Copper-catalyzed Goldberg-type C-N coupling in deep eutectic solvents (DESs) and water under aerobic conditions

Article abstract of DOI:10.1039/d0ob02501a

An efficient and selectiveN-functionalization of amides is first reportedviaa CuI-catalyzed Goldberg-type C-N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules.

Full text of DOI:10.1039/d0ob02501a

Organic &
Biomolecular Chemistry
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Copper-catalyzed Goldberg-type C–N coupling in
deep eutectic solvents (DESs) and water under
aerobic conditions†‡
Cite this: Org. Biomol. Chem., 2021,
9, 1773
1
a,b
a
c
Luciana Cicco, b
Jose A. Hernández-Fernández, Antonio Salomone,
a
d
Paola Vitale,
Marina Ramos-Martín,
Alejandro Presa Soto,
Joaquín García-Álvarez
Javier González-Sabín,
a
b
b
Filippo M. Perna,
Vito Capriati * and
a
*
An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg-
type C–N coupling reaction between aryl iodides and primary/secondary amides run either in Deep
Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction con-
ditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium,
though the employment of DESs expanded and improved the scope of the reaction to include also ali-
phatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up
the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and
the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for
the synthesis of biologically active molecules.
Received 15th December 2020,
Accepted 29th January 2021
DOI: 10.1039/d0ob02501a
rsc.li/obc
nation sphere either soft (containing P- and S- donor atoms) as
Cu(I) or hard donor ligands (like O and N) as Cu(II); and (iv) can
1
. Introduction
The search for organic transformations catalyzed by first-row, participate in both σ- or π-interactions with unsaturated organic
cheap and earth-crust abundant transition metals is nowadays substrates (alkenes or alkynes). Thus, it is not surprising to find
1
playing a pivotal role in synthetic organic chemistry. In this a plethora of applications for Cu-based catalysts in several hot-
2
6
sense and within the coinage metals group (Cu, Ag and Au),
copper occupies a prominent and strategic position as it: (i) is asymmetric synthesis. As for C–N bond formations, typical Cu-
topic areas of catalysis spanning cross-coupling reactions and
7
8
3
4
9
an essential metal in biology and presents moderate toxicity;
ii) displays a versatile reactivity with rich and diverse redox Goldberg reactions are reputed by organic chemists as key and
chemistry [possibility to access different oxidations states: Cu valuable synthetic tools for the formation of C–N bonds either
catalyzed cross-coupling processes like the Ullmann or the
10
(
5
8
(
0); Cu(I); Cu(II) or even Cu(III)]; (iii) can allocate in its coordi- in academic or in industrial laboratories all over the world,
especially considering the ongoing depletion of petroleum
reserves and the severe environmental problems associate with
their use. Thus, the employment of sustainable reaction media
a
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC),
Departamento de Química Orgánica e Inorgánica (IUQOEM), Centro de Innovación
en Química Avanzada (ORFEO-CINQA), Facultad de Química, Universidad de
Oviedo, E-33071 Oviedo, Spain. E-mail: garciajoaquin@uniovi.es
in organic synthesis is today highly sought after in order to
11
fulfill one of the most important Principles of Green Chemistry.
b
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”,
In this context, it is worth mentioning that 80–90% of the mass
balance of chemical reactions is directly related with the volatile
organic solvents (VOCs) employed, either used as a bulk reaction
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy.
E-mail: vito.capriati@uniba.it
c
Dipartimento di Chimica, Università di Bari “Aldo Moro”, Via E. Orabona 4,
12
medium or in the usually required isolation/purification steps.
I-70125 Bari, Italy
d
In this vein, we have recently reported on a variety of highly
EntreChem SL, Vivero Ciencias de la Salud, Santo Domingo de Guzmán, E-33011
Oviedo, Spain
selective and effective transition-metal-catalyzed organic trans-
Dedicated to Professor Robert E. Mulvey on the occasion of his 60th birthday. formations promoted by Ru, Au, or Pd complexes, which
1
3
14
15
†
A truly inspiring pioneer and model for mixed-metal main-group organometallic
chemists worldwide.
have been performed in a new family of sustainable reaction
16
media, that is the so-called Deep Eutectic Solvents (DESs).
‡
Electronic supplementary information (ESI) available: General experimental
procedures, characterization data and NMR spectra for obtained compounds
PDF). See DOI: 10.1039/d0ob02501a
These environmentally friendly and tunable eutectic mixtures
can be obtained by mixing and heating two (binary DESs) or
(
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2
. Results and discussion
We started our investigation by exploring sustainable reaction
media (DESs or water) useful to design a Cu-catalyzed
Goldberg-type C–N coupling under milder and bench-type
reaction conditions. We elected to study, as a model reaction,
the CuI-catalyzed (10 mol%) coupling of 4-iodotoluene (1a)
with 2-methylbenzamide (2a) in the archetypical eutectic
mixture 1ChCl/2Gly, in the absence of protecting atmosphere
(
under air) and at 80 °C. Building on previously reported
2
3
studies on Goldberg-type C–N couplings, we decided to use
t
Fig. 1 Hydrogen-bond-acceptors (HBAs, A) and hydrogen-bond- ethylene diamine (L1) (10 mol%) and BuOK (3 equiv.) as a
donors (HBDs, B) usually employed in the synthesis of sustainable Deep
Eutectic Solvents (DESs).
base. After 12 h reaction time, we observed the formation of
the desired secondary amide 3a in moderate yield (66%), but
with a complete chemoselectivity. No side products were
observed in the crude reaction mixture aside from unreacted
starting materials (1a and 2a) (Table 1, entry 1). At this point,
it is important to note the significant effect of the temperature
on the outcome of the catalytic reaction. Indeed, the yield of
even three (ternary DESs) components that are amenable to
interact through
a
tridimensional hydrogen-bond-type
network, which is established between hydrogen-bond-accep-
tor components [HBAs, usually biorenewable quaternary
1
7
ammonium salts like choline chloride (ChCl) (A, Fig. 1)] and
hydrogen-bond-donors [HBDs, typically natural polyols (like
glycerol (Gly), ethylene glycol (EG), sugars), urea derivatives Table 1 CuI-Catalyzed Goldberg type C–N coupling between 4-iodo-
toluene (1a) and 2-methylbenzamide (2a) under air and at 80 °C in
different sustainable solvents (DESs or water)
and biorenewable carboxylic acids (e.g., oxalic, malonic acid
a
1
8
(
B, Fig. 1)]. At this point, it is important to remark that DESs
have been today used as privileged sustainable solvents in a
1
9
wide variety of chemical applications.
Despite the large number of Pd-catalyzed C–C coupling
reactions successfully run in different eutectic mixtures (e.g.,
Sukuzi, Heck, Stille, Sonogashira and Hiyama-type
1
5c,e–h,20
b
c
couplings),
there are only few examples, independently Entry
X
Solvent
T (°C) Ligand
Base (%) Yield (%)
2
1
22
reported by Shaabani and Capriati research groups, which
illustrate the possibility to perform the Cu-catalyzed Ullman-
type C–N coupling between aryl halides and primary or sec-
ondary amines in sustainable eutectic mixtures. Conversely, as
far as we are aware, the corresponding counterpart studies on
the Cu-catalyzed Goldberg-type C–N coupling in DESs have
t
1
2
3
4
5
6
7
8
9
1
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
Gly
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
1ChCl/2Urea 80
80
60
100
80
80
80
L1
L1
L1
L1
—
BuOK
BuOK
BuOK
66
41
72
0
10
51
74
0
72
0
9
20
27
37
2
10
8
t
t
—
t
BuOK
t
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L1
L1
L1
L1
L1
L1
L1
L1
L1
BuOK
t
BuOK
2
3
—
been totally neglected. Accordingly, we decided to fill this
t
BuOK
t
gap by studying the C–N coupling reaction of aryl halides with
either aromatic or primary and secondary aliphatic amides 11
0
BuOK
t
BuOK
t
1
1
1
2
3
4
BuOK
(Scheme 1): (i) in different DESs or water as sustainable sol-
t
BuOK
t
vents; (ii) under mild and bench-type reaction conditions
BuOK
t
(
presence of air and lower reaction temperature); and (iii) 15
using different bases (KOH or BuOK) and bidentate ligands
like ethylene diamine, glycine, L-proline, bipyridine). The
BuOK
t
t
16
BuOK
t
1
1
7
8
Br 1ChCl/2Urea 80
Cl 1ChCl/2Urea 80
BuOK
t
(
BuOK
0
t
robustness of the proposed methodology was further high- 19
lighted by successful recycling studies of the catalytic system
and its application in drug synthesis.
I
I
I
I
I
I
I
1Bet/1Urea
1ChCl/2H
80
80
80
80
80
80
80
BuOK
60
80
85
92
0
t
20
21
22
23
24
25
2
O
BuOK
t
2
H O
2
H O
2
H O
2
H O
2
H O
BuOK
KOH
Cs
2
CO
CO
PO
3
K
K
2
3
11
4
3
4
a
General conditions: Reactions performed under air, at 60–100 °C
b
using 0.5 mmol of 1a and 2a in 1 mL of the desired solvent. L1 =
ethylene diamine; L2 = N,N-dimethylethylenediamine; L3 = glycine; L4
=
L-proline; L5 = 2,2′-bipyridine; L6 = (1R,2S)-cyclopentane-1,2-diamine;
L7 = (1R,2S)-cyclohexane-1,2-diamine; L8 = benzene-1,2-diamine; L9 =
c
Scheme 1 CuI-Catalyzed Goldberg-type C–N coupling of aryl iodides (1R,2S)-2,3-dihydro-1H-indene-1,2-diamine.
with primary/secondary amides under air in DES or in water.
HPLC.
Yield determined by
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3
a dropped to 41% when the temperature was lowered down to
6
0 °C (Table 1, entry 2). On the other hand, enhancement of
the reaction temperature up to 100 °C only produced a moder-
ate increase of the yield of 3a (72%, Table 1, entry 3). We also
found that the suppression of either the external base (Table 1,
entry 4) or the bidentate ligand ethylene diamine (L1) (Table 1, Scheme 2 CuI-Catalyzed Goldberg type C–N coupling between
4
-iodotoluene (1a) and 2-methylbenzamide (2a) for the scaled-up syn-
entry 5) produced a loss of the catalytic activity or a dramatic
decrease of the 3a yield, respectively. Finally, in accordance
with previous studies on transition-metal-catalyzed organic
thesis of 3a (reaction performed on a 2.5 mmol scale).
1
4
reaction in ChCl-based eutectic mixtures, the Goldberg-type
C–N coupling was similarly found to proceed at higher rates in
the 1ChCl/2Gly eutectic mixture than in pure glycerol (Table 1,
entry 6), thus highlighting the positive effect of this quaternary
ammonium salt in the catalytic procedure when synergistically
combined with Gly.
ditions (80 °C, 10 mol% of CuI, 10 mol% of ethylene diamine,
3
equiv. of KOH and under air; see Table 2). As for aromatic
amides, the presence of electron-donating substituents in the
aromatic ring, like methyl (2a) or methoxy (2b) groups, gave
rise to the corresponding secondary amides 3a–e in good to
quantitative yields (81–99%, Table 2, entries 1–5) when 4-iodo-
toluene (1a), 4-iodobenzene (1b) or 3-iodoanisole (1c) were
employed as coupling partners. However, the presence of elec-
tron-withdrawing substituents in the aromatic ring of the
amide, like in the case of 2-fluorobenzamide (2c), produced a
slight erosion in the yield of the corresponding secondary
amides 3f,g (64–74%; Table 2, entries 6 and 7). This catalytic
system also tolerates the use of secondary amides, like
N-methylbenzamide (2d) giving rise to the expected tertiary
amide 3h in good yield (70%; Table 2, entry 8). One of the
main drawbacks of our aqueous catalytic system is related to
the fact that aliphatic amides proved to be totally unreactive.
Next, we decided to study the effect of different HBDs
forming the eutectic mixture on the outcome of the catalytic
reaction. To this end, we firstly replaced the natural polyol Gly
by urea to form the so-called eutectic mixture reline (1ChCl/
1
8
2
1
Urea).
Under the aforementioned conditions (80 °C,
t
0 mol% of CuI, 10 mol% of L1, 3 equiv. of BuOK, under air),
we observed an increase of the yield of 3a (74%), while main-
taining the total chemoselectivity of the reaction (Table 1,
entry 7). Probably, this result could be related to the enhanced
basic character of the eutectic mixture 1ChCl/2Urea when com-
2
4
pared with 1ChCl/2Gly. At this point, we explored: (i) the
possibility to run the reaction in the absence of base, but no
reaction was observed (Table 1, entry 8); (ii) the effect of
different chelating ligands (10 mol% of L1–L9), with the best
result obtained by the ethylene diamine (Table 1, entries
Pleasantly, switching water for the 1ChCl/2H O eutectic
2
mixture, we observed moderate to good coupling yields (up to
99%) of aliphatic propionamide (2e) with iodo-aryl partners
containing different substituents [4-Me (1a) or 3-MeO (1c);
Table 2, entries 9–11). Finally, in order to promote an efficient
9
–16); (iii) the influence of the halogen atom present in the
aromatic coupling partner (4-Br- or 4-Cl-toluene), observing a
decrease in the yield of the process (Table 1, entries 17 and
1
8); and (iv) the employment of a different HBA, detecting a
decrease of the catalytic activity when using betaine (Bet, Table 2 CuI-Catalyzed Goldberg type C–N coupling between different
aryl iodides (1a–c) and several aromatic/aliphatic amides (2a–e), in
water or 1ChCl/2H O, under air and at 80 °C
2
Table 1, entry 19). To finish with the parametrization studies
on the role of HBD of the eutectic mixture, we decided to
extend our studies to the prototypical HBD present in nature,
a
that is water, thus using the eutectic mixture 1ChCl/2H
solvent. In this case, we found an increased catalytic activity
80%; Table 1, entry 20). This enhancement could even be
improved using bulk water as the solvent (85%; Table 1, entry
1). Finally, a yield as high as 92% could be achieved when
switching from BuOK to KOH (Table 1, entry 22), while the
use of carbonate- or phosphate-containing inorganic bases
considerably decreased the activity of the catalytic system
2
O as a
(
2
1
2
3
b
Entry
R
R /R
Solvent
Yield (%)
t
1
2
3
4
5
6
7
8
9
4-Me (1a)
H (1b)
3-OMe (1c)
4-Me (1a)
H (1b)
H (1b)
4-Me (1a)
H (1b))
2-Me-Ph/H (2a)
2-Me-Ph/H (2a)
2-Me-Ph/H (2a)
3-MeO-Ph/H (2b)
3-MeO-Ph/H (2b)
2-F-Ph/H (2c)
2-F-Ph/H (2c)
Ph/Me (2d)
2
H O
2
H O
2
H O
92 (85, 3a)
95 (90, 3b)
81 (74, 3c)
88 (83, 3d)
99 (95, 3e)
74 (68, 3f)
64 (57, 3g)
70 (65, 3h)
99 (92, 3i)
62 (60, 3j)
45 (42, 3k)
(
Table 1, entries 23–25). At this point, it is worth noting that a
similar yield (90%) was achieved also in 1ChCl/2H O by per-
forming the coupling reaction on 2.5 mmol scale
2
H O
2
H O
2
H O
2
H O
2
a
2
5
(Scheme 2).
H O
2
4-Me (1a)
H (1b)
3-OMe (1c)
Et/H (2e)
Et/H (2e)
Et/H (2e)
1ChCl/2H
1ChCl/2H
1ChCl/2H
2
O
2
O
2
O
Since the use of water was associated to the best catalytic
1
1
0
1
performance, we decided to expand the scope of this reaction
to the coupling of a library of amides 2a–e (aliphatic/aromatic,
secondary/primary amides containing either electron-donor or
electron-withdrawing groups) with a variety of substituted aryl
a
General conditions: Reactions performed under air, at 80 °C using
.5 mmol of 1a–c and 2a–e and 3 equiv. of KOH in 1 mL of the desired
solvent. Yield determined by HPLC. Isolated yields after column
0
b
iodides (1a–c), under the previously optimized catalytic con- chromatography in brackets.
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mass transfer in the synthesis of compounds 3g, 3j and 3k coupling between 4-iodoanisole (1e) and 4-chlorobenzamide
Table 2, entries 7,10 and 11), we performed the coupling reac- (2f), under the previously optimized reaction conditions in the
tion under ultrasonic irradiation using a conventional ultra- 1ChCl/2H O eutectic mixture (Scheme 4), finding that the
(
2
2
6
sound bath operating at 35 kHz and 160 W. However, the use desired secondary amide 3l chemoselectively formed in a 87%
of these new reaction conditions did not improve the yield/ yield. As a final point, it is worth mentioning that the biologi-
reaction times previously observed in any of the studied cases.
In the framework of a sustainable catalysis, the lifetime of when working on a 2.5 mmol scale.
a catalytic system and its level of reusability are key factors that
cally active compound 3l was isolated in the same yield (87%)
2
7
could improve the environmental footprint of a given catalytic
2
8
system. In this sense, and taking into account the feasibility 3. Conclusions
of recycling eutectic mixtures in metal-catalyzed organic reac-
1
6e
In summary, we have developed the first Cu-catalyzed
Goldberg-type C–N coupling working in ChCl-based deep
eutectic solvents and water. The utilization of these sustain-
able reaction media allowed us to carry out this coupling
process: (i) under milder reaction conditions (80 °C; tempera-
tures as high as 110 °C are usually required); (ii) employing
bench-type settings (presence of air); and (iii) with high
chemoselectivity, as a variety of coupling partners with
different electron-donating or electron-withdrawing substitu-
ents are tolerated. The inactivity of the catalytic system in
water when using aliphatic amides was overcome upon simple
switching of water for a water-based eutectic mixture, that is
tions,
we decided to investigate the reusability of our cata-
lytic system taking, as a model reaction, the CuI-catalyzed
Goldberg-type coupling between iodobenzene (1b) and
2
-methylbenzamide (2a), at 80 °C, in the presence of ethylene
diamine (10 mol%) as a ligand and KOH (3 equiv.) as a base,
under air and using the eutectic mixture 1ChCl/2H O as a reac-
2
tion medium (Scheme 3). Under these conditions, the desired
amide 3b was isolated in 87% yield after 12 h reaction time.
Subsequent extraction of the resulting crude with a sustainable
2
9
green solvent like cyclopentyl methyl ether (CPME) and con-
comitant addition of fresh reagents, allowed us to recycle the
catalyst and the DES successfully up to three consecutive runs
with only a negligible erosion of the final yield of 3b
1
ChCl/2H O.
2
Furthermore, we demonstrated: (i) the possibility to scale
(Scheme 3). In order to provide metrics to support the “green-
up the reaction without observing any erosion of the yield/reac-
tion time; (ii) the successful recycle of both the catalyst and
the eutectic solvent up to 4 consecutive runs; and (iii) the com-
petence of our catalytic system for the synthesis of biologically
active organic molecules. Overall, this methodology provides a
synthetic tool for the efficient, sustainable and selective for-
mation of C–N bonds, which is an important endeavour in the
field of metal-catalyzed organic transformations.
ness” profile of the reported methodology, we have calculated
the Sheldon’s environmental factor (E-factor) (total mass of
3
0
31
waste/mass of product), finding a value of 15, which is
3
0
within the recommended range for fine chemicals (5–50).
Finally, we decided to apply our methodology to the syn-
thesis of biologically active molecules. Our target was 4-chloro-
N-(4-methoxyphenyl)benzamide (3l), which belongs to the
N-arylbenzamide class of cyclooxygenase (COX-1) selective
3
2
inhibitors (Scheme 4). We envisaged as a key step to access
this secondary amide, a CuI-catalyzed Goldberg-type C–N
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
L. C., J. A. H. -F., M. R. -M. and J. G. A thanks the Spanish
MINECO (Project CTQ2016-75986-P and CTQ2016-81797-
REDC). M. R. -M. and A. P. S are indebted to Spanish MINECO
(Project CTQ2014-56345-P, CTQ2017-88357-P, and RYC-2012-
Scheme 3 CuI-catalyzed Goldberg type C–N coupling between iodo-
benzene (1b) and 2-methylbenzamide (2a) under air and at 80 °C in the
2
eutectic mixture 1ChCl/2H O: recycling studies.
09800), and Gobierno del Principado de Asturias (FICYT,
Project FC-15-GRUPIN14-106) for financial support. M. R. -M.
thanks “Vicerrectorado de Investigación” from the University
of Oviedo for the award of a predoctoral grant through the
“Plan de Apoyo y Promoción de la Investigación, Universidad
de Oviedo”. A. P. S. is also grateful to the COST action Smart
Inorganic Polymers (SIPs-CM1302—http://www.sips-cost.org/
home/index.html), and Spanish MEC for the Juan de la Cierva
and Ramón y Cajal programs. J. G. -A. thanks: (i) the
Fundación BBVA for the award of a “Beca Leonardo a
Scheme 4 Synthesis of the biologically active aromatic secondary
amide 3l through CuI-catalyzed Goldberg type C–N coupling between
4-iodoanisole (1e) and 4-chlorobenzamide (2f), under air and at 80 °C in
3
3
the eutectic mixture 1ChCl/2H O.
2
Investigadores
y
Creadores Culturales 2017”;
and (ii)
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2
PhosAgro/UNESCO/IUPAC for the award of a “Green Chemistry
for Life Grant”. This work was also carried out under the
framework of the projects: (a) “Development of Sustainable
Synthetic Processes in Unconventional Solvents for the
Preparation of Molecules of Pharmaceutical Interest” realized
with the contribution of Fondazione Puglia, which is gratefully
acknowledged by L. C. and V. C; and (b) “Unlocking
Formation of sp C–N Bonds, ed. M. Taillefer and D. Ma,
Springer, New York, USA, 2014; (e) P. Ruiz-Castillo and
S. L. Buchwald, Chem. Rev., 2016, 116, 12564; (f) J. Luo and
W.-T. Wei, Adv. Synth. Catal., 2018, 360, 2076.
9 (a) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382;
(b) F. Ullmann and P. Sponagel, Ber. Dtsch. Chem. Ges.,
1905, 38, 2211.
Sustainable Technologies Through Nature-inspired Solvents 10 I. Goldberg, Ber. Dtsch. Chem. Ges., 1906, 39, 1691.
NATUREChem) (grant number: 2017A5HXFC_002)” finan- 11 (a) P. T. Anastas and J. C. Warner, Green Chemistry Theory and
(
cially supported by the Ministero dell’Università e della
Ricerca (MUR-PRIN).
Practice, Oxford University Press, Oxford, UK, 1998;
(b) A. S. Matlack, Introduction to Green Chemistry, Marcel
Dekker, New York, USA, 2001; (c) M. Poliakoff,
J. M. Fitzpatrick, T. R. Farren and P. T. Anastas, Science, 2002,
2
97, 807; (d) M. Lancaster, Green Chemistry: An Introductory
Notes and references
Text, RSC Publishing, Cambridge, UK, 2002; (e) R. A. Sheldon,
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The transition-metal-catalyzed C–N bond formation allows
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6 For general reviews or book chapters that cover the use of
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(c) P. Liu, J.-W. Hao, L.-P. Mo and Z.-H. Zhang, RSC Adv.,
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015, 5, 48675; (d) D. A. Alonso, A. Baeza, R. Chinchilla,
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Chem., 2016, 612; (e) C. Vidal and J. García-Álvarez, Metal–
Promoted Organic Transformation in DES, in Deep Eutectic
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D. J. Ramón and G. Guillena, Wiley-VCH, Weinheim,
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7 (2-Hydroxyethyl)trimethylammonium chloride (choline
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8 The term Deep Eutectic Solvent (DES) was firstly coined by
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9 For general reviews and books dealing with the use of Deep
1
Eutectic Solvents as sustainable reaction media in different 21 A. Shaabani and R. Afshari, J. Colloid Interface Sci., 2018,
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2969; (c) Q. Zhang, K. de Oliveira Vigier, S. Royer and 23 For recent examples on Cu-catalyzed Goldberg type C–N
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(n) Z. Cao, Q. Zhu, Y.-W. Lin and W.-M. He, Chin. Chem. Lett.,
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0, 1135; (p) P. Vitale, F. Lavolpe, F. Valerio, M. Di Biase, F.
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5 For more information, see ESI.†
32 Cyclooxygenase-1 (COX-1) is an emerging target for preven-
tion and treatment of atherosclerosis and ovarian epithelial
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6 Ultrasonic irradiation has been previously employed to
improve the yield/reaction time in organic transformations
performed in DESs. For a recent example see: C. Wu,
H.-J. Xiao, S.-W. Wang, M.-S. Tang, Z.-L. Tang, W. Xia,
W.-F. Li, Z. Cao and W.-M. He, ACS Sustainable Chem. Eng.,
2
019, 7, 2169.
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7 In modern organic synthesis, catalysis is considered as a
key concept for sustainability; see: G. Rothenberg,
Catalysis, Wiley-VCH, Weinheim, Germany, 2008.
8 (a) Catalyst Separation, Recovery and Recycling. Chemistry
and Process Design ed. D. Cole-Hamilton and R. Tooze,
Springer, Dordrecht, The Netherlands, 2006; (b) Recoverable
and Recyclable Catalyst ed. M. Benaglia, Wiley, Chichester,
UK, 2009.
2
2
9 U. Azzena, M. Carraro, L. Pisano, S. Monticelli, 33 The Fundación BBVA accepts no responsibility for the
R. Bartolotta and V. Pace, ChemSusChem, 2019, 12, 40.
0 R. A. Sheldon, Green Chem., 2007, 9, 1273.
1 For more details on the E-factor calculation, see ESI.†
opinions, statements and contents included in the project
and/or the results thereof, which are entirely the responsi-
bility of the authors.
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