Exploring the acidic catalytic role of differently structured deep eutectic solvents in the aza-Michael addition of amines to 2-vinylpiridine

Article abstract of DOI:10.1007/s00706-020-02660-z

Abstract: The search for innovative and green reaction media is a prominent topic in the recent research in chemistry. Deep Eutectic Solvents (DESs) are currently gaining relevance in this field thanks to their unique properties in terms of their “greenness” as well as in terms of their catalytic properties. In this work we developed an efficient protocol for the conjugate aza-Michael addition of amines to 2-vinylpyridine using 14 differently structured acid DESs as both reaction media and catalysts, so preventing the use of other acid additives. The results are influenced by the acidity of the components of the DESs, showing the best results with weak acids in the DESs components, with isolated yields up to 86%. The aza-Michael reaction is a widely used synthetic route for the C–N bond formation in organic synthesis. In particular, the addition of amines to 2-vinylpyridine is used for the realization of pharmaceutically relevant compounds with anticancer, antiarrhythmic, and analgesic properties. Comparing the results with the ones observed in literature for the same reaction, this procedure revealed to be a convenient and efficient method for this relevant transformation. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-020-02660-z

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02660-z
ORIGINAL PAPER
Exploring the acidic catalytic role of diferently structured
deep eutectic solvents in the aza‑Michael addition of amines
to 2‑vinylpiridine
Marco Ballarotto1,2 · Federico Cappellini1 · Riccardo Maestri1 · Tiziana Del Giacco1 · Pietro Di Profo3 ·
Matteo Tiecco1 · Raimondo Germani1
Received: 18 April 2020 / Accepted: 3 July 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
The search for innovative and green reaction media is a prominent topic in the recent research in chemistry. Deep Eutectic
Solvents (DESs) are currently gaining relevance in this feld thanks to their unique properties in terms of their “greenness”
as well as in terms of their catalytic properties. In this work we developed an efcient protocol for the conjugate aza-Michael
addition of amines to 2-vinylpyridine using 14 diferently structured acid DESs as both reaction media and catalysts, so pre-
venting the use of other acid additives. The results are infuenced by the acidity of the components of the DESs, showing the
best results with weak acids in the DESs components, with isolated yields up to 86%. The aza-Michael reaction is a widely
used synthetic route for the C–N bond formation in organic synthesis. In particular, the addition of amines to 2-vinylpyridine
is used for the realization of pharmaceutically relevant compounds with anticancer, antiarrhythmic, and analgesic properties.
Comparing the results with the ones observed in literature for the same reaction, this procedure revealed to be a convenient
and efcient method for this relevant transformation.
Graphic abstract
Keywords Aza-Michael addition · Deep eutectic solvents · Acidity · Green chemistry · Solvent efect
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02660-z) contains
supplementary material, which is available to authorized users.
2
* Matteo Tiecco
Department of Pharmaceutical Sciences, University
of Perugia, via del Liceo 1, 06123 Perugia, Italy
matteotiecco@gmail.com
3
1
Department of Pharmacy, University of Chieti-Pescara
“G. D’Annunzio”, via dei Vestini 31, 66100 Chieti, Italy
Department of Chemistry, Biology and Biotechnology,
University of Perugia, via Elce di Sotto 8, 06123 Perugia,
Italy
Vol.:(0123456789)
1 3

M. Ballarotto et al.
biotechnology, etc.), Deep Eutectic Solvents are fnding fruit-
ful applications as reaction media for chemical transformation
[22]. In this feld DESs can play an “innocent” role (if they are
only used for the solubilization of the reactants or of the prod-
ucts) or an “active” role if their components can participate in
the reaction (i.e. acid catalyst, reactants) and this increases the
importance of these liquids [23]. Another advantage of the use
of DESs as solvents in chemical transformations is that they
permit to work in air with reactions that normally need anhy-
drous conditions, such as Pd-catalyzed C–H bond activations
and polar organometallic chemistry [24, 25]. This is because
these liquids can act as water scavengers by incorporation of
water molecules it in their H-bond network [26, 27].
Introduction
Organic solvents and volatile organic compounds (VOCs)
play a fundamental role in the chemical industry as they are
involved in large amounts in diferent processes, from chemi-
cal transformations to the applications as paints, pharmaceu-
ticals, pesticides, cleaners, inks and so on [1–3]. The easy
dispersion of these liquids in the environment, also favoured
by their high volatility, represents a severe ecological problem
because of their toxicity, reduced biocompatibility, and scarce
biodegradability [4, 5]. Moreover, the removal of these pollut-
ants from the environment often requires difcult and expen-
sive procedures [6, 7]. For these reasons, the proper choice of
solvents that can have a lower ecological impact has nowadays
a relevant role.
Following our research fndings in the development of novel
green and catalytic reaction media [28–32], in this paper we
studied the aza-Michael addition of amines to 2-vinylpyridine
as probe acid-catalysed conjugate transformation using a set
of 14 diferent Deep Eutectic Solvents. The solvents acted as
both green reaction media as well as acid catalysts as they are
formed by diferent Brønsted or Lewis acids. The aza-Michael
reaction is widely used and applied in organic synthesis for
the formation of C–N bonds. In particular, the conjugate addi-
tion of nitrogen nucleophiles to 2-vinylpyridine can be used
to obtain pharmaceutically relevant molecules, e.g. with anti-
cancer, antiarrhythmic, and analgesic properties, and efective
chelating molecules for transition metals [33–37].
In the green chemistry framework, many solvents or
approaches have been proposed as alternatives to commonly
used organic solvents and VOCs [8–10]; those systems present
both advantages and disadvantages but they are still widely
used and explored for their favourable green characteristics,
such as their non-volatility, their bio-compatibility, the recycle
capability and so on [11].
In the recent years Deep Eutectic Solvents (DESs) are
gaining importance as ecological green liquids in this topic
for their favourable properties [12–14]. DESs are formed by
mixing two molecules: a halide “onium” salt (or generally a
Hydrogen Bond Acceptor molecule, HBA) with a Hydrogen
Bond Donor component (HBD). The network of intra- and
inter-molecular weak interactions between them causes the de-
structuration of the crystal lattice of the components, leading
to the formation of a liquid at room temperature [15].
We developed a protocol that shows good results in terms
of yields (up to 86% of isolated products) and reaction times
(24 h) when compared to those reported for the same reaction
in literature, where volatile organic protic solvents (such as
methanol or ethanol) were used at refux, resulting in yields
ranging from 25 to 72% and with reaction times from 24 to
48 h [37, 38]. Moreover, the use of harmful and volatile acids
was avoided thanks to the acid properties of the chosen DESs.
The results observed underlined the importance of the choice
of the proper class of Deep Eutectic Solvents for the reaction.
DESs mixtures can be considered as a side-class of Ionic
Liquids (ILs), and they share with them many green properties
such as the low or absent vapor pressure and recycling capa-
bilities [16]. However, they represent a further step ahead in
the development of novel green liquids for diferent reasons:
they are prepared by simply mixing and heating the two solid
components at the proper molar ratio; therefore no solvent is
needed for their preparation, unlike ILs; DESs can be formed
by natural source molecules or primary metabolites (NADESs:
NAtural Deep Eutectic Solvents); they are showing a low (or
in some cases absent) toxicity as it is emerging from the recent
literature [17–19]. The negligible vapor pressure promotes
their use for industrial applications thanks to both the scarce
difusion in the air of polluting organic molecules and their
economic advantages; in fact the reaction systems do not need
any vapor extraction hoods for the reaction solvents. DESs
are classifed in diferent types depending on the molecules
they are formed by; the high number of possible combinations
of the components can lead to diferently structured liquids
with distinct properties [20, 21]. Used in many diferent topics
(such as separation/extraction agents, in electrochemistry, in
Results and discussion
In this work the aza-Michael conjugate addition of ben-
zylamine to 2-vinylpyridine was studied without any added
acid catalyst in diferent acid Deep Eutectic Solvents. The
general reaction scheme is reported in Scheme 1.
Reaction conditions optimization
The frst step of this work was the optimization of the
reaction conditions in terms of the temperatures and the
reaction times. The DES formed by glycolic acid and tri-
methylglycine (molar ratio 2/1) was used as a model acidic
1 3

Exploring the acidic catalytic role of diferently structured deep eutectic solvents in the…
Scheme 1
DES
+
N
N
H
NH
2
N
Scheme 2
DES
+
N
N
H
N
N
N
N
Mono-bza
Bis-bza
solvent. This liquid demonstrated, in fact, remarkable
physico-chemical properties (such as a very low melting
point, low viscosity, and low cost of the starting materials)
and its NADES nature makes it environmentally friendly
and non-toxic, making it a reasonable starting point for
our research [39]; its acidity avoided the use of any other
acid catalyst.
Table 1 Optimization of the reaction conditions in the addition of
benzylamine to 2-vinylpyridine in glycolic acid/trimethylglycine DES
(GLY/TMG molar ratio 2/1)a
Entry
Temperature/°C
Time/h
Mono-bza
yield /%
Bis-bza
yield /%
1
2
3
4
5
6
7
50
70
70
70
70
70
70
24
24
2
4
6
48
72
38
54
35
44
52
62
60
10
3
6
4
4
5
4
In all the analysed samples (also with the other DESs
in the subsequent sections of this work) beside the main
product (Mono-bza) a by-product obtained by addition
of Mono-bza to a second molecule of vinylpyridine was
observed (Scheme 2), in most cases as traces but in some
other with not negligible yields (10–20%; identity con-
1
frmed via H NMR and MS analyses, see Supporting
aReaction conditions: 2-vinylpyridine (1 mmol), benzylamine
(1 mmol), 1 g DES. All the yields are measured by GC
Information). The optimization of the reaction conditions
was made also in order to minimize the formation of this
by-product.
entry 2) as a modest increase of the yield was observed
over this reaction time.
The reaction conditions were optimized subsequently
(Table 1). Initially, the temperature was analysed per-
forming the reaction at 50 °C (Mono-bza GC yield 38%,
entry (1) and 70 °C (Mono-bza GC yield 54%, entry (2);
higher temperatures led to polymerization products of
2-vinylpyridine, while lower ones led to very low yields
(traces). Moreover, an increment to 10% of Bis-bza GC
yield was observed for the sample at 50 °C so the reaction
temperature was set at 70 °C. This also permitted to have
the possibility of using a larger set of DESs by using the
ones with high melting points.
Selection of the media
With the optimized reaction conditions in hand (24 h,
70 °C), we screened a wide array of DESs containing Brøn-
sted or Lewis acids as one of the components and with a
melting point inferior to the reaction temperature. Since this
reaction needs an acid catalysis, by this way we were able to
evaluate the specifc activity of the diferent DESs involved
in this study. The results of this screening are reported in
Table 2.
With the temperature set at 70 °C the reaction time was
optimized, ranging from 2 h (Mono-bza, GC yield 35%,
entry 3) to 72 h (Mono-bza, GC yield 60%, entry 7); in
all the samples the Bis-bza yields were low (< 6%). The
reaction time was set at 24 h (Mono-bza GC yield 54%,
The DESs were chosen with a wide range of acidity in
their components. Depending on the nature of the molecules
forming them, the DESs used can be grouped in diferent
1 3

M. Ballarotto et al.
classes: neutral (choline chloride/urea, entry 1); carboxylic
acids/betaine based liquids [39] (entries 2–7); (1S)-(+)-cam-
phorsulfonic acid/sulfobetaine based ones [40] (entries 8, 9);
p-toluenesulfonic acid/ammonium methanesulfonate-based
ones [41] (entries 10, 11), and Lewis acid-based ones [42]
(entries 12–14). The pKa value of the acid components of the
DESs could not be strictly correlated with the activity of the
DESs when their values are close to one another, as observed
in recent papers in literature [20, 43]. However, the media
chosen in this work display large diferences in the pKa of
the HBD components; therefore, this phenomenon could not
impact on the observed results. Moreover, the zwitterionic
liquids used in this work (entries 2–9) showed advantageous
properties related to their low toxicity, as suggested in some
recent papers [39, 40].
The DES formed by urea and choline chloride (Table 3,
entry 1) was used as reference because it was the frst eutec-
tic mixture that received a widespread recognition in the
feld [44]; this liquid lacks any Brønsted or Lewis acidity
in its components and, as expected, the yields observed are
really low (6%); moreover, a noticeable heterogeneous layer
formed on top of the reaction mixture upon the addition
2-vinylpyridine to urea/choline chloride DES suggested dif-
fculties in the solubilisation in the reaction mixture.
Interestingly, best results were obtained by using aromatic
carboxylic acids as HBD components: phenylacetic, benzoic,
2-Cl-benzoic and 3-Cl-benzoic acids showed yields of 78%,
75%,>95%,>95%, respectively (entries 2, 3, 5, 6); beside
their suitable acidic properties, maybe, this could be due
to their higher solvating properties towards aromatic com-
pounds. Glycolic Acid based-DESs showed a yield of 50%
(entry 4). Oxalic acid/TMG DES (entry 7) is formed by a
carboxylic acid but with lower pKa compared to the previous
ones analysed in this work (pKa1 =1.2, pKa2 =4.4); in this
case no product was observed. Moreover, after the addition
of benzylamine to the eutectic mixture an of-white solid
formed at the contact point, which did not dissolve even
after prolonged heating; so other solubility problems seem
The results demonstrated that the acidity of the Brønsted
acid component plays a crucial role; weaker acids gave the
highest yields of Mono-bza (entries 2–6, yields ranging from
50% to>95%), whereas stronger acids, such as p-TSA and
(1S)-(+)-CSA [32, 40, 41], gave lower yields (entries 8–11,
from traces to 33%). Finally, the mixture urea/choline chlo-
ride (entry 1) furnished very modest results.
Table 2 Addition of benzylamine to 2-vinylpyridine in diferent DESa
Entry
Bronsted/lewis acid
Bronsted/lewis base
DES molar ratio
(acid/base)
Brønsted acid pKa
Yield /%
Mono-bza
Bis-bza
1
2
3
4
5
Urea
ChCl
TMG
TMG
TMG
TMG
2/1
2/1
1.5/1
2/1
1.5/1
n.a.d
4.3
4.2
3.8
2.9
6
78
75
50
Traces
6
10
Phenylacetic acid
Benzoic acid
Glycolic Acid
2-Cl-Benzoic acid
Traces
Traces
>95(70b,58b,c
)
(42b,c
Traces
Traces
Traces
Traces
Traces
Traces
)
6
7
8
9
10
11
12
3-Cl-Benzoic acid
Oxalic acid
(1S)-(+)-CSA
(1S)-(+)-CSA
p-TSA
p-TSA
ZnCl2
TMG
TMG
SB3-Cy
SB3-MIM
CyMsO
BnMsO
Acetamide
1.5/1
2/1
1.5/1
1.5/1
1/1
1/1
1/4
3.8
1.2, 4.4
1.2
>95
Traces
33
1.2
15
− 2.8
− 2.8
n.a
Traces
Traces
81b (56b,c
)
Traces
(26b,c
)
13
14
SnCl2
AlCl3
Acetamide
Acetamide
1/2
1/2
n.a
n.a
65b (26b,c
41b
)
19b (74b,c
14b
)
ChCl choline chloride, TMG trimethylglycine, SB3-Cy 3-(cyclohexyldimethylammonio)propane-1-sulfonate, SB3-MIM 3-(1-methyl-1H-im-
idazol-3-ium-3-yl)propane-1-sulfonate, CyMsO N,N,N-trimethylcyclohexylammonium mesylate, BnMsO N,N,N-trimethylbenzylammonium
mesylate
aReaction conditions: 2-vinylpyridine (1 mmol), benzylamine (1 mmol), 1 g DES, 70 °C, 24 h. All the yields are measured by GC if not stated
otherwise
bIsolated yield
c2-vinylpyridine:benzylamine molar ratio 2.5:1
dpKa of the protonated form=0.1. n.a.=not applicable
1 3

Exploring the acidic catalytic role of diferently structured deep eutectic solvents in the…
to add up to the acidity properties. The stronger the acids
were present as DESs components, the lower the yields were
observed: the (1S)-(+)-camphorsulfonic acid-based DESs
(HBD pKa =1.2) showed quite low yields, irrespective of the
sulfobetaines used as eutectic partner (SB3-Cy: 33%; SB3-
MIM: 15%, entries 8 and 9, respectively); p-toluensulfonic
acid-based mixtures (HBD pKa =− 2.8) gave only traces of
the desired product (entries 10 and 11) independently to the
ammonium salt used as counterpart.
importance of the acidic character of the liquids, irrespective
of their Brønsted or Lewis nature; however, in these reac-
tions a slight increase in the yield of the Bis-bza by-product
was also observed.
To further investigate the behaviour of the DESs of both
classes and the possibility of driving the reaction towards
the double addition by-product Bis-bza, we then repeated the
reaction with an excess of 2-vinylpyridine (2.5 equivalents).
The chosen reaction media were 2-Cl benzoic acid/betaine,
ZnCl2/acetamide, and SnCl2/acetamide, since they gave the
best results using equimolar reagents (entries 5, 12, 13). As
expected, the molar ratio of the reactants has an impact on
the products’ yields, with the yield of the Bis-bza increas-
ing up respectively to 42% (entry 5, 2-Cl-benzoic acid/
TMG DES), 26% (entry 12, ZnCl2/acetamide DES), and
74% (entry 13, SnCl2/acetamide DES). The values obtained
suggested that there is not any peculiar efect of the Lewis
acid-based liquids (i.e. coordination of the nitrogen atoms
with the ions [47]) that can impact on the yields; but that the
molar excess of 2-vinylpyridine can provoke an increase of
the yield of the bis-adduct irrespective of the DES acidic
nature. The yield of 2-Cl-benzoic/TMG liquid (42%, entry
5) is in fact higher than the one of ZnCl2/acetamide liquid
(26%, entry 12), therefore suggesting that even if a coordina-
tion or chelation process could be present, the efects on the
yields observed could be driven much more by the molar
ratio of the reagents.
The Brønsted acidity of the DES can play both roles of
catalysing the reaction by activation of the Michael accep-
tor through protonation of the nitrogen of 2-vinylpyridine
and of hampering it via de-activation of the amine in the
nucleophile through protonation of the nitrogen atom. The
pKa values of the conjugated acids of the two species are
diferent (9.33 for benzylamine; 4.98 for 2-vinylpyridine [45,
46]), but in the presence of carboxylic acids with pKa values
between 2.9 and 4.3 (most in our set except for oxalic acid),
equilibria could occur between the protonated and the depro-
tonated species. On the other hand, stronger acids lead to a
too low amount of the reactive free amine; nevertheless, in
the absence of acids 2-vinylpyridine could not be activated
towards the nucleophilic attack. Therefore, a proper choice
of the DES acidity plays a key role for a successful progress
of the reaction, showing the best results with weak acids as
part of the mixtures; in Fig. 1 a reaction mechanism based
on the acid–base equilibria of the reagents is hypothesized.
In order to explore the acid capability of catalysing the
reaction, also Lewis acid-based DESs were used in this
work: the selected compounds were ZnCl2, SnCl2, and
AlCl3 with acetamide as counterpart (entries 12–14). Even
this class of liquids showed good reaction yields, with
values ranging from 40 to 80%. These results showed the
The obtained Bis-bza by-product could be useful as
chelating agent as the three branches can easily fold and
coordinate transition metals [37]. In Fig. 2 are reported 1H-
1H NOESY (CDCl3) interactions to prove this possibility,
where NOE signals are present between methylene groups
of the branch derived from 2-vinylpyridine and all the other
equilibrium of protonation of reagents
DESs acid components
urea
pKa
7
6
5
H+
4
carboxylic acids
3
H+
2
1
0
+CSA
-1
-2
-3
p-TSA
pKa = 9.33
pKa = 4.98
Fig. 1 Suggested reaction mechanism based on acid/base equilibria of the reagents
1 3

M. Ballarotto et al.
Table 3 Aza-Michael addition of diferent nucleophiles to
functional groups of the molecule, so indicating a possible
folding of the structure (the full spectrum is reported in ESI).
Probably the π–π interactions that can occur between the
aromatic branches could favour this conformation.
2-vinylpyridinea
Entry Reaction medium
R1
R2 Yield /%
Mono- Bis- product
product
Scope and limitations with other amines
1
2
3
4
5
6
7
8
9
2-Cl benzoic acid/
TMGb
Ph
H
H
73
69
87
71
66
86
61
46
86
6
13
–
Traces
Traces
–
Traces
Traces
–
CH2CH2Ph
Morpholine
Ph
CH2CH2Ph
Morpholine
Ph
We then explored the scope of our approach with other
amines (i.e., aniline, 2-phenylethan-1-amine, and morpho-
line) by using the best-performing DESs presenting either
Lewis and Brønsted acidity: 2-Cl-benzoic acid/TMG, ZnCl2/
acetamide, and SnCl2/acetamide (Scheme 3, Table 3). The
three amines were chosen to have a set of diferently struc-
tured nucleophiles to be compared with the benzylamine,
namely an aromatic amine (aniline), a primary aliphatic
acyclic amine (2-phenylethan-1-amine), and a secondary
aliphatic cyclic amine (morpholine).
ZnCl2/acetamide c
SnCl2/acetamide d
H
H
H
H
CH2CH2Ph
Morpholine
aReaction conditions: 2-vinylpyridine (1 mmol), nucleophile
(1 mmol), 1 g DES, 70 °C, 24 h. All the yields are of isolated prod-
ucts
In most cases, the yields range from good to excellent
(61% to 87% of isolated product yields) except for entries
7–9 (SnCl2/acetamide eutectic mixture). When an aromatic
amine was employed (entries 1, 4, 7), the yields of mono-
addition product (73%, 71%, and 61% of isolated product
yields, respectively) were not infuenced by the DESs struc-
tures, with the 2-Cl benzoic acid/TMG (entry 1) showing a
small amount of double addition product (6%). An increase
in the length of the carbon chain spacer between the amine
and the aromatic ring (2-phenylethan-1-amine) led to a slight
decrease in the yields (entries 2, 5, 8 with 69%, 66% and
b2-Cl benzoic acid/TMG 1.5/1
cZnCl2/acetamide ¼
dSnCl2/acetamide 1/2
46% of isolated product yields, respectively). Noticeably, the
yield of the double addition product increased only with the
2-Cl benzoic acid/TMG DES (entry 2, 13%). On the other
hand, by using the cyclic amine morpholine as nucleophile
Fig. 2 1H-1H NOESY interac-
tions observed in the Bis-bza
compound in CDCl3
Scheme 3
DES
1
2
R
R
1
N
H
R
+
N
N
R
70 °C, 24 h
N
2
1 3

Exploring the acidic catalytic role of diferently structured deep eutectic solvents in the…
(entries 3, 6, 9) similar yields were obtained in all reaction
media: 87%, 86%, and 86%, respectively.
Time-of-Flight LC/MS (Q-TOF) system. The UV–Vis detec-
tor was set to read at 254 nm. Thin Layer Chromatography
(TLC) was performed on fuorescent dye-coated silica gel 60
supported on aluminium sheets; fash column chromatography
was performed on silica gel 60.
These results demonstrated that the nature of the amine
did not strongly afect the reaction yields that they still
remain excellent in most of the experiments.
DES preparation
Conclusion
The DESs were prepared by mixing the two weighed com-
ponents in a vial and heating the sample under magnetic
stirring at 70 °C for the proper time (spanning from 20 to
60 min approximately) until homogeneous liquids were
formed. The non-commercial components of the Brønsted
acid-containing DESs were prepared as previously reported
[40, 41]. Choline chloride/urea DES was prepared according
to the literature [44]. The ZnCl2/acetamide and the SnCl2/
acetamide DESs were prepared following the same proce-
dure reported in literature [48].
In conclusion, we explored the use of diferently structured
acid Deep Eutectic Solvents and their catalytic role in the
aza-Michael addition between 2-vinylpyridine and amines.
Thanks to their diferent acid capabilities, the wide set
of used green liquids helped to defne the best reaction sol-
vents that showed excellent yields (between 85 and 95% in
diferent experiments with diferent liquids). The acidity of
the components of the media (in the case of Brønsted acids)
played in fact a key-role in determining yields that are rel-
evant only with weak acid molecules such as the class of
carboxylic acids/trimethylglycine DESs; 2-Cl-benzoic and
3-Cl-benzoic acids as counterpart of the trimethylglycine in
the liquids gave the best results, as they showed over 95%
of GC yields (70% of isolated product). The use of Lewis
acids as DESs components (ZnCl2, SnCl2, and AlCl3 with
acetamide) led to excellent yields as well. The use of other
diferently structured amines as nucleophiles (aniline, 2-phe-
nylethan-1-amine, and morpholine) led as well to excellent
yields in the best-performing DESs of the set.
General experimental procedure
1 g of DES was weighted into a vial (or prepared by weight-
ing its components directly into a vial); the nucleophile was
then added with a syringe. The mixture was homogenized by
heating and mixing, then 2-vinylpyridine was then added with
a syringe. The mixture was put in an oil bath under magnetic
stirring for the proper time. Subsequently, a basic water solu-
tion was added (NaOH 10%) and the water phase was extracted
with ethyl acetate (3×10 cm3); the organic phases were col-
lected, dried over Na2SO4, fltered, and the solvent removed in
vacuo. The products were purifed by fash column chromatog-
raphy using the solvents reported in the product characteriza-
tion and in Electronic Supplementary Material Sections.
Moreover, comparing the results with the ones reported in
literature for the same reaction, this protocol showed many
advantages: high yields, greenness of the media, absence of
harmful acid catalysts, reduced reaction times, possibility
to extend the scope with diferent DESs and nucleophiles.
Products purifcation and characterization
Experimental
1
All the H NMR, 13C NMR, and LC–MS spectra and the
All solvents and reagents were purchased from Sigma-Aldrich,
Merck, Fluka and Alfa Aesar and were used without further
purifcations (purities>98%). Phenethylamine was purifed by
Kugelrohr distillation. Agilent 6850 Series II Network Gas
Chromatography instrument equipped with DB-35MS column
was used for GC analysis. The yields of Mono-bza and Bis-bza
were calculated using dibenzylether as internal standard for the
GC analysis adding specifc amounts of it before the extraction
procedures. The response factors (γ) were determined by a
calibration curve and their values are 0.804 and 1.111, respec-
tively. 1H NMR and 13C NMR spectra were measured at 25 °C
with a Bruker Avance III HD 400 MHz instrument and the
spectra were calibrated on the solvent residual peak. 1H-1H
NOESY experiment was conducted in CDCl3 solution with a
2048×512 sized FID, 16 scans, D8=0.8 s. LC and MS anal-
ysis were performed on an Agilent 6500 Series Quadrupole
purifcation procedures are reported in Electronic Supple-
mentary Material.
N-[2-(2-Pyridyl)ethyl]benzylamine (Mono-bza, entries
1/14) [37], N,N-bis[2-(2-pyridyl)ethyl]benzylamine (Bis-
bza, entries 1/14) [49], N-[2-(2-pyridyl)ethyl]aniline (Mono-
an, Table 3, entries 1, 4, 7) [50], N,N-bis[2-(2-pyridyl)ethyl]-
aniline (Bis-an, Table 3, entries 1, 4, 7) [51], N,N-bis[2-
(2-pyridyl)ethyl]phenethylamine (Bis-ph, Table 3, entries
2, 5, 8) [52], and N-[2-(2-pyridyl)ethyl]morpholine (Mono-
mor, Table 3, entries 3, 6, 9) [53] showed spectral data iden-
tical to the literature (see Supplementary Material).
N‑[2‑(2‑Pyridyl)ethyl]phenethylamine (Mono‑ph, C15H18N2,
Table 3, entries 2, 5, 8) Flash chromatography eluent: ethyl
acetate:methanol:Et3N 49:50:1. A yellow oil was obtained.
1H NMR (400 MHz, CDCl3): δ=8.49 (m, 1H, Pyr-H6), 7.62
1 3

M. Ballarotto et al.
24. Punzi A, Coppi DI, Matera S, Capozzi MAM, Operamolla A,
Ragni R, Babudri F, Farinola GM (2017) Org Lett 19:4754
25. Vidal C, García-Álvarez J, Hernán-Gómez A, Kennedy AR, Hevia
E (2014) Angew Chem 126:6079
(m, 1H, Pyr-H4), 7.34 (t, 2H, Phe-Hortho), 7.27 (m, 3H, Pyr-
H3 and Phe-Hmeta), 7.15 (m, 2H, Pyr-H5 and Phe-Hpara), 4.12
(brs, 1H, H–N), 3.15 (t, 2H, N–CH2–CH2–Phe), 3.05 (m,
4H, N–CH2–CH2–Pyr), 2.91 (t, 2H, N–CH2–CH2–Phe) ppm;
13C NMR (101 MHz, CDCl3): δ=159.90 (Pyr-C2), 149.18
(Pyr-C6), 139.60 (Phe-Cipso), 136.42 (Pyr-C4), 128.75 (Phe-
Cmeta), 128.48 (Phe-Cortho), 126.21 (Phe-Cpara), 123.27 (Pyr-
C3), 121.30 (Pyr-C5), 50.58 (N–CH2–CH2–Phe), 48.72 (N–
CH2–CH2–Pyr), 37.39 (Pyr-CH2), 35.73 (Phe-CH2) ppm;
MS: m/z [M + H]+ calcd for C15H18N2 227.15428, found
227.15502; purity (by LC): 83%.
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