One-pot synthesis of novel (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl) pyrrolidine-2-carboxamides via TiO 2 -NPs and Pd(PPh3)2Cl2 catalysts and investigation of their biological activities

Article abstract of DOI:10.1007/s11030-017-9726-y

Abstract: A new class of (2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide compounds was synthesized by a facile one-pot reaction of trans-4-hydroxy proline and trifluoroacetimidoyl chlorides in the presence of TiO ₂-n

Full text of DOI:10.1007/s11030-017-9726-y

Mol Divers
DOI 10.1007/s11030-017-9726-y
ORIGINAL ARTICLE
One-pot synthesis of novel
(2R,4S)-N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl)
pyrrolidine-2-carboxamides via TiO2-NPs and Pd(PPh3)2Cl2
catalysts and investigation of their biological activities
Ali Darehkordi1 · Mahin Ramezani1
Received: 18 July 2016 / Accepted: 16 January 2017
© Springer International Publishing Switzerland 2017
Abstract A new class of (2R,4S)-N-aryl-4-hydroxy-
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamidecompou-
nds was synthesized by a facile one-pot reaction of trans-
4-hydroxy proline and trifluoroacetimidoyl chlorides in the
presence of TiO2-nanoparticles as a catalyst and sodium
bicarbonate as a base. Synthesized compounds showed
cytotoxicity with IC50 values of 15.3–70.3μM against
K562 (Homo sapiens, human) cells. The results of the
study provide a valuable method for one-pot synthesis of
trans-4-hydroxy proline-based N-(2,2,2-trifluoroacetylated)
compounds. Also, these compounds show significant phar-
maceutical activities as antibacterial and antifungal reagents.
Introduction
N-heterocyclic compounds play an important role in medic-
inal chemistry and especially in drug synthesis [1]. N-
heterocyclic compounds can be used as additives and mod-
ifiers in a wide variety of industries including cosmetics,
reprography, information storage, plastics, solvents, antiox-
idants, and vulcanization accelerators are other important
practical applications of these compounds [2].
Proline derivatives have been used in biologically active
compounds both in nature and in synthetic chemistry. Pyrro-
lidine compounds with either an alcohol or amine at the
4-position have been shown as an antiviral drug in the fight
against influenza [3]. Trans-4-hydroxyproline is a very stere-
ochemically rich compound that offers multiple sites of
functionality. This functionality can be used to attach to
different pharmacophores in an attempt to create various
libraries of compounds for further medical and biological
research.
Graphical Abstract
Among N-containing heterocycles with proline based,
Captopril and Enalapril (Fig. 1) attracted attention because
of their wide pharmaceutical activity range acting as ACE
inhibitors [4].
Keywords TiO2-nanoparticles ·
Bis(triphenylphosphine)palladium(II)dichloride · K562
(Homo sapiens, human) cells · Pharmaceutical
It was considered that the fluorine atoms or fluorinated
compounds play a pivotal role in bioactive compounds, for
which they provide an avenue for further structural elabora-
tion [5–8]. Fluorine is an element of great importance in
medicinal and organic chemistry, because it gives unique
properties to the organic molecules in which it is incorpo-
rated, altering their physicochemical and biological prop-
erties. Particularly, the trifluoromethyl group (CF3) is one
of the most common fluorinated substituents in medicinal,
agricultural, and material sciences [8] because it offers simul-
taneously high lipophilicity, an elevated electron density and
a steric demand similar to that of the isopropyl group [9].
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-017-9726-y) contains supplementary
material, which is available to authorized users.
Ali Darehkordi
darehkordi@vru.ac.ir; adarehkordi@yahoo.com
B
1
Department of Chemistry, Faculty of Science, Vali-e-Asr
University of Rafsanjan, Rafsanjan 77176, Iran
123

Mol Divers
Fig. 1 N-containing
heterocycles with a proline core
In recent years, metal oxide nanoparticles have attracted
attention due to their potential application in different fields
such as catalysis, magnetic recording media, microelectron-
ics, and medicine. Their small size and large specific surface
area allow for certain unique and unusual physicochemi-
cal properties [10–15]. Among these catalysts, TiO2 (NPs)
was introduced as an alternative support material for het-
erogeneous catalysts due to the effect of its high surface
area stabilizing the catalysts in its mesoporous structure
[16,17].
Scheme 1 Imidoyl chloride derivatives
Our interest in fluorine chemistry and trifluoroacetimidoyl
chloride reactions, and our attempt to synthesize bioactive
organofluorine compounds led us to consider the reac-
tion of trans-4-hydroxy proline with trifluoroacetimidoyl
chlorides for the formation of (2R,4S)-N-aryl-4-hydroxy-1-
(2,2,2-trifluoroacetyl) pyrrolidine-2-carboxamides. As such,
in the present paper, an attempt is made to describe a one-
pot synthesis of N-aryl-4-hydroxy-1-(2,2,2-trifluoroacetyl)
pyrrolidine-2-carboxamide compounds to display a range of
biological activities.
useful fluorinated organic compounds. It should be noted
that in the present investigation, the used trifluoroacetimi-
doyl chlorides were prepared in high yield through refluxing
a mixture of trifluoroacetic acid (TFA), amines, PPh3, and
Et3N in CCl4 in a one-pot manner [22–25].
As an initial endeavor, a trial reaction was performed with
1mmol of 2,2,2-trifluoro-N-(2-(trifluoromethyl) phenyl)
acetimidoyl chloride (1c), 1mmol of trans-4-hydroxy pro-
line (2) in acetonitrile or THF as a solvent in the presence
of sodium hydride (NaH) as a base at room temperature
or under reflux conditions. The reaction was kept 18 h
at room temperature and then 12 h under reflux condi-
tions. No products were obtained finding that only 2,2,2-
trifluoro-N-(2-(trifluoromethyl)phenyl)acetimidoyl chloride
was hydrolyzed to 2,2,2-trifluoro-N-(2-(trifluoromethyl)
phenyl)acetamide [24] (Table 1; Scheme 2, entries 1–
4). Therefore, this reaction was repeated with 1mmol
of 2,2,2-trifluoro-N-(2-(trifluoromethyl)phenyl)acetimidoyl
chloride (1c), 1mmol of trans-4-hydroxy proline (2) in
THF as a solvent in the presence of potassium carbonate
(K2CO3) as a base and in the presence of 10 mol% of
Results and discussion
Chemistry
One of the most interesting interdisciplinary topics in chem-
istry is the application of transition metals in organic syn-
thesis. There have been various reactions which would have
been impossible to be achieved by conventional synthetic
methods. However, thesereactionscanbecatalyzedbytransi-
tion metals to afford final products easily. More importantly,
organopalladium chemistry is said to be playing an important
role in organic synthesis [18].
Furthermore, TiO2 nanoparticles (TNPs) have received
special interest due to their multiple potential applications,
which are widespread in industry, chemistry and medicine.
TiO2-NPs has been proved to be a good catalyst in organic
chemistry. Due to its non-toxicity, high activity, easy avail-
ability, reusability, strong oxidizing power, long-term stabil-
ity and Lewis acidity [19–21].
bis(triphenylphosphine)palladium(II)
dichloride
((Pd
(PPh3)2Cl2)) as a catalyst. After 12 h, a precipitate (3c) was
separated out and purified, which was characterized by spec-
troscopic techniques and was found to be (2R,4S)-N-aryl-4-
hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide
derivative (Table 1, entry 5).
2,2,2-Trifluoro-N-(2-(trifluoromethyl)phenyl)acetimidoyl
chloride 1c was chosen as a reprehensive substrate, and opti-
mization studies of catalyst source, solvent, and temperature
were taken (Table 1). The reaction of 1c with trans-4-hydroxy
proline (2) using different catalysts and solvents with various
bases, including K2CO3, NaH, and NaHCO3 at room tem-
Imidoyl chloride 1 (Scheme 1) is composed of three active
functional groups (halogens, C=N double bond, CF3, and N-
aromatic ring) which can be used for the syntheses of new
123

Mol Divers
Table 1 Optimization of the reaction conditions for the formation of 3c from 2 and 1c
Entry
Base
Catalyst
mol%
Solvent
Condition
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
NaH
–
CH3CN
THF
r.t.
18
18
12
12
12
12
12
12
18
12
0
0
NaH
–
r.t.
K2CO3
K2CO3
K2CO3
NaH
–
CH3CN
THF
Reflux
Reflux
r.t.
0
–
0
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
CuI
10
10
10
5
THF
20
20
72
68
0
THF
r.t.
NaHCO3
NaHCO3
NaHCO3
NaHCO3
THF-H2O
THF-H2O
THF
r.t.
r.t.
5
r.t.
CuI
10
THF
Reflux
0
The reaction was carried out with 1a (1mmol) and 2a (1mmol) in the presence of an catalyst (% mol) in solvent (10 mL). b Isolated yield
Scheme 2 Conditions reaction
for Hydrolyze 1c and 1d
perature or under reflux condition were investigated. Over
70% conversion of 1c to 3c (as analyzed by 1H NMR) was
observed with Pd(PPh3)2Cl2 (5 and 10 mol %), NaHCO3,
and THF-H2O being superior (Table 1, entries 7 and 8).
NaHCO3, Pd(PPh3)2Cl2 (10 mol%), and THF-H2O led to
higher conversion at room temperature for 12 h (Table 1,
entry 7). The use of Pd(PPh3)2Cl2 as a catalyst and K2CO3
or NaH, as a base in THF led to low conversion (Table 1,
entries 5 and 6). The use of K2CO3, NaH in CH3CN as a
solvent without a catalyst, and also CuI (10 and 5 mol%) and
NaHCO3 in THF-H2O at room temperature or reflux for 12–
18h resulted in hydrolyzed product [26] (Scheme 2) (Table 1,
entries 1–4, 9 and 10).
Although the fact that bis(triphenylphosphine)palladium
(II) dichloride ((Pd(PPh3)2Cl2)) is a good catalyst in this
reaction, it does not seem to be ideal due to its price and
relatively high catalyst loading.
It has been reported in the literature that copper (I) has
been used as a catalyst in C–C and C–N bond formation
[27,28]. Accordingly, copper (I) was selected because it
is an inexpensive and fairly available catalyst to perform
this reaction. Unfortunately, using CuI failed to yield par-
tial conversion to the desired product (Table 1, entries 9,
10). In a pilot experiment, the reaction of 2,2,2-trifluoro-
N-(2-(trifluoromethyl)phenyl)acetimidoyl chloride 1c with
(2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid 2 in the
presence of Pd(PPh3)2Cl2 in H2O-THF was investigated.
This reaction afforded (2R, 4S)-4-hydroxy-1-(2,2,2-
trifluoroacetyl)-N-(2-(trifluoromethyl)phenyl)pyrrolidine-2-
carboxamide 3c in 72% yield after 12 h (Table 1, entry
9).
Reactions of 2,2,2-trifluoro-N-(3-(trifluoromethyl)phe-
nyl) acetimidoyl chloride (1d) or 2,2,2-trifluoro-N-(2-
(trifluoromethyl)phenyl)acetimidoyl chloride (1c) with
(2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid 2 were
selected as a model reactions, and they were treated with
several different TiO2 sources to obtain the optimal reaction
conditions. The desired products were readily prepared in
123

Mol Divers
Table 2 Optimization of the TiO2-NPs coupling conditions
Entry
Compounds
TiO2-NPS (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
1c
1c
1d
1d
5
10
5
H2O
12
12
8
0
0
H2O
THF-H2O
THF-H2O
70
78
10
8
The reaction was carried out with 1a (1mmol) and 2 (1mmol) in the presence of an catalyst (mol% ) in solvent (10 mL). b Isolated yield
excellent yield from the reaction of 1c and 1d in the presence
of sodium bicarbonate in THF-H2O at room temperature.
As expected, TiO2-NPs showed good catalyst properties
in organic synthesis. Therefore, it was decided TiO2-NPs
to be used as a catalyst in this reaction. The application of
TiO2-NPs as a catalyst for the reaction of 2,2,2-trifluoro-
N-(3-(trifluoromethyl)phenyl)acetimidoyl chloride 1d was,
accordingly, investigated. WhenTiO2 (10mol%)wasusedas
a catalyst in H2O, the resulted yield was very low. In this case,
the2,2,2-trifluoro-N-(3-(trifluoromethyl)phenyl)acetimidoyl
chloride 1d was hydrolyzed to 2,2,2-trifluoro-N-
phenylacetamide [26] (Scheme 2). The use of TiO2 (10 mol
%) led to higher conversion than TiO2 (5 mol %) in THF-H2O
(Table 2, entries 3, 4).
It should be noted that the reaction was subsequently car-
ried out in the presence of TiO2-NPs as a catalyst under the
same reaction conditions. TiO2-NPs showed partially more
efficient catalytic properties than Pd(PPh3)2Cl2, causing to
increase reaction yields and decreasing the reaction time
(Table 1, entry 8). Therefore, TiO2-NPs we selected as a
catalyst for all reactions. The results of these reactions are
shown in Table 3. Eventually, the reusability of this catalyst
was also investigated. For the reaction of 2,2,2-trifluoro-
N-(3-(trifluoromethyl)phenyl)acetimidoyl chloride 1d with
(2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid 2, the cata-
lyst was recovered by filtration after separating two phases
with H2O and ethyl acetate and dried in the oven (70 ◦C, 6
h).
erates the cyclic intermediate 6-hydroxy-3-(arylamino)-3-
(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
(A) which undergoes a Mumm-type rearrangement to give
the4-hydroxy-N-aryl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-
carboxamide 3a (Scheme 3).
Crystal structure of 3a
Eventually confirmation of the reaction was done through
obtaining crystal structure of (2R,4S)-N-aryl-4-hydroxy-1-
(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamides3a(Fig. 2)
as a model. Suitable crystals for X-ray data analysis were
obtained by crystallization from ethanol.
In order to verify the scope and generality of such a
reaction, under the optimized conditions various trifluo-
roacetimidoyl chlorides were reacted with trans-4-hydroxy
proline to generate the desired (2R,4S)-N-aryl-4-hydroxy-1-
(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamides (Table 3).
Trifluoroacetimidoyl chlorides with electron-withdrawing
groups as 2,4-di-F (1a), 3-Cl-4-F (1b), 2-CF3 (1c), 2-CF3
(1d), 4-NO2 (1e), 2,5-di-F (1f), 4-Cl (1g) 2-Br-4-Cl (1h),
3-NO2-4-F (1i) and 3,5-di-CF3 (1j) procured good yields
(Table 3). It should be mentioned that no desired product was
obtained when a similar reaction was performed with com-
pounds containing electron-donating functionalities N-(2,4-
dimethylphenyl)-2,2,2-trifluoroacetimidoyl chloride (1l),
2,2,2-trifluoro-N-(p-tolyl)acetimidoyl chloride (1m) and
2,2,2-trifluoro-N-(2,4,6-tribromophenyl)acetimidoyl chlor-
ide (1k) (Table 3, entries 11–13). The first step (attack of
–NH– group of proline to imidoyl chloride) is suggested to be
very important. Therefore, the electron-withdrawing groups
on the imidoyl chloride increase the reaction rate and the
electron-donating groups on the imidoyl chloride decrease
the reaction rate. In the latter conditions, the speed of hydrol-
ysis is much faster than the attack of l-proline to the imidoyl
The reaction is assumed to be proceeding via the initial
activation of imidoyl by TiO2-nanoparticles or
bis(triphenylphosphine)palladium(II) dichloride to the for-
mation of TiO2- or pd-imidoyl complex. Then, this activated
intermediate is attacked by the nitrogen nucleophilic group
of l-proline to replace the chlorine atom by nitrogen. Subse-
quent attack of the carboxylate anion on the imino group gen-
123

Mol Divers
Table 3 Scope of the reaction with 2,2,2-trifluoro-N-phenylacetimidoyl chloride derivatives (1a–m)
–
–
Entry
1
Substrate
Products
Yieldsa (%)
93
1a
2
3
4
5
1b
1c
1d
1e
70
78
77
73
6
7
8
1f
1g
1h
92
83
87
9
1i
1j
77
70
10
11
12
13
1k
1l
N.R
N.R
N.R
0
0
0
1m
The reaction was carried out with 1 (1mmol) and 2 (1mmol) in the presence of an catalyst TiO2-NPs (10mol%) in THF-H2O (10mL) at r.t. for 8
h. a Isolated yield. Determined by NMR, also X-ray crystal data of 3a
123

Mol Divers
Scheme 3 A plausible reaction pathway
Table 4 IC50 values (μM) of compounds 3a–3j against human cancer
cell line using the MTT assay
Compounds
K562 cell line
24 h
48 h
72 h
3a
8.5
6.3
10.8
11.8
−
12.2
5.3
19.6
22.3
47.5
23.4
45.4
32.4
15.3
70.3
42.1
7.3
3c
3d
15.2
20.1
29.3
50.2
12.6
6.1
3e
3f
3g
−
3h
10
3i
25.7
22.8
−
3j
11.6
2.9
MPK-09
Biology
Fig. 2 Crystal structure of 3a (CCDC 1051505)
Assessment of MTT assay and IC50
The MTT assay is a colorimetric assay for assessing cell
metabolic activity [34]. The MTT was performed for all the
compounds to show the effects. The synthesized compounds
and reference compound MPK-09 mostly showed cytotoxic
activity on K562 (Homo sapiens, human) cells with fol-
lowing IC50 values (listed in Table 4). The cytotoxic and
activity observed for all the compounds depends on concen-
tration. While a viability more than of 50% was observed
for this compound, the concentration of less than 250 μM
was effective on K562 cells. This suggests that compounds
as noticeable factors lead the molecules for cytotoxic activity
against tumor cells (Table 4).
because of the steric effect inhibiting the reaction of 2,4,6-
dibromo imidoyl with l-proline. Although there are several
reports for synthesis of 1-(2,2,2-trifluoroacetyl)pyrrolidine-
2-carboxylic acid(N-trifluoroacetylationo l-proline) using
trifluoroacetic anhydride in the literature, the yields of these
methods are not high enough (<50%) [29,30]. Further-
more, to the best of our knowledge, no reports have been
published for the synthesis of (2R,4S)-4-hydroxy-N-aryl-1-
(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamides in the lit-
erature so far. Moreover, since direct transfer of –COOH
group of l-proline to amide with the use of amine is not
straight forward, this transformation should be carried out in
two or more steps [31–33].
Compounds 3a, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j exhibited
cytotoxic activity on LS174Tcells with IC50 value, as shown
in the diagram (Fig. 3)
123

Mol Divers
Fig. 3 Summary of IC 50 data
from cytotoxicity assays 3a–3j
Examine of the antibacterial and antifungal activity
strains such as Staphylococcus aureus, Escherichia coli,
Pseudomonas aeruginosa, and fungi, including Aspergillus
niger, Penicillium chrysogenum underwent antibacterial and
antifungal assessments. In vitro antimicrobial, examinations
were carried out through employing agar in well-diffused
method against test organisms. Data shown Table 5 are sup-
porting the fact (Table 5, see supporting data).
The synthesized compounds 3a–i were screened for more
antibacterial activities at three various concentrations of 25,
50 and 100 μg/ml. The antibacterial effects of these com-
pounds are presented in Table 5 (see supporting data). All
the tested compounds exhibited more activity toward Gram-
positive bacteria than Gram-negatives. All the examined
compounds inhibited the spore germination against tested
fungi. Generally, the compounds mostly displayed slightly
higher antifungal activity toward Penicillium chrysogenum
than Aspergillus niger. The most antimicrobial activity is
related to 3h with 3e and 3d coming second and third respec-
tively.
The compound 3h displayed adequate levels of activity in
particular against P. chrysogenum equivalent to the standard
blank 100 μg/well, and 3e and 3d are the 2nd and 3rd respec-
tively(Table5, seesupportingdata). Theminimuminhibitory
(MIC), minimum antibacterial (MBC) and minimum anti-
fungal concentration (MFC) of the compounds determined
are listed in Table 6 (see supporting data). The MBC value is
2×MIC in case of S. aureus and MFC value is 2×MIC in case
of P. chrysogenum. However, other compounds demonstrated
bactericidal and fungicidal effects greater than 2 × MIC.
A variety of 3 displayed greatest antimicrobial activity.
This compoundwas apotentantimicrobialagent, particularly
against S. aureus (27mm, MIC 12.5 μg/ml) and P. chryso-
genum (30mm, MIC 12.6 μg/ml) (Table 7, see supporting
data).
Conclusion
In summary, the proline scaffold has already been shown
to be a bioactive small organic molecule in nature and in
pharmacology. In this study, a mild, efficient and one-pot
approach was described for the synthesis of (2R,4S)-N-aryl-
4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxam-
ides via the TiO2-nanoparticle-catalyzed reaction of trans-
4-hydroxy proline with trifluoroacetimidoyl chlorides. Our
TiO2-nanoparticle-catalyzed reaction is simple with the reac-
tion proceeding smoothly from good to excellent yields.
The present investigation includes the modification of the
1- and 2-position of trans-4-hydroxy proline in one-pot. The
combination of these two strategies can potentially lead to
hundreds of small novel molecules that can be tested for
biological activity and further aid drug design. The results of
this study provide a valuable method for one-pot synthesis of
trans-4-hydroxy proline-based N-(2,2,2-trifluoroacetylated)
compounds with using of TiO2-nanoparticles as a cheap
cost, non-toxicity and chemical stability catalyst. Also, the
antimicrobial and cytotoxic activities of the synthesized
compounds. Revealed that compound 3h displayed the best
antimicrobial and antifungal activity among the tested com-
pounds, which then could be applied to further studies for
potent novel board-spectrum antimicrobial agents. Further
studies on the biological activity of these compounds are in
progress in our laboratory.
Biological assays
Compounds 3a–3j were examined for their antimicrobial
activities at three various concentrations of 25, 50 and
100 μg/well. Compounds were dissolved in DMSO at dif-
ferent concentrations of 25, 50 and 100 μg/well. Bacterial
123

Mol Divers
Experimental section
(2R,4S)-N-(2,4-difluorophenyl)-4-hydroxy-1-(2,2,2-trifluo-
roacetyl)pyrrolidine-2-carboxamide (3a) Colorless solid
(314 mg, 93% yield): Mp 225–227 ◦C; IR (KBr, cm−1) 3497,
3281, 3053, 1685, 1615, 1539. 1H NMR (400 MHz, DMSO)
Material and instruments
All reactions were carried out under a nitrogen atmo-
sphere unless otherwise stated. Reactions were monitored
by thin layer chromatography (TLC). All of the NMR spec-
tra were recorded on a Bruker model DRX-300 AVANCE
(1H: 300, 13C: 75, F: 282MHz) and on a Bruker model
DRX-400 AVANCE (1H: 400, 13C: 100) NMR spectrom-
10.10 (s, 1H, NH), 7.82 (m,1H, Ar), 7.33 (m, 1H, Ar), 7.07
δ
(m, 1H, Ar), 5.35 (d, J = 2.8 Hz, 1H, 2-H), 4.78–4.82 (m,
1H, 4-H), 4.43 (br, 1H, OH), 3.63–2.76 (m, 2H, 5-H), 1.92–
2.29 (m, 2H, 3-H) ppm. 13C NMR (100 MHz, DMSO-d6)
169.17 (NHC=O), 159.84 (dd, J = 244.6, 11.9 Hz, C–F
δ
(para)), 154.64(q, J = 36.4, 0.2Hz, CF3–C=O), 153.14(dd,
J = 248.7, 11.9 Hz, C–F (orto)), 125.52 (d, J = 9.6 Hz,
C–Ar), 122.16 (dd, J = 11.9, 3.7 Hz, C–Ar), 115.93 (q,
J = 288.1 Hz, CF3–C=O), 111.08 (dd, J = 21.9, 3.5Hz,
C–Ar), 104.15 (dd, J = 26.6, 24.1Hz, C–Ar), 68.92, 60.07,
55.71, 37.19ppm. Anal. Calcd for C13H11F5N2O3: C, 46.16;
H, 3.28; N, 8.28. Found: C, 46.14; H, 3.24; N, 8.24%.
1
eter. Chemical shifts of H and 13C-NMR are reported in
parts per million (ppm) downfield from tetramethylsilane
(TMS) as an internal standard in DMSO-d6 or CDCl3 as
a solvent and 19F-NMR are reported in parts per million
(ppm) from CFCl3 as an internal standard in DMSO-d6
or CDCl3 as a solvent. Data are presented as follows:
chemical shift, integration, multiplicity (br=broad signal,
s=singlet, d=doublet, q=quartet, m=multiplet), and cou-
pling constant in Hertz (Hz). IR spectra were obtained on
a Matson-1000 FT-IR spectrometer. Optical rotation was
recorded on an Atago AP-300 polarimeter. Melting points
were determined on a Melt-Tem II melting point apparatus
and are uncorrected.
(2R,4S)-N-(3-chloro-4-fluorophenyl)-4-hydroxy-1-(2,2,2-
trifluoroacetyl)pyrrolidine-2-carboxamide (3b)
Bright brown solid (248 mg, 70% yield): Mp 180 dec; IR
(KBr, cm−1) 3491, 3273, 3057, 1670, 1603, 1545.1H NMR
(400 MHz, DMSO) 10.53 (s, 1H, NH), 7.92 (m, 1H, Ar),
δ
7.60 (m, 1H, Ar), 7.40 (m, 1H, Ar), 5.39 (m, 1H, 2-H), 4.60–
4.64 (m, 1H, 4-H), 4.44 (br, 1H, OH), 3.64–3.76 (m, 2H,
5-H), 1.95–2.27 (m, 2H, 3-H) ppm. 13C NMR (100 MHz,
DMSO-d ) 168.77(NHC=O), 154.61 (q, J = 43.9 Hz,
Preparation of nanoparticles
δ
6
CF3–C=O), 151.98 (dd, J = 240.1 Hz), C–F (para), 135.84
(d, J = 3.5 Hz, C–Ar), 120.48 (d, J = 8.4 Hz, C–Ar),
119.57 (d, J = 21.0 Hz, C–Cl), 117.03 (d, J = 21.9 Hz, C–
Ar), 115.38 (q, J = 288.2 Hz, CF3–C=O), 68.93, 60.49,
55.76, 37.10 ppm. Anal. Calcd for C13H11ClF4N2O3: C,
44.02; H, 3.13; N, 7.90. Found: C, 44.00; H, 3.10; N, 7.87%.
Titanium dioxide (TiO2) nanoparticle was prepared by
treatment of titanium dioxide (Merck) by microwave asso-
ciated method, according to the literature [35]. The TiO2-
nanoparticles then was isolated and characterized by X-ray
powder diffraction (XRD) and scanning electron microscope
(SEM).
(2R,4S)-4-hydroxy-1-(2,2,2-trifluoroacetyl)-N-(2-(trifluo-
romethyl)phenyl)pyrrolidine-2-carboxamide (3c)
General procedure for the synthesis of (2R,4S)-N-aryl-4-
hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxami-
des (3a–m) To a stirred solution of trans-4-hydroxy-l-
proline 2 (1.0mmol) in water (5 mL) was added sodium
bicarbonate (1.2mmol) and TiO2-nanoparticles (TNPs)
(10% mol). Then a solution of acetimidoyl chloride deriva-
tives 1 (1.0mmol) in THF (5mL) was added dropwise over
a period of 10 min. The mixture was stirred at room temper-
ature for 8 h. After the reaction was completed (monitored
by TLC); ethyl acetate (10 mL) was added. Then the organic
layer was separated, and aqueous layer was extracted with
ethyl acetate (2x10 mL). The aqueous layer is containing
TiO2 -NPs and therefore was separated by filtration. After
combination of organic layers, organic phase was dried over
MgSO4 and evaporated on a rotary evaporator to give the
crude product, which was purified by washing two times
with diethyl ether and n-hexane (two times) to give pure
products.
Bright brown solid (288 mg, 78% yield): Mp 210–212 ◦C; IR
(KBr, cm−1) 3509, 3272, 3021, 1672, 1589, 1541.1H NMR
(300 MHz, DMSO) 9.94 (s, 1H, NH), 7.66–7.75 (m, 2H,
δ
Ar), 7.40–7.49 (m, 2H, Ar), 5.35 (d, J = 3.2 Hz, 1H, 2-H),
4.74–4.79 (m, 1H, 4-H), 4.42 (br, 1H, OH), 3.60–3.75 (m,
2H, 5-H), 1.93–2.00 (m, 2H, 3-H) ppm. 13C NMR (100 MHz,
DMSO-d ) 169.68 (NHC=O), 158.54 (q, J = 31.5 Hz,
δ
6
CF3–C=O), 137.34 (q, J = 3.8 Hz, C–Ar), 130.19, 126.34,
125.75, 125.00 (q, J = 266.7 Hz), 121.41 (q, J = 30.5 Hz)
119.90, 115.72 (q, J = 268.1 Hz, CF3–C=O), 68.86, 59.94,
55.61, 36.90 ppm. 19F NMR (282 MHz, DMSO) −59.26,
δ
−71.41 ppm. Anal. Calcd for C14H12F6N2O3: C, 45.42; H,
3.27; N, 7.57. Found: C, 45.40; H, 3.24; N, 7.54%.
(2R,4S)-4-hydroxy-1-(2,2,2-trifluoroacetyl)-N-(3-(trifluo-
romethyl)phenyl)pyrrolidine-2-carboxamide (3d)
Colorless solid (285 mg, 77% yield): Mp 194–200 C; IR
(KBr, cm−1) 3503, 3284, 3059, 1676, 1618, 1541. 1H NMR
◦
123

Mol Divers
(400 MHz, DMSO) 10.96 (s, 1H, NH), 8.12 (s, 1H, Ar),
168.64 (NHC=O), 158.08 (q, J = 32.8 Hz, CF –C=O),
δ
δ
3
7.74 (d, J = 8.0 Hz, 1H, Ar), 7.58 (m, 1H, Ar), 7.74 (d,
J = 7.6 Hz, 1H, Ar), 5.42 (d, J = 2.4 Hz, 1H, 2-H), 4.64–
4.68 (m, 1H, 4-H), 4.45 (br, 1H, OH), 3.65–3.77 (m, 2H,
5-H), 1.97–2.29 (m, 2H, 3-H) ppm. 13C NMR (100 MHz,
DMSO-d ) 169.09 (NHC=O), 159.65 (d, J = 32.3 Hz,
135.25, 128.93 (2C, Ar), 128.67, 122.60 (2C, Ar), 114.58
(q, J = 285.7 Hz, CF3–C=O), 68.91, 60.52, 55.74, 37.12
ppm. Anal. Calcd for C13H12ClF3N2O3: C, 46.37; H, 3.59;
N, 8.32; Found: C, 46.30; H, 3.54; N, 8.27%.
δ
6
CF3–C=O), 139.38, 130.10, 129.80 (q, J = 32.1 Hz, C–
CF3), 125.36 (q, J = 282.3 Hz, Ar–CF3), 122.64, 119.90
(q, J = 4.3 Hz, CH–Ar), 115.43 (q, J = 287.6 Hz, CF3–
C=O), 68.94, 60.54, 55.76, 37.10 ppm. Anal. Calcd for
C14H12F6N2O3: C, 45.42; H, 3.27; N, 7.57. Found: C, 45.40;
H, 3.26; N, 7.55%.
(2R,4S)-N-(2-bromo-4-chlorophenyl)-4-hydroxy-1-(2,2,2-
trifluoroacetyl)pyrrolidine-2-carboxamide (3h) White solid
◦
25
◦
α
(360 mg, 87% yield): Mp 231–236 C; [ ]D = +1.0
(c 0.20, MeOH);IR (KBr, cm−1) 3491, 3274, 3027, 1682,
1584, 1572, 1526.1H NMR (400 MHz, DMSO) 9.95 (s,
δ
1H, NH), 7.83 (m, 1H, Ar), 7.53–7.55 (m, 1H, Ar), 7.46–
7.49 (m, 1H, Ar), 5.38 (d, J = 3.2 Hz, 1H, 2-H), 4.79 (m,
1H, 4-H), 4.45 (br, 1H, OH), 3.63–3.77 (m, 2H, 5-H), 2.00–
2.31 (m, 2H, 3-H) ppm. 13C NMR (100 MHz, DMSO-d6)
169.02 (NHC=O), 154.63 (q, J = 37.2 Hz, CF –C=O),
(2R,4S)-4-hydroxy-N-(4-nitrophenyl)-1-(2,2,2-trifluoroac-
etyl)pyrrolidine-2-carboxamide (3e) Brown solid (253 mg,
◦
25
◦
α
73% yield): Mp 250–255 C; [ ]D = +0.45 (c 0.10,
MeOH); IR (KBr, cm−1) 3497, 3283, 1681, 1614, 1597,
1555. H NMR (400 MHz, DMSO) 10.93 (s, 1H, NH),
δ
3
134.85, 131.88, 130.37, 128.34, 128.07, 118.75, 115.99 (q,
J = 287.7 Hz, CF3–C=O), 68.89, 60.08, 55.65, 37.09 ppm.
Anal. Calcd for C13H11BrClF3N2O3: C, 37.57; H, 2.67; N,
6.74; Found: C, 37.53; H, 2.62; N, 6.70%.
1
δ
8.24 (d, J = 9.2 Hz, 2H, Ar), 7.84 (d, J = 8.8 Hz, 2H,
Ar), 5.43 (d, J = 3.2 Hz, 1H, 2-H), 4.58–4.72 (m, 1H,
4-H), 4.46 (br, 1H, OH), 3.66–3.79 (m, 2H, 5-H), 1.98–
2.31 (m, 2H, 3-H) ppm. 13C NMR (100 MHz, DMSO-d6)
169.43(NHC=O), 154.68 (q, J = 36.4 Hz, CF –C=O),
δ
3
(2R,4S)-N-(4-fluoro-3-nitrophenyl)-4-hydroxy-1-(2,2,2-tri-
144.71, 142.41, 125.02, 118.93, 115.94 (q, J = 287.7 Hz,
CF3–C=O), 68.98, 60.63, 55.77, 37.06 ppm. Anal. Calcd
for C13H12F3N3O5: C, 44.96; H, 3.48; N, 12.10; Found: C,
44.93; H, 3.45; N, 12.12%.
fluoroacetyl)pyrrolidine-2-carboxamide (3i) Cream solid
◦
25
(281mg, 77% yield): Mp 201–205 C; [ ]D = +1.35◦ (c
α
0.10, MeOH); IR (KBr, cm−1) 3484, 3272, 3066, 1676, 1626,
1
1544, 1499. H NMR (400 MHz, DMSO) 10.90 (s, 1H,
δ
NH), 7.82–8.36 (m, 3H, Ar), 5.43 (m, 1H, H-2), 4.65 (m, 1H,
4-H), 4.46 (br, 1H, OH), 3.65–3.78 (m, 2H, 5-H), 2.04–2.31
(m, 2H, 3-H) ppm. 13C NMR (100MHz, DMSO-d ) 169.56
(NHC=O), 159.45 (d, J = 32.0 Hz, CF3–C=O), 150.95 (d,
J = 246.8 Hz, CF–Ar), 140.41, 135.66 (d, J = 21.0 Hz,
C–NO2–Ar), 121.15 (d, J = 8.0 Hz, C–Ar), 118.81 (d,
J = 21.0 Hz, C–Ar), 116.48 (d, J = 8.5 Hz, C–Ar), 115.27
(q, J = 285.0 Hz, CF3–C=O), 68.94, 60.61, 55.74, 37.00
ppm. Anal. Calcd for C13H11F4N3O5: C, 42.75; H, 3.04; N,
11.50; Found: C, 42.70; H, 3.00; N, 11.43%.
(2R,4S)-N-(2,5-difluorophenyl)-4-hydroxy-1-(2,2,2-trifluo-
roacetyl)pyrrolidine-2-carbo◦xamide (3f) White solid (310
δ
6
25
mg, 92% yield): Mp 168 C; [ ]D = +2.0◦ (c 0.10,
α
MeOH); IR (KBr, cm−1) 3494, 3280, 3060, 1678, 1631,
1541.1H NMR (400 MHz, DMSO) 10.34 (s, 1H, NH), 7.89
δ
(m, 1H, Ar), 7.35 (m, 1H, Ar), 7.00 (m, 1H, Ar), 5.38 (br, 1H,
2-H), 4.89 (m, 1H, 4-H), 4.44 (br, 1H, OH), 3.64–3.73 (m,
2H, 5-H), 1.96–2.30 (m, 2H, 3-H) ppm. 13C NMR (100 MHz,
DMSO-d ) 169.57 (NHC=O), 159.09 (d, J = 35.7 Hz,
δ
6
CF3–C=O), 157.75 (d, J = 238.8 Hz, C–F (meta)), 149.08
(d, J = 242.2 Hz, C–F (orto)), 126.99 (d, J = 25.0 Hz,
C–Ar), 116.43 (dd, J = 21.9, 10.0 Hz, C–Ar), 115.98 (q,
J = 287.7 Hz, CF3–C=O), 110.93 (dd, J = 24.5, 8.3 Hz,
C–Ar), 109.48 (dd, J = 29.8, 11.6 Hz, C–Ar), 68.95, 60.15,
55.72, 37.13 ppm. Anal. Calcd for C13H11F5N2O3: C, 46.16;
H, 3.28; N, 8.28; Found: C, 46.11; H, 3.23; N, 8.21%.
(2R,4S)-N-(3,5-bis(trifluoromethyl)phenyl)-4-hydroxy-1-(2,
2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (3j) Pink so-
◦
25
lid (306 mg, 70% yield): Mp 250 C; [ ]D = +0.81◦ (c
α
0.10, MeOH); IR (KBr, cm−1) 3490, 3277, 3089, 1675, 1556,
1474. H NMR (400 MHz, DMSO) 10.80 (s, 1H, NH),
1
δ
8.53–8.54 (m, 1H, Ar), 7.84–7.86 (m, 1H, Ar), 7.55–7.60
(m, 1H, Ar), 5.42 (d, J = 3.6 Hz, 1H, H-2), 4.64 (m, 1H,
4-H), 4.46 (br, 1H, OH), 3.65–3.78 (m, 2H, 5-H), 1.98–2.30
(m, 2H, 3-H)ppm. 13C NMR(100MHz, DMSO-d ) 169.10
(NHC=O), 158.54 (q, J = 31.5 Hz, CF3–C=O), 137.96 (d,
J = 1.9 Hz), 132.65, 123.56, 123.50 (q, J = 268.1 Hz,
CF3), 116.89, 115.37 (q, J = 268.0 Hz, CF3–C=O), 68.94,
60.52, 55.75, 37.07 ppm. Anal. Calcd for C15H11F9N2O3: C,
41.11; H, 2.53; N, 6.39; Found: C, 41.08; H, 2.50; N, 6.35%.
(2R,4S)-N-(4-chlorophenyl)-4-hydroxy-1-(2,2,2-trifluoroa-
cetyl)pyrrolidine-2-car◦boxamide (3g) Cream solid (279 mg,
25
83% yield): Mp 86–90 C; [ ]D = +3.52◦ (c 0.20, MeOH);
α
δ
6
IR (KBr, cm−1) 3492, 3298, 30148, 1680, 1615, 1535.
1H NMR (400 MHz, DMSO) 10.44 (s, 1H, NH), 7.37–
δ
7.73 (m, 4H, Ar), 5.63 (d, J = 4.8Hz, 1H, 2-H), 4.64 (m,
1H, 4-H), 4.44 (br, 1H, OH), 3.64–3.76 (m, 2H, 5-H), 1.99–
2.01 (m, 2H, 3-H) ppm. 13C NMR (100 MHz, DMSO-d6)
123

Mol Divers
Supporting information
15. Yamazaki S (1996) Selective synthesis of sulfoxides and sul-
fones by methyltrioxorhenium-catalyzed oxidation of sulfides with
hydrogen peroxide. Bull Chem Soc Jpn 69:2955–2959. doi:10.
1246/bcsj.69.2955
16. Cong P, Doolen RD, Fan Q, Giaquinta DM, Guan S, McFar-
land EW, Poojary DM, Self K, Turner HW, Weinberg WH (1999)
High-throughput synthesis and screening of combinatorial hetero-
geneous catalyst libraries. Angew Chem 38:484–488. doi:10.1002/
(SICI)1521-3773
Experimental procedures and compound characterization
data for all new compounds.
Acknowledgements This work has been supported by the Vail-e-Asr
University of Rafsanjan Faculty Research Grant.
17. Uysal B, Oksal BS (2015) New heterogeneous B(OEt)3-MCM-41
catalyst for preparation of α, β-unsaturated alcohols. Res Chem
Intermediat 41:3893–3911. doi:10.1007/s11164-013-1498-0
18. Amii H, Kageyama K, Kishikawa Y, Hosokawa T, Morioka R,
Katagiri T, Uneyama K (2012) Preparation, structure, and reactions
of trifluoroacetimidoyl palladium (II) complexes. Organometallics
31:1281–1286. doi:10.1021/om201021b
References
1. Martins MAP, Frizzo CP, Moreira DN, Buriol L, Machado P (2009)
Solvent-free heterocyclic synthesis. Chem Rev 109:4140–4182.
doi:10.1021/cr9001098
19. Yamazaki S (1996) Selective synthesis of sulfoxides and sul-
fones by methyltrioxorhenium-catalyzed oxidation of sulfides with
hydrogen peroxide. Bull Chem Soc Jpn 69:2955–2959. doi:10.
1246/bcsj.69.2955
20. Kantam ML, Laha S, Yadav J, Srinivas P (2009) Synthesis
of 2-indolyl-1-nitroalkane derivatives using nanocrystalline tita-
nium(IV) oxide. Synth Commun 39:4100–4108. doi:10.1080/
00397910902883728
21. Reich HJ, Chow F, Peake SL (1978) Seleninic acids as catalysts
for oxidations of olefins and sulfides using hydrogen peroxide.
Synthesis 1978:299–301. doi:10.1055/s-1978-24730
22. Uneyama K (1999) Chemistries of trifluoroacetimidoyl halides:
preparation, reactions, and applications for the synthesis of flu-
orinated heterocycles. J Fluor Chem 97:11–25. doi:10.1016/
S0022-1139(99)00059-7
23. Uneyama K, Amii H, Katagiri T, Kobayashi T, Hosokawa T (2005)
A rich chemistry of fluorinated imidoyl halides. J Fluor Chem
126:165–171. doi:10.1016/j.jfluchem.2004.12.017
24. Tamura K, Mizukami H, Maeda K, Watanabe H, Uneyama K
(1993) One-pot synthesis of trifluoroacetimidoyl halides. J Org
Chem 58:32–35. doi:10.1021/jo00053a011
25. Darehkordi A, Khabazzadeh H, Saidi K (2005) Facile synthesis
of 2,2,2-trifluoroacetimidoyl chloride derivatives. J Fluor Chem
126:1140–1143. doi:10.1016/j.jfluchem.2005.04.013
26. Kim JG, Jang DO (2010) Trifluoroacetylation of amines with
trifluoroacetic acid in the presence of trichloroacetonitrile and
triphenylphosphine. Tetrahedron Lett 51:683–685. doi:10.1016/j.
tetlet.2009.11.105
2. Tajbakhsh M, Alaee E, Alinezhad H, Khanian M, Jahani F,
Khaksar S, Rezaee P, Tajbakhsh M (2012) Titanium dioxide
nanoparticles catalyzed synthesis of Hantzsch esters and polyhy-
droquinoline derivatives. Chinese J Catal 33:1517–1522. doi:10.
1016/S1872-2067(11)60435-X
3. Zhang J, Wang Q, Fang H, Xu W, Liu A, Du G (2007) Design,
synthesis, inhibitory activity, and SAR studies of pyrrolidine
derivatives as neuraminidase inhibitors Bioorgan. Med Chem
15:2749–2758. doi:10.1016/j.bmc.2007.01.020
4. Patchett AA, Harris E, Tristram EW, Wyvratt MJ, Wu MT, Taub
D, Peterson ER, Ikeler TJ, ten Broeke J, Payne LG, Ondeyka DL,
Thorsett ED, Greenlee WJ, Lohr NS, Hoffsommer RD, Joshua
H, Ruyle WV, Rothrock JW, Aster SD, Maycock AL, Robinson
FM, Hirschmann R, Sweet CS, Ulm EH, Gross DM, Vassil TC,
Stone CA (1980) A new class of angiotensin-converting enzyme
inhibitors. Nature 288:280–283. doi:10.1038/288280a0
5. Strekowski L, Lee H (2000) The Friedländer synthesis of 4-
perfluoroalkylquinolines. J Fluor Chem 104:281–284. doi:10.
1016/S0022-1139(00)00252-9
6. Kagoshima H, Akiyama T (2000) Mannich-type reaction with tri-
fluoromethylated N, O-hemiacetal: facile preparation of β-amino-
β-trifluoromethyl carbonyl compounds. Org Lett 2:1577–1579.
doi:10.1021/ol005812e
7. Fuchigami T, Ichikawa S (1994) Electrolytic reactions of fluo-
roorganic compounds. 14. regioselective anodic methoxylation of
N-(Fluoroethyl)amines. Preparation of highly useful fluoroalky-
lated building blocks. J Org Chem 59:607–615. doi:10.1021/
jo00082a018
27. Klapars A, Huang X, Buchwald SL (2002) A general and efficient
copper catalyst for the amidation of aryl halides. J Am Chem Soc
124:7421–7428. doi:10.1021/ja0260465
8. Hudlicky M (1976) Hydrogenolysis of carbon–fluorine bonds in
catalytic hydrogenation. J Fluor Chem 14:189–199. doi:10.1016/
S0022-1139(00)81048-9
28. Lindley J (1984) Tetrahedron report number 163: copper assisted
nucleophilic substitution of aryl halogen. Tetrahedron 40:1433–
1456. doi:10.1016/S0040-4020(01)91791-0
29. McGraw NP, Callery PS, Castagnoli N Jr (1977) In vitro stere-
oselective metabolism of the psychotomimetic amine, 1-(2,5-
dimethoxy-4-methylphenyl)-2-aminopropane. An apparent enan-
tiomeric interaction. J Med Chem 20:185–189. doi:10.1021/
jm00212a001
30. Adams JD, Px J, Woolf TF, Ttrvor AJ, Williams LR, Castag-
noliJr N (1982) Derivatization of chiral amines with (S,S)-
N-trifluoroacetylproline anhydride for GC estimation of enan-
tiomeric composition. J Pharm Sci 71:658–661. doi:10.1002/jps.
2600710613
9. Romero AH, Salazar J, Lopez SE (2015) Synthesis of 2-
(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one derivatives
using trifluoroacetimidoyl chlorides. J Fluorine Chem 169:32–37.
doi:10.1016/j.jfluchem.2014.10.014
10. Polshettiwar V, Varma RS (2010) Green chemistry by nano-
catalysis. Green Chem 12:743–754. doi:10.1039/B921171C
11. Astruc D, Lu F, Aranzaes JR (2005) Nanoparticles as recyclable
catalysts: the frontier between homogeneous and heterogeneous
catalysis. Angew Chem Int Edit 44:7852–7872. doi:10.1002/anie.
200500766
12. Kalidindi SB, Jagirdar BR (2012) Nanocatalysis and prospects
of green chemistry. ChemSusChem 5:65–75. doi:10.1002/cssc.
201100377
31. Pippel DJ, Young LK, Letavic MA, Ly KS, Naderi B, Johnson
AS, Stocking EM, Carruthers NI, Mani NS (2010) Synthesis of
a histamine H3 receptor antagonist-manipulation of hydroxypro-
line stereochemistry, desymmetrization of homopiperazine, and
nonextractive sodium triacetoxyborohydride reaction workup. J
Org Chem 75:4463–4471. doi:10.1021/jo100629z
13. Wang DS, Xie T, Li YD (2009) Nanocrystals: solution-based syn-
thesis and applications as nanocatalysts. Nano Res 2:30–46. doi:10.
1007/s12274-009-9007-x
14. Schlogl R, Abd Hamid SB (2004) Nanocatalysis: mature sci-
ence revisited or something really new? Angew Chem Int Edit
43(13):1628–1637. doi:10.1002/anie.200301684
123

Mol Divers
32. Tian X, Field TB, Switzer AG, Mazur AW, Ebetino FH, Wos
JA, Berberich SM, Jayasinghe LR, Obringer CM, Dowty ME,
Pinney BB, Farmer JA, Crossdoersen D, Sheldon RJ (2006)
Design, synthesis, and evaluation of proline and pyrrolidine based
melanocortin receptor agonists. A conformationally restricted
dipeptide mimic approach. J Med Chem 49:4745–4761. doi:10.
1021/jm060384p
33. Butera JA, Larsen BD, Hennan JK, Kerns E, Di L, Alimar-
danov A, Swillo RE, Morgan GA, Liu K, Wang Q, Rossman EI,
Unwalla R, McDonald L, Huselton C, Petersen JS (2009) Dis-
covery of (2S,4R)-1-(2-Aminoacetyl)-4-benzamidopyrrolidine-2-
carboxylic Acid Hydrochloride (GAP-134)13, an orally active
small molecule gap-junction modifier for the treatment of atrial
fibrillation. J Med Chem 52:908–911. doi:10.1021/jm801558d
34. Martinez-Martos JM, Ramirez-Exposito MJ, Mayas-Torres MD,
Garcia-Lopez MJ, Ramirez-Sanchez M (2000) Utility of the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)
assay to measure mitochondrial activity in K+ and ATP-stimulated
rodent cortex synaptosomes. Neurosci Res Commun 27:103–107.
doi:10.1016/j.tiv.2007.08.006
35. Wu X, Jiang QZ, Ma ZF, Fu M, Shangguan W (2005) Synthesis of
titania nanotubes by microwave irradiation. Solid State Commun
136:513–517. doi:10.1016/j.ssc.2005.09.023
123