Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method Dedicated to the memory of Professor Luis Astudillo Saavedra for his scientific career, support and fraternity.

Article abstract of DOI:10.1016/j.ultsonch.2014.02.021

Given the broad spectrum of uses of acrylonitrile derivatives as fluorescent probes, AChE inhibitors, and others, it is necessary to find easy, efficient and simple methods to synthesize and diversify these compounds. We report the results of a comparative study of the effects of three techniques on the reactions between heterocyclic aldehydes and 2-(benzo[d]thiazol-2-yl) acetonitrile: stirring; ultrasound coupled to PTC conditions (US-PTC); and MW irradiation (MWI) under solvent and catalyst-free conditions. The effects of conditions on reaction parameters were evaluated and compared in terms of reaction time, yield, purity and outcomes. The US-PTC method is more efficient than the MWI and conventional methods. The reaction times were considerably shorter, with high yields (>90%) and good levels of purity. In addition, X-ray diffraction analysis and quantum mechanical calculations, at the level of density functional theory (DFT), ratify obtaining acrylonitrile isomers with E configurations. The crystal structure of 3c is stabilized by weak C-H _o?N intermolecular interactions (H_o?NC = 2.45 ?, C_o?NC = 3.348(3) ?, H_o? NC = 162°), forming centrosymmetric ring R₂² (20) along the crystallographic a axis.

Full text of DOI:10.1016/j.ultsonch.2014.02.021

Ultrasonics Sonochemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Ultrasound-assisted phase-transfer catalysis method in an aqueous
medium to promote the Knoevenagel reaction: Advantages over the
conventional and microwave-assisted solvent-free/catalyst-free method
b
b
b
c
Pedro De-la-Torre a,b, , Edison Osorio , Jans H. Alzate-Morales , Julio Caballero , Jorge Trilleras ,
⇑
Luis Astudillo-Saavedra a, Iván Brito d, Alejandro Cárdenas e, Jairo Quiroga f, Margarita Gutiérrez a,
⇑
a Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca, Chile
b Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile
c Research Group Heterocyclic Compounds, Chemistry Program, Universidad del Atlántico, Km 7 vía Puerto Colombia, Barranquilla, Colombia
d Department of Chemistry, Universidad de Antofagasta, Av. Angamos 601, Casilla 170, Antofagasta, Chile
e Department of Physics, Universidad de Antofagasta, Av. Angamos 601, Casilla 170, Antofagasta, Chile
f Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Given the broad spectrum of uses of acrylonitrile derivatives as fluorescent probes, AChE inhibitors, and
others, it is necessary to find easy, efficient and simple methods to synthesize and diversify these com-
pounds. We report the results of a comparative study of the effects of three techniques on the reactions
between heterocyclic aldehydes and 2-(benzo[d]thiazol-2-yl)acetonitrile: stirring; ultrasound coupled to
PTC conditions (US-PTC); and MW irradiation (MWI) under solvent and catalyst-free conditions. The
effects of conditions on reaction parameters were evaluated and compared in terms of reaction time,
yield, purity and outcomes. The US-PTC method is more efficient than the MWI and conventional meth-
ods. The reaction times were considerably shorter, with high yields (>90%) and good levels of purity. In
addition, X-ray diffraction analysis and quantum mechanical calculations, at the level of density func-
tional theory (DFT), ratify obtaining acrylonitrile isomers with E configurations. The crystal structure of
3c is stabilized by weak C–Hoꢀ ꢀ ꢀN intermolecular interactions (Hoꢀ ꢀ ꢀNC = 2.45 Å, Coꢀ ꢀ ꢀNC = 3.348(3) Å,
Received 26 November 2013
Accepted 20 February 2014
Available online xxxx
Dedicated to the memory of Professor Luis
Astudillo Saavedra for his scientific career,
support and fraternity.
Keywords:
Knoevenagel reactions
Phase-transfer catalysis
Microwave
Ultrasound
Density functional theory
X-ray crystallography
Hoꢀ ꢀ ꢀNC = 162°), forming centrosymmetric ring R2 (20) along the crystallographic a axis.
2
Ó 2014 Published by Elsevier B.V.
1. Introduction
Some derivatives and analogs have interesting biological prop-
erties, including antifungal, antitumor, and antibacterial activities
Knoevenagel condensation has been extensively studied and
used for the preparation of a broad spectrum of substituted alkenes
[1], including the antimalarial drug lumefrantine [2], and some
acrilonitrile derivatives [3]. The 2-(benzo[d]thiazol-2-yl)acetoni-
trile 1 (Fig. 1) is a heterocyclic system used in the synthesis of
libraries of compounds by Knoevenagel condensation [3,4].
[5–9]. In addition, they have been used as b-glucuronidase inhibi-
tors [10], as scaffolds for the design of dendrimers [11], and as ace-
tylcholinesterase (AChE) inhibitors [4]. They have also been
reported in the literature as versatile precursors for building mol-
ecules with potential biological or pharmaceutical applications
[2,12–17].
Several methodologies have been developed to carry out
Knoevenagel condensation, including the use of strong bases
[18], micro reactors using zeolite catalysts [19,20], ionic liquids
[21,22], inorganic and organic supports [23–25], reactions in aque-
ous medium [26], ultrasound [27], and microwave-assisted irradi-
ation [3]. However, many of these methodologies involve the use of
organic solvents and costly reagents, the formation of reaction
byproducts, and toxicity, as well as presenting the problem of
disposal.
⇑
Corresponding authors at: Organic Synthesis Laboratory and Biological Activity
(LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca,
Casilla 747, Talca, Chile. Tel.: +56 71 200 389 (P. De-la-Torre). Tel.: +56 71 200 389;
fax: +56 71 200 448 (M. Gutiérrez).
E-mail addresses: pdelatorre@utalca.cl (P. De-la-Torre), eosorio@utalca.cl
(E. Osorio), jalzate@utalca.cl (J.H. Alzate-Morales), jcaballero@utalca.cl (J. Caballero),
jorgetrilleras@mail.uniatlantico.edu.co (J. Trilleras), lastudi@utalca.cl (L. Astudillo-
Saavedra), ibrito@uantof.cl (I. Brito), acardenas@uantof.cl (A. Cárdenas), jairo.quiroga@
correounivalle.edu.co (J. Quiroga), mgutierrez@utalca.cl (M. Gutiérrez).
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021
1350-4177/Ó 2014 Published by Elsevier B.V.
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

2
P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
2.2. General procedure for the synthesis of acrylonitriles 3
2.2.1. Method A (rt)
Compounds were synthesized as described in recent publica-
tions [4], using ethanol (10 mL) as a solvent, catalytic amounts of
trietylamine (0.2 mL) and stirring at rt (19 °C). The solid products
were isolated by simple filtration of the reaction mixture and crys-
tallization from ethanol.
Fig. 1. 2-(benzo[d]thiazol-2-yl)acetonitrile structure.
2.2.2. Method B (US)
The use of ultrasound irradiation (USI) to promote reactions in
(a) Ultrasonic irradiation was performed using a ultransonic
reactor (Elma transsonic 460, Elma, Singen, Germany), with a
mechanical timer (60 min with continuous hold) and heater
switch, frequency of 35 kHz using ethanol (10 mL), and triethyl-
amine (0.2 mL). (b) US-PTC, TEA (0.2 mL), 5 mL of ethanol:H2O
(50%), tetrabutylammonium bromide (TBAB) 20 mol%, 35 kHz.
The solid products were collected by filtration and washed with
ethanol:H2O (50%) to remove the TBAB and TEA to yield com-
pounds 3.
organic chemistry has had a major impact in recent years, [28–33]
because it offers versatility, rapidity and high reaction yields, while
being eco-friendly by employing water as a solvent [34]. Some
investigations have coupled USI with other synthetic methods in
order to promote organic reactions more efficiently, such as ultra-
sound coupled with phase transfer catalysis (PTC) [35].
Reactions using PTC conditions are among the most attractive
synthetic methods from the environmental point of view because
they make minimal use of toxic organic solvents and reagents, cou-
pled with higher yields and reduced reaction times. However, clas-
sical PTC conditions often require strong basic conditions with
NaOH as a catalyst and the presence of quaternary ammonium
salts (Quats) or crown ethers as nucleophile stabilizers [36]. Thus,
the search for facile protocols to produce Knoevenagel adducts by
eco-friendly synthetic methods, with high yields, short reaction
times and high levels of purity, is of interest in synthetic and
medicinal chemistry.
2.2.3. Method C (MW)
Reactions were performed in a focused microwave reactor (CEM
Discover TM), with power of 105 W and a temperature of 373 K.
The solid products were isolated by crystallization of the reaction
mixture from ethanol and washed with a mixture of hexane/etha-
nol (7:3) to give the corresponding compounds. The solid products
obtained were purified by flash column chromatography using
ethyl acetate–ether (3:7) or dichloromethane as an eluent to ob-
tain pure compounds.
The spectral data and melting point of compound 3a–l were con-
sistent with values in the literature [3,4]. The authenticity of the
3m–v products was established by their 1H NMR, IR, and MS data.
The yields obtained and times are summarized in Tables 1 and 2.
Data for (E)-2-(benzo[d]thiazol-2-yl)-3-[5-(4-nitrophenyl)furan-
2-yl]acrylonitrile (3m): red solid, yield by US 70%, mp 239–242 °C.
IR (KBr) cmꢁ1: 3120, 3052, 29176, 2213 (CN). 1H NMR (400 MHz,
CDCl3): d ppm 8.33 (d, 2H, J = 8.81 Hz, Ho), 8.08 (s, 1H, HAC@), 8.06
(d, 1H, J = 8.07 Hz H40BT), 8.01 (d, 2H, J = 8.80 Hz, Hm), 7.91 (d, 1H,
J = 8.07 Hz, H70BT), 7.53 (t, 1H, H60BT), 7.43 (t, 1H, H50BT), 7.27 (d,
1H, H3furanyl), 7.10 (d, 1H, J = 3.91 Hz, H4furanyl); EI-MSMS (m/z):
373.0313 (M+, 100.00), 372.0096 (33.69), 326.0505 (7.57),
298.0530 (7.11), 251.0288 (14.68), 222.0257 (7.86), 198.0231
(8.28), 76.0310 (2.28).
In this work, we compared stirring at room temperature (rt),
ultrasound (USI), and MWI-assisted (MWI) and USI-PTC techniques
to promote the Knoevenagel reaction for the synthesis of (E)-2-
(benzo[d]thiazol-2-yl)-3-heteroaryl-acrylonitriles
3 in order to
ascertain the most useful methodology in general terms. We con-
ducted X-ray diffraction analysis and made quantum mechanical
calculations to gain a better understanding of the minimum energy
conformation for acrylonitriles.
2. Experimental
2.1. Materials and methods
Three methods (A, B and C) were used for the reactions, which
were monitored by thin layer chromatography (TLC), with visuali-
zation of the spots by UV light. TLC was done on plates pre-coated
with silica gel (Merck). Solvents employed for the reactions and
recrystallization were of analytical grade. Nuclear magnetic reso-
nance spectra were recorded in diluted solutions of CDCl3 and
DMSO-d6 using tetramethylsilane (TMS) as an internal standard.
1H NMR and 13C NMR spectra were recorded on a Bruker AM 400
instrument. Melting points were recorded on a Buchi apparatus
and are uncorrected, IR spectra, KBr pellets, 500–4000 cmꢁ1 were
recorded on a Thermo Nicolet NEXUS 670 FT-IR spectrophotome-
ter. High-resolution mass spectrometry ESI-MS and ESI-MS/MS
analyses were conducted in a high-resolution hybrid quadrupole
(Q) and orthogonal time-of-flight (TOF) mass spectrometer
(Waters/Micromass Q-TOF micro, Manchester, UK) with a constant
nebulizer temperature of 100 °C. The experiments were carried out
in positive ion mode, and the cone and extractor potentials were
set at 10 and 3.0 V, respectively, with a scan range of m/z 100–
600. MS/MS experiments were carried out by mass selection of a
specific ion in Q1, which was then submitted to collision-induced
dissociation (CID) with helium in the collision chamber. The MS
product ions were analyzed with a high-resolution orthogonal
TOF analyzer. The samples were infused directly into the ESI source
(E)-2-(Benzo[d]thiazol-2-yl)-3-[5-(methylacetate)furan-2-
yl]acrylonitrile (3n): Yellow solid, yield by US 42%, mp 116–118 °C.
IR (KBr) cmꢁ1: 3118, 3054, 2923, 2201 (CN), 1588, 1741 (C@O),
1
1229. H NMR (400 MHz, CDCl3): d ppm 8.05 (d, 1H, H40BT), 8.03
(s, 1H, HAC@), 7.90 (d, 1H, J = 8.07 Hz, H70BT), 7.51 (t, 1H, H60BT),
7.41 (t, 1H, H50BT), 7.32 (d, 1H, J = 3.43 Hz, H3furanyl), 6.63 (d, 1H,
J = 3.42 Hz, H4furanyl), 5.15 (s, 2H, CH2–O), 2.13 (s, 1H, CO–CH3);
EI-MSMS (m/z): 324.0538 (M+, 34.39), 281.9926 (11.70),
251.0176 (100.00), 222.0245 (8.18), 198.0252 (3.23).
(E)-2-(Benzo[d]thiazol-2-yl)-3-[2-(chloroquinolin)-3-yl]acrylo-
nitrile (3o): Yellow solid, yield by US 58%, mp 198–201 °C. IR (KBr)
cmꢁ1: 3081, 3056, 2218 (CN), 1571, 1479. 1H NMR (400 MHz,
CDCl3): d ppm 9.07 (s, 1H, H4quinoline), 8.66 (s, 1H, HAC@), 8.16
(d, 1H, J = 8.32 Hz, H8quinoline), 8.00 (d, 1H, J = 8.07 Hz, H40BT), 7.94
(d, 1H, J = 8.07 Hz, H70BT), 7.85 (t, 1H, H6quinoline), 7.66 (t, 1H, H7quin-
oline), 7.57 (t, 1H, H60BT), 7.48 (t, 1H, H50BT). EI-MSMS (m/z):
346.9782 (M+, 100), 312.8994 (57.32), 179.7984 (38.57),
(E)-2-(Benzo[d]thiazol-2-yl)-3-(6-chloro[1,3]dioxolo[4,5-
g]quinoline-7-yl)acrylonitrile (3p): Yellow solid, yield by US 57%,
mp 288–290 °C. IR (KBr) cmꢁ1: 3041, 2996, 2220 (CN), 1574,
1485, 1251. 1H NMR (400 MHz, CDCl3): d ppm 8.90 (s, 1H, H4quino-
line), 8.62 (s, 1H, HAC@), 8.15 (d, 1H, J = 8.31 Hz, H40BT), 7.94 (d, 1H,
J = 8.07 Hz, H70BT), 7.58 (t, 1H, H60BT), 7.49 (t, 1H, H50BT), 7.33 (s, 1H,
via a syringe pump at flow rates of 5
injection valve.
l
L minꢁ1, via the instrument’s
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
3
Table 1
Products of Knoevenagel condensation and comparisons of methods A [4], B and C.
CN
N
S
R
Compound
3a[4]
R
mp (°C)[4]
209–211
241–243
228–230
Yield (%)
rta[4]
84
Time reaction min
USIb
87
MWIc
88
rta
USIb
MWIc
9
18
10
O
O
O
N
N
N
CH3
3b[4]
87
85
90
88
89
90
15
17
8
9
7
8
3c[4]
F
3d[4]
3e[4]
244–246
190–192
40
80
46
83
47
85
21
40
13
12
9
N
O
11
N
N
H
3f[4]
3g[4]
3h[4]
155–157
185–187
188–190
66
59
59
70
82
61
75
68
67
18
25
26
5
7
7
4
10
7
N
Cl
O
H3C
N
N
Cl
3i[4]
138–140
51
60
62
22
8
8
O
3j[4]
191–193
158–160
84
83
84
86
85
87
20
14
7
6
10
4
3k[4]
N
3l[3]
170–172[3]
25
48
50[3]
42
19
20[3]
NO2
Conditions.
a
Method A: Ethanol/Trietylamine/Stirring/rt: 19 °C.
Method B: Ethanol/Trietylamine/Ultrasound, 35 kHz/rt: 19 °C.
Method C: Catalyst/Solvent Free/MW/100 °C/105 W.
b
c
Table 2
Conditions and results of ultrasound-assisted phase-transfer catalysis in aqueous medium to promote the Knoevenagel reaction.
Compound
Enty
Conditions*
Method A
Method B
Method C
(conventional)*
(US-35 kHz)*
(105 W/100 °C)c
Solvent
Catalyst
Time (min)/Yield (%)
Time (min)/Yield (%)
Time (min)/Yield (%)
d
1
None
Ethanol
H2O
Catalyst free
TEA
NaOH(aq):TBAB
TEA:TBAB
–
–
12/47
13/44
–
N
O
N
S
2[4]
21/40
8/13
20/41
13/46
4/10
9/88
3a
4b
Ethanol:H2O
–
N
3d
1a
None
Ethanol
H2O
Catalyst free
TEA
NaOH(aq):TBAB
TEA:TBAB
–
–
8/62
8/61
–
N
S
2a[4]
22/51
6/15
20/53
8/60
3/17
1.5/79
O
3aa
4ab
Ethanol:H2O
–
N
3i
1b[3]
2b
None
Ethanol
H2O
Catalyst free
TEA
NaOH(aq):TBAB
TEA:TBAB
–
–
20/50[3].
19/52
–
–
NO2
N
S
25/42
5/9
7/55
19/48
5/14
8/75
3ba
4bb
Ethanol:H2O
N
3l
Entry 1a is also empty to highlight the conditions of the entries 2–4.
a
Ratios: NaOH 50%: TBAB 20 mol%.
Ratios: EtOH:H2O (50%), TEA: 0.2 mL, TBAB 20 mol%.
Method A and B at ambient temperature 19 °C; MWI at 100 °C.
Entries 1 and 1b are empty with the rt and USI methods because the aldehydes used as precursors are in the solid-state and could not react under conditions of stirring at
b
c
d
rt or USI.
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

4
P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
H5quinoline), 7.20 (s, 1H, H8quinoline), 6.19 (s, 1H, O–CH2–O);
EI-MSMS (m/z): 391.9835 (M+, 0.91), 390.9780 (3.54), 356.9911
(23.53), 355.9853 (100.00), 298.0354 (10.06), 177.7071 (14.42).
(E)-2-(Benzo[d]thiazol-2-yl)-3-(1-methyl-1H-imidazol-2-
yl)acrylonitrile (3q): Yellow solid, yield by US 61%, mp 235–237 °C.
IR (KBr) cmꢁ1: 3045, 2211 (CN), 1596, 1478, 1416. 1H NMR
(400 MHz, CDCl3): d ppm 8.17 (s, 1H, HAC@), 8.03 (d, 1H,
J = 8.31 Hz, H40BT), 7.93 (d, 1H, J = 8.07 Hz, H70BT), 7.53 (t, 1H,
H60BT), 7.46 (s, 1H, H4imidazole), 7.42 (t, 1H, H50BT), 7.11 (s, 1H,
H5imidazole), 3.90 (s, 1H, N–CH3); EI-MSMS (m/z): 266.0629 (M+,
100.00), 265.0554 (45.55), 240.0594 (10.12), 233.0829 (10.27),
198.0238 (19.07), 132.0571 (12.58).
(E)-2-(Benzo[d]thiazol-2-yl)-3-(6-isopropyl-4-oxo-4H-chromen-
3-yl)acrylonitrile (3r): Yellow solid, yield by US 36%, mp 198–199 °C.
IR (KBr) cmꢁ1: 2958, 2915, 2859, 2195 (CN), 1663, 1612 (C@O). 1H
NMR (400 MHz, DMSO-d6): d ppm 8.06 (d, 1H, J = 7.82 Hz, H40BT),
7.77–7.76 (m, 2H, H70BT and HAC@), 7.69 (s, 1H, HbC@O), 7.62–
7.56 (m, 2H, H60BT and C8chromone) 7.47 (t, 1H, H50BT), 7.33 (s, 1H,
C5chromone), 7.06 (d, 1H, J = 8.56 Hz, C7chromone), 2.95 (m, 1H, CHisopro-
pyl), 1.21 (d, 6H, CH3-isopropyl); EI-MSMS (m/z): 372.0662 (M+, 100.00),
356.9871 (99.69), 343.0783 (46.47), 328.9936 (20.46), 301.0415
(6.63), 210.0246 (8.00), 164.1818 (16.16), 91.0540 (5.9).
6.97 (d, 1H, J = 8.32 Hz, C7chromone), 2.66 (q, 2H, CH2), 1.24 (t, 3H,
CH3); EI-MSMS (m/z): 358.0247 (M+, 100.00), 342.9775 (36.21),
329.9837 (30.64) 328.9803 (96.79), 315.0053 (17.90), 210.0213
(9.44), 157.1292 (10.37).
(E)-2-(Benzo[d]thiazol-2-yl)-3-(6-methyl-4-oxo-4H-chromen-
3-yl)acrylonitrile (3t): Yellow solid, yield by US 59%, mp 257–
259 °C. IR (KBr) cmꢁ1: 3087, 2201 (CN), 1668, 1611 (C@O). 1H
NMR (400 MHz, CDCl3): d ppm 7.82 (s, 1H, HAC@), 7.70 (d, 1H,
J = 8.07 Hz, H70BT), 7.61 (d, 1H, J = 8.32 Hz, H40BT), 7.53 (t, 1H,
H60BT), 744–7.4 (m, 4H, HbC@O, H50BT, C8chromone and C5chromone),
6.94 (d, 1H, J = 8.31 Hz, C7chromone), 2.66 (s, 3H, CH3); EI-MSMS
(m/z): 343.9991 (M+, 60.10), 315.0551 (100.00), 290.0611 (7.89),
210.0269 (5.97).
(E)-2-(Benzo[d]thiazol-2-yl)-3-(4-oxo-4H-chromen-3-yl)acry-
lonitrile (3u): Yellow solid, yield by US 51%, mp 205–207 °C. IR
(KBr) cmꢁ1
:
3085, 2201 (CN), 1668, 1611 (C@O). 1H NMR
(400 MHz, CDCl3): d ppm 8.08 (d, 1H, J = 7.83 Hz, H40BT), 7.88 (d,
1H, C8chromone), 7.82 (s, 1H, HAC@), 7.79 (d, 1H, 7.82 Hz, H70BT),
7.68 (t, 1H, H50BT), 764 (m, 1H, C6chromone), 7.49 (t, 1H, H70BT),
7.37 (s, 1H,
HbC@O), 7.23 (t, 1H, C7chromone), 7.12 (d, 1H,
J = 8.31 Hz, C5chromone); EI-MSMS (m/z): 330.9170 (M+, 12.45),
329.9822 (49.50), 301.0385 (100.00), 276.0476 (3.26), 210.0185
(5.23), 108.0035 (4.58).
(E)-2-(Benzo[d]thiazol-2-yl)-3-(6-ethyl-4-oxo-4H-chromen-3-
yl)acrylonitrile (3s): Yellow solid, yield by US 34%, mp 229–230 °C.
IR (KBr) cmꢁ1: 3187, 2963, 2196 (CN), 1655, 1610 (C@O). 1H NMR
(400 MHz, CDCl3): d ppm 7.85 (s, 1H, HAC@), 7.70 (d, 1H,
J = 8.07 Hz, H70BT), 7.61 (d, 1H, J = 8.31 Hz, H40BT), 7.53 (t, 1H,
H60BT), 744–7.4 (m, 4H, HbC@O, H50BT, C8chromone and C5chromone),
(E)-2-(benzo[d]thiazol-2-yl)-3-pyridin-4-ylacrylonitrile
(3v):
Yellow solid, yield by US 61%, mp 252–254 °C. IR (KBr) cmꢁ1
:
3170, 2212 (CN), 1588. 1H NMR (400 MHz, CDCl3): d ppm 8.82
(d, 2H, J = 5.87 Hz, H2-pyridine), 8.20 (s, 1H, HAC@), 8.13 (d, 1H,
J = 8.07 Hz, H40BT), 7.95 (d, 1H, 8.07 Hz, H70BT), 7.81 (d, 2H,
Table 3
Results of ultrasound-assisted phase-transfer catalysis to obtain heteroaryl-acrylonitrile derivatives.
Compound
R
mp (°C)
USI/TEA/Ethanolb
Time (min)
USI/TEA:TBAB/Ethanolb
Time (min)
Yield (%)
70
Yield (%)
81
3m
3n
3o
239–242
116–118
198–201a
10
30
20
4
9
3
42
58
56
92
O
O
O
Cl
Cl
N
3p
3q
288–290a
235–237
9
7
57
61
6
2
80
78
O
O
N
N
N
CH3
O
3r
3s
3t
198–199
229–230
257–259
205–207
252–254
25
5
36
34
59
51
61
4
4
3
5
8
50
49
62
60
94
O
O
O
O
6
CH3
O
O
3u
3v
20
15
O
N
a
The compounds exhibit a narrow range of fusion with evidence of decomposition (darkening).
Ratios: Ethanol (10 mL), TEA (0.2 mL), TBAB (20 mol%) US 35 kHz.
b
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
5
Table 4
2.4. Computational details
X-ray crystallographic data and structural refinement for (E)-2-(Benzo[d]thiazol-2-
yl)-3-[5-(4-fluorophenyl)isoxazol-3-yl]acrylonitrile 3c.
Conformational energy for all structures was assessed at three
levels of theory: B3LYP [41,42]/6-311++G⁄⁄ [43,44], TPSS [45]/6-
311++G⁄⁄ and MO6-2X [46]/6-311++G⁄⁄. The imaginary frequen-
cies were absent in all the evaluated models, which ensures that
the structures correspond to a true minimum in the potential en-
ergy surface (PES) at these levels of theory. All the calculations
were made with the Gaussian 03 program [47] (see Table 5).
Empirical formula
C19H10FN3OS
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
347.36
293(2) K
1.54184 Å
Triclinic
Pꢁ1
a = 5.8784(8) Å
a
= 88.145(8)°
b = 7.5099(8) Å b = 87.031(10)°
c = 17.9799(13) Å
785.14(15) Å3
2
c = 82.230(11)°
Volume
Z
Calculated density
Absorption coefficient
F(000)
3. Results and discussion
1.469 Mg/m3
2.039 mmꢁ1
356
In the pursuit of a facile protocol to obtain heteroaryl-acryloni-
trile derivatives by Knoevenagel condensation, a series of (E)-2-
(benzo[d]thiazole-2-yl)-3-heteroaryl-acrylonitriles 3a–l [3,4] were
synthesized by reaction between 2-(benzo[d]thiazol-2-yl)acetoni-
trile 1 (1.0 mmol) and different substituted heteroaryl-aldehydes
2a–l (1.0 mmol). Catalytic amounts of triethylamine (TEA)
(0.2 mL) were used to promote these reactions by stirring at room
temperature with ethanol (10 mL) as a solvent (Method A) [4]. Pre-
vious reports have shown that this solvent is advantageous to pro-
mote the Knoevenagel reaction [27]. To find the specific effect of
ultrasound on this reaction with respect to parameters like reac-
tion times and improved yields, we carried out the same reactions
with Method B (US), using the same amount of reagents and sol-
vent, and evaluating the effects of the microwave on solvent-free
and catalyst-free conditions (MWI). The results of the different
reaction setup conditions on the interaction between 1 and the
aldehydes 2a–l (rt, USI and MWI) are summarized in Scheme 1
and Table 1. The products were obtained in high purity, low to high
yields and at varying reaction times.
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
0.300 ꢂ 0.120 ꢂ 0.090 mm
2.462–73.250°
ꢁ6 6 h 6 7, ꢁ9 6 k 6 9, ꢁ22 6 l 6 21
5044/3021 [R(int) = 0.0341]
67.684° 99.4%
None
Full-matrix least-squares on F2
3021/0/226
1.080
r(I)]
R1 = 0.0465, wR2 = 0.1262
R1 = 0.0546, wR2 = 0.1437
n/a
0.214 and ꢁ0.342 e Åꢁ3
J = 5.62 Hz, H3-pyridine), 7.57 (t, 1H, H50BT), 7.48 (t, 1H, H60BT); EI-
MSMS (m/z): 263.0457 (M+, 91.01), 262.0394 (100.00), 235.0326
(14.86), 210.0256 (14.58), 118.0699 (5.55).
The reactions by USI were performed in an ultrasonic reactor
(Elma transsonic 460, Elma, Singen, Germany), at 19 °C (rt) and
35 kHz. The use of different frequencies from 45 to 100 kHz did
not significantly affect yields. The reactions by MWI were per-
formed in a focused microwave reactor (CEM Discover TM). The
reaction mixture of 1 and 2 was irradiated at 105 watts (the same
output power of 35 kHz was used in order to maintain similar con-
ditions [27]) for 4–20 min at 373 K. The increases in irradiation
periods did not significantly affect yields.
Generally, USI and MWI methods gave superior yields with
shorter reaction times than did the rt method. The shorter process-
ing time could be due to the physical phenomenon of acoustic cav-
itation [30–33] and, because of purely thermal/kinetic effects of
the MWI method [48]. There were no significant improvements
in terms of the yields of compounds 3a–3e, 3j, 3k and 3l. However,
improvements were observed with the USI and MWI methods.
In the series of compounds, 3d gave low yields with rt, USI and
MWI, although, there was a slight improvement in yield with USI
and MWI, combined with a more significant reduction in reaction
time. The yield for the compound 3g significantly improved with
USI, while the yields for compounds 3f, 3h, 3i and 3l were signifi-
cantly higher with MWI than with the rt method. They were also
higher with the USI than with the rt method, although the difference
was not as pronounced as with MWI. This analysis does not defini-
tively demonstrate which technique is the most effective in terms
of decreasing reaction times while increasing yields at the same
time.
2.3. X-ray crystallography
A 0.300 ꢂ 0.120 ꢂ 0.090-mm yellow needle crystal of 3c was
mounted on a goniometer head for X-ray measurements [37]. Cell
unit parameters were determined on the setting angles of 5044
centered reflections in the range 2.46 6 h 6 73.25°. The intensities
of 3021 reflections were collected from
x/2 h scans in the range
2.46 6 h 6 73.25°. The collected reflections were corrected for Lor-
entz and polarization effects [38]. The structure was solved by di-
rect methods with SHELXS-97 [39] and refined by a full-matrix
least-squares procedure based on F2 with SHELXL-97 [39]. The
molecular structure was drawn with the aid of the OLEX2 program
[40] and is presented in this article. All non-hydrogen atoms were
refined anisotropically. H atoms were placed at idealized positions,
with C–H distances of 0.93 Å and Uiso = 1.2 Ueq(C). The complete
crystallographic data is presented in Table 4.
Table 5
Relative energies for hypothetical conformations, calculated for the products 3e, 3f
and 3i at three DFT levels of theory. The values are given in kcal/mol. All calculations
were performed at the 6-311++G⁄⁄ basis set.
Products
B3LYP
TPSS
MO6-2X
3eEa
3eEb
3eZb
3eZa
3fEa
3fEb
3fZb
3fZa
3iEa
3iEb
3iZb
3iZa
0.0
3.0
4.2
5.8
0.0
1.6
6.8
5.8
0.0
1.6
5.8
6.4
0.0
2.8
3.7
6.2
0.0
1.6
7.0
5.2
0.0
1.6
6.7
6.1
0.0
3.2
4.4
5.3
0.0
1.9
5.4
6.5
0.0
1.8
7.7
6.5
The improved yields under catalyst and solvent-free conditions
could lead to the conclusion that MWI is more advantageous than
the USI and rt methods. However, considering the previous results,
it is not clear if the MWI method is particularly better than USI.
MWI requires high temperatures (100 °C) to promote Knoevenagel
condensation and organic solvents to purify products (use 30 mL of
ethanol by compounds), and in some cases, it requires purification
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

6
P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
by column chromatography. In comparison to the room tempera-
ture (rt of 19 °C), USI only requires filtering and washing products
(30 mL of ethanol:H2O 50%). Thus, weighing the benefits of MWI
against the energy costs and the use of recrystallization with sol-
vents and chromatography to purify derivatives, it can be argued
that USI is more advantageous.
Moreover, regardless of the method of synthesis, it is worth not-
ing as can be seen in Table 1, that the electronic effects of the elec-
tron-withdrawing and electron-releasing substituents at position 3
of R of the acrylonitrile derivatives had a slight effect on reaction
times and yields of the products. We observed that compounds ob-
tained from aldehydes with five member substituents, such as
furanyl had lower yields, while products containing isoxazole sub-
stituents had higher yields. However, reductions in reaction times
due to the influence of the furan and isoxazole nuclei were very di-
verse; whereby, it was not observed the same behavior.
catalyze Knoevenagel condensation, activating the reagents with
increased reaction rates and yields. In this sense, the use of USI-
PTC conditions surpasses the rt and solvent and catalyst-free
MWI methods.
The main advantages of the US-PTC procedure are shorter reac-
tion times, room temperature, lower reaction temperatures, higher
yields, green chemistry protocols with water instead of organic sol-
vents and simple purification procedures. The miscibility of TBAB
and TEA with water allows the development of clean reactions,
as the catalyst can be removed from the product simply by wash-
ing the product with 50% aqueous alcohol.
We tested the catalysis with TEA/ethanol under USI-PTC condi-
tions freeing the synthesis of novel acrylonitrile derivatives.
Acrylonitriles 3m–v were synthesized with the optimum fre-
quency of 35 kHz for effective Knoevenagel condensation. The
compounds were obtained in short reaction times, with good
yields at room temperature (Table 3).
As shown in Table 3, the compounds were obtained in 5–30 min
using USI/TEA:ethanol, with yields of 42–70%. The results were
better with the USI-PTC method for both process time (2–9 min)
and yield (50–94%). The majority of compounds were obtained
with moderate to high yields, 3m (81%), 3o (92%), 3p (80%), 3q
(78%), 3v (94%), representing increases of 11%, 34%, 23%, 17% and
33%, respectively over the yields with the USI/TEA/ethanol meth-
ods. Yields of compounds 3n and 3r–u were moderate (the lowest
yields of the series) 56%, 50%, 49%, 62% and 60% respectively, but
the reaction times were short in all cases. We believe that the
low yields of compounds 3n and 3r–u were due to complex mix-
tures of products related possibly to Michael addition adducts or
hydrolysis and aperture products because of having added water
Compounds 3d, 3i, and 3l had low yields with all three methods.
To improve yields, we carried out a study of the influence of different
catalysts and solvents in synthesizing these compounds. Once again,
we evaluated the same methods (rt, USI and MWI), but this time an
ultrasound-assisted phase-transfer catalysis in aqueous medium
(USI-PTC, entries 3 and 4 in Table 2) was performed.
As shown in Table 2, a slight improvementin the reaction yields is
evident in the MW-reaction (entries 1, 1a and 1b) between 1 and 4-
(morpholin-4-yl)benzaldehyde, furfuraldehyde and 4-NO2-benzal-
dehyde to obtain 3d, 3i and 3l, respectively, but not in the reaction
time using MWI at 100 °C and 105 W, compared to the rt method
and USI at room temperature and with 35 kHz (entries 2, 2a and 2b).
The results are striking when US is coupled with PTC conditions
(entries 3–4, 3a–4a and 3b–4b). Using classical PTC conditions in
the presence of aqueous sodium hydroxide and tetrabutylammo-
nium bromide (TBAB) with the rt and USI methods, time and yields
decreased for 3d (8 min/13%, rt) and (4 min/10%, US). The same
behavior was observed for 3i and 3l using rt and USI, respectively.
This behavior could be due to the strong base conditions used,
which caused the formation of reaction by-products that could
not be isolated [49]. We expect that the MWI technique at high
temperatures would yield poorer results. Finally, the results with
USI, catalyst and solvent reaction conditions (ethanol and TEA) in
the presence of TBAB in an aqueous medium (entries 4, 4a and
4b) are better than those with the solvent and catalyst-free MWI
method (entry 1). Under mild USI-PTC conditions with TEA as a
weak base in ethanol:H2O (50%), the formation of reaction by-
products is avoided and an efficient Knoevenagel reaction obtains
3d, 3i and 3l in only 9, 1.5 and 8 min with PTC yields of 88%, 79%
and 75%, respectively. These results indicate that the conditions
are optimal to obtain acrylonitrile derivatives, which confirms that
USI-PTC conditions in the presence of TBAB and water efficiently
to the acetate group of 3n and in the
a,b-unsaturated system of
the chromone ring, respectively; which were not isolated [49–52].
The compounds 3a–l reported in this work were characterized
by comparing their spectroscopic data and melting points against
previously reported data [4]. The new compounds 3m–v were
characterized by 1H NMR spectra, IR and ESI-MS. 1H NMR analysis
for all the derivatives revealed a single olefinic proton, which was
consistent with the formation of a single isomer, which was con-
sidered as the thermodynamically more stable E configuration
[4]. However, 1H NMR analysis does not effectively clarify the dou-
ble-bond configuration in heteroaryl-acrylonitriles.
Since these acrylonitriles are potential candidates for biological
activity tests, and in order to gain better understanding of the min-
imum energy conformation, we conducted an analysis of their
structure and the possible conformations. Since only 3c gave the
suitable crystals for X-ray diffraction analysis, crystallographic
data of this compound were collected (Fig. 2). The X-ray diffraction
analysis and the quantum mechanic calculations identified the
Fig. 2. X-ray crystallography data for compound 3c.
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
7
Fig. 3. The hypothetical structural conformations for product 3e. DFT methods were able to identify that the E isomers a–b are more stable than the Z isomers c–d.
most stable energy conformations for the acrylonitriles, namely
the E configurations.
(Fig. 2B). The crystal structure is stabilized by weak C–Hꢀ ꢀ ꢀN inter-
molecular interaction (Hoꢀ ꢀ ꢀN2 = 2.45 Å, Coꢀ ꢀ ꢀN1 = 3.348(3) Å, Co–
Fig. 2A shows the atomic numbering scheme. Displacement
ellipsoids are drawn at 50% probability for non-H atoms. The
essentially planar benzothiazole system [maximum devia-
tion = ꢁ0.013(1) Å for the C20 atom] is oriented at a dihedral angle
of 3.74 (11)° with respect to the isoxazole ring, whereas in the fluo-
rophenyl moiety the dihedral twist is 3.03 (11)°. The packing of the
molecules in the unit cell contains a hydrogen bond network
Hoꢀ ꢀ ꢀN2 = 162°), forming a centrosymmetric ring R2 (20) [53] along
2
the crystallographic a axis, (see Fig. 2B). Crystallographic data is
presented in Table 4.
We did a conformational energy study to determine by medium
level quantum mechanic calculations which configuration (E or Z
with respect to R group and the benzothiazole scaffold) is more
stable (see Figs. 3 and 4). For simplicity, and in order to reduce
Fig. 4. The rotamers conversion energy represented as a scan profile between the 3fEa and 3fEb conformations. The low energy barrier of 5 kcal molꢁ1 allows intro-
conversion between the two E isomer conformations.
Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

8
P. De-la-Torre et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
Acknowledgements
PDM thanks the Doctoral Program of Applied Sciences of the
Universidad de Talca, as well as the Chilean International Cooper-
ation Agency (AGCI) and CONICYT-Chile for a doctoral fellowship.
The authors thank ‘Becas Universidad de Talca’, FONDECYT project
1100481, Universidad del Atlántico and Universidad del Valle. The
authors also thank the Centro de Bioinformática y Simulación
Molecular (CBSM) for allowing computer time, and Horacio Poblete
and Ariela Vergara for their valuable scientific comments and
discussions.
Scheme 1. Synthesis of heteroaryl-acrylonitriles. Experimental data of the Knoe-
venagel reaction using stirring at room temperature, microwave or ultrasound
irradiation.
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and 3eZa are considered as rotamer A where the S atom of the ben-
zothiazole framework and the CN group are eclipsed, and 3eEb and
3eZb are rotamer B where the N atom of the benzothiazole frame-
work and the CN group are eclipsed. Density functional theory
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match with the X-ray diffraction analysis because the E isomer is
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Authors’ contributions
PDM carried out the synthesis and spectroscopic characteriza-
tion of synthesized compounds and monitored the experimental
setup. EO implemented and carried out the computer studies. JC,
JAM, LAS, MG, JT and JQ contributed with technical support and
data analysis and interpretation. IB and AC carried out the X-ray
diffraction analysis. All authors participated in drafting the manu-
script, as well as reading and approving the final version of the
manuscript.
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Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
http://dx.doi.org/10.1016/j.ultsonch.2014.02.021

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Please cite this article in press as: P. De-la-Torre et al., Ultrasound-assisted phase-transfer catalysis method in an aqueous medium to promote the
Knoevenagel reaction: Advantages over the conventional and microwave-assisted solvent-free/catalyst-free method, Ultrason. Sonochem. (2014),
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