Electrochemical synthesis of 5-amino-4-benzoyl-3-phenylfuran-2- carbonitrile

Article abstract of DOI:10.3987/com-99-8843

Cathodic reduction of 2-bromo-2-cyanoacetophenone afforded 5-amino-4- benzoyl-3-phenylfuran-2-carbonitrile in an one pot reaction. The process is discussed and all the secondary products are isolated and characterized.

Full text of DOI:10.3987/com-99-8843

HETEROCYCLES, Vol. 53, No. 6, 2000, pp. 1337 - 1342, Received, 27th December, 2000
ELECTROCHEMICAL SYNTHESIS OF 5-AMINO-4-
BENZOYL-3-PHENYLFURAN-2-CARBONITRILE
Belén Batanero, Mariano Vago, and Fructuoso Barba*
Department of Organic Chemistry, University of Alcalá, 28871 Alcalá de
Henares (Madrid), Spain
*Tel: +34 91 8854617; fax: 34/91 8854686; e-mail: fructuoso.barba@uah.es
Abstract-Cathodic reduction of 2-bromo-2-cyanoacetophenone afforded
5-amino-4-benzoyl-3-phenylfuran-2-carbonitrile in an one pot reaction.
The process is discussed and all the secondary products are isolated and
characterized.
2-Aminofurancarbonitriles are useful compounds from a synthetical point of view. Some of them
react with vinyl ketones to afford anthranilic acid,1 with malonic acid to form pyridines,2 or with
urea to give pyrrols.2
Contrary to the widely accepted theory that the mutagenic and carcinogenic activity of 2-
substituted 5-nitrofuran derivatives is due to the reduction of the nitro group into active amino
metabolites, their direct isolation and identification have shown major problems.3 Only one
attempt at preparative-scale to the corresponding 5-aminofurans via cathodic reduction
involving 2-substituted 5-nitrofurans has been reported.4
Catalytic reduction of 2-nitrofurans gives low yields of 2-aminofurans which have not been
isolated
but
were
trapped
using
ethyl
ethoxymethylenecyanoacetate
or
ethoxymethylenemalononitrile.5 However, their stability was greatly improved by introduction of
electron withdrawing groups to the ring.6 There are several studies on synthetic procedures
towards these systems.7,8,9
RESULTS AND DISCUSSION
The cathodic reduction of 2-bromo-2-cyanoacetophenone (1) (obtained from phenacyl cyanide
by bromination 10 ) at a mercury cathode using DMF/LiClO4 as solvent supporting electrolyte,
affords 5-amino-4-benzoyl-3-phenylfuran-2-carbonitrile (2) as the main product (67% yield)

together with 5-amino-4-bromo-2-phenylfuran-3-carbonitrile (3) (8% yield), dibenzoylacetonitrile
(4) (14% yield) and traces of phenacyl cyanide.
The characterization of 2 was made based on the following spectroscopic and spectrometric
data.
A carbonyl band at 1644 cm-1, two primary amine signals at 3396 and 3247 cm-1 and a strong cyano
band at 2224 cm-1 appeared in IR. MS spectrometry (electronic impact) showed a molecular ion M+
1
with a m/z value of 288 units. In HNMR spectrum a broad singlet corresponding to the amine
protons at 6.61 ppm disappeared in the presence of D2O. The relationship between the integration
of this singlet and the corresponding to the aromatic signals was 1:5. In 13CNMR the more indicative
signals appeared at 189.3 ppm (correlating to a carbonyl group), at 162.1 ppm (due to the carbon
directly linked to NH2 and to the oxigen in the furan ring) and at 151.1 ppm, which corresponds to
the other carbon atom, directly linked to the oxigen and to the cyanide group, in the furan ring. The
carbon of the cyano group appeared at 113.7 ppm.
Related to the spectroscopical properties of 3, a molecular M+ and a M+ +2 ions with the same
intensity, typical of a monobrominated compound, appeared in MS with a m/z values of 262 and
264 units respectively. The IR of 3 showed no carbonyl bands, two primary amine bands at 3438
1
and 3347 cm-1 and a nitrile band at 2199 cm-1. In HNMR a broad singlet corresponding to the
amine protons at 4.1 ppm disappeared in the presence of D2O.
MS of 4 showed a molecular ion M+ with a m/z value of 249 units and a base peak (100% relative
intensity) of 105 m/z units. Physical and spectroscopical properties of 4 are the same as those
described in the literature.11
The formation of these compounds can be explained as follows. In the first step, the cleavage of the
C-halogen bond takes place in a 2e-/ molecule process to afford the corresponding enolate under a
constant cathodic potential of -0.25V (vs. SCE) (see Scheme). This enolate adds to the carbonyl
group of another substrate molecule to give the intermediate (i), which can follow different
pathways. The main process is the nucleophilic attack to the halogenated carbon losing a bromide
anion to form 2 as shown in the Scheme.The expected 2,4-diphenylfuran-3,5-carbodinitrile was
not obtained, due to the hindered aproximation of the bulky groups in the addition step.
However, the intermediate (i) can regenerate the second carbonyl group (pathway a) affording 4
and anion (ii), which attacks, via a nucleophilic substitution, the C-halogen bond of another
substrate molecule giving 3. The total experimental consumption of charge was arround 320 C
(slightly lower than 1e-/ 1 substrate molecule) due to the fact that, according to the proposed
mechanism the major product (2) (67%) needs 2e-/ 2 substrate molecule to be formed, the

secondary product (4) (14%) needs 2e-/ 2 substrate molecule to be obtained, and the minoritary
product (3) (8%) needs 2e-/ 3 substrate molecule.
On the other hand, the electroreduction of phenacyl cyanide in DMF-Et4NBr on mercury cathode
afforded 2 (5%). This can be explained as the bromide migration towards the anodic compartment,
where it is oxidized to bromine cation. Subsequent attack to the electrogenerated enolate gives 2-
bromo-2-cyanoacetophenone (1) which is further reduced to 2 as described before. When solid
sodium thiosulfate was added into the anodic compartment, no aminofuran (2) was observed.
_
O
O
O
O
-
+ 2e
1
CN
Ph
C CH CN
Br
C CH CN
Ph
Ph
C CH
Ph
C CH CN
-
- Br
b
A
N
Br
Ph C CH
-
- Br
C
Ph
O
CN
O
a
_
1
a
b
CH
CN
i
_
O
CH
NC
Br
C CH CN
C O
Ph
+
H
COPh
Ph
ii
+
+
4
Ph
-
- Br
1
_
COPh
NC
N
Ph
NC
O
CN
CN
C CH
O
Ph
NH2
C C
Ph
O
CH Br
N
Br
COPh
CH
Ph
OH
2
C
NC
_
NC
O
NH
CN
C
C
O
Ph
CH Br
NH
Br
NC
Ph
C
NH2
O
3
Scheme. Proposed route for the formation of the aminofurans (2,3).
Electrolysis in DMF-LiClO4 on graphite working electrode and at a constant applied potential of -
1.5V (vs. SCE) did not yield 2, as expected; the main product was lithium enolate of the starting
phenacyl cyanide which was regenerated when salt was poured onto acidic water. Finally, when
phenacyl cyanide was reduced in MeCN-Bu4NBr at more negative potential (-1.8V (vs. SCE)), the
corresponding pinacol: [Ph-C(OH)-CH2-CN]2 (5) was obtained as a secondary product (10% yield)
due to carbonyl reduction.

EXPERIMENTAL
The electrolyses were carried out using an Amel potentiostat Model 552 with an electronic
integrator Amel Model 721. MS spectra (EI, ionizing voltage 70 eV) were determined using a
Hewlett-Packard Model 5988A mass-selective detector equipped with a Hewlett-Packard MS Chem
Station. IR spectra were obtained, as dispersions in KBr, on a Perkin-Elmer Model 583
1
spectrophotometer. H NMR (300 MHz) and 13C NMR (75.4 MHz) spectra were recorded on a
Varian Unity 300 apparatus with deuteriochloroform or CD3OD as internal standard. The chemical
shifts are given in ppm. Melting points were determined on a Reichert Thermovar microhot stage
apparatus, and are uncorrected. Elemental analyses were performed on a Perkin-Elmer Model 240-
B analyzer. Polarography was carried out on a Metrohm apparatus Model 663 VA Stand and a
Scanner 626 Polarecord. E1/2 of 1 in DMF/LiClO4(0.1M) is –0.2 V (reference electrode: Ag/Ag+, 5
mV/s). Analytical HPLC was performed on a Hewlett-Packard 5033 instrument, using a reverse
phase column and 80% methanol/ water as the eluent. The temperature was maintained constant
by use of a criostat Grant, Model LTD6G. The products were purified by silica gel 60 (230-400
mesh) in a (25 × 3 cm) column, using Hexane/EtOAc (5:1) as eluent.
Treatment of 2-bromoacetophenone with potassium cyanide gave rise to 2-
cyanoacetophenone. The electroactive 2-bromo-2-cyanoacetophenone (1) was prepared
9
according to the literature with some modifications: the reaction was carried out by adding the
bromine (1.6 g, 0.01 mol) in CHCl3 (10 mL)as solvent into a 2-cyanoacetophenone (1.45 g, 0.01
mol) chloroform solution (40 mL) in the presence of pyridine (0.8 g, 0.01 mol) during 2 h at 45
ºC. The mixture was maintained on stirring for 12 h. When the reaction was finished the
precipitation was filtered and the organic CHCl3 solution, was washed with water and dried with
sodium sulfate. The expected 2-bromo-2-cyanoacetophenone (98% yield) was obtained when
the chloroform was evaporated.
General Electrochemical Procedure.
The electrochemical reduction was carried out under the following conditions:
Anode: Platinum. Anolyte: lithium perchlorate (0.53 g, 5.10-3 mol) in DMF (10 mL) Cathode:
mercury pool. Catholyte: LiClO4 (1.6 g, 0.015 mol) in DMF (25 mL) and 1 (0.9 g , 4.10-3 mol)
Electrolysis cell: divided cell equipped with a magnetic stirrer containing a piece of glass tubing
with a glass frit of medium porosity at one end (anodic compartment). Solid sodium carbonate
(2 g, 1.42 mmol) was added to the anodic compartment for “in situ” neutralization of the
generated perchloric acid. Solid sodium thiosulphate (1 g, 6.3 mmol) was added to the anodic

compartment to avoid bromine generation. A constant cathodic potential of -0.25 V (vs. SCE)
was applied. The temperature during the electrolysis was 15 ºC, and the reaction time about 1
h. At the end of this time the cathodic solution was poured over ice water. The precipitated
solid was filtered after 12 h and dried under reduced pressure.
The crude was chromatographed and the obtained products characterized.
5-Amino-4-benzoyl-3-phenylfuran-2-carbonitrile (2). 67% yield; mp 200-202 ºC (EtOH); IR
(KBr) : 3396, 3247, 2224, 1644, 1598, 1488, 920, 752, 688 cm-1. 1 HNMR (300 MHz, CDCl3) δ :
6.61 (br s, 2H, NH2 ), 7.35-7.65 (m, 6HAr), 7.70 (d, J= 6.8 Hz, 2HAr), 7.70 (d, J= 6.8 Hz, 2HAr).
13CNMR (75.4 MHz, CDCl3) δ : 90.6, 97.5, 113.7 (CN), 124.7, 126.9, 127.8, 127.9, 128.7, 129.5,
131.6, 138.2, 151.1, 153.7, 162.1, 189.3 (C=O). MS m/z (rel. inten.) : 289 (M++1, 10), 288 (M+,
56), 287 (M+-1, 74), 105 (100), 77 (82), 51 (14). Anal. Calcd for C18 H12 N2 O2 : C,75; H, 4.16.
Found: C, 74.88; H, 4.13.
5-Amino-4-bromo-2-phenylfuran-3-carbonitrile (3). 8% yield; mp 180-182 ºC (EtOH); IR
(KBr) : 3438, 3347, 2199, 1635, 1446, 950, 686 cm-1. 1 HNMR (300 MHz, CDCl3) δ : 4.10 (br s,
2H, NH2 ), 7.40-7.50 (m, 3HAr), 7.90-8.00 (m, 2HAr).13CNMR (75.4 MHz, CDCl3) δ : 90.1, 107.8,
111.8 (CN), 125.9, 127.8, 128.4, 129.6, 144.3, 152.1. MS m/z (rel. inten.): 264 (M++2, 20), 262
(M+, 20), 183 (M+-Br, 60), 128 (78), 105 (100), 77 (72), 51 (39). Anal. Calcd for C11 H7 N2 O Br:
C, 50.19; H, 2.66. Found: C, 50.31; H, 2.63.
3,4-Diphenyl-3,4-dihydroxyhexanedinitrile (5). 10% yield; mp 230 ºC (EtOH); IR (KBr): 3407,
2261, 1338, 1252, 1068, 700 cm-1. 1 HNMR (300 MHz, CDCl3) δ : 2.34 (d, 2H, J=17 Hz), 3.43 (d,
2H, J=17 Hz), 7.20-7.35 (m, 6HAr), 7.47-7.57 (m, 4HAr).13CNMR (75.4 MHz, CDCl3) δ : 29.3,
113.9 (CN),128.4, 129.1, 134.3, 134.7. MS m/z (rel. inten.): 293 (M++1, 3), 292 (M+, 12), 234
(11), 105 (100), 77(84), 51 (34). Anal. Calcd for C18 H16 N2 O2 : C, 73.97; H, 5.47. Found: C,
73.81; H, 5.63.
ACKNOWLEDGMENT
This study was financed by the Spanish Ministry of Education and Culture. PB97-0753.
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