/malonic acid
4. Experimental section
(Fig. 3). The NaDES was recovered and used again for a second
4.1 Materials
run through the above described procedure. To minimize waste
Flasks and all equipment used for the generation and reaction
of moisture-sensitive compounds were dried by using an elec-
tric heat gun under nitrogen. Unless specified, all reagents
were used as received without further purification. Anhydrous
THF was obtained by distillation over LiAlH4, followed by dis-
tillation over Na-benzophenone; benzaldehyde was distilled
under vacuum. Flash column chromatography was performed
over silica gel (40–63 μm, 230–400 mesh); Rf values refer to
TLC carried out on silica gel plates. 1H NMR and 13C NMR
spectra were recorded on a Jeol ECZR600, in CDCl3, using a
residual solvent peak as an internal standard (CHCl3, 1H:
7.26 ppm, 13C: 77.16 ppm). NMR spectra of DESs were
recorded in a capillary tube, using D2O as the locking solvent.
Multiplicities are reported as follows: s (singlet), d (doublet), t
(triplet), q (quartet), quin (quintet), sext (sextet), m (multiplet),
and br (broad). GC-MS spectra were recorded at an ionizing
voltage of 70 eV. Deep eutectic solvents were prepared by
methods reported in the literature (see the ESI† for details).
Divinyl ketone substrates 1a–q were synthesized according to
the literature (see the ESI† for details).
in this scale preparation, the water recovered at the rotavapor
after the first cycle was used again for the second cycle.
The overall process afforded 2.01 g of cyclopentenone 2a by
using only 4.0 g of ChCl/malonic acid 1 : 1. The E-factor para-
meter for the process is 19.5, a value that confirms the green
chemistry credentials of our protocol (see the ESI† for the
calculations).42
4.2 General procedure for the Nazarov cyclization in DESs
A vial was charged with the dienone substrate (0.2–0.5 mmol),
then the DES (5 g per mmol of substrate) was added and the
mixture was stirred at 60 °C for 16 h. Water was added and the
mixture was extracted three times with cyclopentyl methyl
ether (CPME); the combined organic layers were dried over
Fig. 3 Two-cycle, gram-scale reaction.
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anhydrous Na2SO4 and filtered and the solvent was evaporated
under reduced pressure. When required, the crude product
was purified by flash column chromatography.
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A vial was charged with the dienone 1a (1.0–4.0 mmol), then
ChCl/malonic acid 1 : 1 (5 g or 1 g per mmol of substrate) was
added and the mixture was stirred at 60 °C for 16 h. Water was
added, causing the precipitation of the product. The solid
product was recovered by filtration, while water was evaporated
under reduced pressure to afford the eutectic mixture, which
was used for the next reaction cycle.
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2,5-Dimethyl-3,4-diphenylcyclopent-2-en-1-one (2a).24
Synthesized according to the general procedure with ChCl/
malonic acid 1 : 1. White solid, 92% yield, trans/cis ratio
83 : 17. Rf 0.25 (PE/Et2O 9 : 1). trans-2a 1H NMR (600 MHz) δ
(ppm): 7.34–7.24 (m, 5H), 7.23–7.19 (m, 2H), 7.15–7.11 (m, 1H),
7.09–7.06 (m, 2H), 3.98 (quin, 1H, J = 2.2 Hz), 2.41 (qd, 1H, J =
7.3, 2.8 Hz), 2.03 (d, 3H, J = 2.0 Hz), 1.36 (d, 3H, J = 7.5 Hz). 13
C
NMR (150 MHz) δ (ppm): 211.1 (Cq), 167.2 (Cq), 142.2 (Cq),
136.9 (Cq), 135.3 (Cq), 129.1 (CH), 128.9 (CH), 128.5 (CH), 128.4
(CH), 127.7 (CH), 126.8 (CH), 56.5 (CH), 51.4 (CH), 15.4 (CH3),
10.3 (CH3). GC-MS m/z (%): 262 [M]+ (100), 247 (88), 219 (38),
1
115 (36). cis-2a H NMR (600 MHz) δ (ppm): 7.40–7.37 (m, 2H),
7.34–7.24 (m, 4H), 7.24–7.19 (m, 2H), 7.18–7.16 (m, 1H), 7.00
(br s, 1H), 4.63–4.60 (m, 1H), 2.92 (quin, 1H, J = 7.4 Hz), 2.09 (d,
3H, J = 1.7 Hz), 0.76 (d, 3H, J = 7.5 Hz). 13C NMR (150 MHz)
δ (ppm): 211.6 (Cq), 166.4 (Cq), 139.3 (Cq), 137.1 (Cq), 135.9
(Cq), 129.1 (CH), 128.5 (CH), 128.5 (CH), 128.4 (CH), 127.7 (CH),
127.0 (CH), 52.7 (CH), 45.6 (CH), 12.4 (CH3), 10.4 (CH3). GC-MS
m/z (%): 262 (100), 247 (92), 219 (40), 115 (40).
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
The authors acknowledge Prof. Vito Capriati for helpful discus-
sions and advice, Dr Matteo Tiecco for providing the betaine/
malonic acid DES, and Huvepharma srl, CRT (Cassa di
Risparmio di Torino), Regione Piemonte and the Italian
Ministry of Research for financial support.
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