Electrochemical carboxylation of fluorocontaining imines with preparation of fluorinated N-phenylphenylglycines

Article abstract of DOI:10.1016/j.jfluchem.2008.06.010

A possibility of obtaining fluorine-containing N-phenylphenylglycine derivatives at yields of up to 85% via the electrochemical carboxylation of corresponding benzalanilines was shown. The influence of imine's electron structure, the nature of supporting

Full text of DOI:10.1016/j.jfluchem.2008.06.010

Journal of Fluorine Chemistry 129 (2008) 701–706
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Electrochemical carboxylation of fluorocontaining imines with preparation
of fluorinated N-phenylphenylglycines
*
V.G. Koshechko, V.E. Titov , V.N. Bondarenko, V.D. Pokhodenko
L.V. Pisarzhevsky Institute of Physical Chemistry, National Academy of Sciences of Ukraine, Pr. Nauki 31, 03028 Kyiv, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
A possibility of obtaining fluorine-containing N-phenylphenylglycine derivatives at yields of up to 85%
via the electrochemical carboxylation of corresponding benzalanilines was shown. The influence of
imine’s electron structure, the nature of supporting electrolyte and cathodic material on such processes is
examined. It was found, that increasing electron accepting ability of the substituents in benzylidene and
aniline fragments of the imine molecule lead to decrease of amino acid yields. The dependence of the N-
phenyl-p-fluorophenylglycine yield on the cathode material (Zn, GC, Cu, Ag, Pt) and on the nature of the
supporting electrolytes (Bu4NBr, Et4NBr, Et4NClO4, PhCH2Me3NClO4, LiBF4, LiClO4, NaBF4 and KBF4) was
investigated. The highest amino acid yields were obtained at cathodes (GC and Zn) that do not exhibit
specific adsorption of fluorine-containing imines, as well as in the presence of background salts (Alk4NBr)
whose cations do not show tendency to strong ion pairing with anion radicals formed by the
electrochemical activation of the imines.
Received 31 January 2008
Received in revised form 23 May 2008
Accepted 11 June 2008
Available online 21 June 2008
Keywords:
Fluorocontaining N-phenylphenylglycines
and benzalanilines
Electrochemical carboxylation
Carbon dioxide
ß 2008 Elsevier B.V. All rights reserved.
1. Introduction
chemically activated introduction of CO2 to the C N bond can
result in
a-amino acids [13,14].
Fluorocontaining amino acids and their derivatives already
found widespread application in medicine, pharmacology, etc. [1].
Fluorine atoms appreciably influence on the acid–base properties
of functional groups of amino acids, lend them the ability to form
hydrogen bonds Fꢀ ꢀ ꢀH and increase the lipophilicity of amino acid
molecules [2,3]. Owing to this features fluorocontaining amino
acids show various types of biological activity, different from
natural amino acids. Also it makes possible to study their
conversion routes in the organism by 19F NMR spectroscopy.
Among amino acids and their derivatives N-phenylphenylgly-
cine derivatives that are structural analogues of glycine’s natural
amino acid are of considerable interest to researchers [4–7].
However fluorine-containing N-phenylphenylglycine derivatives
are still practically unexplored [7], due to the synthetic difficulties
[4,5,7], particularly via a multi-step process, frequently involving
the use of expensive and toxic reactants (cyanides, bromine).
As is known, electrochemically activated insertion of carbon
dioxide into various organic substrates [8–12] opens up broad
possibilities for preparation of various carboxylic acids, that, in
some cases, enable to carry out synthesis via a simpler route and
use more available and cheaper reactants. In particular, electro-
In this paper the possibility to produce fluorocontaining N-
phenylphenylglycine derivatives through electrochemical carbox-
ylation of corresponding imines with the fluorine atom (or
fluorine-containing group) retained to give fluorine-containing
amino acids. As is known [15,16], electrochemical activation of
some fluorine-containing organic substrates may proceed with the
elimination of the fluorine. Taking this into consideration, in the
case of fluorine-containing imines one could expect at least three
ways for the process to unfold in the course of the imines’ cathodic
activation in the presence of CO2: carboxylation at fluorine atom
with its replacement by carboxy group as in the case of
trifluoromethylarenes [15]; detachment of the fluorine as fluoride
ion and follow-on carboxylation at the carbon atom of the imine’s
C
C
N bond to give defluorinated amino acid; carboxylation at the
N bond’s carbon atom to retain the fluorine atom (or fluorine-
containing group), which would open up a possibility of obtaining
fluorine-containing amino acids.
2. Results and discussion
Used as the objects have been the following imines containing
the fluorine atoms in different positions in the benzylidene
fragment (1–3), and imines with fluorine atom in the para-position
of the benzylidene fragment and electron-donor (4, 5) or electron–
acceptor (6–10) substituents in the aniline fragment.
* Corresponding author. Tel.: +380 44 525 4160; fax: +380 44 525 6216.
E-mail address: titov@inphyschem-nas.kiev.ua (V.E. Titov).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.06.010

702
V.G. Koshechko et al. / Journal of Fluorine Chemistry 129 (2008) 701–706
Scheme 1. 1, R1 = para-F, R2 = H; 2, R1 = meta-F, R2 = H; 3, R1 = ortho-F, R2 = H; 4, R1 = para-F; R2 = OCH3; 5, R1 = para-F; R2 = CH3; 6, R1 = para-F, R2 = F; 7, R1 = para-F, R2 = Cl; 8,
R1 = para-F, R2 = Br; 9, R1 = para-F, R2 = CF3; 10, R1 = para-F, R2 = COOEt.
2.1. Electrochemical activation of fluorocontaining imines
attributed to the oxidation of the imine anion radical formed in
primary step of the process (Fig. 1b; Scheme 2). Similar CVs are
observed also in the case of electrochemical activation of other
studied imines. However for imines 2 and 3 the anodic peaks were
observed already at low potential scan rates ðv ¼ 0:2 V=sÞ, whereas
for imines 8–10 it does not appear even at comparatively high scan
rates (100.0 V/s). This may be relevant to the fact that their anion
radicals are less stable, and faster undergo further conversions in
the solution. On the base of CVs of imines we estimated the
stability of forming anion radicals. They can be dispose in follow-
ing consecution: (ia/ik) = 3(0.46) > 2(0.11) > 5(0.09) > 1(0.05) >
4(0.04) = 6(0.04) > 7(0.01) ꢂ 8(0) = 9(0) = 10(0) ðv ¼ 1:0 V=sÞ in
accordance with ia/ik value diminution.
As a result of preliminary study we have found that the
employed fluorine-containing imines 1–10 undergo electroche-
mical reduction at less negative potentials (Epc = ꢁ1.53V
to ꢁ1.98 V) than carbon dioxide does (Epc < ꢁ2.2 V) under
comparable conditions. Hence, the imines activation can be the
key step in carboxylation process via the assumed route as
represented by Scheme 1. Therefore we studied the electro-
chemical behaviour of the imines 1–10 in the absence and in the
presence of carbon dioxide.
The cyclic voltammogram (CV) of reduction of 1 shows two
cathodic peaks with Ep1 = ꢁ1.86 V and Ep2 = ꢁ2.41 V (Fig. 1a), with
the intensity of the first peak being noticeably higher than that of
the second one. The evaluation of the number of electrons involved
in the first step of the imine reduction (Ep1 = ꢁ1.86 V) by
coulometric and computational methods [17–19], points to the
value being close to unity. Consequently, this peak corresponds to
one electron reduction of imine to corresponding anion radical. The
second peak on CV of imine 1 reduction may be relevant to the
transfer of the second electron, resulting in imine dianion
formation (Scheme 2).
Unlike other studied imines, in the case of bromocontaining
imine 8 the first and second cathodic peaks partially overlap and
the later has current intensity higher than the former, which may
be due to the C–Br bond cleavage in the electrochemical reduction
of the imine.
The imines anion radicals can undergo different conversions, in
particular they can interact with the starting imines and/or with
themselves to produce dimers (Scheme 3a). The possibility of
forming similar dimers has been shown in Refs. [13,14] in the case
of some imines, that does not contain fluorine atoms. The similar
dimers can be formed in the case of electrochemical reduction of
fluorocontaining imines that confirm with results of chromato-
graphy–mass spectrometry study of the products of preparative
electrolysis of imine 1 (cathode, GC; anode, Al; Bu4NBr, DMF). At
that there is intensive signal of the main product with m/z = 401 in
mass-spectra which corresponds to the dimer of starting imine.
To size up the probability of the dimer formation process
preferentially proceeding via anion radical—starting imine inter-
action or dimerisation of two anion radicals we have computed the
rate constants of these reactions, using Digielch.2.0 software [17–
19]. The first reaction has been found to be likely to proceed at a
much higher rate (for the explored imines the rate constants of the
reaction of the anion radical with the starting imine are in the
range of 102 l/mol s to 105 l/mol s than the second one 10 l/mol s to
104 l/mol s, due to the Coulomb repulsion of similarly charged
species in the case of dimerisation of two anion radicals.
Studying the electrochemical activation of imine 1 at different
scan rates showed, that an increase of potential scan rate from
0.2 V/s to 2.0 V/s leads to the increase of both cathodic peaks
intensity and to the appearance of an anodic peak, which can be
We have studied the electrochemical behavior of imines in the
presence of CO2. With carbon dioxide added into a solution of
imine 1 in the course of electrochemical reduction there is
observed growth the first cathodic peak and its shift into more
anodic region as well as the complete disappearance of the second
cathodic peak attributed to the imine dianion formation, and of the
anodic peak (Fig. 1c). This is also the case for the other explored
imines being electrochemically activated in the presence of CO2.
The observed changes may be relevant to the interaction of the
imine anion radical with the CO2 molecule. As CO2 is stronger
electrophile, than imine, the carboxylation reaction (Scheme 3,
route b) must dominate the dimer formation (Scheme 3, route a).
The first cathodic peak shift into the less negative potential region
may be caused by both subsequent chemical reactions of the anion
radicals with the carbon dioxide and by the formation of imine
complexes with the CO2 molecule. Similar association of CO2 with
ketones has been revealed recently [20].
Fig. 1. CV of electrochemical reduction of imine 1 (a) without CO2 at v ¼ 0:2 V=s, (b)
without CO2 at v ¼ 2:0 V=s, (c) saturated with CO2 at v ¼ 0:2 V=s
(dimethylformamide (DMF) + 0.1 M tetrabutylammonium bromide (Bu4NBr),
cathode, glassy carbon (GC); anode, Pt; reference electrode Ag/AgCl,
C(1) = 5 ꢃ 10ꢁ3 M).
Scheme 2.

V.G. Koshechko et al. / Journal of Fluorine Chemistry 129 (2008) 701–706
703
Scheme 3.
2.2. Electrocarboxylation of imines in preparative scale
decreasing may be related to the decrease in electron density on the
carbon atom, that diminishes nucleophilic properties and as a
consequence—the reactivity of imine anion radical towards CO2. In
particular, unsubstituted acid yield (R1 = R2 = H) under conditions
implied is 84%, whereas introduction of fluorine atom into para-
(imine 1) and ortho- (imine 3) positions of the imines’ benzylidene
fragment falls the amino acid 1a and 3a yields to 47% and 44%,
respectively. On the contrary, fluorine atom in meta-position (imine
2) that is not conjugated to the reaction site, does not impact on the
amino acid yield so very critically. The lower amino acid yield in the
carboxylation of imines 4 and 8 is evidently linked to various side
reactions. In particular, for imine 8, there can occur electrochemical
reduction and carboxylation at the C-Br bond (the corresponding
diacid has been found among the electrosynthesis products; its
formation is attested to by 13C NMR data and the peak with m/z 289
in the mass spectrum).
Our comparative study of electrochemical study and prepara-
tive electrolysis data shows that the amino acid yield significantly
depends on the stability of the imines’ anion radicals, which is
defined by their electron structure. An increase in the stability of
the imine’s anion radical decreases the probability of its
dimerisation, promoting to the process preferentially running
via carboxylation (Scheme 3b). More specifically, for imines 1–3, 5
and 6 their anion radicals possess a higher stability, that is
confirmed by the higher anodic peak currents in CVs of the
corresponding imines at a low potential scan rate (0.2 V/s), and the
corresponding acids yields are. In the case of imines that do not
display anodic peak in CVs at a potential scan rate of 0.2 V/s (and
for imines 8–10 upto 100 V/s), corresponding anion radicals are
less stable under these conditions, with amino acid derivatives (4a,
7a–10a) forming at low yields (39–15%).
To confirm the possibility of imine anion radical–CO2 interaction
to form carboxylation products we have carried out preparative
electrolysis of imines in the presence of CO2. The preparative
carboxylation was made in a DMF solution, under a constant CO2
flow, in an undivided cell using the different cathodes and a soluble
aluminium anode. After electrolysis DMF was distilled off and the
carboxylation product was isolated via acidification of the residue
followed by extraction with diethyl ether, purified and analysed by
1H, 13C, 19F NMR and IR spectroscopy, mass spectrometry and
elemental analysis. The conditions for preparative electrosyntheses
and analytical data of the products are given in detail in Section 4.
We found, that electrochemical activation of imines 1–10 in the
presence of carbon dioxide leads to carboxylation products with
the fluorine atoms retained in the molecule, which enables the
fluorocontaining amino acids 1a–10a to be obtained at sufficiently
high yields (Table 1).
2.2.1. Effect of the electron structure of imines on the N-
phenylphenylglycine derivatives yields
It was of interest to elucidate the influence of the nature of
different substituents in the imines’ benzylidene and aniline
fragments on the yields of the corresponding fluorocontaining N-
phenylphenylglycine derivatives (1a–10a). The results of prepara-
tive carboxylation of the various imines are present in Table 1. As
follows from listed data, the amino acid derivative yields are
critically dependent on the electron structure of the imines. In
general, there can be discerned a trend for decreasing amino acids
yields withintroduction of electron–acceptorsubstituents inof both
the benzylidene and aniline fragments of the imines molecules,
which are conjugated with the reaction center (the carbon atom of
the C N bond) where the carboxylation occurs. The observed yields’
The current efficiency is higher than yield almost in all cases.
This can be connected with one-electron competing reaction of
dimer formation in contrast to two-electron process of cathodic
carboxylation of imines (Scheme 3b). The imines 4 and 8 are
exceptions. For them the current efficiency is lesser than yield that
may be due to the mentioned earlier two-electron side reactions.
Table 1
Results of electrochemical carboxylation of fluorocontaining imines (DMF, Bu4NBr
(0.1 M), C (1–10) = 0.1 M; cathode, Zn; anode, Al)
Imine
N-Phenylphenylglycine
N-Phenylphenylglycine
2.2.2. Effect of the nature of the supporting electrolyte on the N-
phenylphenylglycine derivatives yields
Yield (%)
Current efficiency (%)
To study the influence of the nature of supporting electrolyte on
carboxylation process we carried out preparative electrochemical
carboxylation of imine 1 as a model compound (it has the simplest
structure and is prevented from steric effects) using different
background salts. The results of the conducted research are shown
in Table 2. As it follows from the listed data, varying the supporting
electrolyte anion does not lead to an appreciable change in the
amino acid 1a yield (entries 2 and 3), owing to negligible effect of
the anion on the similarly charged reaction intermediates (anion
1
2
1a
2a
47
85
44
28
54
46
39
15
30
27
56
87
58
20
85
70
42
11
42
29
3
3a
4
4a
5
5a
6
6a
7
7a
8
8a
9
9a
10
10a

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V.G. Koshechko et al. / Journal of Fluorine Chemistry 129 (2008) 701–706
Table 2
Table 3
The results of electrochemical carboxylation of imine
1
using the different
Results of the electrochemical carboxylation of imine 1 using different cathodes
(DMF; Bu4NBr (0.1 M); C (1) = 0.1 M; anode, Al)
supporting electrolytes (DMF; background salt (0.1 M); C (1) = 0.1 M; cathode, Zn;
anode, Al)
Entry
Cathode
1a
Entry
Supporting electrolyte
1a
Yield (%)
Current efficiency (%)
Yield (%)
Current efficiency (%)
1
2
3
4
5
6
7
Zn
GC
Cu
Pt
47
45
18
17
13
31
35
56
49
22
34
22
37
40
1
2
3
4
5
6
7
8
Bu4NBr
Et4NBr
47
35
34
24
0
56
36
38
31
0
Et4NClO4
PhCH2Me3NClO4
LiBF4
Ag
Mg
Al
LiClO4
0
0
NaBF4
0
0
KBF4
0
0
on the GC surface may be lower than that on the other electrodes.
This should decrease the possibility of any competitive side process
of consumption of anion radical via dimerisation (Scheme 3, route a)
and should contribute to carboxylation route (Scheme 3, route b). A
different scenario can take place on a silver cathode, which display
pronounced specific adsorption toward halogen-containing com-
pounds (RHal) [23,24], owing to the formation of complexes of RHal
with the silver atoms on the electrode surface RHalꢀ ꢀ ꢀAg, which
generally causes a RHal reduction potential shifts to a less cathodic
field, compared to those obtained at a GC cathode. There is the same
effect in the case of reduction of imine 1: Ep = ꢁ1.86 V on GC and
ꢁ1.77 V at Ag. Specific adsorption can lead to an increase in the
imines concentration on the electrode surface and to raise the
dimers formation rates, whichdiminishesthecarboxylationproduct
yields.
radicals). On the contrary, the nature of cation effects crucial on the
carboxylation of imines. Unlike the background salts with
tetraalkylammonia cations (entries 1–4), when using salts with
cations of metals (entries 5–8) as supporting electrolytes in the
electrochemical activation of the imine in the presence of CO2 no
amino acid was formed. No oxidation peaks of the imines anion
radicals in CVs of imines reduction appear in the absence of carbon
dioxide even at a high scan rate (100 V/s), which indicates the low
stability of these species in the presence of alkali metals cations. As
is known [21], alkali metal cations have tendency to strong ion
pairing with organic anion radicals in aprotic solvents. Formation
of the close ion pairs leads to compensation of negative charge on
the imine’s anion radical, which decreases its nucleophilicity and
lowers its reactivity toward CO2. Moreover, increasing the extent of
ion paring can raise the rate of anion radical dimerisation (by
decreasing of repulsion of equally charged species) (Scheme 3,
route a), which decreases the efficiency of electrochemical
carboxylation of imines.
For the background salts with organic cations the amino acid
yields decrease in following order Bu4NBr > Et4NBr ꢄ Et4NClO4 >
PhCH2Me3NClO4. Perhaps, in the case of organic cations there are
formed loose ion pairs with anion radicals or there occurs no ion
pairsformation atall. The largestradius may causethehighestyields
1a in the case of Bu4NBr and, consequently, the lowest charge
density of cation Bu4N+ among the other salts with organic cations
employed. Therefore, compared with the other salts, it is less
inclined to forming tight ion pairs, which does not decrease in the
nucleophilicity of anion radicals and a rise in the rate of their
dimerisation to result in by-products. The somewhat lower product
yields in the case of trimethylbenzylammonium perchlorate (entry
4) may be accounted for substantial decomposition of the latter
under preparative electrolysis conditions.
3. Conclusions
A possibility was shown of obtaining fluorocontaining N-
phenylphenylglycine derivatives at yields up to 85% via the
electrochemical carboxylation of corresponding benzalanilines.
The influence of electron structure of imines was studied. The
enhanced stabilityofthe imines’anion radicalscan lead toa decrease
in the probability of anion radical dimerisation and to an increase in
the amino acid derivative yields. The influence of nature of
supporting electrolyte (Bu4NBr, Et4NBr, PhCH2Me3NClO4, LiBF4,
NaBF4 and KBF4) on these processes is examined. The amino acid
yields decrease in following row of organic supporting electrolytes:
Bu4NBr > Et4NBr ꢄ Et4NClO4 > PhCH2Me3NClO4 with no carboxyla-
tion products being formed at all, when the background salt includes
a metal cation. Analysis of CVs of reduction of the imines enables to
evaluate the N-phenylphenylglycine yields prior to preparative
carboxylation. The high acids yields can be expected in the case of
imines, those CVs show anodic peaks at low potential scan rates.
2.2.3. Effect of the cathode material on the N-phenylphenylglycine
derivatives yields
4. Experimental
Taking imine 1 as a model compound, we studied the effect of the
cathode material on the corresponding amino acid yields with Zn,
Cu, Pt, Ag and GC used as the cathodes. The data obtained are
presented in Table 3, from which it follows that the highest amino
acid yields were obtained on zinc and glassy carbon among the
cathodes employed when conducting preparative electrolysis.
Similar results were obtained by Silvestri et al. [14] in the
electrochemical carboxylation of unsubstituted benzalaniline on
Zn and GC electrodes. One reason for the varying amino acid yields
on cathodes of the different materials could be the singularities of
the imines’ adsorption on them which effects on subsequent
electrochemical and chemical processes. It was reported [22], that
glassy carbon does not exhibit specific adsorption toward haloge-
nated compounds. In the absence of specific adsorption, with other
conditionsbeingequal, theconcentrationoffluorocontainingimines
DMF was purified according to Ref. [25]. Supporting electrolytes
Bu4NBr (Fluka), Et4NBr, PhCH2Me3NClO4, LiBF4, NaBF4 and KBF4
before experiments were dried in vacuo during 24 h at 100 8C.
Tetraethylammonium perchlorate Et4NClO4 (Fluka) was crystal-
lized twice from ethanol and dried in a vacuum oven at 60 8C. For
all experiments supporting electrolytes concentration was
0.1 mol/l. Fluorocontaining imines were prepared similarly to
Ref. [26] via reaction of equimolar amounts of corresponding
aldehydes and amines in ethanol solution and were purified via
double crystallization from ethanol (imine’s yields after purifica-
tion were ꢄ80–90%). The 1H NMR spectra for imines 1 [27] and 4
[28] were consistent with literature data and the elemental
analysis results were in agreement with calculated. The 1H and 19
NMR spectra and the elemental analysis data for other imines are
F

V.G. Koshechko et al. / Journal of Fluorine Chemistry 129 (2008) 701–706
705
given below. Before experiments imines were dried for several
hours in vacuo at room temperature.
(4H, m), 7.63 (2H, d), 7.91 (2H, dd), 8.36 (1H, s). 19F NMR (90 MHz,
CDCl3)
ꢁ63.3 (3F, s), ꢁ108.2 (1F, s).
4-Fluorobenzylidene-4-ethylcarboxyaniline (10); mp: 98 8C
(lit. 97 8C [26]). 1H NMR (90 MHz, CDCl3)
1.42 (3H, t), 4.38
(2H, q), 7.22 (4H, m), 8.18–7.81 (4H, m), 8.41 (1H, s). 19F NMR
(200 MHz, CDCl3)
d
Cyclic voltammetry experiments were carried out in DMF with
different background salts in a three-electrode cell using a glassy
carbon disc S = 0.0314 cm2 as a working electrode. The counter
electrode and the reference electrode were a Pt foil and Ag/AgCl,
respectively. Imine’s concentration was 5 ꢃ 10ꢁ3 M. All solutions
were deaerated with high-purity argon before electrochemical
experiments.
Preparative-scale carboxylation reactions were performed in an
undivided three-electrode 50 cm3 cell using GC, Zn, Ag, Pt or Cu as
cathode (S = 10 cm2) and a sacrificial Al anode (S = 10 cm2) and Pt
wire as reference electrode (0.31V vs. Ag/AgCl). Starting concentra-
tion of imines was 0.1 mol/l. Before electrolysis metallic electrodes
(Zn, Pt, Ag, Cu) were immersed in 10% hydrochloric acid solution for
several minutes, and then rinsed with distilled water and acetone,
and several times with DMF. Carbon dioxide was bubbled into
electrolytic cell after pre-drying over P2O5. For imines 1–7, 9 and 10
process was carried out in potentiostatic conditions at a cathode
potential of ꢁ1.80 V, with the initial values of current constituting
2 ꢃ 10ꢁ2 A to 3 ꢃ 10ꢁ2 A. Electrolysis was stopped when current fell
to 2 ꢃ 10ꢁ3 A. For imine 8 controlled potential electrolysis was run
potentiostatically at a potential of the first cathodic peak ꢁ1.38 V
(Istart = 8 ꢃ 10ꢁ3 A), until current fall to 1 ꢃ 10ꢁ3 A.
d
d
ꢁ108.3 (s).
(4-Fluoro-phenyl)-phenylamino-acetic acid (1a), CAS 124573-
81-5, white solid; mp 191–193 8C (lit. 186–189 8C [7]). 1H NMR
(300 MHz, d-Me2SO) d 5.13 (1H, s, a-CH), 6.56 (1H, t, J = 7.16 Hz, H-
40), 6.66 (2H, d, J = 8.10 Hz, H-20and H-60), 7.05 (2H, t, J = 7.78 Hz, H-
30 and H-50), 7.20 (2H, dd, J = 8.72 Hz, H-3 and H-5), 7.56 (2H, dd,
J1 = 5.60 Hz, J2 = 8.70 Hz, H-2 and H-6). 13C NMR (300 MHz, d-
Me2SO) d 58.9 (s, a
-CH), 113.1 (s, C-20, C-60), 115.3 (d, J = 21.27 Hz,
C-3, C-5), 116.7 (s, C-40), 128.8 (s, C-30, C-50), 129.5 (d, J = 8.44 Hz, C-
2, C-6), 134.8 (d, J = 2.94, C-1), 146.9 (s, C-10), 161.7 (d,
J = 243.93 Hz, C-4), 172.9 (s, COOH). 19F NMR (90 MHz, d-Me2SO)
d
ꢁ115.3 (s). Anal. Calcd for C14H12O2NF: C, 68.57; H, 4.90; N, 5.71.
Found: C, 69.29; H, 4.74; N, 5.75. MS TOF LDI, 3.3 ꢃ 1014 eV, m/z
(rel. int.): 245 [M]+ (100), 246 [MH]+ (90).
(3-Fluoro-phenyl)-phenylamino-acetic acid (2a), white solid;
mp: 184–185 8C. 1H NMR (400 MHz, d-Me2SO)
d 5.18 (1H, s, a-CH),
6.56 (1H, t, J = 7.26 Hz, H-40), 6.67 (2H, d, J = 7.80 Hz, H-20 and H-60),
7.04 (2H, t, J = 7.48 Hz, H-30 and H-50), 7.13 (1H, t, J = 8.12 Hz, H-4),
7.39 (3H, m, W1/2 = 24 Hz, H-2, H-5, H-6). 13C NMR (400 MHz, d-
To isolate the electrolysis products DMF was distilled off in
vacuo, the residue was acidified with 8 ml of 3% solution
hydrochloric acid and extracted three times with 50 ml of ether.
Ether extracts were collected and after evaporation of ether the
residue was treated with 25–30 ml of 3% water solution of NaHCO3.
The suspension was extracted three times with 50 ml of diethyl
ether for removing of organic contaminants. Water solution was
acidified with 4% hydrochloric acid to pH 5–6 with precipitated
amino acid being filtered off. For final purification products were
recrystallized from ethanol/water mixture.
1H NMR spectra were measured using ‘‘Varian XL-300’’ or
‘‘Bruker-CXP-90’’, 19F NMR using ‘‘Gemini VXR-200’’ or ‘‘Bruker-
CXP-90’’ and 13C NMR using ‘‘Bruker AVANCE 400’’ spectrometers.
Chemical shifts were measured relative to TMS (internal standard)
and trichlorofluoromethane (internal standard). Mass-spectra
were recorded using ‘‘Autoflex II Bruker Daltonics’’ spectrometer
and chromatomass study was performed with LC/MSD agilent
1100 Series.
Me2SO) d 59.0 (s, a
-CH), 113.0 (s, C-20, C-60), 114.1 (d, J = 22.01 Hz,
C-2), 114.5 (d, J = 21.27 Hz, C-4), 116.7 (s, C-40), 123.7 (d,
J = 2.93 Hz, C-6), 128.7 (s, C-30, C-50), 130.4 (d, J = 8.07, C-5),
141.5 (d, J = 6.60, C-1), 146.7 (s, C-10), 162.2 (d, J = 243.56 Hz, C-3),
172.5 (s, COOH). 19F NMR (200 MHz, d-Me2SO)
d
ꢁ113.4 (s). Anal.
Calcd for C14H12O2NF: C, 68.57; H, 4.90; N, 5.71. Found: C, 68.66; H,
5.05; N, 5.74. MS TOF LDI, 3.8 ꢃ 1014 eV, m/z (rel. int.): 245 [M]+
(100), 199 [MꢁH–COOH]+ (23); 245 [M]ꢁ (100), 199 [M–H–
COOH]ꢁ (25).
(2-Fluoro-phenyl)-phenylamino-acetic acid (3a), white solid;
mp: 127–128 8C. 1H NMR (400 MHz, d-Me2SO)
d 5.32 (1H, s, a-CH),
6.56 (1H, t, J = 7.26 Hz, H-40), 6.65 (2H, d, J = 8.23 Hz, H-20 and H-60),
7.05 (2H, t, J = 7.48 Hz, H-30 and H-50), 7.21 (2H, m, W1/2 = 16 Hz, H-
4 and H-5), 7.35 (1H, q, J = 7.16 Hz, H-3), 7.51 (1H, t, J = 7.48 Hz, H-
6). 13C NMR (400 MHz, d-Me2SO)
d 53.0 (d, J = 2.20, a-CH), 112.8 (s,
C-20, C-60), 115.2 (d, J = 22.01 Hz, C-3), 116.8 (s, C-40), 124.7 (d,
J = 2.93 Hz, C-5), 125.9 (d, J = 14.68 Hz, C-1), 128.8 (d, J = 3.67, C-6),
128.9 (s, C-30, C-50), 129.9 (d, J = 8.07, C-4), 146.7 (s, C-10), 160.3 (d,
J = 245.03 Hz, C-2), 172.1 (s, COOH). 19F NMR (200 MHz, d-Me2SO)
3-Fluorobenzylideneaniline (2), CAS 58606-65-8; mp: 33–34 8C
(lit. 30–30.5 8C [29]). 1H NMR (90 MHz, CDCl3)
d
7.1–7.7 (9H, m),
ꢁ113.7 (s).
2-Fluorobenzylideneaniline (3), CAS 39087-92-8, 135663-15-9;
mp: 13–14 8C. 1H NMR (90 MHz, CDCl3)
7.05–7.45 (8H, m), 8.19
(1H, t), 8.74 (1H, s). 19F NMR (90 MHz, CDCl3)
ꢁ122.3 (s).
4-Fluorobenzylidene-4-methylaniline (5), CAS 397-69-11-4;
mp: 60–61 8C (lit. 58 8C [30]). 1H NMR (90 MHz, CDCl3)
2.37 (3H,
s), 7.17 (6H, t), 7.89 (2H, dd), 8.43 (1H, s). 19F NMR (90 MHz, CDCl3)
d
ꢁ119.1 (s). Anal. Calcd for C14H12O2NF: C, 68.57; H, 4.90; N, 5.71.
8.43 (1H, s). 19F NMR (90 MHz, CDCl3)
d
Found: C, 68.79; H, 4.85; N, 5.94. MS TOF LDI, 3.8 ꢃ 1014 eV, m/z
(rel. int.): 245 [M]+ (90), 244 [MꢁH]+ (45), 200 [MꢁCOOH]+ (10),
199 [M–HꢁCOOH]+ (100); 244 [MꢁH]ꢁ (45), 200 [MꢁCOOH]ꢁ
(100).
d
d
(4-Fluoro-phenyl)-(4-methoxy-phenylamino)-acetic acid (4a),
CAS 124573-83-7, white solid; mp: 167–171 8C (lit. 171–174 8C
d
[7]). 1H NMR (300 MHz, d-Me2CO)
a
d
3.61 (3H, s, OCH3), 5.06 (1H, s,
-CH), 6.64 (4H, m, J = 9.03 Hz, J = 10.89 Hz, H-20, H-30, H-50, H-60),
7.18 (2H, dd, J = 8.72 Hz, H-3 and H-5), 7.54 (2H, dd, J1 = 5.50 Hz,
J2 = 8.70 Hz, H-2 and H-6). 13C NMR (400 MHz, d-Me2SO)
55.2 (s,
OCH3), 60.5 (s,
-CH), 114.0 (s, C-30, C-50), 114.4 (s, C-20, C-60), 114.8
d
ꢁ109.7 (s).
4-Fluorobenzylidene-4-fluoroaniline (6), CAS 39769-09-0; mp:
51–53 8C (lit. 65 8C [26], 58 8C [30]). 1H NMR (90 MHz, CDCl3)
7.14 (6H, m), 7.88 (2H, dd), 8.41 (1H, s). 19F NMR (90 MHz, CDCl3)
ꢁ118.3 (s), ꢁ109.2 (s).
d
d
d
a
(d, J = 21.28 Hz, C-3, C-5), 129.2 (d, J = 8.44 Hz, C-2, C-6), 136.3 (d,
J = 2.56, C-1), 141.2 (s, C-10), 150.9 (s, C-40), 161.3 (d, J = 242.46 Hz,
4-Fluorobenzylidene-4-chloroaniline (7), CAS 39769-10-3,
103749-63-9; mp: 72–73 8C (lit. 74–75 8C [30]). 1H NMR
C-4), 172.7 (s, COOH). 19F NMR (200 MHz, d-Me2SO)
d
ꢁ114.9 (s).
(90 MHz, CDCl3)
(1H, s). 19F NMR (90 MHz, CDCl3)
4-Fluorobenzylidene-4-bromoaniline (8), CAS 64222-86-2;
mp: 60 8C. 1H NMR (90 MHz, CDCl3)
7.15 (4H, m), 7.51 (2H, d),
7.91 (2H, dd), 8.39 (1H, s). 19F NMR (90 MHz, CDCl3)
ꢁ108.8 (s).
4-Fluorobenzylidene-4-trifluoromethylaniline (9), CAS 39769-
13-6; mp: 47 8C (lit. oil [26,30]). 1H NMR (90 MHz, CDCl3)
7.21
d
7.19 (4H, m), 7.36 (2H, d), 7.92 (2H, dd), 8.39
Anal. Calcd for C15H14O3NF: C, 65.45; H, 5.09; N, 5.09. Found: C,
64.93; H, 5.31; N, 5.27. MS TOF LDI, 1.6 ꢃ 1014 eV, m/z (rel. int.):
243 [MꢁH–OCH3]+ (100); 2.6 ꢃ 1014 eV, 274 [MꢁH]ꢁ (30), 231
[MꢁCOOH]ꢁ (75), 230 [MꢁCOOH]ꢁ (100), 200 [MꢁCH3–COO]ꢁ
(50).
d
ꢁ108.8 (s).
d
d
(4-Fluoro-phenyl)-(4-methyl-phenylamino)-acetic acid (5a),
white solid; mp: 205–208 8C. 1H NMR (300 MHz, d-Me2CO)
d 2.13
d

706
V.G. Koshechko et al. / Journal of Fluorine Chemistry 129 (2008) 701–706
(3H,s,CH3),5.09(1H,s,
a
-CH),6.58(2H,d,J = 8.40 Hz, H-20 andH-60),
J = 31.74 Hz, C-40), 125.21 (q, J = 270.08 Hz, CF3), 126.1 (s, C-30, C-50),
129.5 (d, J = 8.10 Hz, C-2, C-6), 134.4 (d, J = 2.70, C-1), 150.0 (s, C-10),
161.7 (d, J = 243.75 Hz, C-4), 172.3 (s, COOH). 19F NMR (90 MHz, d-
6.87 (2H, d, J = 8.09 Hz, H-30 and H-50), 7.11 (2H, dd, J = 8.71 Hz, H-3
and H-5), 7.59 (2H, dd, J1 = 5.30 Hz, J2 = 8.70 Hz, H-2 and H-6). 13C
NMR (400 MHz, d-Me2SO):
d
20.0 (s, CH3), 59.2 (s,
a
-CH), 113.3 (s, C-
Me2SO)
d
ꢁ114.9 (s, 1F), ꢁ59.4 (s, 3F, CF3). Anal. Calcd for
20, C-60), 115.2 (d, J = 21.27 Hz, C-3, C-5), 125.1 (s, C-40), 129.2 (s, C-30,
C-50), 129.4 (d, J = 8.44 Hz, C-2, C-6), 134.9 (d, J = 2.93, C-1), 144.5 (s,
C-10), 161.6 (d, J = 243.20 Hz, C-4), 172.9 (s, COOH). 19F NMR
C15H11NO2F4: C, 57.51; H, 3.51; N, 4.47. Found: C, 57.42; H, 3.68;
N, 4.59. MS TOF LDI, 3.3 ꢃ 1014 eV, m/z (rel. int.): 244 [MꢁCF3]+; 313
[M]ꢁ (80), 269 [MꢁCOO]ꢁ (100).
(200 MHz, d-Me2SO)
d
ꢁ114.8 (s). Anal. Calcd for C15H14O2NF: C,
(4-Fluoro-phenyl)-(4-ethoxycarbonyl-phenylamino)-acetic
acid (10a), white solid; mp: 148–150 8C. 1H NMR (300 MHz, d-
69.50; H, 5.41; N, 5.41. Found: C, 69.63; H, 5.65; N, 5.53. MS TOF LDI,
3.8 ꢃ 1014 eV, m/z (rel. int.): 259 [M]+ (55), 258 [MꢁH]+ (100), 214
[MꢁCOOH]+ (100); 259 [M]ꢁ (35), 258 [MꢁH]ꢁ (95), 215 [MꢁCOO]ꢁ
(45), 214 [MꢁCOOH]ꢁ (100), 200 [MꢁCH3–COO]ꢁ (100).
Me2SO)
d 1.30 (3H, t, CH3), 4.24 (2H, q, J = 7.15 Hz, CH2), 5.32 (1H, s,
a
-CH), 6.75 (2H, d, J = 9.03 Hz, H-20 and H-60), 7.15 (2H, dd,
J = 8.72 Hz, H-3 and H-5), 7.63 (2H, dd, J1 = 5.60 Hz, J2 = 8.80 Hz, H-
2 and H-6), 7.76 (2H, d, J = 9.03 Hz, H-30 and H-50). 13C NMR
(400 MHz, d-Me2SO)
(4-Fluoro-phenyl)-(4-fluoro-phenylamino)-acetic acid (6a),
CAS 124573-82-6, white solid; mp: 184–187 8C (lit. 178–182 8C
d 14.3 (s, CH3), 58.4 (s, a-CH), 59.6 (s, CH2),
[7]). 1H NMR (90 MHz, d-Me2CO)
d
5.10 (1H, s,
W1/2 = 78 Hz, H-2, H-30, H-50, H-6), 7.20 (2H, s, H-3 and H-5), 7.52
(2H, d, J = 20 Hz, H-20 and H-60). 13C NMR (400 MHz, d-Me2SO)
59.3 (s,
-CH), 114.0 (d, J = 7.34 Hz, C-20, C-60), 115.2 (d,
a
-CH), 6.77 (4H, m,
112.1 (s, C-20, C-60), 115.3 (d, J = 21.64 Hz, C-3, C-5), 117.3 (s, C-40),
129.5 (d, J = 8.07 Hz, C-2, C-6), 130.6 (s, C-30, C-50), 134.2 (s, C-1),
151.0 (s, C-10), 161.7 (d, J = 243.92 Hz, C-4), 165.7 (s, COOEt), 172.2
d
a
(s, COOH). 19F NMR (200 MHz, d-Me2SO)
d
ꢁ114.0 (s). Anal. Calcd
J = 22.01 Hz, C-3, C-5), 115.3 (d, J = 21.27 Hz, C-30, C-50), 129.4 (d,
J = 8.43 Hz, C-2, C-6), 134.7 (d, J = 2.93, C-1), 143.5 (d, J = 1.47, C-10),
154.7 (d, J = 232.15 Hz, C-40), 161.7 (d, J = 243.56 Hz, C-4), 172.7 (s,
for C17H16NO4F: C, 64.35; H, 5.05; N, 4.42. Found: C, 64.44; H, 5.10;
N, 4.54. MS TOF LDI, 2.9 ꢃ 1014 eV, m/z (rel. int.): 273 [MꢁCOO]+
(30), 244 [MꢁCOOEt]+ (45), 243 [MꢁCOOEt–H]+ (100); 317 [M]ꢁ
(35), 273 [MꢁCOO]ꢁ (100).
COOH). 19F NMR (90 MHz, d-Me2SO)
d
ꢁ115.0 (s, p-FPhCH), ꢁ128.9
(s, p-FPhNH). Anal. Calcd for C14H11O2NF2: C, 63.88; H, 4.18; N,
5.32. Found: C, 64.16; H, 4.39; N, 5.38. MS TOF LDI, 3.8 ꢃ 1014 eV,
m/z (rel. int.): 263 [M]+ (5), 244 [MꢁF]+ (10), 243 [MꢁF–H]+ (100),
219 [MꢁCOO]+ (90); 263 [M]ꢁ (50), 262 [MꢁH]ꢁ (100), 218
[MꢁCOOH]ꢁ (90).
Acknowledgements
We thank Dr. V.V. Trachevskiy for 13C NMR spectra registration
and their analysis, Prof. V.A. Pokrovskiy and Dr. T.U. Gromovoy for
conducting the mass spectroscopic studies and help in interpreta-
tion of results.
(4-Fluoro-phenyl)-(4-chloro-phenylamino)-acetic acid (7a),
white solid; mp: 175–177 8C. 1H NMR (300 MHz, d-Me2CO)
d
5.13 (1H, s, a
-CH), 6.66 (2H, d, J = 8.72 Hz, H-20 and H-60), 7.06 (2H,
d, J = 8.71 Hz, H-30 and H-50), 7.19 (2H, dd, J = 8.72 Hz, H-3 and H-
5), 7.53 (2H, dd, J1 = 5.60 Hz, J2 = 8.70 Hz, H-2 and H-6). 13C NMR
References
(400 MHz, d-Me2SO) d 58.8 (s, a
-CH), 114.5 (s, C-20, C-60), 115.3 (d,
J = 21.27 Hz, C-3, C-5), 120.0 (s, C-40), 128.4 (s, C-30, C-50), 129.5 (d,
J = 8.07 Hz, C-2, C-6), 134.5 (d, J = 3.00, C-1), 145.8 (s, C-10), 161.7
(d, J = 243.56 Hz, C-4), 172.6 (s, COOH). 19F NMR (200 MHz, d-
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d
ꢁ115.0 (s). Anal. Calcd for C14H11O2NClF: C, 60.11; H,
3.94; N, 5.01; Cl, 12.70. Found: C, 59.52; H, 4.01; N, 4.89; Cl, 13.67.
MS TOF LDI, 3.3 ꢃ 1014 eV, m/z (rel. int.): 281 [M37Cl]+ (5), 279
[M35Cl]+ (15), 244 [MꢁCl]+ (60), 243 [MꢁCl–H]+ (100), 236
[MꢁCOOH]+ (20), 234 [MꢁCOOH]+ (50); 2.9 ꢃ 1014 eV, 281
[M37Cl]ꢁ (20), 279 [M35Cl]ꢁ (100).
(4-Fluoro-phenyl)-(4-bromo-phenylamino)-acetic acid (8a),
white solid; mp: 147–151 8C. 1H NMR (90 MHz, d-Me2SO)
d
5.12
-CH), 6.63 (2H, d, J = 33 Hz, H-20, H-60), 7.18 (4H, m, W1/
2 = 72 Hz, H-3, H-5, H-30, H-50), 7.54 (2H, dd, J1 = 5.60 Hz,
J2 = 8.70 Hz, H-2 and H-6). 13C NMR (400 MHz, d-Me2SO)
58.7
(s,
-CH), 107.4 (s, C-40), 115.1 (s, C-20, C-60), 115.3 (d, J = 21.65 Hz,
(1H, s,
a
d
a
C-3, C-5), 129.5 (d, J = 8.07 Hz, C-2, C-6), 131.2 (s, C-30, C-50), 134.4
(d, J = 3.67, C-1), 146.2 (s, C-10), 161.7 (d, J = 241.72 Hz, C-4), 172.5
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(s, COOH). 19F NMR (90 MHz, d-Me2SO)
d
ꢁ115.0 (s). Anal. Calcd for
C
14H11O2NBrF: C, 51.85; H, 3.39; N, 4.32; Br 24.69. Found: C, 51.62;
H, 3.57; N, 4.51; Br 25.21. MS TOF LDI, 2.1 ꢃ 1014 eV, m/z (rel. int.):
244 [MꢁBr]+ (10), 243 [MꢁBr–H]+ (100); 2.9 ꢃ 1014 eV, 325
[M81Br]ꢁ (20), 324 [M81Br–H]ꢁ (100), 323 [M79Br]ꢁ (20), 322
[M79Br–H]ꢁ (100), 280 [M81Br–COOH]ꢁ (55), 278 [M79Br–COOH]ꢁ
(50), 244 [MꢁBr]ꢁ (45), 200 [MꢁBr–COO]ꢁ (40), 81 [81Br]ꢁ (40), 79
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[
79Br]ꢁ (40).
(4-Fluoro-phenyl)-(4-trifluoromethyl-phenylamino)-acetic acid
(9a), white solid; mp: 137–139 8C. 1H NMR (300 MHz, d-Me2SO)
d
5.22(1H, d, J = 6.85 Hz, a
-CH),6.77(2H, d, J = 8.40 Hz,H-20 and H-60),
6.99 (1H, d, J = 7.16 Hz, NH), 7.20 (2H, dd, J = 8.72 Hz, H-3 and H-5),
7.35 (2H, d, J = 8.40 Hz, H-30 and H-50), 7.54 (2H, dd, J1 = 5.50 Hz,
J2 = 8.70 Hz,H-2andH-6). 13CNMR(400 MHz, d-Me2SO)
d
58.6(s,
a-
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CH), 112.5 (s, C-20, C-60), 115.3 (d, J = 21.61 Hz, C-3, C-5), 116.3 (q,