First aromatic ring acetamidation by anodic oxidation

Article abstract of DOI:10.1016/j.elecom.2014.08.028

Anodic oxidation of 1-(trifluoromethyl)benzene in dry acetonitrile/Bu₄NBF₄under constant potential conditions led to 2-(trifluoromethyl) acetanilide in 86% yield. Other experimental conditions, as the use of constant current or the c

Full text of DOI:10.1016/j.elecom.2014.08.028

Electrochemistry Communications 48 (2014) 115–117
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Electrochemistry Communications
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Short communication
First aromatic ring acetamidation by anodic oxidation
a,
b
a
Fructuoso Barba ⁎, Isidoro Barba , Belen Batanero
a
Department of Organic Chemistry, University of Alcala, 28871 Alcala de Henares, Madrid, Spain
Department of Organic Chemistry, University of Alicante, Ap. 99, 03080 Alicante, Spain
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2014
Received in revised form 25 August 2014
Accepted 27 August 2014
Available online 6 September 2014
Anodic oxidation of 1-(trifluoromethyl)benzene in dry acetonitrile/Bu NBF under constant potential conditions
led to 2-(trifluoromethyl) acetanilide in 86% yield. Other experimental conditions, as the use of constant current
or the change in the supporting electrolyte were considered.
4
4
©
2014 Elsevier B.V. All rights reserved.
Keywords:
Acetanilides
Anode
1
-(Trifluoromethyl)benzene
Acetonitrile/Bu NBF
Potentiostatic conditions
4
4
1
. Introduction
hydrolysis of the generated cation during the work-up, to produce the
corresponding side-chain acetamide, as indicated in Scheme 1.
As far as we know aromatic ring anodic acetamidation has never
been achieved; once the anodic discharge was displayed, the target
of acetonitrile has been always the side aliphatic chain. In 2008
and 2011, Kumar et al. [11] published two articles describing the
electrochemical ring acetamidation of aromatic compounds using a
0.1 M solution of starting material in acetonitrile (25 mL)/water
(25 mL)/KCl 0.1 M as a solvent and supporting electrolyte (SSE). We
have tried to reproduce these results, under their experimental condi-
tions, with acetophenone [11a] and p-xylene [11b] as substrates. We
have not observed any acetamidation of acetophenone. Instead, the
expected benzoic acid was obtained as the main product. In the case
of p-xylene, these authors reported a 97% yield of 2,5-dimethyl acetan-
ilide. In this case we have found some aliphatic acetamidation but none
of the mentioned aromatic acetamidation.
Trifluoromethylated arenes are important motifs in many pharma-
ceuticals, agrochemicals and organic materials due to the strong
electron-withdrawing nature and the large hydrophobic domain of a
CF
3
-group [1,2].
The interest of acetamidated 1-(trifluoromethyl)benzene deals
notably with the utility of the acetamido group providing other oppor-
tunities to transform it into different functional groups, opening new
access to many synthetic therapeutic agents [1,3,4].
Conventional preparations of these acetamidated 1-(trifluoromethyl)
benzenes have been recently described, as the Pd(II)-catalyzed
trifluoromethylation of the aromatic C\H bond in acetanilides, which
provides the highly biological potential key structure of ortho-CF
acetanilides [5] or the ortho-trifluoromethylation of N-aryl-benzamide
catalyzed by Pd using the Umemoto reagent as the CF source [6]. Direct
3
3
Cu-catalyzed trifluoromethylation of pivalamido arenes with Togni
reagent takes place with high selectivity at the ortho-position [7].
On the other hand, the metabolism of 2-trifluoromethylacetanilide
in the rat has been determined [8].
In the present communication we describe for the first time an
aromatic acetamidation reaction at the electrode.
The electrochemical acetamidation reaction of alkyl aromatic
compounds (arenes) was studied in depth by Eberson et al. [9] in
acetonitrile/alkaline perchlorate at a platinum anode. The accepted mech-
anistic proposal [10] is the aromatic ring oxidation in a 2e−/substrate
molecule process, followed by a Ritter-type reaction with further
2. Experimental section
The electrolyses were carried out using an Amel potentiostat Model
552 with electronic integrator Amel Model 721. Mass spectra (EI, ioniz-
ing voltage 70 eV) were determined using a THERMOFISHER ITQ-900
DIP/GC-MSn mass-selective detector. IR spectra of the compounds
were recorded as dispersions in KBr or NaCl films on a Perkin-Elmer
⁎
Corresponding author at: The Department of Organic Chemistry of the University of
FT-IR spectrometer Spectrum 2000. 1H and 13C NMR spectra were
Alcala, Facultad de Farmacia, Campus Universitario, 28871 Alcala de Henares, Madrid,
Spain. Tel.: +34 918854617; fax:+34 918854686.
3
recorded in CDCl on Varian Unity 300 (300 MHz) spectrometer with
E-mail address: fructuoso.barba@uah.es (F. Barba).
tetramethylsilane (TMS) as the internal standard. The chemical shifts
http://dx.doi.org/10.1016/j.elecom.2014.08.028
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F. Barba et al. / Electrochemistry Communications 48 (2014) 115–117
However, when anodic acetoxylation is performed, substitution at
the aromatic ring or at the aliphatic side chain can occur depending on
the SSE employed. The use of weak nucleophile solvent-supporting
4
electrolyte systems such as HOAc/NaClO drives the reaction to the
aliphatic acetate [14], however when the SSE contains a stronger nucle-
ophile: HOAc/NaOAc the obtained product is the arylacetate [15]
because once the aromatic cation radical is formed the acetate as nucle-
ophile attacks the ring before any side chain proton is evolved.
The preparative-scaled electrolysis of (1), when carried out under
our best experimental conditions, allowed getting the aromatic ring
acetamidation product (2), after a charge consumption corresponding
to a theoretical 2e−/substrate molecule process. Once finished and
further elaborated (2) was obtained in 86% yield together with a 10%
mixture of 3-(trifluoromethyl)acetanilide and 4-(trifluoromethyl)
acetanilide in a 3:1 respectively relationship determined by GC and
Scheme 1. Accepted mechanistic proposal in the electrochemical arene acetamidation.
1
H-NMR.
Concerning the mechanism proposal that explains the formation of
(2), it is sumarized in Scheme 2.
are given in ppm. Melting points were measured on a Reichert
Thermovar microhot stage apparatus and are uncorrected.
After the first electron transfer to the anode, the cation radical
cannot be further stabilized by lose of a fluorine cation, as in the case
of alkyl aromatic substrates that evolve, as already Eberson described,
leaving a proton. Now the Ritter-type reaction with the solvent, acetoni-
trile, takes place at the ring.
The 2-(trifluoromethyl)acetanilide (2) is the major isomer because
the strong withdrawing inductive effect of the trifluoromethyl substitu-
ent makes charge deficient the adjacent positions, more easily to be
attacked by nucleophiles.
It is important to notice that the best results were obtained using
4 4 4
Bu NBF as electrolyte. When it was substituted by LiClO , under the
applied potential conditions, aromatic chlorinated products were
obtained and the reaction was dirty.
2
.1. General electrochemical procedure
-(Trifluoromethyl)benzene (1) (5.10−3 mol, 0.73 g) was dissolved
1
in 60 mL SSE: anhydrous acetonitrile/Bu NBF (0.05 M) and electro-
4
4
lyzed in a concentric and divided cell (glass-frit D4-diaphragm)
equipped with a magnetic stirrer under constant potential conditions
(
+2.8 V, vs Ag/AgCl(sat)) at temperature of 18 °C maintained constant
2
with a cryostat. A platinum plate (10 cm ) was used as working and
counter electrode and a Ag/AgCl (sat) electrode as the reference.
Once the reaction was finished, the solvent in the anodic solution
was removed under reduced pressure. The residue was extracted with
When the electrolysis was performed under constant current condi-
tions (300 mA applied during 1 h) while maintaining identical the rest
of the reaction parameters, the yield of 2-trifluoroacetanilide was 54%.
This lower yield is due to the competing formation of some
monoacetamide dimers through coupling of the trifluoromethyl
benzene cation radical, in addition to the 3- and 4-trifluoroacetanilide
isomers.
ether/water and the organic phase dried over Na
by evaporation. The resulting solid was chromatographed on silica gel
0 (35–70 mesh) in a (22 × 3 cm) column, using CH Cl :EtOH (20:1)
as eluent. Spectroscopic data of the obtained compounds are given
below.
2 4
SO and concentrated
6
2
2
2
9
1
-(Trifluoromethyl)acetanilide (2): (870 mg, 86% yield). Mp
6 °C. [Lit. [12] 96–96.5 °C]. IR(KBr) ν = 3286, 3037, 2962,
4. Conclusions
674, 1531, 1320, 1125, 1036, 764 cm−1
.
1
H NMR (300 MHz,
CDCl
3
) δ: 2.15(s, 3H), 7.16 (t, 1H, J = 7.5 Hz), 7.36 (bs, 1H), 7.49
The anodic discharge of (trifluoromethyl)benzene under constant
(
t, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 7.5 Hz), 8.08 (d, 1H, J =
potential conditions of +2.8 V (vs Ag/AgCl (sat)) and acetonitrile/
Bu NBF as SSE, provides the first example of high yielded aromatic
ring acetamidation.
1
3
7
1
2
7
3
.8 Hz). C NMR (75.4 MHz, CDCl ) δ: 24.6, 122.2, 124.5, 124.7,
4
4
25.8, 126.0, 132.8, 135.1, 168.4. MS m/e (relative intensity) EI:
03(M ,18), 184(M+-19, 3), 161(98), 141(100), 114(46),
5(5), 63(9).
+
3
-(Trifluoromethyl)acetanilide: Mp 102 °C. [Lit. [13] 100–102 °C].
+
+
MS m/e (relative intensity) EI: 203(M ,17), 184(M -19, 9),
61(100), 142(10), 114(12), 63(9).
1
3
. Results and discussion
When 1-(trifluoromethyl)benzene (1) was exposed to the experi-
mental oxidative conditions described above, using acetonitrile as the
solvent (it means with a weak nucleophile), it was transformed into
the corresponding 2-(trifluoromethyl)acetanilide (2) in very good
yield.
The reason why the alkyl aromatic derivatives afford the side
chain acetamidation reaction, instead of the ring acetamidation (see
Scheme 1), is that the initially electrogenerated cation radical at the
ring, due to the weak nucleophilic character of acetonitrile, loses an
aliphatic proton to produce the more stable benzyl radical that is further
oxidized to the cation and subsequently attacked by the acetonitrile
through a Ritter-type reaction.
Scheme 2. Aromatic ring acetamidation mechanism.

F. Barba et al. / Electrochemistry Communications 48 (2014) 115–117
117
[
[
4] K. Muller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886.
5] L.-S. Zhang, K. Chen, G. Chen, B.-J. Li, S. Luo, Q.-Y. Guo, J.-B. Wei, Z.-J. Shi, Org. Lett. 15
The methodology described herein to get trifluoromethylated
acetanilides could be easily scaled up under constant current conditions
and opens a new access to biological and therapeutic agents.
(2013) 10–13.
[6] X.-G. Zhang, H.-X. Dai, M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 134 (2012) 11948–11951.
[
[
7] S. Cai, Ch. Chen, Z. Sun, Ch. Xi, Chem. Commun. 49 (2013) 4552–4554.
8] M. Tugnait, E.M. Lenz, M. Hofmann, M. Spraul, I.D. Wilson, J.C. Lindon, J.K. Nicholson,
J. Pharm. Biomed. Anal. 30 (2003) 1561–1574.
Conflict of interest
[
9] L. Eberson, K. Nyberg, Tetrahedron Lett. (1966) 2389–2393.
The authors declare no conflict of interest.
Acknowledgments
[10] L. Eberson, B. Olofson, Acta Chem. Scand. 23 (1969) 2355–2366.
[
11] a) L.K. Sharma, S. Kumar, P. Yadav, R.K.P. Singh, Ind. J. Chem. Sect. B 47 (2008)
277–1280;
1
b) S. Kumar, S. Singh, R.K.P. Singh, J. Indian Chem. Soc. 88 (2011) 1041–1045.
12] M.J. Fifolt, J. Org. Chem. 50 (1985) 4576–4582.
13] F. Shi, Org. Lett. 8 (2006) 1411–1414.
14] L. Eberson, J. Am. Chem. Soc. 89 (1967) 4669–4677.
15] L. Eberson, K. Nyberg, J. Am. Chem. Soc. 88 (1966) 1686–1691.
[
[
[
[
This work was supported by the Spanish Ministry of Science and
Education through B. Batanero I3 program the financial support.
References
[1] M. Schlosser, Angew. Chem. Int. Ed. 45 (2006) 5432–5446.
[2] T. Furuya, A.S. Kamlet, T. Ritter, Nature 473 (2011) 470–477.
[3] W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369.