Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents

Article abstract of DOI:10.3762/bjoc.16.158

We report that phenacyl azides are key compounds for a regiodivergent synthesis of valuable, functionalized imidazole (32–98% yield) and pyrimidine derivatives (45–88% yield), with a broad substrate scope, when using deep eutectic solvents [choline chloride (ChCl)/glycerol (1:2 mol/mol) and ChCl/urea (1:2 mol/mol)] as environmentally benign and non-innocent reaction media, by modulating the temperature (25 or 80 °C) in the presence or absence of bases (Et₃N).

Full text of DOI:10.3762/bjoc.16.158

Regiodivergent synthesis of functionalized pyrimidines and
imidazoles through phenacyl azides in deep eutectic solvents
Paola Vitale*1, Luciana Cicco1, Ilaria Cellamare1, Filippo M. Perna1, Antonio Salomone2,3
and Vito Capriati*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1915–1923.
1Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari
“Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125
Bari, Italy, 2Dipartimento di Scienze e Tecnologie Biologiche ed
Ambientali, Università del Salento, Prov.le Lecce-Monteroni, 73100
Lecce, Italy and 3Dipartimento di Chimica, Università di Bari “Aldo
Moro”, Via E. Orabona 4, I-70125 Bari, Italy
doi:10.3762/bjoc.16.158
Received: 30 May 2020
Accepted: 20 July 2020
Published: 05 August 2020
This article is part of the thematic issue "Green chemistry II".
Guest Editor: L. Vaccaro
Email:
Paola Vitale* - paola.vitale@uniba.it; Vito Capriati* -
vito.capriati@uniba.it
© 2020 Vitale et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
deep eutectic solvents; imidazoles; phenacyl azides; phenacyl
halides; pyrimidines
Abstract
We report that phenacyl azides are key compounds for a regiodivergent synthesis of valuable, functionalized imidazole (32–98%
yield) and pyrimidine derivatives (45–88% yield), with a broad substrate scope, when using deep eutectic solvents [choline chlo-
ride (ChCl)/glycerol (1:2 mol/mol) and ChCl/urea (1:2 mol/mol)] as environmentally benign and non-innocent reaction media, by
modulating the temperature (25 or 80 °C) in the presence or absence of bases (Et3N).
Introduction
In a world with dwindling petroleum resources, the setting up of engage in reciprocal hydrogen-bond interactions, and that form
more and more sustainable routes for the preparation of hetero- fluids at a specified mixing ratio at the desired temperature.
cyclic compounds is an ongoing synthetic endeavor as these Owing to the broad tunability of their physicochemical proper-
scaffolds are ubiquitous motifs in many biologically active ties and the ability to act not only as solvents but also as cata-
compounds and pharmaceuticals. In this context, in the last lysts and reagents, DESs have progressively replaced toxic and
decades, the so-called deep eutectic solvents (DESs) have volatile organic solvents (VOCs) in countless heterocyclodehy-
received an increasing attention due to their biodegradability, dration processes and multicomponent reactions (MCRs) [1-3].
high thermal stability, non-flammability, and low volatility.
These are mixtures usually obtained from the combination of 2 As part of our ongoing research in DES chemistry, we reported
or 3 safe, inexpensive and nature-inspired components able to recently on the preparation of valuable heterocycles by
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(a) nucleophilic substitution (tetrahydrofuran derivatives) [4], condensation of α-azido ketones in iPrOH in the presence of
(b) heterocyclodehydration reactions (2-aminoimidazoles, potassium ethylxanthate as a catalyst [28], (b) by exploiting the
2-pyrazinones, benzoxazines, thiophenes) [5-8], reaction of arylglyoxals with an excess amount of ammonium
(c) carbon–sulfur bond-forming reactions [9], (d) directed acetate in water [29], (c) by the cathodic reduction of 2-azido-1-
ortho-metalation and nucleophilic acyl substitution strategies phenylethanone in a DMF/LiClO4 medium [30], (d) by radical
[10], (e) Pd-catalyzed aminocarbonylation of aryl iodides, chain reactions of α-azido ketones with tributyltin hydride [31],
Suzuki–Miyaura and Sonogashira cross-coupling reactions [11- or (e) by a modified Radziszewski’s synthesis when using
13], (f) Cu-catalyzed C–N coupling reactions [14], and phenylglyoxals, benzaldeydes, and ammonium acetate as
(g) heterogeneous “click” cycloaddition reactions [15] using ammonia source in acetic acid or methylene chloride or N,N-
DESs as environmentally responsible and non-innocent reac- dimethylformamide as the solvent [32], there are no adequate
tion media. Telescoped, one-pot transformations of phenacyl studies covering the preparation of aroylpyrimidines. In 1995,
halides to symmetrical 2,5-disubstituted pyrazines (A), through Yamamoto et al. reported the direct introduction of acyl groups
phenacyl azides as intermediates, were also found to take place into pyrimidine rings by reacting trimethylstannyl derivatives
smoothly using such neoteric solvents (Scheme 1, path a) [16]. with acylformyl chlorides in dry benzene under a N2 stream
[33].
Results and Discussion
During our studies on the synthesis of symmetrical pyrazines,
we observed that phenacyl bromide (1a, 1.5 mmol) could be
almost quantitatively converted into phenacyl azide (2a, 97%
yield), within 4 h, when treated with NaN3 (1.65 mmol) as the
azide source in a choline chloride (ChCl)/glycerol (Gly)
(1:2 mol/mol) eutectic mixture at room temperature (rt, 25 °C)
(Scheme 2) [16]. By warming the mixture up to 50 °C, the yield
of 2a dropped to 89% after 1 h, and we noticed in the crude the
appearance of an additional product, which was detected as a
fluorescent spot on TLC, whose amount increased by increas-
ing the temperature. After 4 h warming at 50 °C, we were able
to isolate by column chromatography on silica gel a product
which was characterized as 2-benzoyl-(4 or 5)-phenyl-(1H)-
imidazole (3a/3a', Scheme 2). This adduct was formed as a
mixture of two tautomers (3a and 3a'; 3a/3a' ratio: 57:43, Sup-
Scheme 1: One-pot synthesis of 2,5-diarylpyrazines (A) (path a) or
porting Information File 1) [28,29] in an overall 16% yield, the
remaining being mainly 2a, which was isolated in 75% yield
(Scheme 2). We thus became interested in improving the yield
of 3a/3a'.
2-aroyl-(4 or 5)-aryl-(1H)-imidazoles (B) (path b), or 2,4-diaroyl-6-
arylpyrimidines (C) (path c) in DES from phenacyl azides (rt = room
temperature).
Among nitrogen-containing heterocyles, imidazoles and pyrim-
idines are important structural scaffolds commonly found in After careful evaluation of the reaction parameters (tempera-
natural products [17,18], light-emitting devices [19,20], and ture and time) and the amount of NaN3 used, we found that the
pharmacologically active compounds as anticancer, anti-inflam- treatment of phenacyl chloride (1b) with NaN3 (1.5 equiv) in
matory, antitubercular, antihypertensive, antihistaminic, anti- ChCl/Gly at 80 °C gave the best results, as it provided the
obesity, antiviral, and other medicinal agents [21-27]. Herein, adducts 3a/3a' in an overall 88% yield after 12 h reaction time
we wish to report that either 2-aroylimidazoles (B) (Scheme 1, (Table 1, entries 1–4). Of note, imidazoles 3a/3a' were found to
path b) or 2,4-diaroylpyrimidines (C) (Scheme 1, path c) can precipitate directly from the aforementioned eutectic mixture
regioselectively be prepared from the same phenacyl azide as during the reaction, and thus they could be isolated by simple
starting material by properly selecting the nature of the eutectic decantation or centrifugation and washing with a few drops of
mixture and the temperature, in the presence or absence of EtOAc or Et2O. This procedure left azide 2a in solution. The
bases.
latter could be quantified (10% yield) by simple dilution with an
equal volume mixture of water and EtOAc, followed by the sep-
To the best of our knowledge, while there are a few reports aration of the organic layer from water, and removal of the vol-
for the synthesis of 2-aroylimidazoles (a) through the atiles under reduced pressure.
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
Scheme 2: Transformation of phenacyl bromide (1a) in ChCl/Gly into phenacyl azide (2a) and 2-benzoyl-(4 or 5)-phenyl-(1H)-imidazole (3a and 3a')
depending on the temperature.
Table 1: Optimization of the reaction conditions for the synthesis of 3a/3a'.a
entry
T (°C)
t (h)
NaN3 (equiv)
2a yield (%)b
3a/3a' yield (%)b
1
2
3
4
80
4
1.2
1.2
0.9
1.5
37
7
55
60c
32
88
100
80
16
16
12
68
10
80
aReaction conditions: 1b (0.5 mmol), ChCl/Gly (1.0 g); byield refers to products isolated after column chromatography on silica gel; c15% of 2,4-diben-
zoyl-6-phenylpyrimidine was also isolated (see main text and Table 2).
To examine the scope and limitation of this transformation, undergo dimerization to give 6 followed by dehydration. The
various functionalized phenacyl halides (1c–i) were tested as two tautomers 3/3' would most probably originate by two
substrates. As can be seen from the results compiled in competitive pathways (a and b; Scheme 4) via a [1,5]-hydrogen
Scheme 3, the reaction is amenable to “neutral” (Me), electron- shift [28,29]. Hydrogen-bond catalysis promoted by DES com-
withdrawing (Cl, Br, CN) and electron-donating (MeO, OH) ponents may be playing an important role in favoring the loss of
substituents as the desired imidazoles 3b/3b'–3h were isolated nitrogen under mild conditions from a putative azide tautomer
in 78–98% yield. The presence of additional halogen groups 4, the latter deriving from the corresponding α-phenacyl azide
such as chlorine and bromine in 3c/3c' and 3d allows further precursor 2 via an acid-catalyzed enolization process [34]. The
downstream diversification by cross-coupling reactions. A pyrolysis of α-azido ketones in conventional VOCs (trichloro-
4-fluoro-substituted phenacyl chloride as well as a bromo- benzene) is known to take place under harsh conditions, which
methyl 2-naphthyl ketone proved to be competent substrates as are based on heating the mixture between 180 °C and 240 °C
well, thus furnishing the corresponding imidazoles 3i/3i' and 3j [35].
in 67–87% yield. Conversely, a phenacyl halide decorated with
an additional phenyl group at the para-position delivered the The investigation of the thermal stability of phenacyl azides 2
expected adduct 3k/3k' in 32% yield even by prolonging the led to the fortuitous discovery of the competitive formation of a
reaction time to 16 h, most probably because of the poor solu- different heterocycle. Indeed, while phenacyl azide (2a) was
bility in the eutectic mixture and/or the higher thermal stability stable per se in a ChCl/Gly mixture after stirring at rt for 12 h, a
towards the loss of N2 (vide infra) of the corresponding new fluorescent spot was detected on TLC plate in the presence
phenacyl azide 2k as it is formed. The latter was indeed isolat- of an excess of Et3N (3 equiv). After column chromatography
ed as the main product (68% yield, Scheme 3).
on silica gel, we were able to isolate a new product that was
characterized as 2,4-dibenzoyl-6-phenylpyrimidine (7a, 55%
A plausible mechanism for the formation of the 2-aroylimida- yield) in addition to 3a/3a' (26% yield), the remaining being
zoles 3/3' is depicted in Scheme 4. A key intermediate may be starting material only (conversion: 81%, Table 2, entry 1). The
the in situ generated α-imino ketone 5. The latter is known to employment of ChCl/urea (1:2 mol/mol) as the eutectic mix-
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
Scheme 3: Synthesis of 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles 3. Scope of the reaction. Typical conditions: 1 (0.5 mmol), NaN3 (0.75 mmol), ChCl/Gly
(1.0 g), 80 °C, 4–16 h; yield refers to products isolated after column chromatography on silica gel; only one tautomer has been depicted for simplicity;
imidazoles 3c/3c', 3i/3i', 3j, 3k/3k' were found to precipitate as they formed, and were isolated by filtration/centrifugation and washing with a few
drops of AcOEt or Et2O; synthesis of imidazoles 3k/3k': 10% (w/w) EtOH was added to the eutectic mixture to improve the solubility of 2k.
Scheme 4: Proposed mechanism for the formation of 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles 3/3' from α-phenacyl azides 2 in ChCl/Gly.
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
Table 2: Investigation of the reaction conditions in the synthesis of 7a.a
entry
solvent
7a yield (%)b
3a/3a' yield (%)b
conversion yield (%)
1
2
3
4
5
6
7
ChCl/Glyc
ChCl/ureac
ChCl/uread
ChCl/ureae
ChCl/ureaf
Glyc
55
57
41
37
33
52
27
26
43
33
25
31
37
–
81
full
74
62
66
89
27
Et3Nc
aReaction conditions: 2a (0.3 mmol), solvent (0.5 g); byield refers to products isolated after column chromatography on silica gel; cEt3N: 3 equiv;
dEt3N: 2 equiv; eEt3N: 1 equiv; fK2CO3: 3 equiv.
ture provided 7a in 57% yield and 3a/3a' in 43% yield, but with be highly base sensitive and to undergo a base-promoted loss of
full conversion (Table 2, entry 2). By lowering the equivalents nitrogen to form α-imino ketones upon protonation [38].
of Et3N up to 1, or alternatively using K2CO3 (3 equiv) as a
base, in ChCl/urea, the yield of 7a dropped down up to 33% and A plausible mechanism for the formation of pyrimidine deriva-
that of 3a/3a' up to 25% (Table 2, entries 3–5). By changing the tive 7a from 2a, in competition with imidazoles 3a/3a', is
solvent to pure Gly, 7a and 3a/3a' now formed in 52 and 37% depicted in Scheme 5.
yield, respectively (Table 2, entry 6). When Et3N (3 equiv) was
alternatively used as the sole solvent, the formation of 7a was The key intermediate 5a, formed by elimination of nitrogen
suppressed dramatically (27% yield, Table 2, entry 7) [36]. This from the enol-azide 4a, would undergo either dimerization to
last result is consistent with a synergistic cooperation of the give 6a, and then imidazoles 3a/3a' after cyclization and dehy-
basic ChCl/urea eutectic mixture [37] with Et3N in promoting dration (see Scheme 5), or trimerization to afford adduct 8a
the transformation at rt. α-Azido ketones are, indeed, known to further to an additional attack of 5a to the internal imino group
Scheme 5: Proposed mechanism for the formation of 2-benzoyl-(4 or 5)-phenyl-(1H)-imidazoles 3a/3a' and 2,4-dibenzoyl-6-phenylpyrimidine (7a)
from α-phenacyl azide (2a) in ChCl/urea in the presence of Et3N.
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
of 6a and dehydration. Consecutive tautomerization, followed aforementioned conditions. The latter, however, could be easily
by an intramolecular nucleophilic attack to the terminal imino isolated by column chromatography. The presence of strong
group of 9a, provides cyclized adduct 10a, and finally pyrimi- electron-donating groups like MeO was not tolerated. Indeed,
dine derivative 7a by aromatization/elimination of NH3. To the phenacyl azides 2f, and 2g remained unreacted when stirred in
best of our knowledge, this is the first one-pot synthesis of func- ChCl/urea at rt even for 12 h.
tionalized pyrimidines using phenacyl azides as the sole starting
material [39]. Variation of the phenacyl azides was next investi- Conclusion
gated in the preparation of various pyrimidines 7 (Scheme 6).
In summary, we have shown that phenacyl halides can be
straightforwardly converted, via phenacyl azides, into valuable
The results shown in Scheme 6 demonstrate that this protocol 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles when a solution in ChCl/
allows the use of phenacyl azides as starting material also for Gly (1:2) is heated to 80 °C for 4–16 h in the presence of NaN3
the preparation of a variety of 2,4,6-trisubstituted pyrimidines. (1.5 equiv). In most cases, their isolation can be performed by a
The cyclotrimerization of phenacyl azides containing an alkyl very gentle procedure: decantation/centrifugation as soon as
group (4-Me, 2b), halides (4-Cl, 4-Br and 4-F, 2c, d, and 2i) or they form from the above eutectic mixture. The reaction
strong electron-withdrawing groups (2-CF3, 4-CF3, 2l, m) proceeds in very good yields (67–98%) when phenacyl azides
occurs smoothly at rt generally within 4 h in a ChCl/urea are soluble in the eutectic mixture and is applicable to a range
eutectic mixture, thereby providing the desired pyrimidines of substrates. Phenacyl azides, in turn, can also be competi-
7b–h in 45–88% yield. Variable amounts of difunctionalized tively converted into 2,4-diaroyl-6-arylpyrimidines (45–88%
imidazoles 3/3' (20–40%), deriving from a dimerization yield) via an unprecedented cyclotrimerization reaction the key
process, also formed competitively in some cases under the intermediate α-imino ketone undergoes when a solution in
Scheme 6: Scope of the synthesis of 2,4-diaroyl-6-arylpyrimidines 7. Typical conditions: 2 (0.3 mmol), Et3N (0.9 mmol), ChCl/urea (0.5 g), rt, 4 h;
yield refers to products isolated after column chromatography on silica gel; synthesis of pyrimidine derivatives 7b and 7d, reaction time: 12 h.
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
ChCl/urea is stirred at rt for 4 h in the presence of Et3N fied by column chromatography on silica gel (hexane/EtOAc
(3 equiv) as a base. These cyclizations proved to be relatively 5:1–4:1) to afford the desired α-azido ketone 2. Characteriza-
sensitive to the electronic properties of the starting phenacyl tion data of the isolated 2-azido ketones are provided in Sup-
azides as they did not take place in the presence of strong elec- porting Information File 1.
tron-donating groups like MeO. Studies to expand even more
the scope and the selectivity of such DES-promoted heterocycli- Synthesis of 2-benzoyl-4-phenyl-1H-imidazole (3a)
zation reactions and to elucidate their mechanism are in and 2-benzoyl-5-phenyl-1H-imidazole (3a'). Typical
progress.
procedure
Experimental
General methods
Deep eutectic solvents [choline chloride (ChCl)/glycerol (Gly)
(1:2 mol/mol); choline chloride (ChCl)/urea (1:2 mol/mol)]
were prepared by heating under stirring up to 80 °C for
10–15 min the corresponding individual components until a
clear solution was obtained. 1H NMR and 13C NMR spectra
were recorded on a Varian Mercury 300 or on a Bruker 400 or
600 MHz spectrometer and chemical shifts are reported in parts
per million (δ); CDCl3, (CD3)2CO and (CD3)2SO were used as
solvents. GC–MS analyses were performed on a HP 6890 gas Sodium azide (0.75 mmol) was added to a solution of
chromatograph, Series II by using a HP1 column (methyl 2-chloroacetophenone (1a, 0.5 mmol) in ChCl/Gly
siloxane; 30 m × 0.32 mm × 0.25 μm film thickness) equipped (1:2 mol/mol, 1.0 g) under air and with vigorous stirring. The
with a mass-selective detector operating at 70 eV. Analytical mixture was then warmed to 80 °C. After 12 h, 10 mL of water
thin-layer chromatography (TLC) was carried out on pre-coated were added and the solid 3a was recovered by decantation (or
0.25 mm thick plates of Kieselgel 60 F254; visualization was filtration) from the reaction mixture and washed with a few
accomplished by UV light (254 nm) or by spraying with a solu- drops of EtOAc or Et2O. The solution was extracted with
tion of 5% (w/v) ammonium molybdate and 0.2% (w/v) EtOAc (3 × 10 mL). The combined organic phases were dried
cerium(III) sulfate in 100 mL 17.6% (w/v) aq. sulfuric acid and over anhydrous Na2SO4 and the solvent was concentrated in
heating to 473 K until blue spots appeared. Column chromatog- vacuo. The addition of Et2O to the crude mixture allowed the
raphy was conducted by using silica gel 60 with a particle size further precipitation of 3a, which was finally recovered in 88%
distribution of 40–63 μm and 230–400 ASTM, using hexane/ yield. Characterization data of the isolated imidazoles are provi-
EtOAc mixtures as the eluent. High-resolution mass spectrome- ded in Supporting Information File 1.
try (HRMS) analyses were performed using a Bruker microTOF
QII mass spectrometer equipped with an electrospray ion source Synthesis of 2,4-dibenzoyl-6-phenylpyrimidine (7a).
(ESI). NaN3, 2-haloketones, and all other reagents, unless other- Typical procedure
wise specified, were purchased from Sigma-Aldrich (Sigma-
Aldrich, St. Louis, MO, USA), and used without any further
purification.
Experimental procedures
General procedure for the synthesis of 2-azido
ketones 2d, 2e, 2f, 2k, 2l and 2m
Et3N (0.930 mmol, 0.130 mL) was added to a solution of
α-Haloketone 1 (1.5 mmol) and NaN3 (107 mg, 1.65 mmol) 2-azidoacetophenone (2a, 0.31 mmol, 0.05 g) in ChCl/ urea
were sequentially added to the ChCl/Gly (1:2 mol/mol, 2.0 g) (1:2 mol/mol, 0.5 g) eutectic mixture at 25 °C, under air and
eutectic mixture. The reaction mixture was stirred at 25 °C with vigorous stirring. The reaction was monitored by TLC
under air for 3–12 h until complete consumption of the starting (hexane/EtOAc 7:3). After 4 h, 5 mL of water were added and
material (monitored by thin-layer chromatography). Then, water the reaction mixture was extracted with EtOAc (3 × 5 mL). The
was added, and the mixture was extracted with EtOAc combined organic phases were dried over anhydrous Na2SO4
(3 × 10 mL). The collected organic layers were dried using an- and the solvent was concentrated under reduced pressure.
hydrous Na2SO4, filtered, and the volatile evaporated under Purification by column chromatography on silica gel (hexane/
reduced pressure to afford the crude product, which was puri- EtOAc 9:1) provided pyrimidine 7a in 57% yield. A mixture of
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Beilstein J. Org. Chem. 2020, 16, 1915–1923.
6. Mancuso, R.; Maner, A.; Cicco, L.; Perna, F. M.; Capriati, V.;
Gabriele, B. Tetrahedron 2016, 72, 4239–4244.
doi:10.1016/j.tet.2016.05.062
imidazoles 3a/3a' (43% yield) was also isolated. Characteriza-
tion data of the isolated pyrimidines are provided in Supporting
Information File 1.
7. Perrone, S.; Capua, M.; Messa, F.; Salomone, A.; Troisi, L.
Tetrahedron 2017, 73, 6193–6198. doi:10.1016/j.tet.2017.09.013
8. Behalo, M. S.; Bloise, E.; Mele, G.; Salomone, A.; Messa, F.;
Carbone, L.; Mazzetto, S. E.; Lomonaco, D. J. Heterocycl. Chem.
2020, 57, 768–773. doi:10.1002/jhet.3818
Supporting Information
9. Dilauro, G.; Cicco, L.; Perna, F. M.; Vitale, P.; Capriati, V. C. R. Chim.
2017, 20, 617–623. doi:10.1016/j.crci.2017.01.008
10.Ghinato, S.; Dilauro, G.; Perna, F. M.; Capriati, V.; Blangetti, M.;
Prandi, C. Chem. Commun. 2019, 55, 7741–7744.
doi:10.1039/c9cc03927a
Supporting Information File 1
Compound characterization data and NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-158-S1.pdf]
11.Messa, F.; Perrone, S.; Capua, M.; Tolomeo, F.; Troisi, L.; Capriati, V.;
Salomone, A. Chem. Commun. 2018, 54, 8100–8103.
doi:10.1039/c8cc03858a
Acknowledgements
12.Dilauro, G.; García, S. M.; Tagarelli, D.; Vitale, P.; Perna, F. M.;
Capriati, V. ChemSusChem 2018, 11, 3495–3501.
doi:10.1002/cssc.201801382
The authors are also indebted to Dr. Francesco Lavolpe, Dr.
Walter Barella, Dr. Giuseppe Dilauro, and Dr. Francesco Messa
for their contribution to the experimental work.
13.Messa, F.; Dilauro, G.; Perna, F. M.; Vitale, P.; Capriati, V.;
Salomone, A. ChemCatChem 2020, 12, 1979–1984.
doi:10.1002/cctc.201902380
Funding
This work was carried out under the framework of the national
14.Quivelli, A. F.; Vitale, P.; Perna, F. M.; Capriati, V.
Front. Chem. (Lausanne, Switz.) 2019, 7, 723.
PRIN project “Unlocking Sustainable Technologies Through
doi:10.3389/fchem.2019.00723
Nature-inspired Solvents (NATUREChem) (grant number: 15.Vitale, P.; Lavolpe, F.; Valerio, F.; Di Biase, M.; Perna, F. M.;
Messina, E.; Agrimi, G.; Pisano, I.; Capriati, V. React. Chem. Eng.
2017A5HXFC_002) financially supported by the University of
2020, 5, 859–864. doi:10.1039/d0re00067a
Bari “A. Moro” (codes: SFARMA.RicercaLocale.Vitale Fondi
16.Vitale, P.; Cicco, L.; Messa, F.; Perna, F. M.; Salomone, A.; Capriati, V.
Ateneo 17-18, PernaF.18 FondiAteneo15-16, VitaleP.18 Fondi-
Eur. J. Org. Chem. 2019, 5557–5562. doi:10.1002/ejoc.201900722
Ateneo15-16), the University of Salento, the Interuniversity
17.De Luca, L. Curr. Med. Chem. 2006, 13, 1–23.
Consortium C.I.N.M.P.I.S., and the Ministero dell’Università e
della Ricerca (MIUR-PRIN).
18.Lagoja, I. M. Chem. Biodiversity 2005, 2, 1–50.
doi:10.1002/cbdv.200490173
19.Han, H.-B.; Tu, Z.-L.; Wu, Z.-G.; Zheng, Y.-X. Dyes Pigm. 2019, 160,
863–871. doi:10.1016/j.dyepig.2018.09.017
ORCID® iDs
20.Chen, W.-C.; Zhu, Z.-L.; Lee, C.-S. Adv. Opt. Mater. 2018, 6, 1800258.
doi:10.1002/adom.201800258
Paola Vitale - https://orcid.org/0000-0001-8132-2893
Luciana Cicco - https://orcid.org/0000-0003-4126-3993
Filippo M. Perna - https://orcid.org/0000-0002-8735-8165
Antonio Salomone - https://orcid.org/0000-0002-3161-385X
Vito Capriati - https://orcid.org/0000-0003-4883-7128
21.Zhang, L.; Peng, X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou, C.-H.
Med. Res. Rev. 2014, 34, 340–437. doi:10.1002/med.21290
22.Sharma, A.; Kumar, V.; Kharb, R.; Kumar, S.; Chander Sharma, P.;
Pal Pathak, D. Curr. Pharm. Des. 2016, 22, 3265–3301.
doi:10.2174/1381612822666160226144333
23.Kuzu, B.; Tan, M.; Taslimi, P.; Gülçin, İ.; Taşpınar, M.; Menges, N.
Bioorg. Chem. 2019, 86, 187–196. doi:10.1016/j.bioorg.2019.01.044
24.Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S.
Bioorg. Med. Chem. 2005, 13, 4645–4650.
References
1. Alonso, D. A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I. M.;
Ramón, D. J. Eur. J. Org. Chem. 2016, 612–632.
doi:10.1002/ejoc.201501197
doi:10.1016/j.bmc.2005.04.061
2. Ramón, D. J.; Guillena, G., Eds. Deep Eutectic Solvents: Synthesis,
Properties, and Applications; Wiley-VCH: Weinheim, Germany, 2019.
doi:10.1002/9783527818488
25.Shipe, W. D.; Sharik, S. S.; Barrow, J. C.; McGaughey, G. B.;
Theberge, C. R.; Uslaner, J. M.; Yan, Y.; Renger, J. J.; Smith, S. M.;
Coleman, P. J.; Cox, C. D. J. Med. Chem. 2015, 58, 7888–7894.
doi:10.1021/acs.jmedchem.5b00983
3. Perna, F. M.; Vitale, P.; Capriati, V.
Curr. Opin. Green Sustainable Chem. 2020, 21, 27–33.
doi:10.1016/j.cogsc.2019.09.004
26.Kaur, R.; Kaur, P.; Sharma, S.; Singh, G.; Mehndiratta, S.;
Bedi, P. M. S.; Nepali, K. Recent Pat. Anti-Cancer Drug Discovery
2015, 10, 23–71. doi:10.2174/1574892809666140917104502
27.Farag, A. K.; Elkamhawy, A.; Londhe, A. M.; Lee, K.-T.; Pae, A. N.;
Roh, E. J. Eur. J. Med. Chem. 2017, 141, 657–675.
doi:10.1016/j.ejmech.2017.10.003
4. Cicco, L.; Sblendorio, S.; Mansueto, R.; Perna, F. M.; Salomone, A.;
Florio, S.; Capriati, V. Chem. Sci. 2016, 7, 1192–1199.
doi:10.1039/c5sc03436a
5. Capua, M.; Perrone, S.; Perna, F. M.; Vitale, P.; Troisi, L.;
Salomone, A.; Capriati, V. Molecules 2016, 21, 924.
doi:10.3390/molecules21070924
28.Chen, J.; Chen, W.; Yu, Y.; Zhang, G. Tetrahedron Lett. 2013, 54,
1572–1575. doi:10.1016/j.tetlet.2013.01.042
1922

Beilstein J. Org. Chem. 2020, 16, 1915–1923.
29.Khalili, B.; Tondro, T.; Hashemi, M. M. Tetrahedron 2009, 65,
6882–6887. doi:10.1016/j.tet.2009.06.082
30.Batanero, B.; Escudero, J.; Barba, F. Org. Lett. 1999, 1, 1521–1522.
doi:10.1021/ol990200j
31.Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Strazzari, S.; Zanardi, G.; Calestani, G. Tetrahedron 2002, 58,
3485–3492. doi:10.1016/s0040-4020(02)00302-2
32.Zuliani, V.; Cocconcelli, G.; Fantini, M.; Ghiron, C.; Rivara, M.
J. Org. Chem. 2007, 72, 4551–4553. doi:10.1021/jo070187d
33.Yamamoto, Y.; Ouchi, H.; Tanaka, T.; Morita, Y. Heterocycles 1995,
41, 1275–1290. doi:10.3987/com-95-7055
34.Skulcova, A.; Russ, A.; Jablonsky, M.; Sima, J. BioResources 2018,
13, 5042–5051.
35.Boyer, J. H.; Straw, D. J. Am. Chem. Soc. 1952, 74, 4506–4508.
doi:10.1021/ja01138a011
36.Patonay, T.; Juhász-Tóth, É.; Bényei, A. Eur. J. Org. Chem. 2002,
285–295.
doi:10.1002/1099-0690(20021)2002:2<285::aid-ejoc285>3.0.co;2-j
37.Mjalli, F. S.; Ahmed, O. U. Korean J. Chem. Eng. 2016, 33, 337–343.
doi:10.1007/s11814-015-0134-7
38.Reddy, C. N.; Sathish, M.; Adhikary, S.; Nanubolu, J. B.; Alarifi, A.;
Maurya, R. A.; Kamal, A. Org. Biomol. Chem. 2017, 15, 2730–2733.
doi:10.1039/c7ob00299h
39.Hu, M.; Wu, J.; Zhang, Y.; Qiu, F.; Yu, Y. Tetrahedron 2011, 67,
2676–2680. doi:10.1016/j.tet.2011.01.062
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