Electrosynthesis of N-substituted imidazole-2-thiones

Article abstract of DOI:10.1055/s-1999-3585

The electrochemical eduction of phenacyl azide thiosemicarbazones 2 in aprotic DMF/LiClO₄ medium at the mercury cathode in a divided cell and under controlled potential leads to N-substituted imidazolethiones 3 in a one-pot reaction with good y

Full text of DOI:10.1055/s-1999-3585

PAPER
1809
Electrosynthesis of N-Substituted Imidazole-2-thiones
Belén Batanero, José Escudero, Fructuoso Barba*
Department of Organic Chemistry. University of Alcalá. 28871 Alcalá de Henares, Madrid, Spain
Fax +34(91)8854686
Received 19 January 1999; revised 19 April 1999
For the synthesis of the corresponding imidazolethiones
in a similar way, we tried to prepare phenacyl bromide thi-
osemicarbazones from phenacyl bromide and thiosemi-
carbazide, but this reaction afforded 1,3,4-thiadiazines5a,b
and 1,3-thiazoles5c by the nucleophilic attack of the sulfur
atom on the C–Br bond. To avoid this, bromide was re-
placed by an azide group. The reductive cleavage of the
C–N3 bond was already reported by Lund, 6describing the
transformation of phenacyl azide into acetophenone under
protic conditions in a 2e-/2H+ process.
Abstract: The electrochemical eduction of phenacyl azide
thiosemicarbazones 2 in aprotic DMF/LiClO4 medium at the mercu-
ry cathode in a divided cell and under controlled potential leads to
N-substituted imidazolethiones 3 in a one-pot reaction with good
yields.
Key words: cathodic reduction, phenacyl azide thiosemicarba-
zones, nucleophilic addition, cyclization, imidazole-2-thiones
Several years ago, we reported the cathodic reduction of
phenacyl bromide semicarbazones in aprotic medium
leading to the dimeric semicarbazones, in almost quanti-
tative yield, which were converted into either 1,4-diaryl-
butane-1,4-diones and 2,5-diarylfurans1 or 3,6-diarylpy-
ridazines.2 However, when these reactions were carried
out under highly dilution conditions 3,7-diaryl-2H-imida-
zo[2,1-b][1,3,4]oxadiazines were obtained.3 The subse-
quent reduction in protic medium, EtOH/LiClO4, at a
constant potential [between –1.52 V and –1.65 V vs. SCE
(saturated calomel electrode) depending on the oxadiaz-
ine] using mercury as working electrode, yielded 4-aryl-
1-(1-arylethylidenamino)-1,3-dihydro-2-imidazolones.4
This process is similar to the conversion of phenacyl bro-
mide semicarbazones into N-substituted imidazolones,
previously reported by us, but in this case two steps were
implicated and the first step had to be carried out under
conditions of high dilution because competition between
a substitution and an addition reaction could take place.
Compounds 2 were electrolyzed under aprotic conditions
in order to obtain the expected thiadiazines. However,
compounds 3 were obtained in good yields from the one-
pot reaction (Scheme).
Voltammetric studies in DMF/LiClO4 as solvent-support-
ing electrolyte employing mercury cathode as working
Scheme
Synthesis 1999, No. 10, 1809–1813 ISSN 0039-7881 © Thieme Stuttgart · New York

1810
B. Batanero et al.
PAPER
a
Table 1 Peak Potentials (vs. Ag/AgCl) for 2 a–e in DMF/LiClO4
IR spectra and is in a good agreement with the expected
reduction of the C–N3 bond instead of the C=S bond. The
electrogenerated compounds 3a–e showed in H NMR
2
a
b
c
d
e
1
spectra a singlet for three protons at d = 2.22 correspond-
ing to a methyl group at an unsaturated carbon. A broad
singlet at d = 8.9 was assigned to the NH of the imidazo-
lethione ring. A singlet corresponding to the proton on C-
5 appears at d = 6.9. The chemical shift in 13C NMR spec-
tra for the signal corresponding to C-5 is d = 103.9. Other
relevant 13C NMR signals are at d = 12.9 and 169.2 be-
longing to the methyl group and the C=S respectively.
Ar
C6H5
4-MeOC6H4 4-MeC6H4 4-ClC6H4 4-BrC6H4
Epc (V) –1.72 –1.89
–1.84
–1.69b
–1.68c
a n = 0.5 V/s.
b n = 0.1 V/s.
c n = 0.3 V/s.
The first step takes place with the cleavage of the C–N3 to
give the corresponding anion A (Scheme). The presence
of this anion was confirmed by running the electrolysis in
the presence of phenol. In this case, acetophenone thio-
semicarbazone was isolated as the only product with a
current consumption of two electrons per molecule of sub-
strate.
electrode, glassy carbon as auxiliary and Ag/AgCl as ref-
erence, gave for the thiosemicarbazones 2a–e the Epc
shown in Table 1. Under these conditions the C–N3 group
is easly reduced than the C=S in the thiosemicarbazone as
was demonstrated by running the cyclic voltammetry of
phenacyl azide (Epc = –0.97 V) and acetophenone
thiosemicarbazone (Epc = –1.95 V) in DMF/LiClO4 and a
HMDE (hanging mercury drop electrode) at 0.5 V/s.
Subsequent nucleophilic attack of anion A to the C=S
bond of another substrate molecule followed by ammonia
and thiourea elimination led to the formation of the corre-
sponding 3,7-diaryl-2H-imidazo[2,1-b][1,3,4]thiadiazine
B as a not isolable intermediate (due to the cleavage of the
C–S bond at the applied working potential, in a similar
way to the imidazooxadiazine which yielded the corre-
The electrochemical reduction of 2a–e using DMF/
LiClO4 on a mercury cathode at constant working poten-
tial between –1.68 and –1.89 V vs. SCE (depending on the
phenacyl azide thiosemicarbazone) gave 4-aryl-1-(1-aryl-
ethylidenamino)-1,3-dihydroimidazole-2-thiones 3.
The assignment of product structure is based on the disap- sponding N-substituted 2-imidazolone4 at potentials
pearance of the strong azide band at n = 2100 cm-1 in the around –1.6 V vs. SCE). The presence of thiourea in the
Table 2 Physical and Spectroscopic Data of 1a
Prod- Ar
uct
mp
IR (KBr or film
1H NMR (CDCl3), δ, J, (Hz)
13C NMR (CDCl3) δ
CH2 arom C=O others
MS
m/z (%)
(ºC)b
CH2
arom
others
nC=O N3
1a
1b
1c
1d
1e
C6H5
17c
1696 2105
4.53
7.4–7.7
54.8 127.8, 128.1, 193.1
129, 134.1
161 (M+, 0.2), 136
(0.9), 105 (100), 91
(3), 77 (55), 51 (21)
(s, 2 H) (m, 3 H)
7.8–8
(m, 2 H)
4-MeOC6H4 74–76 1684 2126
4-MeC6H4 63–65 1690 2102
4.48
6.93 (d, 2 H, 3.86
54.5 114.1, 127.5, 191.6 55.5
130.2, 164.3
191 (M+, 1), 135
(100), 107 (7), 92
(11), 77 (12)
(s, 2 H) J = 8.8)
(s, 3 H
7.86 (d, 2 H,
J = 8.8)
4.52
7.28 (d, 2 H, 2.42
(s, 2 H) J = 8.1) (s, 3 H)
7.79 (d, 2 H,
54.7 127.9, 129.6, 192.7 21.6
131.9, 145.1
175 (M+, 0.1), 119
(100), 105 (12), 91
(64), 65 (15)
J = 8.1)
4-ClC6H4
4-BrC6H4
58–60 1695 2106
4.5
7.45 (d, 2 H,
54.8 129.3, 130.9, 192.0
132.6, 140.6
195 (M+, 0.2), 141
(33), 139 (100), 113
(16), 111 (50), 104
(2), 75 (40), 51 (8)
(s, 2 H) J = 8.7)
7.82 (d, 2 H,
J = 8.7)
86c
1695 2117
4.51
7.62 (d, 2 H,
54.8 129.4, 132.3, 192.3
133.1, 138.1
241 (M+ + 2, 0.1),
239 (M+, 0.1), 185
(100), 184 (100),
157 (40), 155 (40),
131 (1.4), 129 (1.5),
104 (3.6), 75 (24)
(s, 2 H) J = 9)
7.75 (d, 2 H,
J = 9)
a Satisfactory microanalyses obtained for all new compounds: C 0.24; H 0.14; N 0.17.
b Uncorrected.
c 1a Lit15a mp 17ºC. 1e Lit15a mp 86–87ºC.
Synthesis 1999, No. 10, 1809–1813 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Electrosynthesis of N-Substituted Imidazole-2-thiones
1811
Table 3 Compound 2a–e Prepareda
Prod- mp (ºC) b IR (KBr or film
1H NMR (CDCl2); d J (Hz)
13C NMR (CDCl3), d
MS
m/z (%)
uct
ν (cm–1)
CH2
arom
others
CH2 arom
C=S others
179.4 147.4
2a
110–112 3406, 3192,
3157, 2105,
4.15
(s, 2 H)
7.3–7.7
(m, 5 H)
3.86 (s, 3 H)
6.62 (s, 2 H)
8.77 (s, 1 H)
55.1 127, 130.1,
130.9, 135.8
235 (M + + 1, 1),
234 (M+, 7), 177
(100), 136 (6), 103
(14), 77 (21), 60
(15)
1606, 1511,
1263, 1104
2b
2c
125–126 3422, 3270,
3160, 2100,
4.12
(s, 2 H)
7.02 (d, 2 H, 3.84 (s, 3 H)
J = 8.8) 6.4 (s, 2 H)
7.26 (d, 2 H, 8.8 (s, 1 H)
55.2 115.5, 122,
128.7, 147,
161.3
179.3 55.4
264 (M+, 3), 208
(100), 166 (8), 133
(25), 77 (8), 60
(16).
1600, 1498,
1248, 1106
J = 8.8)
126–128 3415, 3256,
3167, 2101,
4.13
(s, 2 H)
7.22 (d, 2 H, 2.39 (s, 3 H)
55
126.9, 130.7, 179.5 21.3
132.5, 140.9,
249 (M+ + 1, 1),
248 (M+, 4), 192
(100), 150 (12),
118 (22), 91 (24),
75 (12), 60 (24).
J = 8.9)
6.58 (s, 2 H)
1604, 1500,
1293, 1107
7.54 (d, 2 H, 8.76 (s, 1 H)
J = 8.9)
143.9
2d
2e
157–159 3426, 3282,
3170, 2112,
4.13
(s, 2 H)
7.26 (d, 2 H, 6.45 (s, 2 H)
55.3 128.4, 128.6, 179.6
130.6, 137.4,
270 (M+ + 2, 1),
268 (M+, 5), 214
(34), 212 (100),
170 (5), 139 (7),
137 (18), 111 (12),
102 (13), 75 (12),
60 (17).
J = 8.5)
8.65 (s, 1 H)
1604, 1488,
1268, 1092
7.52 (d, 2 H,
J = 8.5)
146.0
159–160 3428, 3282,
3170, 2114,
4.13
(s, 2 H)
7.19 (d, 2 H, 6.45 (s, 2 H)
54.6 124, 128.6,
132.3, 129.3,
145
178.9
314 (M+ + 2, 3),
312 (M+, 3), 258
(76), 256 (77), 183
(22), 181 (21), 155
(18), 157 (17),102
(66), 75 (74), 60
(100), 104 (3.6),
75 (24)
J = 8.4)
8.62 (s, 1 H)
1603, 1502,
1284, 1114
7.69 (d, 2 H,
J = 8.4)
a Satisfactory microanalyses obtained for all new compounds: C 0.22, H 0.17, N 0.21.
b Uncorrected.
(EI, ionizing voltage 70 eV) were determined using a Hewlett-Pack-
ard Model 5988A mass-selective detector equipped with a Hewlett-
Packard MS Chem Station. IR spectra of the compounds were re-
corded as dispersions in KBr or as film on NaCl plates, on a Perkin-
Elmer Model 583 spectrometer. 1H NMR (300 MHz) and13C NMR
(75.4 MHz) spectra were recorded on a Varian Unity 300 apparatus
with CDCl3 (1H, 13C) as internal standard. Melting points were de-
termined on a Reichert Thermovar microhot stage apparatus, and
are uncorrected. Elemental analyses were performed on a Perkin-
Elmer Model 240-B analyzer. Cyclic voltammetric potentials were
determined on a Metrohm apparatus Model 663 VA Stand and a
Scanner VA E612. The potential values are given in volts. Analyti-
cal HPLC was performed on a Hewlett-Packard 5033 instrument,
using a reverse phase column and 80% MeOH/H2O as the eluent.
All products were purified by silica gel 60 (230–400 mesh) using
toluene/MeOH (20:1) or (40:1) as eluent.
crude reaction mixture was detected by reaction with
monochloroacetic acid and sodium 1,2-naphthoquinone-
4-sulfonate.7 The total consumption of current, deter-
mined by coulometry, was 2 F mol-1.
These N-substituted imidazole-2-thiones can be obtained
in a one-pot reaction. It is not necessary to work at a very
low substrate concentration, as in the case of phenacyl
bromide semicarbazones because of the higher reactivity
of the C=S versus the C=O group towards the electrogen-
erated nucleophile.
Imidazolethiones have been used as polymerization
initiators8 or as vulcanization accelerators9 of neoprene
rubber. Some 4-aryl-2-imidazolethiones have been em-
ployed in medicine as antidepressants,10 other have shown
antimicrobial,11 antibacterial12 or analgesic13 activity.
Thus 4-phenylimidazolidine-2-thione is an inhibitor of
human alkaline phosphatase and diamine oxidase.14
Phenacyl bromides and the thiosemicarbazide are commercially
available and were used without purification. Phenacyl azides were
prepared according to the general method15 with the following mod-
ifications: solutions of phenacyl bromides (25 mmol) in MeOH (40
mL) were poured over an aqueous solution of NaN3 (1.63 g, 25
mmol, 40 mL) in an ice bath. After 2 h the phenacyl azides 1 were
obtained in almost quantitative yields by removing the solvent in
vacuum to dryness, extracting the crude mixture with Et2O (80 mL)
The electrolyses were carried out using an Amel potentiostat Model
552 with an electronic integrator Amel Model 721. Mass spectra
Synthesis 1999, No. 10, 1809–1813 ISSN 0039-7881 © Thieme Stuttgart · New York

1812
B. Batanero et al.
PAPER
Table 4 Compounds 3a–e Prepareda
Prod- Ar
uct
Yield mp
(%)
(mg)
IR (KBr or MS
(ºC)b film)
m/z (%)
n (cm–1)
1H NMR (CDCl3); d, J (Hz)
arom CH= NH others
13C NMR (CDCl3), d
CH3
CH= arom C=S CH3 others
3a
C6H5
78
130– 3059, 2924, 293 (M+, 2.22
7.27– 6.9
8.9
103.9 125.9, 169.2 12.9
(227) 132 1601, 1555, 53), 278 (s, 3 H) 7.4 (m, (s,
(br s,
1 H)
127.7,
128.2,
128.4,
128.6,
128.9,
134.8,
137.7,
145.9,
151.4
1443, 1325, (10), 193
1271, 1129, (53), 178
1053, 763, (100), 149
6 H)
1 H)
7.75–
7.8 (m,
4 H)
691, 631
(19), 134
(66), 133
(26), 118
(50), 103
(42), 91
(50), 77
(98).
3b
4-Me 70
165– 3109, 2926, 353 (M+, 2.2
6.92 (d, 6.75
(s,
J = 8.7) 1 H)
7.73 (d,
4 H,
8.75 3.82
(br s, (s, 3 H)
1 H) 3.85
(s, 3 H)
102
113.8, 169.3 12.8 55.3
114,
OC6H4 (247) 167 1608, 1568, 45), 205 (s, 3 H) 4 H,
1510, 1250, (12), 164
1175, 1029, (49), 148
127.2,
127.3,
128,
130.5,
145.7,
151.2,
159.4,
160.4
832
(100), 134
(27), 121
(16), 103
(8),92(35),
77 (40).
J = 8.7)
3c
4-Me 74
C6H4
142– 3028, 2923, 321 (M+, 2.16
(237) 145 1611, 1559, 62), 306 (s, 3 H) 7.26 (m, (s,
7.2–
6.84
9.25 2.36
(br s, (s, 3 H)
1 H) 2.38
(s, 3 H)
103
125.8, 169.4 12.9 21.2
129.1,
129.3,
129.4,
132.2,
135,
137.5,
139,
146.1,
151.5
1510, 1449, (7), 203
1340, 1273, (16), 189
1127, 1054, (22), 174
4 H)
7.6–
7.8 (m,
4 H)
1 H)
819, 729,
609
(11), 148
(53), 147
(39), 132
(100), 118
28), 103
(7),91(89),
77 (8), 65
(34).
3d
4-Cl
76
148– 3068, 2927, 363 (M+ + 2.22
7.3–
6.9
8.9
104.4 127.2, 169.1 12.7
C6H4
(275) 150 1600, 1556, 2,2), 361 (s, 3 H) 7.4 (m, (s,
(br s,
1 H)
128.7,
128.8,
132.2,
133.3,
133.5,
135.1,
136.1,
144.8,
150.4
1490, 1474, (M+, 2),
1340,1263, 291 (6),
1139, 1088, 289 (8),
1010, 841, 229 (35),
4 H)
1 H)
7.7–7.8
(m, 4 H)
726, 693
227 (91),
214 (34),
212 (100),
169 (16),
167 (46),
152 (48),
113 (16),
111 (45),
76 (57), 75
(64), 60
(46).
Synthesis 1999, No. 10, 1809–1813 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Electrosynthesis of N-Substituted Imidazole-2-thiones
1813
Table 4 (continued)
Prod- Ar
uct
Yield mp
(%)
(mg)
IR (KBr or MS
(ºC)b film)
m/z (%)
n (cm–1)
1H NMR (CDCl3); d, J (Hz)
arom CH= NH others
13C NMR (CDCl3), d
CH3
CH= arom C=S CH3 others
3e
4-Br
C6H4
76
213– 3045, 2922, 453 (M+ 2.18
7.46– 6.9
7.6 (m, (s,
8.8
(br s,
1 H)
104.5 121.7, 169.3 12.8
(342) 215 1600, 1550, +4), 451 (s,
123.3,
127.4,
131.6,
131.7,
132.8,
133.6,
136.5,
145,
1480, 1392, (M+ +
3 H)
4 H)
1 H)
1268, 1072, 2,12), 449
7.6–
7.7 (m,
4 H)
1004, 824, (M+, 7),
728
379 (17),
256 (25),
254 (25),
196 (44),
174(100),
157 (67),
155 (66),
102 (86),
77 (90),
150.3
76 (92),
51 (42).
a Satisfactory microanalyses obtained for all new compounds: C 0.31, H 0.16, N 0.21.
b Uncorrected.
and H2O (80 mL) and drying the ethereal solution with MgSO4.
References
Physical and spectroscopic properties of 1 are summarized in Table
2.
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Phenacyl Azide Thiosemicarbazones 2; General procedure
A solution of 1 (20 mmol) in MeOH (20 mL) was slowly added
dropwise in MeOH/H2O (80 mL, 1:1) and 5% HCl (2 mL) to a so-
lution of thiosemicarbazide (3.64 g, 40 mmol) under rapid stirring
below 10 ºC. The stirring was maintained during 24 h to complete
the reaction. The quantitatively precipitated solids 2a–e was isolat-
ed by suction and crystallized from EtOH. Physical and spectro-
scopic properties of 2 are summarized in Tables 3.
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Electrosynthesis of Imidazole-2-thiones 3; General Procedure
The electrochemical reductions were carried out using a concentric
cell with two compartments separated by a porous (D3) glass tubing
diaphragm and equipped with a magnetic stirrer. The solvent sup-
porting electrolyte (SSE) was DMF 0.05M in LiClO4. Anhyd solid
K2CO3 (2.0 g, 145 mmol) was added to the anodic compartment for
"in situ" neutralization of the generated HClO4. Anode: platinum.
Anolyte: LiClO4 (0.42 g, 4.0 mmol) in DMF (≤ 0.01% H2O) (10
mL). Cathode: mercury pool (20 cm2). Catholyte: LiClO4 (1.5 g, 14
mmol) and the corresponding thiosemicarbazone (2.0 mmol) in an-
hyd DMF (30 mL). A constant cathodic potential between –1.68
and –1.89 V vs. SCE (depending on the nature of 2) was applied.
The reaction time was about 1 h. At the end of the electrolysis (it
was considered finished when the current fell down to zero) the ca-
thodic solution was poured onto ice water (500 mL). After 12 h, the
precipitated solid was filtered and dried under reduced pressure and
chromatographed on a silica gel (17 × 2.5 cm) column, using tolu-
ene/MeOH (20:1) as eluent. Solid compounds were crystallized
from EtOH. Compounds 3a–e are described now for the first time
(Table 4).
Article Identifier:
1437-210X,E;1999,0,10,1809,1813,ftx,en;H00699SS.pdf
Acknowledgement
This study was supported by the Spanish Ministery of Education
and Culture. PB97-0753.
Synthesis 1999, No. 10, 1809–1813 ISSN 0039-7881 © Thieme Stuttgart · New York