The synergistic effect of copper chromite spinel nanoparticles (CuCr2O4) and basic ionic liquid on the synthesis of cyclopropanecarboxylic acids

Article abstract of DOI:10.1007/s11164-016-2572-1

Abstract: An efficient synthesis of cyclopropanecarboxylic acids using copper chromite spinel nanoparticles and basic ionic liquid is described. In this study, a relatively simple method starting with trans-cinnamic acid for the synthesis of (±)-trans-2-phenylcyclopropanecarboxylic acid, a key intermediate in the synthesis of tranylcypromine sulfate as an active pharmaceutical ingredient, was employed. Using a combination of basic ionic liquid [Bmim]OH and copper chromite spinel nanoparticles as a catalytic system, the best results were obtained in THF as a polar solvent. This method is a useful alternative to other approaches described in the literature. The use of commercially available chemicals, decreased environmental hazards, with no need for the separation of stereoisomers, and consequently a reduced number of overall steps, are the advantages of this approach that make it an appropriate choice at an increased scale. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2572-1

Res Chem Intermed
DOI 10.1007/s11164-016-2572-1
The synergistic effect of copper chromite spinel
nanoparticles (CuCr2O4) and basic ionic liquid
on the synthesis of cyclopropanecarboxylic acids
Mohammad Hadi Ghasemi1 Elaheh Kowsari1
•
Received: 24 December 2015 / Accepted: 4 May 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract An efficient synthesis of cyclopropanecarboxylic acids using copper chromite
spinel nanoparticles and basic ionic liquid is described. In this study, a relatively simple
method starting with trans-cinnamic acid for the synthesis of ( )-trans-2-phenylcyclo-
propanecarboxylic acid, a key intermediate in the synthesis of tranylcypromine sulfate as
an active pharmaceutical ingredient, was employed. Using a combination of basic ionic
liquid [Bmim]OH and copper chromite spinel nanoparticles as a catalytic system, the
best results were obtained in THF as a polar solvent. This method is a useful alternative
to other approaches described in the literature. The use of commercially available
chemicals, decreased environmental hazards, with no need for the separation of
stereoisomers, and consequently a reduced number of overall steps, are the advantages of
this approach that make it an appropriate choice at an increased scale.
Graphical Abstract
CuCr2O4 / [Bmim]OH
THF, 50°C, 4h
COOH
+ CHI3
R
R
COOH
R =
Me
Cl
MeO
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2572-1)
contains supplementary material, which is available to authorized users.
&
Elaheh Kowsari
kowsarie@aut.ac.ir
1
Department of Chemistry, Amirkabir University of Technology, Hafez Avenue, No. 424,
P.O. Box: 159163-4413, Tehran, Iran
123

M. H. Ghasemi, E. Kowsari
Keywords Copper chromite spinel nanoparticles Á Basic ionic liquid Á ( )-Trans-2-
phenylcyclopropanecarboxylic acid Á Trans-cinnamic acid Á Cyclopropanation
Introduction
Ionic liquids (ILs) are organic salts with low melting points and negligible vapor
pressures [1]. Ionic liquids have polar characteristics and are excellent media to hold
polar species such as transition-metal catalysts [2–5], and so they have been used for
the immobilization of homogeneous catalysts [6, 7]. The application of ILs in
catalysis has been increasing due to their ability as solvents for many transition
metal-catalyzed reactions [8]. The IL phase efficiently induces catalyst immobi-
lization and has a low miscibility with organic reaction products; as a consequence,
liquid–liquid biphasic processes using ILs incorporating transition metal catalysts
have been widely examined [9]. Functional nanoparticles have also been
synthesized using ionic liquids [10, 11]. The use of metal nanocatalysts and the
heterogenization of homogeneous catalysts in ILs are among attractive new
concepts in the ILs area.
Copper chromite composite oxide (CuCr2O4) is an excellent catalyst for some
chemical reactions such as alkylation, oxidation, hydrogenation, dehydrogenation,
etc. [12]. Similar types of spinel ferrite materials have been prepared by microwave,
and by conventional and plant extract-assisted combustion methods [13–18]. Due to
the tetragonally distorted normal spinel structure and the arrangement of copper in
its structure, copper chromite is a remarkably effective catalyst [19]. However,
although this catalyst has been widely used in many chemical reactions, it has not
been well investigated for the catalytic cyclopropanation of vinyl compounds as an
interesting topic in chemical synthesis.
In recent years, many efforts have been made to synthesize ( )-trans-2-
phenylcyclopropanecarboxylic acid (Scheme 1, A), a key intermediate in the
synthesis of tranylcypromine sulfate as an active pharmaceutical ingredient [20–26].
The search for efficient synthesis methods of tranylcypromine sulfate under mild
conditions is of continuing interest for pharmaceutical chemists. The most
commonly used synthetic method to synthesize tranylcypromine sulfate is shown
in Scheme 1. According to this method, tranylcypromine sulfate is synthesized in
seven steps starting with styrene, in which the synthesis of ( )-trans-2-phenylcy-
clopropanecarboxylic acid A is of extreme importance.
As shown in Scheme 1, there are three successive steps for the synthesis of ( )-
trans-2-phenylcyclopropanecarboxylic acid A. Firstly, the reaction of styrene with
ethyldiazoacetate, a mixture of the ( )-cis and ( )-trans-2-phenylethyl esters of
cyclopropane carboxylic acid, is prepared (Scheme 1, a). The isomerization of the
( )-cis isomer to the ( )-trans isomer is carried out by reacting the ester with
metallic sodium in anhydrous ethyl alcohol (Scheme 1, b). The obtained ester is
then hydrolyzed to a mixture of ( )-cis and ( )-trans-2-phenylcyclopropane
carboxylic acid. Full separation of the ( )-trans isomers from the ( )-cis/trans
mixture is carried out by recrystallization several times in hot water (Scheme 1, c).
123

The synergistic effect of copper chromite spinel…
O
O
O
b
a
+
OEt
OEt
OEt
N2
65% ( )-trans isomer
35% ( )-cis isomer
95% ( )-trans isomer
5% ( )-cis isomer
O
O
O
c
e
d
N3
OH
Cl
A
( )-trans-2-phenyl cyclopropane carboxylic acid
The key intermediate
+
NH3
f
g
NH2
2-
.SO4
2
Tranyl Cypromine Sulf ate
Scheme 1 General method for the synthesis of tranylcypromine. Reagents and conditions: (a) i
125–140 °C/N2/4 h, ii Distillation of styrene under vacuum; (b) i sodium metal in anhydrous ethanol/N2/
reflux/20 h, ii Extraction by benzene; (c) i NaOH/absolute ethanol:water/reflux/20 h, ii HCl (conc.);
(d) SOCl2/benzene/reflux/16 h; (e) NaN3/toluene/80 °C/4 h; (f) i HCl (conc.)/reflux/15 h, ii KOH (60 %);
(g) ethanolic solution of concentrated sulfuric acid
Although this method also overcomes the isolation of stereoisomers, it has some
disadvantages, as follows. First, this method uses styrene as a raw material. The use of
styrene is limited due to its high polymerization potential. Styrene can be easily
polymerized under the reaction conditions. So, before starting the reaction, the styrene
should be purified by distillation under reduced pressure. Additionally, further
purification of the polystyrene formed during the reaction must be carried out. On the
other hand, ethyl diazoacetate, used in the first step of this method, is a hazardous
chemical and considerations of safe industrial handling should be established. Since, in
most cases, it is hard to access commercial ethyl diazoacetate, it must be synthesized in
the laboratory, which involves the addition of one or two steps to the overall synthesis
steps. The long reaction times, using metallic sodium in refluxing ethanol for a long
period of time (20 h), which incurs considerable risks, and the use of toxic solvents such
as benzene are among other disadvantages of this procedure which has made it
laborious to scale up. In addition, the overall low yield of this process means that
production on an industrial scale is not economically feasible. An alternative method to
avoid the formation of a mixture of cis and trans isomers is the use of special chemical
raw materials, which chemoselectively produce the desired isomer without any chiral
catalyst. Trans-cinnamic acid is one such specific raw material that can be used to
synthesize the key intermediate A in the cyclopropanation reaction. Therefore, our
efforts have been particularly focused on the synthesis of compound A as the key
intermediate using chromium (II) reagents in tranylcypromine synthesis.
123

M. H. Ghasemi, E. Kowsari
We have developed a novel simple method for the synthesis of ( )-trans-2-
phenylcyclopropane carboxylic acid A using copper chromite spinel nanoparticles
(CuCr2O4) and basic ionic liquid by reducing the number of steps and improving the
overall yield. In this paper, we suggest an excellent method for the synthesis of
intermediate A which has many benefits without the disadvantages mentioned in the
previous methods. The use of trans-cinnamic acid as commercial raw material is a
possible alternative to prevent the formation of a mixture of cis/trans isomers. Our
recommended method is briefly summarized in Scheme 2. In order to reduce costs,
iodoform is effectively produced by the reaction of commercial acetone and iodine.
The key intermediate A is readily synthesized by the reaction of trans-cinnamic acid
and iodoform in dry THF in the presence of a catalytic system (Scheme 2).
Experimental
Materials and general techniques
Chemicals were purchased from the Merck or Sigma-Aldrich. Progression of the
reactions was monitored by TLC using silica-gel SIL G/UV 254 plates. Melting
points were accurately recorded with an Electrothermal-9100 apparatus. Fourier
transform infrared (FT-IR) spectra were achieved by a BRUKER EQUINOX 55
Fourier-transform spectrophotometer using the KBr pellet technique. NMR spectra
were recorded on a Brucker Avance DPX instrument at 300 and 400 MHz,
respectively; d is reported in parts per million (ppm) and J in Hz. Transmission
electron microscopy (TEM; Jeol JEM-1230, with an acceleration voltage of
100 kV) was carried out using to characterize the catalyst morphology. The X-ray
diffraction (XRD) patterns were reported with a Philips X’Pert MPD diffractometer
equipped with Cu Ka radiation (k = 0.154 nm) in the range 10°–80° (2h) at a speed
of 0.05°/min to characterize the crystallographic nanoparticle structure. The
qualitative analyses of products were conducted with a HP 6890/5973 GC–MS
equipped with an FID detector.
Catalyst preparation
The CuCr2O4 spinel nanoparticles catalyst were prepared according to the literature
[27]. CuSO4Á5H2O (2.0 g) and Cr2(SO4)3Á12H2O (10.0 g) were completely
dissolved in a mixture of water (200 mL) and ethanol (20 mL). The pH of the
clear dark blue solution was carefully adjusted to 8 by addition of an aqueous
ammonia solution. Cetyltrimethylammonium bromide (1.50 g) was added to the
CuCr2O4 / [Bmim]OH
THF
COOH
COOH
+
CHI3
A
Scheme 2 Recommended synthesis of ( )-trans-2-phenylcyclopropane carboxylic acid A
123

The synergistic effect of copper chromite spinel…
solution and stirred for a few minutes. Hydrazine hydrate solution (0.6 g) was added
gradually to the dark green gel to produce a brown gel. The resultant gel was aged
under air at 40 °C for 1 h and properly sealed in an autoclave for 18 h at 180 °C.
After cooling to room temperature, the precipitate was collected by centrifugation,
washed with water (2 9 1000 mL) and ethanol (2 9 100 mL) and dried at 100 °C
for 6 h. Finally, the powder was calcinated at 750 °C for 6 h to yield CuCr2O4
spinel nanoparticles.
The basic ionic liquid was prepared and purified according to the procedure
described previously [28]. The CuCr2O4 spinel nanoparticles catalyst (2.0 g) and the
[Bmim]OH (10 mL) were added to methanol (50 mL), and the resulted mixture was
stirred for 6 h at 50 °C. The solvent was removed by evaporation under reduced
pressure to produce an ionic liquid incorporating copper chromite nanoparticles.
The synthesis of A starting with trans-cinnamic acid
A mixture of trans-cinnamic acid (0.3 g, 2 mmol) and 1.18 g iodoform (3 mmol) in
dried THF (5 mL) was stirred at room temperature. The ionic liquid prepared in the
previous step (1 mL), was added to the stirring mixture and the resultant liquid–liquid
biphasic system was vigorously stirred at 50 °C for 4 h. Then, the reaction mixture
was poured into an aqueous hydrochloric acid (1 M, 10 mL) and stirred for 60 min at
room temperature. The mixture was extracted with dried THF (3 9 10 mL). The
aqueous phase was stored in order to recycle the IL catalyst for subsequent reactions.
The combined organic phases were then evaporated under reduced pressures. The
residue was added to sodium hydroxide (33 %, 5 mL) and then acidified with
concentrated hydrochloric acid to pH = 2. The precipitate was filtered, recrystallized
in boiling water and dried to yield 0.3 g (93 %) ( )-trans-2-phenylcyclopropanecar-
boxylic acid A. 1H NMR, 13C NMR and IR spectra of A as a key intermediate in the
tranylcypromine synthesis are indicated in the supplementary material.
(–)-Trans-2-phenylcyclopropanecarboxylic acid (A)
1
C10H10O2; m.p.: 93–98 °C; MW: 162.2; HNMR (300 MHz, CDCl3) d(ppm): 1.42
(ddd, J = 8.1, 6.5, 4.8 Hz, 1 H), 1.67 (dt, J = 14.4, 5.1 Hz, 1 H), 1.91 (dt,
J = 12.9, 4.8 Hz, 1 H), 2.61 (ddd, J = 8.8, 6.2, 4. 5 Hz, 1 H), 7.11–7.33 (m, 5 H);
13CNMR (75 MHz, CDCl3) d(ppm): 17.5, 23.9, 27.1, 126.3, 126,7, 128.5, 139.5,
179.4; IR (KBr) m (cm-1): 754, 934, 1232, 1331, 1443, 1603, 1683, 2862, 3050,
ꢀ
3381; Rf = 0.40 (hexane:ethyl acetate 4:1)
Results and discussion
Catalyst characterization
The X-ray diffraction (XRD) patterns were analyzed to confirm the catalyst
structure using reference standards [27]. The XRD profiles of the copper chromite
catalyst are shown in Fig. 1 with the maximum intensity peak at 2h = 35.7°.
123

M. H. Ghasemi, E. Kowsari
Fig. 1 XRD pattern of copper chromite spinel nanoparticles (CuCr2O4); 2h (°): 30.0, 31.0, 35.7, 37.7,
42.7, 46.4, 53.8, 56.8, 58.1, 62.3, 64.8
For further understanding the catalyst structure, the TEM images of CuCr2O4
catalysts are shown in Fig. 2.
Synergistic effect of the copper chromite nanoparticles and ionic liquid
on the cyclopropanation reaction
In this study, we have successfully employed a simple and efficient procedure for
the synthesis of intermediate A without using any extremely unsafe conditions. For
this special purpose, some experiments were performed to determine the best
conditions, beginning with trans-cinnamic acid as the starting raw material. In this
study, different conditions including various solvents were assessed and the results
are briefly described in Table 1. Furthermore, to evaluate the catalyst repeatability,
further experiments using other functionalized trans-cinnamic acids were per-
formed, with the results given in Table 2.
Initially, we performed the reaction in water as the solvent without any catalyst
and stirred up to 24 h at 50 °C without any progress in the reaction (Table 1, entry
1). The reaction progress was continuously monitored by TLC. The reaction was
also carried out using aqueous solution of sodium carbonate and sodium hydroxide,
and the cyclopropanation reaction was performed with low yield (Table 1, entries 2,
3). The use of basic ionic liquid [Bmim]OH was also accompanied with poor results
(Table 1, entries 4, 5). The reaction efficiency was significantly improved using
copper chromite spinel nanoparticles (CuCr2O4) in tetrahydrofuran as the solvent
(Table 1, entry 6). When [Bmim]OH was used without any catalyst, the product
yield was comparable to that of alkali aqueous solutions. As a consequence, the use
of [Bmim]OH incorporating nanoparticles as an immiscible heterogeneous catalytic
system was preferred.
To investigate the synergistic effect of copper chromite spinel nanoparticles and
basic ionic liquid in the cyclopropanation reaction, the reaction was also performed in
some more immiscible solvents with water such as dichloromethane, diethylether,
ethylacetate and toluene (Table 1, entries 7–12). It was clearly confirmed that using a
combination of ionic liquid [Bmim]OH and CuCr2O4 spinel nanoparticles as a
catalytic system, the best results were obtained in THF as a polar solvent (Table 1,
123

The synergistic effect of copper chromite spinel…
Fig. 2 TEM images of copper chromite spinel nanoparticles (CuCr2O4)
entry 13). The reaction was performed at room temperature; as a consequence, the
reaction yield was dramatically decreased (Table 1, entry 14). In order to replace
sensitive basic ionic liquid [Bmim]OH in the reaction media, in a further experiment,
we used commercially ionic liquid [Bmim]Cl and an alkali solution of sodium
hydroxide (NaOH, 10 %) together with copper chromite spinel nanoparticles (Table 1,
entry 15). The main advantage of this reaction is the generation of ionic liquid
[Bmim]OH in situ. Therefore, there is no need for the separately synthesis of
[Bmim]OH. On the other hand, despite a slight decrease in the reaction yield, the use of
basic ionic liquid is significantly reduced. The results in Table 1 indicate that the
present method is applicable for the cyclopropanation of trans-cinnamic acid under
mild conditions. Impurities were eliminated by recrystallization of the solid product in
boiling water. Simple filtration was needed to collect the product.
To evaluate the repeatability of the catalyst efficiency on the cyclopropanation
reaction, this reaction was performed with some more functionalized trans-cinnamic
acids. The reaction condition is similar to the procedure described above for the trans-
123

M. H. Ghasemi, E. Kowsari
Table 1 The one-pot reaction of trans-cinnamic acid with iodoform under various conditions
COOH
Catalyst / Solvent
COOH
CHI3
+
i
ii
A
trans-( )-2-phenyl-
trans-cinnamic acid
iodo form
cyclopropanecarboxylic acid
Entry
Molar ratio
(i:ii)
Catalyst
Solvent
H2O
Time (h)
Yield (%)a
1
1:1
–
–
–
24
Trace
25
2
1:1
H2O (Na2CO3, 10 %)
H2O (NaOH, 10 %)
24
24
24
24
24
24
4
3
1:1
22
4
1:1
[Bmim]OH
H2O
26
5
1:1
[Bmim]Cl
H2O (NaOH, 10 %)
25
6
1:1
CuCr2O4
THF
47
7
1:1
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]OH/CuCr2O4
[Bmim]Cl/CuCr2O4
THF
73
8
1:1
THF
68
9
1:1
CH2Cl2
4
61
10
11
12
13
14
15
1:1
Et2O
4
59
1:1
EtOAc
4
55
1:1
Toluene
4
47
1:1.5
1:1.5
1:1.5
THF
4
93
THF
4
65b
90c
THF/H2O (NaOH, 10 %)
4
Reactions conditions: solvent (5 mL), catalyst (5 mL), 50 °C
a
GC yield of A including trans-cinnamic acid as the starting material
b
The reaction was carried out room temperature
c
Reaction conditions: [Bmim]Cl (1 mL), CuCr2O4 (5 mol%), dried THF (5 mL), H2O (NaOH, 10 %,
5 mL), 50 °C
cinnamic acid. (E)-3-p-tolylacrylic acid, (E)-3-(4-methoxyphenyl)acrylic acid and (E)-
3-(4-chlorophenyl)acrylic acid were used to produce ( )-trans-2-p-tolylcyclo-
propanecarboxylic acid B, ( )-trans-2-(4-methoxyphenyl)cyclopropanecarboxylic
acid C and ( )-trans-2-(4-chlorophenyl)cyclopropanecarboxylic acid D, respectively
(Table 2).TLCanalysis, FT-IR,meltingpointanalysis, 1HNMRand13CNMRindicated
elevated yields and high purity. Tranyl cypromine sulfate as an API is also synthesized
and the results of this part of the research are provided in the supplementary material.
Synthesis of tranylcypromine sulfate starting with (–)-trans-2-phenylcyclo-
propanecarboxylic acid (A)
A mixture of 1.62 g ( )-trans-2-phenylcyclopropanecarboxylic acid A (10 mmol),
1.63 g of ethylchloroformate (15 mmol) and 1.5 ml of triethylamine in 10 ml of
toluene in an ice-bath was continuously stirred for 4 h. A suspension of 0.975 g
sodium azide (15 mmol) in 5 ml of toluene was added dropwise over 1 h at 80 °C.
123

The synergistic effect of copper chromite spinel…
Table 2 The cyclopropanation reaction of functionalized trans-cinnamic acids
CuCr2O4 / [Bmim]OH
THF, 50°C, 4h
H
COOH
Me
CHI3
+
R
COOH
R
R =
Cl
MeO
Entry
1
Reagent
Product
Yield (%)a
93
drb
Reference
[29]
COOH
A
B
[98/2
COOH
COOH
2
90
[98/2
[29]
COOH
Me
Me
MeO
Cl
COOH
3
4
C
D
95
81
[98/2
[98/2
[29]
[29]
COOH
COOH
MeO
Cl
COOH
Reaction conditions: functionalized trans-cinnamic acid (2 mmol, 1 equiv.), iodoform (3 mmol, 1.5
equiv.), [Bmim]Cl (1 mL), CuCr2O4 (5 mol%), dried THF (5 mL), H2O (NaOH, 10 %, 5 mL), 50 °C, 4 h
a
GC yield
Diastereoisomeric ratio (dr) was determined by GC and 1H NMR analysis of the crude products
b
Slow evolution of nitrogen was observed during the addition. Then, the reaction
mixture was refluxed for 4 h. The completion of the reaction was regularly checked
by TLC. The mixture was cooled and the precipitate was filtered and washed with
2 9 5 ml toluene. The organic phases were combined and concentrated. The obtained
azide intermediate as a viscous oil was used directly in the next step in which 10 ml
of hydrochloric acid (37 %) was gently added to the cooled oil in an ice-bath. Gradual
evolution of carbon dioxide gas was observed. After the loss of gas evolution, the
reaction mixture was refluxed overnight. Then, the mixture was concentrated under
reduced pressure. The residue was made strongly basic with 33 % sodium hydroxide
to pH C 12 and extracted with 2 9 10 ml dichloromethane. The combined organic
phase was dried over anhydrous sodium sulfate, and concentrated at reduced pressures
to obtain a yellowish viscous oil of ( )-trans-2-phenylcyclopropylamine. This viscous
oil was completely dissolved in 5 ml of 2-propanole in an ice-bath. An ethanolic
solution of concentrated sulfuric acid was added gradually to the solution until
pH = 2. The white precipitate was filtered, washed with absolute ethanol and dried in
an oven at 60°C for 6 h. Finally, 2.66 g ( )-trans-2-phenylcyclopropylamine sulfate
(tranylcypromine sulfate) as an API was obtained (Ra = 73 %).
(–)-Trans-2-phenylcyclopropylamine sulfate
C18H24N2O4S; m.p.: 242–243 °C; MW: 364.4; 1HNMR (400 MHz, CDCl3) d(ppm):
1.54 (ddd, J = 8.5, 6.3, 4.9 Hz, 1 H), 1.78 (dt, J = 12.9, 5.3 Hz, 1 H), 1.92 (dt,
J = 12.5, 5.1 Hz, 1 H), 2.92 (ddd, J = 8.5, 5.9, 4.7 Hz, 1 H), 7.22–7.45 (m, 5 H);
123

M. H. Ghasemi, E. Kowsari
N
N
N
N
+
+
OH-
Heat
CHI3
CI3- + H2O
I-
H
..
Carbene :CI2
I
I
ILSC
I
H
H
CuCr2O4
COO-
H
I
H2O
ILSC
H
-
O
H
COO-
CuCr2O4
R
R
H
H
R
O
H
[Bmim]I-
H
H
H+
H
COOH
R
H
A-D
R =
Me
MeO
Cl
Scheme 3 Plausible mechanism for carbene stabilization and cyclopropanation by [Bmim]OH/CuCr2O4
13CNMR (100 MHz, CDCl3) d(ppm): 19.3, 27.1, 32.5, 125.2, 127.8, 129.3, 142.3;
IR (KBr) m (cm-1): 695, 745, 917, 964, 1020, 1107, 1465, 1495, 1555, 2876, 3049,
3400; Rf = 0.60 (methanol:ammonia: 9:1).
ꢀ
The best results were obtained using (E)-3-(4-methoxyphenyl)acrylic acid as
starting material (Table 2, entry 3) which indicates that the electron-donating
groups such as a methoxy group (–OMe) stabilized the transition state (Scheme 3).
Mechanistic aspects
The hydrogen bond has an important role in both the structure of [Bmim]OH and the
carbene structure. The imidazolium cation in IL acts as a powerful hydrogen-bond
donor, and the anion can acts as an acceptor [30]. The carbene produced by the
impact hydroxide ions to iodoform generally possess high basicities, which makes it
very strong hydrogen-bond acceptor (Scheme 3).
According to the donor–acceptor properties, a hydrogen bond between 1-butyl-3-
methylimidazolium cation and the carbene was observed. A polar interaction
between the iodide anions and carbene also helps to stabilize the complex formed.
123

The synergistic effect of copper chromite spinel…
Due to the relatively strong hydrogen bond and the polar interaction, the
complexes (Scheme 3, ILSC) which have been formed in this way are low-energy
intermediates. So, the formation of the ionic liquid stabilized thr carbene ILSC, and
subsequently the product is preferred. As a result, using this catalyst, the reaction
efficiency and product yield are increased (Table 2, entries 6–13). The best results
were achieved when a polar aprotic solvent such as THF was used (Table 2, entry
12). It seems that the polar aprotic solvent helps the substrate dissolution and the
intermediate ILSC stabilization through the polar–polar intermolecular interactions.
Indeed, the reaction products can be recovered from the organic phase, while the
catalyst remains immobilized in the ionic liquid phase. Therefore, this strategy has a
good potential for catalyst immobilization and to prevent transition metal leakage
into the products.
As mentioned in the ‘‘Introduction’’, the cyclopropanation step is the predom-
inant challenge in tranylcypromine total synthesis. This could be due to a number of
reasons: first, due to angle strain in small-size cycloalkanes, the cyclopropanation
reaction is performed under harsh conditions. Second, because of the chirality of the
resulting composition, this cyclopropanation reaction is diastereoselective. Consid-
ering that there are two stereogenic centers in 2-phenylcyclopropanecarboxylic acid
A, the key intermediate, there is the possibility of the formation of four
stereoisomers. The application of styrene and ethyl diazoacetate as raw materials
leads to the formation of a mixture of ( )-cis and ( )-trans stereoisomers. The most
important step during the synthesis of tranylcypromine sulfate is the cyclopropa-
nation of styrene, so that trans isomers can only be generated in a diastereoselective
manner. On the other hand, the complete separation of stereoisomers involves the
addition of several purification steps, thereby reducing the overall yield of the final
product. However, the single trans isomer lacks some side effects that the racemate
exhibits, and ( )-trans isomers have been already approved as racemates in
pharmaceutical formulations [31]. So, there is no need to further separate the
racemic mixture of the ( )-trans isomers.
Reusability of catalyst
The reusability performance of a catalytic system was investigated in the
cyclopropanation reaction. After completion of the reaction and work-up of the
products, the aqueous phase incorporating the basic ionic liquid and copper
chromite spinel nanoparticles was concentrated under vacuum and recycled for
subsequent reactions without further purification. The catalytic system was reused
for 5 reactions along with a gradual decrease in activity (Fig. 3). Although there is a
possibility of catalyst leakage into the organic phase, due to the relatively strong
interactions between the polar ionic liquid and the copper chromite spinel
nanoparticles, the leakage is minimal. As a consequence, the catalytic performance
remains almost constant without any remarkable reduction in activity for the
subsequent reactions (93, 90, 88, 85 and 84 % for the 1st, 2nd, 3rd, 4th and 5th runs,
respectively).
123

M. H. Ghasemi, E. Kowsari
Fig. 3 Recyclability of the catalytic system for the cyclopropanation reaction of trans-cinnamic acid
with iodoform
Conclusion
In conclusion, this method for the synthesis of ( )-trans-2-phenylcyclopropanecar-
boxylic acid A as a key intermediate for tranylcypromine sulfate synthesis is, as
reported in this paper, an efficient procedure with clean work-up. This method is a
useful alternative to other methods described in the literature: the number of overall
steps was reduced; commercially available chemicals were used; the heterogeneous
catalytic system was easy separable; and environmental hazards were decreased
with no need for the separation of the stereoisomers. These advantages of this
approach, along with the increased overall yield, make it a suitable choice to
produce tranylcypromine sulfate on an increased scale.
Acknowledgments The authors wish to gratefully thank the Research Affairs Division at Amir Kabir
University of Technology (AUT), Tehran, for financial support and the TEMAD Pharmaceutical Co. for
financial supports.
References
1. H. Weingartner, Angew. Chem. Int. Ed. 47, 654 (2008)
2. V.I. Parvulescu, C. Hardacre, Chem. Rev. 107, 2615 (2007)
3. V. Plechkova, K.R. Seddon, Chem. Soc. Rev. 37, 123 (2008)
4. D. Zhao, M. Wu, Y. Kou, E. Min, Catal. Today 74, 157 (2002)
5. H. Olivier-Bourbigou, L. Magna, J. Mol. Catal. A 182, 419 (2002)
6. A. Riisager, R. Fehrmann, M. Haumann, P. Wasserscheid, Top. Catal. 40, 91 (2006)
7. C.P. Mehnert, Chem. Eur. J. 11, 50 (2005)
8. J.S. Wilkes, J. Mol. Catal. A: Chem. 214, 11 (2004)
9. A. Riisager, R. Fehrmann, S. Flicker, R.V. Hal, M. Haumann, P. Wasserscheid, Angew. Chem. Int.
Ed. 44, 815 (2005)
10. B. Meenatchi, V. Renuga, A. Manikandan, J. Inorg. Organomet. Polym. Mater. 26, 423 (2016)
11. B. Meenatchi, V. Renuga, A. Manikandan, Korean J. Chem. Eng. 33, 934 (2016)
123

The synergistic effect of copper chromite spinel…
12. S. Roy, J. Ghose, Mater. Res. Bull. 34, 1179 (1999)
13. A. Manikandan, R. Sridhar, S.A. Antony, S. Ramakrishna, J. Mol. Struct. 1076, 188 (2014)
14. A. Manikandan, M. Durka, S.A. Antony, J. Supercond. Nov. Magn. 28, 209 (2015)
15. A. Manikandan, M. Durka, S.A. Antony, J. Inorg. Organomet. Polym. Mater. 25, 1019 (2015)
16. A. Manikandan, M. Durka, S.A. Antony, J. Supercond. Nov. Magn. 27, 2841 (2014)
17. A. Manikandan, E. Hema, M. Durka, K. Seevakan, T. Alagesan, S.A. Antony, J. Supercond. Nov.
Magn. 28, 1783 (2015)
18. A. Manikandan, M. Durka, S.A. Antony, J. Supercond. Nov. Magn. 28, 2047 (2015)
19. P.S. Sathiskumar, C.R. Thomas, G. Madras, Ind. Eng. Chem. Res. 51, 10108 (2012)
20. I. Arai, A. Mori, H. Yamamoto, J. Am. Chem. Soc. 107, 8254 (1985)
21. J. Vallgarda, U. Appelberg, L.E. Arvidsson, S. Hjorth, B.E. Svensson, U. Hacksell, J. Med. Chem. 39,
1485 (1996)
22. H. Abe, Y. Kazuta, A. Matsuda, S. Shuto, K. Yamaguchi, J. Org. Chem. 68, 9255 (2003)
23. D.J. Gorin, M.J. Johansson, S.T. Staben, F.D. Toste, J. Am. Chem. Soc. 127, 18002 (2005)
24. S.J. Cho, N.H. Jensen, T. Kurome, S. Kadari, M.L. Manzano, J.E. Malberg, B. Caldarone, B.L. Roth,
A.P. Kozikowski, J. Med. Chem. 52, 1885 (2009)
25. K. Cheng, A.E. Jacobson, K.C. Rice, Y.S. Lee, R.W. Bittman, C.M. Dersch, R.B. Rothman, J. Med.
Chem. 54, 957 (2011)
26. S. Yonezawa, K. Higashino, Y. Tanaka, T. Nakano, T. Yamamoto, H. Yamakawa, C. Muto, M.
Hosono, K. Hattori, T. Yutsudo, M. Sakagami, H. Takemoto, H. Iwamoto, Y. Kondo, H. Togame, M.
Arisawa, S. Shuto, J. Med. Chem. 55, 8838 (2012)
27. S.S. Acharyya, S. Ghosh, R. Bal, Ind. Eng. Chem. Res. 53, 20056 (2014)
28. I. Yavari, E. Kowsari, Synlett 6, 897 (2008)
´
´
29. J.M. Concellon, H. Rodrıguez-Solla, C. Simal, Org. Lett. 9, 2685 (2007)
30. M. Thomas, M. Brehm, O. Holloczki, B. Kirchner, Chem. Eur. J. 20, 1622 (2014)
31. R. Csuk, M.J. Schabel, Y.V. Scholz, Tetrahedron Asymmetry 7, 3505 (1996)
123