Choline chloride-urea deep eutectic solvent as an efficient media for the synthesis of propargylamines via organocuprate intermediate

Article abstract of DOI:10.1002/aoc.5895

A facile method for the synthesis of various propargylamines derivatives with different structural parts has been reported. The reaction has consisted of one-pot coupling between aldehydes, secondary amines and terminal alkynes using CuCl as a catalyst an

Full text of DOI:10.1002/aoc.5895

Received: 19 August 2019
DOI: 10.1002/aoc.5895
Revised: 9 October 2019
Accepted: 30 May 2020
F U L L P A P E R
Choline chloride-urea deep eutectic solvent as an efficient
media for the synthesis of propargylamines via
organocuprate intermediate
Bahareh Abtahi | Hossein Tavakol
Department of Chemistry, Isfahan
A facile method for the synthesis of various propargylamines derivatives with
different structural parts has been reported. The reaction has consisted of one-
pot coupling between aldehydes, secondary amines and terminal alkynes using
CuCl as a catalyst and choline chloride/urea DES as a cheap and biocompati-
ble reaction media. The procedure is free of using toxic solvents and used CuCl
as an available, inexpensive and non-toxic catalyst. Using this methodology,
University of Technology, Isfahan,
84156-83111, Iran
Correspondence
Hossein Tavakol, Department of
Chemistry, Isfahan University of
Technology, Isfahan 84156-83111, Iran.
Email: h_tavakol@cc.iut.ac.ir
ꢀ
15 different propargylamine derivatives were successfully synthesized at 60 C
in 15 hr, mostly in good yields.
K E Y W O R D S
choline, DES, green, Organocopper, Propargylamine
1 | INTRODUCTION
avoiding toxic reagents and high atom economy.[16,17] Via
this methodology, both homogeneous and heterogeneous
In the recent years, propargylamine scaffolds have been
widely considered due to their enormous utilities in syn-
thetic organic chemistry and pharmaceuticals.[1,2] They
have been used not only as key synthetic intermediates
for biologically active compounds,[3,4] but also as
useful precursors and versatile building blocks for the
synthesis of various nitrogen containing heterocyclic
compounds.[5–7] According to the recent studies, some
propargylamine derivatives have been used for the treat-
ment of neurological disorders such as Parkinson's and
Alzheimer's.[8] In Scheme 1, some propargylamine-con-
taining structures were showed, which they have been
used as monoamine oxidase inhibitors (MAOI) for
Alzheimer's treatment.[9]
Due to the significance of these compounds, several
synthetic methodologies have been developed by chem-
ists.[10] Among various reports, three-component reaction
between aldehydes, alkynes, and amines (briefly named
as A3-coupling) have been the most popular and efficient
method for this synthesis.[11–15] The importance of the
one-pot A3-coupling is related to the use of mild and envi-
ronmental friendly conditions, no moisture-sensitivity,
catalysts have been employed in several studies. For
example, various transition metal catalytic systems such
as copper,[18,19] gold,[20] silver,[21] indium,[22] iron,[23]
iridium,[24] zinc,[25] nickel[26] and cobalt[27] have been
used for the C-H activation of terminal alkynes and
performing the reaction. Among these catalysts, copper
salts are more useful candidates due to their availabilities,
low-cost, low-toxicities and high-reactivity.[28] However,
the most of the presented methodologies suffers from
some disadvantages such as using toxic solvents,
employing expensive and non-reusable catalysts and
performing the reaction at high temperature.[29–31] There-
fore, it is highly desirable to develop new efficient, envi-
ronmental friendly and green synthetic methodologies
for the synthesis of propargylamines using A3-coupling
reaction. Decreasing environmental pollutions and
employing
a secure, non-toxic and biodegradable
solvent is necessary for a green process.[32,33] Recently,
toxic and volatile organic solvents have been substituted
by ionic liquids to decrease their environmental issues.
However, despite all desirable properties of ionic liquids
such as negligible vapor pressure, non-flammability,
Appl Organomet Chem. 2020;e5895.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5895

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ABTAHI AND TAVAKOL
2.1 | Preparation of deep eutectic
solvents-catalyst mixtures
Choline chloride based DESs and their mixtures with cat-
alyst were prepared by combination of ChCl with other
components like CuCl2.2H2O, FeCl3.6H2O, SnCl2.2H2O,
ZnCl2.2H2O, NiCl2.6H2O, urea and ascorbic acid in
accordance with the methodologies described in the
literature.48–51 For example (for the final media), ChCl
(0.28 g), urea (0.24 g) and CuCl (0.005 g) were simply
ꢀ
mixed, heated and stirred at 80 C for 1 hr to obtain a
SCHEME 1 Propargylamine moiety containing drugs
clear green liquid. The successful syntheses of these DESs
were confirmed by comparing their IR spectra with the
related reports.
thermal stability and recyclability, their uses have been
restricted by various disadvantages and limitations such
as high cost and difficult preparation.[34,35] Deep
eutectic solvents (DESs) are a new generation of ionic
liquids, which introduced by Abbott et al. (2003).[36]
DESs are more promising alternatives of ionic liquids
due to their low costs and the employing biodegradable,
renewable and available starting materials.[37,38] After
the first report on this class of compounds, several
studies have been reported on the synthesis and
applications of DESs in various fields like chemical
synthesis, biochemistry, separation, adsorption processes
and pharmacy.[39–44] Therefore, in continuation of the
previous efforts of our research group in the develop-
ment of synthetic methodologies using DESs,[45–47] the
use of these useful media for the preparation of
propargylamines using A3-coupling reaction has been
considered. In this study, CuCl in choline chloride/urea
DES has been used as a green and efficient media for
the synthesis of propargylamines derivatives. The details
of experiments and the results will be discussed in the
next sections.
2.2 | General procedure for preparation of
propargylamines
In a round-bottom flask, ChCl/urea/CuCl (1 ml), alde-
hyde (1 mmol), amine (1.2 mmol) and alkyne (1.2 mmol)
were mixed. The reaction mixture has been stirred
for 15 hr at 60 ꢀC (Scheme 2). The progress of the
reaction was monitored by TLC (eluent phase: 3:1 ratio
of n-hexane: EtOAc). After the completion of the
reaction, the mixture was cooled to room temperature
and diluted with EtOAc and H2O. Next, triphasic mixture
was obtained which includes organic phase, aqueous
phase and CuCl between two other phases. The organic
phase was separated and dried over MgSO4 and it was
concentrated by using a rotary evaporator. The residue
was purified by thin-layer chromatography on
20 × 20 cm2 silica gel plate to afford the pure product.
The aqueous phase containing DES was separated and
dried under vacuum. Finally, it was reused for the next
cycle. However, during the work-up step, CuCl was not
completely recycled and after recyclization, the desired
amount of CuCl was added to the ChCl/urea mixture.
The structures of all products were confirmed by com-
paring their physical properties and spectral data with
the reported values. The spectral data for all products
were listed below and all of the original spectra were
shown in supporting information.
2 | EXPERIMENTAL
All chemical compounds have purchased from Sigma-
Aldrich and Merck companies and used without further
purification. Thin layer chromatography was employed
to monitor the progress of the reactions using n-hexane-
ethyl acetate (3:1 ratio) as eluent. IR spectra were
recorded on KBr disks using JASCO FT-IR spectropho-
tometers in the range of 400 to 4,000 cm−1 1HNMR
.
(400 MHz, CDCl3) and 13CNMR (100 MHz, CDCl3) spec-
tra were recorded on Bruker Ultra shield spectrometer.
1H and 13C chemical shifts were referenced to TMS as an
internal standard. Mass spectra were recorded using AB
SCIEX 3200 QTRAP instrument (USA) with ESI TURBO
ionization source.
SCHEME 2 The general reaction for the synthesis of
propargylamine derivatives

ABTAHI AND TAVAKOL
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DES (Choline chloride.2urea): mp = 12–14 ꢀC; IR
(KBr, cm−1) 3200–3,400 (s), 2,150 (w), 1,645 (s), 1,440 (s),
1,330 (m), 1,160 (m), 1,080 (m), 958 (m), 868 (w),
784 (m), 580 cm−1 (s).
1H, CH-N), 6.92 (m, 2H, CHaromatic), 7.40 (m, 3H,
CHaromatic), 7.59 (m, 3H, CHaromatic), 10.81 (s, 1H, OH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 49.2 (CH-N), 60.7
(CH2-N), 66.9 (CH2-O), 81.6 (acetylenic carbon), 90.4
(acetylenic carbon), 116.5, 119.5, 120.6, 122.3, 128.5,
128.8, 129.8, 131.9, 157.0 (all for aromatic rings) ppm.
4g: methyl 4-(1-morpholino-3-aromaticprop-2-yn-
4a: 4-(1,3-diaromaticprop-2-yn-1-yl) morpholine:
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 2.55 (m, 4H,
CH2-N), 3.65 (m, 4H, CH2-O), 4.71 (s, 1H, CH-N), 7.27
(m, 6H, CHaromatic), 7.43 (m, 2H, CHaromatic), 7.55 (d,
J = 7.4 Hz, 2H, CHaromatic) ppm. 13C NMR (100 MHz,
CDCl3): δ = 49.9 (CH-N), 62.0 (CH2-N), 67.2 (CH2-O),
85.0 (acetylenic carbon), 88.5 (acetylenic carbon), 123.0,
127.8, 128.3, 128.3, 128.3, 128.6, 131.8, 137.8 (all for
aromatic rings) ppm.
4b: 4-(1-(4-chloroaromatic)-3-aromaticprop-2-yn-
1-yl) morpholine: yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 2.63 (m, 4H, CH2-N), 3.75 (m, 4H, CH2-O),
4.78 (s, 1H, CH-N), 7.36 (m, 5H, CHaromatic), 7.53 (m, 2H,
CHaromatic), 7.6 (d, J = 8.3 Hz, 2H, CHaromatic) ppm. 13C
NMR (100 MHz, CDCl3): δ = 48.8 (CH-N), 60.3 (CH2-N),
66.1 (CH2-O), 83.3 (acetylenic carbon), 87.9 (acetylenic
carbon), 121.7, 127.3, 127.4, 127.4, 128.9, 130.8, 132.6,
135.4 (all for aromatic rings) ppm.
ꢀ
1-yl) benzoate: white solid, m.p: 171-173 C, IR (KBr,
cm−1): 2925, 1,718, 1,383, 1,107, 887, 742. 1H NMR
(400 MHz, CDCl3): δ = 2.65 (m, 4H, CH2-N), 3.77 (m,
4H, CH2-O), 3.95 (s, 3H, OMe), 4.86 (s, 1H, CH-N), 7.37
(m, 3H, CHaromatic), 7.55 (m, 2H, CHaromatic), 7.75 (d,
J = 8.3 Hz, 2H, CHaromatic), 8.07 (d, J = 8.3 Hz, 2H,
CHaromatic) ppm. 13C NMR (100 MHz, CDCl3): δ = 49.8
(CH-N), 52.2 (OMe), 61.8 (CH2-N), 67.1 (CH2-O), 84.1
(acetylenic carbon), 89.1 (acetylenic carbon), 122.7, 128.4,
128.5, 128.5, 129.6, 129.7, 131.8, 143.0 (all for aromatic
rings), 166.9 (C=O ester) ppm. ESI-MS (m/z): 336 [M]+,
263, 249, 219, 165, 149, 143, 121.
4h: 4-(1-aromaticpent-1-yn-3-yl) morpholine: pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.00 (t,
J = 7.4 Hz, 3H, CH3(connected to CH2)), 1.67 (m, 2H,
CH2 (connected to Me)), 2.50 (m, 2H, CH2-N), 2.67 (m,
2H, CH2-N), 3.34 (t, J = 7.4 Hz, 1H, CH-N), 3.69 (m, 4H,
4c: 4-(1-(3-methoxyaromatic)-3-aromaticprop-2-
1
yn-1-yl) morpholine: yellow oil. H NMR (400 MHz,
CDCl3): δ = 2.64 (m, 4H, CH2-N), 3.55 (m, 4H, CH2-O),
3.85 (s, 3H, OCH3), 4.77 (s, 1H, CH-N), 6.86 (d,
J = 7.9 Hz, 1H, CHaromatic), 7.29 (m, 6H, CHaromatic), 7.51
(m, 2H, CHaromatic) ppm. 13C NMR (100 MHz, CDCl3):
δ = 49.9 (CH-N), 55.3 (OMe), 62.0 (CH2-N), 67.2 (CH2-
O), 85.0 (acetylenic carbon), 88.4 (acetylenic carbon),
113.1, 114.3, 121.0, 122.9, 128.3, 128.3, 129.2, 131.8, 139.4,
159.6 (all for aromatic rings) ppm.
4d: 4-(1-(naphthalen-2-yl)-3-aromaticprop-2-yn-1-yl)
morpholine: yellow oil. 1H NMR (400 MHz, CDCl3): δ = 2.71
(m, 4H, CH2-N), 3.78 (m, 4H, CH2-O), 4.98 (s, 1H, CH-N), 7.38
(m, 3H, CHaromatic), 7.51 (m, 2H, CHaromatic), 7.59 (m, 2H,
CHaromatic), 7.78 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H, CHaromatic), 7.88
(m, 3H, CHaromatic), 8.12 (s, 1H, CHaromatic) ppm. 13C NMR
(100 MHz, CDCl3): δ = 50.1 (CH-N), 62.2 (CH2-N), 67.2 (CH2-
O), 85.0 (acetylenic carbon), 88.8 (acetylenic carbon), 123.0,
126.1, 126.1, 126.5, 127.6, 127.6, 128.0, 128.1, 128.3, 128.4, 131.9,
133.1, 135.4 (all for aromatic rings) ppm.
CH2-O), 7.22 (m, 3H, CHaromatic), 7.36 (m, 2H, CHaromatic)
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2 (CH3 (con-
nected to CH2)), 26.1 (CH2 (connected to Me)), 49.7 (CH-
N), 59.8 (CH2-N), 67.1 (CH2-O), 86.2 (acetylenic carbon),
87.0 (acetylenic carbon), 123.2, 128.0, 128.2, 131.7 (all for
aromatic rings) ppm.
4i: 4-(1-aromatichex-1-yn-3-yl) morpholine: pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.28 (t,
J = 7.2 Hz, 3H, CH3 (connected to CH2)), 1.76 (m, 2H,
CH2 (connected to Me)), 2.06 (m, 2H, CH2(between CH2
and CH-N), 2.59 (m, 2H, CH2-N), 2.77 (m, 2H, CH2-N),
3.43 (t, J = 7.4 Hz, 1H, CH-N), 3.78 (m, 4H, CH2-O), 7.38
(m, 5H, CHaromatic) ppm. 13C NMR (100 MHz, CDCl3):
δ = 11.2 (CH3 (connected to CH2)), 14.2 (CH2 (connected
to Me)), 26.1(CH2(between CH2 and CH-N), 59.8 (CH2-
N), 60.4 (CH-N), 67.2 (CH2-O), 86.2 (acetylenic carbon),
87.0 (acetylenic carbon), 123.2, 128.0, 128.2, 131.7 ppm.
4j: 4-(1-(4-(tert-butyl) aromatic)-4-methylpent-1-yn-3-yl)
morpholine: pale yellow oil. IR (KBr, cm−1): 2960, 1,385, 1,113,
787. 1H NMR (400 MHz, CDCl3): δ = 1.05 (d, J = 6.6 Hz, 3H,
CH3 (connected to CH)), 1.12 (d, J = 6.6 Hz, 3H, CH3(connected
to CH)), 1.33 (s, 9H, t-Bu group), 1.92 (m, 1H, CH (i-Pr group)),
2.53 (m, 2H, CH2-N), 2.72 (m, 2H, CH2-N), 3.03 (d, J = 9.5 Hz,
1H, CH-N), 3.76 (m, 4H, CH2-O), 7.34 (d, J = 8.6 Hz, 2H,
CHaromatic), 7.40 (d, J = 8.6 Hz, 2H, CHaromatic) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.8 (CH3(connected to CH)), 20.3
(CH3(connected to CH)), 29.8 (CH (i-Pr group)), 31.2 (3Me for t-
Bu group), 34.7 (C of t-Bu group), 50.0 (CH-N), 65.2 (CH2-N),
67.2 (CH2-O), 85.97 (acetylenic carbon), 86.6 (acetylenic carbon),
4e: 4-(3-aromatic-1-(thiophen-2-yl) prop-2-yn-1-yl) mor-
pholine: yellow oil. 1H NMR (400 MHz, CDCl3): δ = 2.72 (m,
4H, CH2-N), 3.79 (4H, m, CH2-O), 5.03 (s, 1H, CH-N), 7.00 (m,
1H, CHaromatic), 7.33 (m, 5H, CHaromatic), 7.55 (m, 2H, CHaromatic
)
ppm. 13C NMR (100 MHz, CDCl3): δ = 49.7 (CH-N), 57.8 (CH2-
N), 67.1 (CH2-O), 84.3 (acetylenic carbon), 87.6 (acetylenic car-
bon), 122.7, 125.8, 126.3, 126.4, 128.4, 128.4, 131.9, 142.8 (all for
aromatic rings) ppm.
4f: 4-bromo-2-(1-morpholino-3-aromaticprop-2-
yn-1-yl) phenol: yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 2.81 (m, 4H, CH2-N), 3.83 (m, 4H, CH2-O), 5.12 (s,

4 of 11
ABTAHI AND TAVAKOL
120.4, 125.2, 131.4, 151.1 (all for aromatic rings) ppm. ESI-MS
(m/z): 300 [M]+, 263, 214, 213, 164, 157, 149, 129, 114.
J = 2.6 Hz, 1H, CHaromatic), 7.43 (d, J = 8.6 Hz, 2H,
CHaromatic), 7.52 (d, J = 8.6 Hz, 2H, CHaromatic), 7.56 (m,
1H, CHaromatic), 10.59 (bs, 1H, OH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 31.2 (3Me for t-Bu group), 34.9
(C of t-Bu group), 48.6 (CH-N), 60.4 (CH2-N), 66.8 (CH2-
O), 79.9 (acetylenic carbon), 91.1 (acetylenic carbon),
117.8, 118.9, 122.2, 124.2, 125.5, 128.7, 129.6, 131.7, 152.4,
155.7 (all for aromatic rings) ppm. ESI-MS (m/z):
384 [M]+, 300, 299, 298, 297, 282, 267, 219, 165, 149,
143, 121.
4k: 4-(3-(4-(tert-butyl) phenyl)-1-(3-methoxyphenyl)
prop-2-yn-1-yl) morpholine: yellow oil. IR (KBr, cm−1):
1
2960, 2,224, 1,385, 1,115, 835, 704. H NMR (400 MHz,
CDCl3): δ = 1.35 (s, 9H, t-Bu group), 2.67 (m, 4H, CH2-N),
3.77 (m, 4H, CH2-O), 3.85 (s, 3H, OMe), 4.79 (s, 1H, CH-N),
6.87 (d, J = 7.3 Hz, 1H, CHaromatic), 7.29 (m, 3H, CHaromatic),
7.38 (d, J = 8.4 Hz, 2H, CHaromatic), 7.48 (d, J = 8.4 Hz, 2H,
CHaromatic) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.2
(3Me for t-Bu group), 34.8 (C of t-Bu group), 49.9 (CH-N),
55.3 (OMe), 61.9 (CH2-N), 67.2 (CH2-O), 84.3 (acetylenic car-
bon), 88.5 (acetylenic carbon), 113.1, 114.3, 112.0, 121.0,
125.3, 129.2, 131.6, 139.6, 151.5, 159.6 (all for aromatic rings)
ppm. ESI-MS (m/z): 364 [M]+, 278, 277, 262, 247.
4o: 1-(1,3-diphenylprop-2-yn-1-yl)pyrrolidine: yel-
1
low oil. H NMR (400 MHz, CDCl3): δ = 1.91 (m, 4H,
CH2 (connected to -CH2N)), 2.94 (m, 4H, CH2-N), 5.23 (s,
1H, CH-N), 7.38 (m, 6H, CHaromatic), 7.54 (m, 2H,
CHaromatic), 7.70 (d, J = 8.6 Hz, 2H, CH aromatic) ppm. 13
C
4l: 4-(3-(4-(tert-butyl) phenyl)-1-(thiophen-2-yl)
prop-2-yn-1-yl) morpholine: yellow oil. IR (KBr, cm−1):
2960, 1,385, 1,265, 1,117. H NMR (400 MHz, CDCl3):
NMR (100 MHz, CDCl3): δ = 23.6 (CH2 (connected to
-CH2N)), 50.0 (CH-N), 59.0 (CH2-N), 85.3 (acetylenic car-
bon), 88.0 (acetylenic carbon), 123.0, 128.1, 128.4, 128.5,
128.5, 128.7, 131.9, 137.3 (all for aromatic rings) ppm.
1
δ = 1.35 (s, 9H, t-Bu group), 2.70 (m, 4H, CH2-N), 3.78
(m, 4H, CH2-O), 5.02 (s, 1H, CH-N), 6.99 (m, 1H,
CHaromatic), 7.26 (m, 1H, CHaromatic), 7.31 (m, 1H,
CHaromatic), 7.38 (d, J = 8.4 Hz, 2H, CHaromatic), 7.48 (d,
J = 8.4 Hz, 2H, CHaromatic) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.2 (3Me for t-Bu group), 34.8 (C of t-Bu
group), 49.6 (CH-N), 57.8 (CH2-N), 67.1 (CH2-O), 83.5
(acetylenic carbon), 87.7 (acetylenic carbon), 119.6, 125.3,
125.8, 126.3, 126.4, 131.6, 142.9, 151.7 (all for aromatic
rings) ppm. ESI-MS (m/z): 339 [M]+, 255, 252, 238,
223, 143.
3 | RESULTS AND DISCUSSION
By considering the importance of green chemistry, the
development of environmental friendly synthetic
methods using green solvents is essential. Therefore, the
use of various deep eutectic solvents (based on ChCl) for
the preparation of propargylamines has been investigated
in this study. First, a three-component reaction between
benzaldehyde, morpholine and phenylacetylene was
selected as a model reaction to optimize the values of var-
ious parameters and obtain the best conditions (solvent,
catalyst amount, temperature and time). The results of
these optimization processes were listed in Table 1.
Surely, the reaction was not preceded without using any
catalyst or reaction media. To obtain the best green reac-
tion media under Lewis acid condition, various reported
DESs, formed from choline chloride and a different Lewis
acid such as CuCl2, ZnCl2, SnCl2, FeCl3 and NiCl2 were
4m: 4-(3-(4-(tert-butyl) phenyl)-1-(naphthalen-1-
yl)prop-2-yn-1-yl) morpholine: yellow oil. IR (KBr,
cm−1): 2960, 2,220, 1,606, 1,477, 1,385, 1,267, 1,115,
1
829, 586. H NMR (400 MHz, CDCl3): δ = 1.36 (s, 9H, t-
Bu group), 2.73 (m, 4H, CH2-N), 3.70 (m, 4H, CH2-O),
5.46 (s, 1H, CH-N), 7.40 (d, J = 8.6 Hz, 2H, CHaromatic),
7.47 (d, J = 8.1 Hz, 1H, CHaromatic), 7.51 (d, J = 8.6 Hz,
2H, CHaromatic), 7.57 (m, 2H, CHaromatic), 7.85 (d,
J = 8.1 Hz, 1H, CHaromatic), 7.90 (d, J = 7.8 Hz, 1H,
CHaromatic), 7.95 (d, J = 7.0 Hz, 1H, CHaromatic), 8.41 (d,
J = 8.3 Hz, 1H, CHaromatic) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.2 (3Me for t-Bu group), 34.8 (C of t-Bu
group), 49.8 (CH-N), 60.1 (CH2-N), 67.2 (CH2-O), 84.2
(acetylenic carbon), 89.1 (acetylenic carbon), 120.0, 124.8,
124.8, 125.3, 125.7, 125.9, 127.1, 128.5, 128.8, 131.5, 131.7,
133.3, 134.0, 151.5 (all for aromatic rings) ppm. ESI-MS
(m/z): 382 [M]+, 338, 297, 282, 256, 219, 165, 149,
143, 121.
4n: 2-(3-(4-(tert-butyl) phenyl)-1-morpholinoprop-
2-yn-1-yl)-4-chlorophenol: yellow oil. IR (KBr, cm−1):
2960, 2,218, 1,604, 1,279, 1,115, 835, 762. 1H NMR
(400 MHz, CDCl3): δ = 1.36 (s, 9H, t-Bu group), 2.80 (m,
4H, CH2-N), 3.82 (m, 4H, CH2-O), 5.11 (s, 1H, CH-N), 6.81
(d, J = 8.6 Hz, 1H, CHaromatic), 7.21 (dd, J = 8.6 Hz,
[48–51]
ꢀ
employed (entries 1–5) at 60 C in 24 h.
Among
these DESs, ChCl/CuCl2 has shown the highest yield but
not high enough. Therefore, it was also decided to try the
other Cu (I) and Cu (II) salts as a catalyst of this reaction.
Based on the recent studies, Cu (I) could be a better alter-
native than Cu (II) for employing as the catalyst reaction.
Therefore, it was focused on these salts at the next step.
However, any report related to the formation of DES
from ChCl and Cu (I) salts has not been found. There-
fore, the mixture of Cu (I) salts and ChCl/urea DES was
considered as a reaction media. The selection of
ChCl/urea DES was based on its availability, low price,
biocompatibility and good solubility of transition metal
salt (according to the reports) in this DES. Moreover,

ABTAHI AND TAVAKOL
5 of 11
TABLE 1 The results of optimization of the reaction conditions for the model reactiona
Entry
Reaction media
Metal salt (mol%)
Temp (ꢀC)
Time (hr)
Yield (%)b
Optimization of the reaction media (based on various DESs)
1
ChCl/CuCl2 (1:2) DES
-
60
60
60
60
60
60
60
60
60
60
60
60
60
60
24
24
24
24
24
24
24
24
24
24
24
24
24
24
50
trace
-
2
ChCl/ZnCl2 (1:2) DES
-
3
ChCl/SnCl2 (1:2) DES
-
4
ChCl/FeCl3 (1:2) DES
-
-
5
ChCl/NiCl2 (1:2) DES
-
-
6
CuCl in ChCl/Urea (1:2) DES
CuI in ChCl/Urea (1:2) DES
CuSO4 in ChCl/Urea (1:2) DES
CuCl2 in ChCl/Urea (1:2) DES
ChCl/urea (1:2) DES
5
5
5
5
-
60
52
25
37
-
7
8
9
10
11
12
13
14
CuCl in ChCl/Ascorbic acid (4:1) DES
CuCl in water
5
5
5
5
65
24
39
32
CuCl in Ethanol
CuCl in H2O:Ethanol (1:1)
Optimization of the reaction temperature and time
15
16
17
18
19
20
21
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
5
5
5
5
5
5
5
60
60
40
50
70
80
100
15
10
15
15
15
15
15
75
60
27
35
51
53
35
Optimization of the catalyst's amount
22
23
24
25
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
CuCl in ChCl/Urea (1:2) DES
1
60
60
60
60
15
15
15
15
51
66
70
70
3
10
15
aThe model reaction: benzaldehyde (1 mmol), morpholine (1.2 mmol) and phenylacetylene (1.2 mmol) in 1 ml DES or solvent.
bIsolated yield.
ChCl/urea DES is well known as green media and the
basicity of urea beside the Lewis acid salt, provide a dual
acid–base rule for the produced media. In the entries 6–9,
different Cu (I) and Cu (II) salts were employed in com-
bination with ChCl/urea DES to obtain the most appro-
priate copper salt for this reaction. According to these
entries, the most efficiency was devoted to the implemen-
tation of CuCl as catalyst in ChCl/urea DES (yield = 60%)
and CuCl was chosen as a final catalyst of the reaction. It
should be noticed that by using only ChCl/urea DES and
without using Lewis acid, the reaction was not performed
at all (entry 10). To use another DES, in attendant with
CuCl, ChCl/Ascorbic acid DES was used as an appropri-
ate DES (entry 11, based on the reported studies). In this
reaction, 65% yield was obtained that was comparable
with the use of ChCl/urea DES. However, because of the
oxidation, destruction and leaching of ascorbic acid dur-
ing the reaction,[52] the purification of the product was
harder and the recycling of this DES was impossible.
Therefore, this DES was ignored in the next parts of this
study. This reaction was also investigated using CuCl in
traditional green solvents such as H2O, Ethanol and H2O:
Ethanol (1:1) mixture (entries 12–14) to compare their
results with the employed DES. Under the same reaction
conditions, these solvent showed much less efficiencies
(yields between 24–39%) versus ChCl/urea DES for the
model reaction and they have been ignored. After the
selection of CuCl in ChCl/urea DES as a reaction

6 of 11
ABTAHI AND TAVAKOL
TABLE 2 The prepared propargylamine derivatives, based on the presented reaction in scheme 1 a
Structure
4a
R1
R2
Amine
Product
Yield(%)b
[Ref]
[53]
Phenyl-
Phenyl-
morpholine
75
[54]
4b
4-chloro-C6H4-
Phenyl-
morpholine
73
[55]
4c
3-methoxy-C6H4-
Phenyl-
morpholine
81
[56]
4d
4e
4f
2-naphtyl-
Phenyl-
Phenyl-
Phenyl-
morpholine
morpholine
morpholine
85
91
65
[57]
2-thiophenyl-
[57]
5-bromo-2-hydroxy-C6H4-

ABTAHI AND TAVAKOL
7 of 11
TABLE 2 (Continued)
Structure
4 g
R1
R2
Amine
Product
Yield(%)b
[Ref]
4-CO2Me-C6H4-
Phenyl-
morpholine
89
-
[56]
4 h
Propyl-
henyl-
morpholine
38
[58]
4i
butyl-
Phenyl-
morpholine
42
4j
isobutyl-
ert-butyl-C6H4-
morpholine
52
-
4 k
3-methoxy-C6H4-
tert-butyl-C6H4-
morpholine
90
-
4 l
2-thiophenyl-
tert-butyl-C6H4-
morpholine
85
-
(Continues)

8 of 11
ABTAHI AND TAVAKOL
TABLE 2 (Continued)
Structure
R1
R2
Amine
Product
Yield(%)b
[Ref]
4 m
1-naphtyl-
tert-butyl-C6H4-
morpholine
90
-
4n
5-chloro-2-hydroxy-C6H4-
tert-butyl-C6H4-
morpholine
54
-
[59]
4O
Phenyl-
Phenyl-
pyrrolidine
83
aRwaction conditions: mixture of aldehyde derivatives (1 mmol), amine (1.2 mmol), phenylacetylene derivatives (1.2 mmol), ChCl/urea
(1 ml), CuCl (5 mol%), 60 ꢀC, 15 hr; b Isolated yield.
medium (entry 10), the reaction's time was optimized.
After the monitoring of the reaction, it was observed that
by the increase of the reaction's time to 24 h, the amounts
of unknown by-products were increased and the yield
was decreased. Therefore, the less values for the reac-
tion's time were examined and two new experiments in
15 and 10 hr were performed (entries 15 and 16, compar-
ing with entry 10). According to these values, 15 hr (entry
15) showed the highest yield and this time was chosen as
the best time for this reaction. Moreover, it was tried to
use the other reaction temperatures (40, 50, 70, 80,
(entries 17–21, comparing with entry 15). The results
indicated that increasing temperature has wrecking effect
on the yield of product because of the formation of vari-
ous by-products and decreasing the temperature make
the reaction much slower. Therefore, 60 ꢀC (entry 15)
was selected as the best temperature for this reaction. At
the final optimization step, the catalyst amount was opti-
mized and in addition to using 5 mol% of the catalyst
(entry 15); 1, 3, 10 and 15 mol% of catalysts were used at
the optimized conditions (entries 22–25). By the increase
of the amount of catalyst from 1 to 5 mol%, the yield was
increased and by more increase to 10 and 15 mol%, the
ꢀ
100 C) to obtain the best temperature for the reaction

ABTAHI AND TAVAKOL
9 of 11
yield has not been changed. Therefore, 5 mol% (entry 15)
is the optimized value of the employed catalyst for this
reaction.
After the optimization of the reaction conditions, to
show the efficiency of the introduced reaction and
determine the effects of various substituents on the
yield of the reaction, in addition to the model reaction,
15 different reactions were performed and the results
were shown in Table 2. In these experiments,
phenylacetylene and (4-tert butyl phenyl) acetylene
were used as alkyne sources, in combination with vari-
ous aliphatic and aromatic aldehydes. The yields were
in the range of 38–52% for aliphatic aldehyde, 54–65%
for salicylaldehyde and 73–91% for the other aromatic
aldehydes. Unfortunately, the reaction did not produce
the desired product when acyclic amines (such as
dibutylamine, dicycloheylamine and dihexylamine)
were used. The yields for the reactions of aliphatic
aldehydes (propanal, butanal and 2-methyl propanal)
were low, maybe because of the lower boiling points
of these aldehydes, as the temperature used may
exceed their boiling points.[60] The yields for the reac-
tions involving salicylaldehyde derivatives (5-bromo
and 5-chloro) were low because of the possible forma-
tion of benzofuran derivatives.[61] Among aromatic
aldehydes, the derivatives with electron donor groups
showed higher yields than the other aldehydes and the
highest yields were belong to the reactions involving
thiophen carbaldehyde.
FIGURE 1 The result of the experiments related to the
reusability of the DES
Figure 1. After each run, the eutectic solvent (ChCl-urea)
was isolated from the product and reused in the next run.
As shown in this figure, ChCl-urea could be reused at
least three runs with 30% loss of its activity.
The main outcome of this research is the successful
synthesis of propargylamines under green conditions and
using available and inexpensive catalysts. Due to the
applicability of this protocol for this synthesis, it has been
compared with the previous related reports. The results
of this comparison were presented in Table 3 and the
advantages of this work are using DESs instead of toxic
and volatile organic solvents and employing inexpensive
and available metal salts instead of expensive catalysts
with time-consuming methods. Moreover, using little
mass value of catalyst in reaction under relatively low
temperature condition is another advantage of this
research.
To complete this work, the recoverability of ChCl-
urea in the model reaction using the optimized condi-
tions was examined and the results were shown in
TABLE 3 Comparisons of ChCl-urea/CuCl with other recent reports of reaction condition for the synthesis of propargylamine
Entry
Catalyst
reaction conditions
toluene/reflux
DCE/70 ꢀC
Time (hr)
14–17
12–20
4–10
4–6
Catalyst amount
Yield (%)
68–98
78–91
81–93
89–94
42–94
81–89
43–96
90–99
21–82
89–97
80–94
85–94
68–96
36–91
[Ref]
[56]
1
Zn (OAC)2.2H2O
[Cu(N2S2)]Cl@Y-zeolite
MCM-TSCuI
ZnS nano
CuBr
10%
10%
10%
10%
20%
30%
20%
10%
20%
25 mg
25 mg
10%
20%
5%
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
2
3
toluene/80 ꢀC
CH3CN/reflux
toluene/MW/100 ꢀC
[Bmim]PF6
4
5
0.42
6
CuBr
3.5–6.5
24
7
SiO2-NHC-CuI
Cu (OTf)2
CuI
Solventless/r.t
Ball-milling/25 Hz
Neat/MW/100 ꢀC
DMSO/90 ꢀC
8
0.17–0.5
0.42
9
10
11
12
13
14
Au-NPs-Fe3O4-rGO
Ag@HNT-T
CuI
6
H2O/100 W/r.t
PEG/100 ꢀC
0.25–0.67
12
CuBr
toluene/25 ꢀC
ChCl-urea/60 ꢀC
36
CuCl
15
This work

10 of 11
ABTAHI AND TAVAKOL
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4 | CONCLUSION
In summary, using ChCl/urea DES as a substitution for
toxic and volatile organic solvents and CuCl as a catalyst,
a green and applicable methodology for the synthesis
propargylamine derivatives was presented. The employed
media and catalyst were non-expensive, biocompatible
and the used methodology and work-up process were
easy. 15 different derivatives with various structural parts
were prepared mostly in good yields. Using aromatic
aldehydes give higher yield than aliphatic ones. The
smaller yields were due to the lower boiling point of the
employed aliphatic aldehydes and formation of
benzofuran byproduct in the use of salicylaldehyde deriv-
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substituents showed higher yields because of the easier
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ACKNOWLEDGEMENTS
This work was supported by the research affairs of
Isfahan University of technology. We acknowledge the
institute of organic chemistry, University of Innsbruck
(UIBK) for providing NMR facility. We have special
thanks to Professor Ronald Micura (the head of the insti-
tute) and Professor Christoph Kreutz for their valuable
assistances.
SUPPLEMENTARY DATA
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at DOI:
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ORCID
Hossein Tavakol https://orcid.org/0000-0002-3296-9575
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How to cite this article: Abtahi B, Tavakol H.
Choline chloride-urea deep eutectic solvent as an
efficient media for the synthesis of
propargylamines via organocuprate intermediate.
Appl Organomet Chem. 2020;e5895. https://doi.org/
10.1002/aoc.5895
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