Design, synthesis and antioxidant properties of ovothiol-derived 4-mercaptoimidazoles

Article abstract of DOI:10.1039/a703741d

Fourteen 4-mercaptoimidazoles derived from the naturally occurring family of antioxidants, the ovothiols, have been synthesized by cyclization of thioamides with trimethylsilyl trifluoromethane-sulfonate (triflate). These compounds have been assayed for their radical-scavenging activity.

Full text of DOI:10.1039/a703741d

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Design, synthesis and antioxidant properties of ovothiol-derived
4-mercaptoimidazoles
Vincent Zoete, Fabrice Bailly,* Jean-Pierre Catteau and Jean-Luc Bernier
Laboratoire de Chimie Organique Physique, URA CNRS 351, Bât C3, UST Lille I,
59655 Villeneuve d’Ascq, France
Fourteen 4-mercaptoimidazoles derived from the naturally occurring family of antioxidants, the
ovothiols, have been synthesized by cyclization of thioamides with trimethylsilyl trifluoromethane-
sulfonate (triflate). These compounds have been assayed for their radical-scavenging activity.
groups R2 and R5 could enhance the radical stabilization
according to a possible captodative effect.27,28
Here we report the synthesis of
mercaptoimidazole derivatives providing a large range of sub-
stitution patterns. The radical scavenging properties of the
newly synthesized compounds were evaluated by using 2,2-
diphenyl-1-picrylhydrazyl and Fremy’s salt radicals.
Introduction
Oxidative stress1–5 has been implicated in the initiation, main-
tenance and aggravation of diverse biological processes such as
ischemia, cataract, atherosclerosis, inflammation, ageing, car-
cinogenesis and even AIDS.6–8 These observations have led to
the design and evaluation of antioxidant agents.9–14 Of the
chemical structural features responsible for antioxidant activity,
phenol and thiol functions are frequently encountered.15–19
Our attention has recently turned to a new structure, ovo-
thiol,20,21 found in a family of 4-mercaptohistidines which pro-
a
series of 4-
Results and discussion
Synthesis
Fourteen imidazole-4-thiols were synthesized (Table 1). Except
for entry 4a, i.e. 1,5-dimethyl-4-mercaptoimidazole (reported as
DMI),26 each compound includes a phenyl ring which is
electron-donating when introduced on the N-1 atom (entries
4b–d) and electron-withdrawing when introduced on the C-2
atom (entries 4e–i and 4n). The C-5 atom is substituted either
with an electron-withdrawing phenyl group (entries 4j–l) or
with electron-donating phenyl groups (entries 4m and 4n). For
compounds 4e–n, N-1 was methyl substituted, as found in the
original ovothiol structure.
Several synthetic schemes are available for the preparation of
4-mercaptoimidazoles. The thiol function can be selectively
introduced at position 4 of a pre-formed imidazole ring by
nucleophilic displacement of a halogen atom with a sulfur
compound (sodium thiophosphate for example);29 nevertheless,
bromination of imidazoles is non-selective and renders this
scheme inadequate. An alternative method consists of condens-
ing appropriate synthons to obtain the 4-mercaptoimidazole
ring after a final cyclization. In this approach, imines can be
condensed with α-oxo thioamides,30,31 ethyl valeramidocyano-
acetate with alkyl (aryl) thiols32 and cyano amines with chloride
acids.33 Although 4-mercaptoimidazoles can also be obtained
by intramolecular addition to an isothiocyanate function,34 this
scheme does not allow easy and complete substitution of the
imidazole ring.
For our purposes, we have adopted the method developed by
Spaltenstein et al.33 (Scheme 1) since it has few steps, uses sim-
ple starting materials and allows for a wide variety of substitu-
tion patterns of the imidazole ring. The initial three steps gave
the intermediates 1–3 in high yield but the final key cyclization
was much more difficult. Spaltenstein et al. performed the cycli-
zation by treating the thioamides 3 at Ϫ78 ЊC with an excess
of triethylamine and trimethylsilyl trifluoromethanesulfonate
and then with a mixture of methanol and sodium fluoride.33
Attempts to repeat the cyclization under these conditions
failed. Several points are worth making. The cyclization sub-
strate must be extremely pure to avoid the formation of by-
products, with a 0.1  solution in dichloromethane providing the
best yields. The silane reagent efficiency was markedly depend-
ent on the experimental conditions. In each case trimethylsilyl
R1
Me
CO2H
R5
R2
N
N
NMe2
N
N
SH
Ovothiol C
SH
4-Mercaptoimidazoles
tect sea urchin eggs against hydrogen peroxide-induced oxid-
ation during fertilization.22,23 These compounds are believed to
mimic the glutathione peroxidase system (GPx).21–24 Such a
GPx-like activity was verified in vitro and could be attributed to
the large predominance of the thiolate form at physiological
pH, this form being active in a manner similar to that of the
selenolate form of the glutathione peroxidase enzyme (GPx).
Differences in protonation state, nucleophilicity, one-electron
donating ability and redox properties between 4-mercapto-
imidazoles and glutathione were also evaluated. This led to the
conclusion that the thiol groups of ovothiols and glutathione
are chemically distinct.25,26 The most striking difference
resides in the thiol acidity since the 1,5-dimethyl-4-mercapto-
imidazole and glutathione have pKa values of 2.3 and 8.6,
respectively.25
Given the current interest in the design of antioxidant mol-
ecules, we have developed a series of ovothiol derivatives having
various substituents on the imidazole ring. The zwitterionic
side-chain at position 5, which is not essential for the anti-
oxidant activity, was omitted to give us the possibility of
functionalizing this position. Phenyl rings with electron-
withdrawing groups were introduced at position 2, to favour the
stabilization of the thiolate negative charge and, as a con-
sequence, to potentiate the GPx-like activity. In contrast,
phenyl rings with electron-donating groups were used as sub-
stituents of the aromatic nitrogen atom at position 1 to stabilize
the thiyl form of the SH function.
It is believed indeed that the radical scavenging activity of the
4-mercaptoimidazoles results in the formation of thiyl radicals
which could be delocalized on the opposite N-1 nitrogen
atom.25 Moreover, the combined action of an electron-releasing
(donor) substituent R1 and electron-withdrawing (captor)
J. Chem. Soc., Perkin Trans. 1, 1997
2983

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Table 1 Yields for the synthesis of 4-mercaptoimidazoles from the thioamides 3 and their radical scavenging activities
Entry
R1
R2
R5
Yielda (%)
IC50 b/µ
kc/l molϪ1 sϪ1
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
Me
H
H
H
H
Me
H
H
H
H
H
H
H
45
22
39
25
35
40
25
20
40
21
25
30
63
13
2900
775
1345
2090
505
33
19
39
19
23
19
20
1310
23
0.065
0.025
0.020
—
3,4-di-MeOC6H3
4-MeOC6H4
2-MeOC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-ClC6H4
3-ClC6H4
2-ClC6H4
2-CF3C6H4
3-CF3C6H4
H
H
H
H
CF3
—
19.2
12.5
54.0
52.5
2.63
2.82
2.68
—
H
2-CF3C6H4
2-ClC6H4
4-ClC6H4
4-MeOC6H4
2-MeOC6H4
15.2
a Yields are evaluated after recrystallization. b Concentration of radical scavengers necessary to decrease by 50% the absorbance at 517 nm of a
solution in alcohol of 2,2-diphenyl-1-picrylhydrazyl radical (50 µ). c Second-order rate constants for the reaction of radical scavengers (300 µ) with
Fremy’s salt (300 µ) in a pH = 7.0 phosphate buffer (50 m). The disappearance of the nitroxide radical was followed by UV spectroscopy at 248 nm.
4d, 4e and 4m are unreactive.
Radical scavenging activity
O
C
R1
N
Two stable radicals, potassium nitrodisulfonate (Fremy’s salt)35
and the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH)36 were
used to assess the one-electron-donating abilities of the 4-
mercaptoimidazoles. The reduction of these free radicals was
followed spectrophotometrically at 248 and 517 nm for Fremy’s
salt and DPPH, respectively. Glutathione and vitamin C were
also tested as reference antioxidants.
R5CHO
R1NH2
NaCN
HR1N
NC
R2
i
ii
R5
R5
NC
1
2
iii
R1
R1
N
O
C
Reaction with the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH)
The reaction results are presented in Table 1. Compounds 4f–l
and 4n show the highest reducing effects, their activity being
similar to that of glutathione (IC50 = 26 µ). Compounds 4g, 4i
R5
R2
N
R2
iv
R5
H2N
C
N
SH
S
and 4k (IC50 = 19 µ) are nearly as potent as vitamin C (IC50
13 µ).
=
4
3
Scheme 1 Reagents and conditions: i, H2O–MeOH, HCl; ii, HCO2H–
Ac2O or R2COCl–Et3N; iii, H2S, EtOH–Et3N; iv, Me3SiOTf, CH2Cl2,
Et3N, Ϫ5 ЊC to Ϫ10 ЊC
Reaction with Fremy’s salt (Table 1)
Eight molecules exhibit activity higher than glutathione
(k = 0.23 l molϪ1 Ϫ1): vitamin C (k = 1650 l molϪ1 Ϫ1), com-
s
s
triflate (MeSiOTf) was used because chlorotrimethylsilane was
completely unreactive. tert-Butyl(dimethyl)silyl triflate was not
used because it failed to improve the cyclization yield. The reac-
tion temperature had to be rigorously controlled: whilst
Spaltenstein et al. reported reactions at Ϫ78 to 25 ЊC depending
on the substrates,33 we found that the cyclization is hindered at
very low temperatures whereas at temperatures >30 ЊC hydro-
gen sulfide was evolved with formation of the nitrile intermedi-
ates 1 as well as several by-products. The silane was, therefore,
slowly added to the reaction mixture for 30 min at Ϫ10 ЊC to
Ϫ5 ЊC after which it was continued for 2 h at Ϫ10 ЊC to 0 ЊC.
The optimal reactivity of the silane around Ϫ10 ЊC is likely due
to the particular structures of the substrates containing aro-
matic rings.33 Since for entries 4b, 4g, 4h and 4i, 4-mercapto-
imidazoles and oxidized disulfide compounds form simul-
taneously, cyclizations must be complete in 1 h to limit the
proportion of disulfides. To optimize the reaction rates 6 and 4
equiv. of triethylamine and Me3SiOTf, respectively, compared
to the thioamide 3 concentration, were required. If the reactiv-
ity of the silane was too low, 3 and 2 equiv. of NEt3 and Me3Si-
OTf could be further added after the reaction had run for 1 h.
Spaltenstein et al. used sodium fluoride after treatment with
the silane.33 This nucleophilic reagent, which easily cleaves silyl
ethers, failed to improve the cyclization rate. Table 1 gives the
yields for the conversion of the intermediate compounds 3 into
final 4-mercaptoimidazoles 4 and shows that the cyclization is
the limiting step of the synthetic scheme with yields in the range
13–63% after recrystallization. The identity of the products as
the thiol tautomers was unambiguously demonstrated by NMR
spectroscopy which revealed the presence of the thiol proton at
2–2.5 ppm.
pounds 4f–i and 4n and compounds 4j–l with slower kinetics.
All other compounds are far less reactive than glutathione.
In both tests, compounds 4f–i and 4n are the most active
imidazole derivatives. Thus, compounds bearing a strong elec-
tron-withdrawing group at C-2 appear as the most promising
ones in the antioxidant family of 4-mercaptoimidazoles. Their
reactivity towards oxygen-derived species is currently being
investigated.
Experimental
General
All starting materials were purchased from Aldrich. Kieselgel
60 (70–230 mesh) and (40–63 mesh) of Merck were used for
column chromatography and flash column chromatography,
respectively. Mass spectral analyses were performed on a Rib-
ermag R 10-10 mass spectrometer (EI) with a kinetic energy of
70 eV or a Finnigan MAT Vision 2000 mass spectrometer
(MALDI-TOF). High-resolution mass spectra were recorded
on a Kratos MS80 instrument. 1H NMR spectra were recorded
on a Bruker AM 300 WB (300 MHz). Chemical shifts were
reported from tetramethylsilane as an internal reference and are
given in δ/ppm units; coupling constants are given in Hz. UV
measurements were made on
a UVIKON 932 spectro-
photometer. Elemental analyses were determined by the CNRS
microanalysis center.
Synthesis of the cyano amines 1
For entries 4e–i, the cyanoamine 1e–i i.e. (cyanomethyl)methyl-
amine was commercially available as the hydrochloride salt.
2984
J. Chem. Soc., Perkin Trans. 1, 1997

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Otherwise the intermediate compounds 1 were easily obtained
on a multigram scale (1–5 g) by the condensation of appropri-
ate aldehydes, amines and sodium cyanide. Compounds 1c–d
and 1j–n were prepared by the method described for 1b and 1a
respectively.
and 1250; δH(CDCl3) 1.82 (1 H, br s, NH), 2.59 (3 H, s, CH3),
3.89 (3 H, s, OCH3), 4.84 (1 H, d, J 9.0, CH), 6.87–7.05 (2 H, m,
ArH) and 7.28–7.48 (2 H, m, ArH).
Synthesis of the cyano amides 2
2-Methylamino-2-methylacetonitrile 1a. Acetaldehyde (3.35
cm3, 59.9 mmol) was added dropwise to a solution of sodium
cyanide (2.94 g, 59.9 mmol) and methylamine hydrochloride
(4.04 g, 59.9 mmol) in water (20 cm3) at 0 ЊC. The solution was
stirred for 3 h at 0 ЊC and for 30 min at room temperature. After
extraction with CH2Cl2, drying (Na2SO4) and concentration in
vacuo of the extract gave 1a as a yellow oil (4.53 g, 90%)
(Found: Mϩ, 84.0683. C4H8N2 requires M, 84.0687);
νmax(KBr)/cmϪ1 3340, 3000–2800, 2230, 1450 and 1140;
δH(CDCl3) 1.20 (1 H, br, s, NH), 1.42 (3 H, d, J 7.0, CH3CH),
2.43 (3 H, s, CH3NH) and 3.40 (1 H, q, J 7.0, CH).
2-(3,4-Dimethoxyphenylamino)acetonitrile 1b. Formaldehyde
(37% solution; 2.40 cm3, 32.0 mmol) was added to a mixture of
3,4-dimethoxyaniline (4.90 g, 32.0 mmol) in methanol (40 cm3)
and sodium cyanide (1.57 g, 32.0 mmol) in water (20 cm3) at
0 ЊC in presence of 1 equiv. of hydrochloric acid (6  solution;
5.4 cm3). The mixture was stirred for 3 h at 0 ЊC and then over-
night at room temperature. Extraction of the solution with
CH2Cl2, followed by drying (Na2SO4) and concentration in
vacuo of the extract afforded 1b as a brown solid (5.9 g, 96%),
mp 110 ЊC (Found: Mϩ, 192.0899. C10H12N2O2 requires M,
192.0899); νmax(KBr)/cmϪ1 3300, 3080–2800, 2240, 1620, 1500,
1450 and 1230; δH(CDCl3) 3.60 (1 H, s, NH), 3.81 (6 H, 2 s, 2
OCH3), 3.98 and 4.07 (2 H, 2 s, CH2), 6.23–6.31 (2 H, m, ArH)
and 6.70 and 6.79 (1 H, 2 s, ArH).
2-(4-Methoxyphenylamino)acetonitrile 1c. This compound
was prepared in a similar manner to that reported for the syn-
thesis of 1b except that an excess of each reactant (1.2 equiv.)
relative to p-anisidine was used. It was a brown solid (61%),
mp 72 ЊC (Found: Mϩ, 162.0797. C9H10N2O requires M,
162.0793); νmax(KBr)/cmϪ1 3360, 3080–2810, 2250, 1600, 1510
and 1250; δH(CDCl3) 3.69 (1 H, t, J 7.2, NH), 3.75 (3 H, s,
OCH3), 4.05 (2 H, d, J 7.2), 6.67 (2 H, d, J 4.3, ArH) and 6.85 (2
H, d, J 4.3, ArH).
2-(2-Methoxyphenylamino)acetonitrile 1d. Pink solid (94%),
mp 68 ЊC (lit.,37 no mp given) (Found: Mϩ, 162.0790. C9H10N2O
requires M, 162.0793); νmax(KBr)/cmϪ1 3400, 3080–2840, 2240,
1600, 1510 and 1220; δH(CDCl3) 3.75 (3 H, s, OCH3), 4.10 (2 H,
d, J 7.0, CH2), 4.55 (1 H, t, J 7.0, NH) and 6.68–6.98 (4 H, m,
ArH).
2-(Methylamino)-2-(2-trifluoromethylphenyl)acetonitrile 1j.
Yellow oil (77%) (Found: Mϩ, 214.0724. C10H9F3N2 requires M,
214.0718); νmax(KBr)/cmϪ1 3340, 3060–2800, 2240, 1605, 1450,
1310 and 1240; δH(CDCl3) 1.71 (1 H, br s, NH), 2.52 (3 H, s,
CH3), 4.95 (1 H, s, CH) and 7.39–7.82 (4 H, m, ArH).
2-(Methylamino)-2-(2-chlorophenyl)acetonitrile 1k. Yellow oil
(91%) (Found: Mϩ, 180.0451. C9H9ClN2 requires M, 180.0454);
νmax(KBr)/cmϪ1 3320, 3080–2720, 2190, 1600, 1450 and 1280;
δH(CDCl3) 1.62 (1 H, br s, NH), 2.59 (3 H, s, CH3), 5.05 (1 H, s,
CH), 7.29–7.47 (3 H, m, ArH) and 7.60 (1 H, m, ArH).
2-(Methylamino)-2-(4-chlorophenyl)acetonitrile 11. Yellow
oil (89%) (Found: Mϩ, 180.0455. C9H9ClN2 requires M,
180.0454); νmax(KBr)/cmϪ1 3340, 3100–2800, 2240, 1600, 1590
and 1250; δH(CDCl3) 1.58 (1 H, br s, NH), 2.55 (3 H, s, CH3),
4.73 (1 H, s, CH), 7.38 (2 H, d, J 5.3, ArH) and 7.45 (2 H,
d, J 5.3, ArH).
2-(Methylamino)-2-(4-methoxyphenyl)acetonitrile 1m. Yellow
oil (91%) (Found: Mϩ, 176.0954. C10H12N2O requires M,
176.0949); νmax(KBr)/cmϪ1 3340, 3100–2800, 2230, 1600, 1460
and 1260; δH(CDCl3) 1.58 (1 H, br s, NH), 2.57 (3 H, s, NCH3),
3.82 (3 H, s, OCH3), 4.74 (1 H, s, CH), 7.37 (2 H, d, J 4.7, ArH)
and 7.47 (2 H, d, J 4.7, ArH).
2-(Methylamino)-2-(2-methoxyphenyl)acetonitrile 1n. Yellow
oil (95%) (Found: Mϩ, 176.0958. C10H12N2O requires M,
176.0950); νmax(KBr)/cmϪ1 3340, 3060–2800, 2230, 1600, 1460
The cyano amides 2 were easily obtained on a multigram scale
(1–5 g). The intermediate compounds 2a–d and 2j–m (R2 = H)
were prepared from the corresponding precursor molecules 1a–
d and 1j–m by formylation with acetic formic anhydride; 2e–i
(R2 = Ar) were prepared by condensation of 1e–i with
appropriate chloride acids whilst 2n was prepared by conden-
sation of 1n with trifluoroacetic anhydride.
N-(2-Cyanoethyl)-N-methylformamide 2a. Acetic anhydride
(5.35 g, 52.4 mmol) was added dropwise to a 96% formic acid
solution (9.87 cm3, 251 mmol) at 0 ЊC. The mixture was stirred
for 10 min at 0 ЊC and then 1 h at room temperature. The mixed
anhydride was then treated dropwise with the cyano amine 1a
(1.10 g, 13.1 mmol) in CH2Cl2 (10 cm3) at 0 ЊC. Stirring was
stopped when TLC analysis showed the reaction to be complete
(1 h). After several washings with 1  aq. NaOH and water,
drying of the organic layer (Na2SO4) and removal of the volat-
iles in vacuo gave 2a (1.08 g, 74%) as a brown oil (Found: Mϩ,
112.0648. C5H8N2O requires M, 112.0637); νmax(KBr)/cmϪ1
3160–2840, 2260 and 1680; δH(D2O) 1.25 and 1.40 (3 H, 2 d,
ratio 2:1, J 7.0, CH3CH), 2.68 and 2.80 (3 H, 2 s, ratio 1:2,
NCH3), 4.57 and 5.22 (1 H, 2 q, ratio 1:2, J 7.0, CH) and 7.72
and 7.88 (1 H, 2 s, ratio 2:1, HCO).
N-(Cyanomethyl)-N-(3,4-dimethoxyphenyl)formamide
2b.
Brown solid (86%), mp 100–102 ЊC (Found: Mϩ, 220.0844.
C11H12N2O3 requires M, 220.0848); νmax(KBr)/cmϪ1 3100–
2810, 2240 and 1680; δH(CDCl3) 3.90 (6 H, 1 s, 2 OCH3), 4.59 (2
H, s, CH2), 6.59–6.92 (3 H, m, ArH) and 8.29 (1 H, s, HCO).
N-(Cyanomethyl)-N-(4-methoxyphenyl)formamide 2c. Brown
oil (83%) (Found: Mϩ, 190.0744. C10H10N2O2 requires M,
190.0742); νmax(KBr)/cmϪ1 3140–2800, 2250 and 1680;
δH(CDCl3) 3.80 (3 H, s, OCH3), 4.60 (2 H, s, NCH2), 6.95 (2 H,
d, J 9.0, ArH), 7.15 (2 H, d, J 9.0, ArH) and 8.25 (1 H, s,
HCO).
N-(Cyanomethyl)-N-(2-methoxyphenyl)formamide 2d. The
reaction was slow and the mixture needed to be stirred for 3 h
at 0 ЊC and 24 h at room temperature. Pink solid (70%), mp
62–64 ЊC (Found: Mϩ, 190.0747. C10H10N2O2 requires M,
190.0742); νmax(KBr)/cmϪ1 3120–2840, 2250 and 1685;
δH(CDCl3) 3.88 (3 H, s, OCH3), 4.57 (2 H, s, NCH2), 7.05 (2 H,
m, ArH), 7.18 (1 H, m, ArH), 7.40 (1 H, m, ArH) and 8.15 (1
H, s, HCO).
N-(Cyanomethyl)-N-methyl-4-chlorobenzamide
2e.
4-
Chlorobenzoyl chloride (1.00 g, 5.7 mmol) and triethylamine
(0.79 cm3, 5.7 mmol) in dichloromethane (5 cm3) were added
dropwise at 0 ЊC to a solution of (methylamino)acetonitrile
hydrochloride (0.61 g, 5.7 mmol) and triethylamine (0.79 cm3,
5.7 mmol) in CH2Cl2 (5 cm3). After 2 h at 0 ЊC and 2 h a room
temperature, the mixture was washed successively with 0.1  aq.
HCl, 0.1  aq. NaOH and water. The organic layer was dried
(Na2SO4) and concentrated in vacuo to afford 2e as a white solid
(1.02 g, 85%), mp 49 ЊC (lit.,38 mp 42–44 ЊC) (Found: Mϩ,
208.0405. C10H9ClN2O requires M, 208.0403); νmax(KBr)/cmϪ1
3140–2840, 2240 and 1640; δH(CDCl3) 3.09 (3 H, s, NCH3),
4.38 (2 H, br s, NCH2) and 7.38 (4 H, m, ArH).
N-(Cyanomethyl-N-methyl-3-chlorobenzamide 2f. White solid
(91%), mp 54 ЊC (Found: Mϩ, 208.0407. C10H9ClN2O requires
M, 208.0403); νmax(KBr)/cmϪ1 3120–2820, 2250 and 1650;
δH(CDCl3) 3.19 (3 H, s, NCH3), 4.43 (2 H, s, NCH2) and 7.29–
7.48 (4 H, m, ArH).
N-(Cyanomethyl)-N-methyl-2-chlorobenzamide 2g. Yellow oil
(93%) (Found: Mϩ, 208.0404. C10H9ClN2O requires M,
208.0403); νmax(KBr)/cmϪ1 3140–2810, 2230 and 1650;
δH(CDCl3) 2.95 and 3.19 (3 H, 2 s, ratio 4:1, NCH3), 4.05
and 4.52 (2 H, 2 s, ratio 1:4, NCH2) and 7.25–7.45 (4 H, m,
ArH).
J. Chem. Soc., Perkin Trans. 1, 1997
2985

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N-(Cyanomethyl)-N-methyl-2-trifluoromethylbenzamide 2h.
Yellow oil (90%) (Found: Mϩ, 242.0674. C11H9F3N2O requires
M, 242.0667); νmax(KBr)/cmϪ1 3130–2820, 2240 and 1650;
δH(CDCl3) 2.90 (3 H, s, NCH3), 4.32–4.75 (2 H, m, NCH2)
and 7.25–7.72 (4 H, m, ArH).
N-(Cyanomethyl)-N-methyl-3-trifluoromethylbenzamide 2i.
Yellow oil (95%) (Found: Mϩ, 242.0665. C11H9F3N2O requires
M, 242.0667); νmax(KBr)/cmϪ1 3120–2840, 2250 and 1650;
δH(CDCl3) 3.10 (3 H, s, NCH3), 4.45 (2 H, 2 br s, NCH2) and
7.50–7.65 (4 H, m, ArH).
N-[1-Cyano-1-(2-trifluoromethylphenyl)methyl]-N-methyl-
formamide 2j. Brown oil (92%) (Found: Mϩ, 242.0668.
C11H9F3N2O requires M, 242.0667); νmax(KBr)/cmϪ1 3140–
2770, 2250 and 1680; δH(CDCl3) 2.71 (3 H, s, NCH3), 5.50, 6.15
(1 H, 2 s, ratio 1:2, CH), 7.52–7.77 (3 H, m, ArH), 7.90 (1 H, m,
ArH) and 8.06 and 8.30 (1 H, 2 s, ratio 2:1, HCO).
N-[1-Cyano-1-(2-chlorophenyl)methyl]-N-methylformamide
2k. Brown oil (66%) (Found: Mϩ, 208.0403. C10H9ClN2O
requires M, 208.0403); νmax(KBr)/cmϪ1 3150–2790, 2245 and
1680; δH(CDCl3) 2.75 (3 H, s, NCH3), 6.05, 6.89 (1 H, 2 s, ratio
2:3, CH), 7.39–7.49 (3 H, m, ArH), 7.77 (1 H, m, ArH) and
8.11 and 8.42 (1 H, 2 s, ratio 3:2, HCO).
(1 H, s, HCO); m/z (EI) 254 (Mϩ, 30), 191 (33), 160 (35), 129
(39), 83 (100) and 64 (70).
2-[N-Formyl-N-(4-methoxyphenyl)amino]thioacetamide 3c.
H2S was bubbled through the reaction mixture after which the
crude product was purified by column chromatography on silica
gel (solvent system: CHCl3–MeOH, 95:5) to give 3c as a
brown solid (60%), mp 104 ЊC (Found: Mϩ, 224.0622.
C10H12N2O2S requires M, 224.0619); νmax(KBr)/cmϪ1 3320,
3170, 1640, 1510 and 1450; δH(CDCl3) 3.80 (3 H, s, OCH3), 4.75
(2 H, s, NCH2), 6.95 (2 H, d, J 9.0, ArH), 7.15 (2 H, d, J 9.0,
ArH), 7.55 (1 H, br s, CSNH2), 8.05 (1 H, br s, CSNH2) and
8.45 (1 H, s, HCO); m/z (EI) 224 (Mϩ, 40), 161 (35) and 130
(100).
2-[N-Formyl-N-(2-methoxyphenyl)amino]thioacetamide 3d.
Brown crystals from CHCl3–MeOH (95:5) (94%); mp 152–
154 ЊC (Found: Mϩ, 224.0614. C10H12N2O2S requires M,
224.0619); νmax(KBr)/cmϪ1 3340, 3150, 1680, 1500 and 1350;
δH(CDCl3) 3.87 (3 H, s, OCH3), 4.75 (2 H, s, NCH2), 7.00–7.40
(4 H, m, ArH), 7.55 (1 H, br s, CSNH2), 8.20 (1 H, s, HCO) and
8.27 (1 H, br s, CSNH2); m/z (EI) 224 (Mϩ, 61), 161 (45) and
130 (100).
2-[N-(4-Chlorobenzoyl)-N-methylamino]thioacetamide
3e.
N-[Cyano-(4-chlorophenyl)methyl]-N-methylformamide
2l.
White solid (90%), mp 146–148 ЊC (Found: Mϩ, 242.0281.
C10H11ClN2OS requires M, 242.0280); νmax(KBr)/cmϪ1 3440,
3290, 3190, 1600, 1490 and 1405; δH(CDCl3) 3.10 (3 H, s, N-
CH3), 4.50 (2 H, s, NCH2), 7.41 (4 H, s, ArH), 7.70 (1 H, s,
CSNH2) and 8.47 (1 H, s, CSNH2); m/z (EI), 242 (Mϩ, 100),
208 (98), 182 (99), 168 (42), 156 (34), 141 (74), 111 (81), 103
(53), 87 (50), 75 (87) and 42 (90).
Brown oil (95%) (Found: Mϩ, 208.0409. C10H9ClN2O requires
M, 208.0403); νmax(KBr)/cmϪ1 3160–2800, 2245 and 1680;
δH(CDCl3) 2.75 (3 H, s, NCH3), 6.05 and 6.86 (1 H, 2 s, ratio
2:3, CH), 7.38–7.49 (3 H, m, ArH), 7.77 (1 H, m, ArH) and
8.09 and 8.41 (1 H, 2 s, ratio 3:2, HCO).
N-[Cyano-(4-methoxyphenyl)methyl]-N-methylformamide2m.
Brown oil (84%) (Found: Mϩ, 204.0896. C11H12N2O2 requires
M, 204.0899); νmax(KBr)/cmϪ1 3080–2800, 2240 and 1680;
δH(CDCl3) 2.75 and 2.81 (3 H, 2 s, ratio 1:3, NCH3), 3.80 (3 H,
1 s, OCH3), 5.74 and 6.73 (1 H, 2 s, ratio 1:3, CH), 6.91 (2 H, d,
J 5.1, ArH), 7.31 (2 H, d, J 5.1, ArH) and 8.10 and 8.35 (1 H, 2 s,
ratio 3:1, HCO).
2-[N-(3-Chlorobenzoyl)-N-methylamino]thioacetamide
3f.
White solid (90%), mp 109 ЊC (Found: Mϩ, 242.0285.
C10H11ClN2OS requires M, 242.0280); νmax(KBr)/cmϪ1 3360,
3300, 3180, 1610 and 1420; δH(CDCl3) 3.12 (3 H, s, NCH3),
4.50 (2 H, s, NCH2), 7.30–7.48 (4 H, m, ArH), 7.53 (1 H, br s,
CSNH2) and 8.48 (1 H, br s, CSNH2).
N-[Cyano-(2-methoxyphenyl)methyl]-N-methyltrifluoroacet-
amide 2n. Trifluoroacetic anhydride (1.072 g, 5.10 mmol) was
added dropwise at 0 ЊC to a solution of the amine 1n (0.768 g,
4.26 mmol) and triethylamine (1.80 cm3, 12.76 mmol) in di-
chloromethane (60 cm3). The mixture was stirred for 4 h at
0 ЊC and then overnight at room temperature. After this it was
washed successively with 1  aq. HCl and water, dried (Na2SO4)
and concentrated in vacuo to afford 2n as a brown oil (0.868 g,
69%) (Found: Mϩ, 272.0775. C12H11F3N2O2 requires M,
272.0772); νmax(KBr)/cmϪ1 3100–2800, 2240 and 1680;
δH(CDCl3) 2.89 (3 H, s, NCH3), 3.83 (3 H, s, OCH3), 6.90 (1 H,
s, CH), 6.92–7.10 (2 H, m, ArH), 7.40–7.50 (1 H, m, ArH) and
7.61 (1 H, m, ArH).
2-[N-(2-Chlorobenzoyl)-N-methylamino]thioacetamide
3g.
Beige solid (95%), mp 115–117 ЊC (Found: Mϩ, 242.0277.
C10H11ClN2OS requires M, 242.0280); νmax(KBr)/cmϪ1 3280,
3120, 1615, 1450 and 1400; δH(CDCl3) 3.00 (3 H, s, NCH3),
4.30–4.75 (2 H, m, NCH2), 7.30–7.45 (4 H, m, ArH), 7.55 (1 H,
br s, CSNH2) and 8.15 (1 H, br s, CSNH2); m/z (EI) 242 (100),
208 (95), 156 (42), 141 (82), 103 (60), 75 (90) and 42 (85).
2-[N-(2-Trifluoromethylbenzoyl)-N-methylamino]thioacet-
amide 3h. Beige solid (91%), mp 118–120 ЊC (Found: Mϩ,
276.0548. C11H11F3N2OS requires M, 276.0544); νmax(KBr)/
cmϪ1 3380, 3280, 3200, 1610 and 1395; δH([2H6]-DMSO) 2.89
and 2.95 (3 H, 2 s, ratio 1:1, NCH3), 4.05 and 4.35 (2 H, 2 s,
ratio 1:1, NCH2), 7.60–7.75 (4 H, m, ArH), 9.25 (1 H, br s,
CSNH2) and 9.80 (1 H, br s, CSNH2); m/z (EI) 276 (100) and
242 (98).
Synthesis of the thioamides 3
The thioamides 3 were obtained on a multigram scale by the
method described for 3a.
2-[N-(3-Trifluoromethylbenzoyl)-N-methylamino]thioacet-
amide 3i. Beige solid (85%), mp 145 ЊC (Found: Mϩ, 276.0541.
C11H11F3N2OS requires M, 276.0544); νmax(KBr)/cmϪ1 3350,
3300, 3180, 1610 and 1340; δH(CDCl3) 3.10 (3 H, s, NCH3),
4.50 (2 H, s, NCH2), 7.42–7.60 (4 H, m, ArH), 7.65 (1 H, br s,
CSNH2) and 8.30 (1 H, br s, CSNH2); m/z (EI) 276 (Mϩ, 13),
173 (100), 145 (39) and 75 (21).
2-(N-Formyl-N-methylamino)-2-(2-trifluoromethylphenyl)-
thioacetamide 3j. Brown crystals from CHCl3 (50%), mp 156–
158 ЊC (Found: Mϩ, 276.0550. C11H11F3N2OS requires M,
276.0544); νmax(KBr)/cmϪ1 3240, 3100, 1670, 1380 and 1310;
δH([2H6]-DMSO) 2.62 (3 H, s, NCH3), 5.80 and 6.30 (1 H, 2 s,
ratio 1:2, CH), 7.57–7.83 (4 H, m, ArH), 7.99 and 8.15 (1 H, 2
s, ratio 2:1, HCO), 9.30 and 9.45 (1 H, 2 s, ratio 2:1, CSNH2)
and 10.03 and 10.15 (1 H, 2 s, ratio 2:1, CSNH2).
2-(N-Formyl-N-methylamino)-2-methylthioacetamide
3a.
Hydrogen sulfide was bubbled into a solution of the cyano
amide 2a (2.32 g, 20.7 mmol) and triethylamine (28.9 cm3, 20.7
mmol) in ethanol (20 cm3) until TLC analysis confirmed the
absence of cyanide (20 min). Removal of the volatile com-
ponents of the mixture in vacuo gave 3a as a dark brown solid
(2.57 g, 85%), mp 80–82 ЊC (Found: Mϩ, 146.0515. C5H10N2OS
requires M, 146.0514); νmax(KBr)/cmϪ1 3400–3200, 1660 and
1225; δH(D2O) 1.53, 1.63 (3 H, 2 d, ratio 1:1.5, J 7.2, CH3CH),
2.79 and 3.05 (3 H, 2 s, ratio 1.5:1, CH3N), 4.56 and 4.98 (1 H,
2 q, ratio 1.5:1, CH) and 8.07 and 8.21 (1 H, 2 s, ratio 1:1.5,
HCO); m/z (EI) 146 (Mϩ, 68), 86 (87) and 58 (100).
2-[N-Formyl-N-(3,4-dimethoxyphenylamino)]thioacetamide
3b. Brown crystals from CHCl3–MeOH 95:5 (82%), mp 142 ЊC
(Found: Mϩ, 254.0731. C11H14N2O3S requires M, 254.0725);
νmax(KBr)/cmϪ1 3340, 3150, 1635, 1510 and 1360; δH(CDCl3) 3.89
(6 H, s, 2 OCH3), 4.74 (2 H, s, NCH2), 6.67–6.96 (3 H, m, ArH),
7.60 (1 H, br s, CSNH2), 8.24 (1 H, br s, CSNH2) and 8.47
2-(N-Formyl-N-methylamino)-2-(2-chlorophenyl)thioacet-
amide 3k. White solid (83%), mp 132–134 ЊC (Found: Mϩ,
242.0283. C10H11ClN2OS requires M, 242.0280); νmax(KBr)/
cmϪ1 3280, 3120, 1680 and 1400; δH(CDCl3) 2.84 (3 H, s,
NCH3), 5.85 and 6.47 (1 H, 2 s, ratio 2:3, CH), 7.28–7.55
2986
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(4 H, m, ArH), 7.70 (1 H, br s, CSNH2), 7.87 (1 H, br s, CSNH2)
and 8.13 and 8.20 (1 H, 2 s, ratio 2:3, HCO).
2830, 1605 and 1510; λmax(H2O)/nm 198 and 246; δH([2H6]-
DMSO) 3.05 (1 H, br s, SH), 3.70 (3 H, s, OCH3), 7.07 (2 H, d, J
8.8, ArH), 7.69 (2 H, d, J 8.8, ArH), 8.15 (1 H, s, 2-H) and 8.75
(1 H, s, 5-H); m/z (EI) 206 (Mϩ, 93), 179 (10), 134 (51), 77 (36)
and 64 (100).
1-(2-Methoxyphenyl)-4-mercaptoimidazole 4d. Flash chrom-
atography (solvent system: ethyl acetate) gave 4d as a beige
solid (25%), mp 137–138 ЊC (Found: C, 58.3; H, 4.8; N, 13.5;
S, 15.5. C10H10N2OS requires C, 58.2; H, 4.9; N, 13.6; S,
15.6%); νmax(KBr)/cmϪ1 3100, 3030–2840, 1600 and 1515;
λmax(H2O)/nm 197 and 275; δH(CDCl3) 2.10 (1 H, br s, SH),
3.75 (3 H, s, OCH3), 6.90–7.34 (4 H, m, ArH), 7.35 (1 H, s,
2-H) and 7.75 (1 H, s, 5-H); m/z (EI), 206 (Mϩ, 100) and 134
(65).
1-Methyl-2-(4-chlorophenyl)-4-mercaptoimidazole 4e. Flash
chromatography (solvent system: CH2Cl2–MeOH, 95:5) gave
an orange solid (35%), mp 196–198 ЊC (Found: C, 53.3; H, 4.1;
N, 12.5; S, 14.3. C10H9ClN2S requires C, 53.5; H, 4.0; N, 12.5; S,
14.3%); νmax(KBr)/cmϪ1 3100, 2920, 2820, 2690, 1605 and 1495;
λmax(H2O)/nm 195 and 258; δH(CDCl3) 2.03 (1 H, br s, SH), 3.69
(3 H, s, 1-CH3), 7.12 (1 H, s, 5-H), 7.30–7.39 (2 H, d, J 7.5, ArH)
and 7.45–7.52 (2 H, d, J 7.5, ArH); m/z (EI), 224 (Mϩ, 100), 86
(98) and 42 (95).
1-Methyl-2-(3-chlorophenyl)-4-mercaptoimidazole 4f. This
compound was obtained by recrystallization of the crude prod-
uct from ethyl acetate as a beige solid (40%), mp 182–184 ЊC
(Found: C, 53.2; H, 4.2; N, 12.4; S, 14.1. C10H9ClN2S requires C,
53.5; H, 4.0; N, 12.5; S, 14.3%); νmax(KBr)/cmϪ1 3120, 2900,
2800, 2690, 1592 and 1490; λmax(H2O)/nm 198 and 276;
δH(CDCl3) 1.91 (1 H, br s, SH), 3.73 (3 H, s, 1-CH3), 7.13 (1 H,
s, 5-H) and 7.29–7.50 (4 H, m, ArH); m/z (MALDI-TOF) 225
(Mϩ, 45).
2-(N-Formyl-N-methylamino)-2-(4-chlorophenyl)thio-
acetamide 3l. White solid (83%), mp 144 ЊC (Found: Mϩ,
242.0288. C10H11ClN2OS requires M, 242.0280); νmax(KBr)/
cmϪ1 3300, 3120, 1680 and 1400; δH(CDCl3) 2.83 (3 H, s,
NCH3), 5.85 and 6.47 (1 H, 2 s, ratio 2:3, CH), 7.30–7.70 (4 H,
m, ArH), 7.75 (1 H, br s, CSNH2), 7.90 (1 H, br s, CSNH2) and
8.13 and 8.18 (1 H, 2 s, ratio 2:3, CHO).
2-(N-Formyl-N-methylamino)-2-(4-methoxyphenyl)thio-
acetamide 3m. White solid (89%), mp 123 ЊC (Found: Mϩ,
238.0772. C11H14N2O2S requires M, 238.0776); νmax(KBr)/cmϪ1
3320, 3160, 1640, 1505 and 1400; δH(CDCl3) 2.84 and 2.90 (3 H,
2 s, ratio 1:3, NCH3), 3.83 (3 H, s, OCH3), 5.48, 6.24 (1 H, 2 s,
ratio 1:3, CH), 6.92 (2 H, d, J 8.6, ArH), 7.34 (2 H, d, J 8.6,
ArH), 7.77 (1 H, br s, CSNH2), 7.92 (1 H, br s, CSNH2) and
8.18 (1 H, s, HCO).
2-(N-Trifluoroacetyl-N-methylamino)-2-(2-methoxyphenyl)-
thioacetamide 3n. Yellow solid (45%), mp 117–119 ЊC (Found:
Mϩ, 306.0652. C12H13F3N2O2S requires M, 306.0650);
νmax(KBr)/cmϪ1 3300, 3160, 1670 and 1465; δH(CDCl3) 2.89 (3
H, s, NCH3), 3.83 (3 H, s, OCH3), 6.49 (1 H, s, CH), 6.85–7.05
(2 H, m, ArH), 7.06 (1 H, br s, CSNH2), 7.34–7.50 (2 H, m,
ArH) and 7.74 (1 H, br s, CSNH2).
Synthesis of the 4-mercaptoimidazoles
For the very moisture-sensitive cyclization steps, dry glassware
was obtained by oven-drying and assembly under Ar; an inert
atmosphere was obtained with a stream of dry Ar. Calcium
chloride cartridges were placed at the inlet and outlet of the
reaction apparatus. Dichloromethane and triethylamine were
distilled from calcium hydride. Compounds 4b–n were prepared
by the method described for 4a. Except for 4a, the best yields
were obtained with small-scale experiments [thioamides (1–2
g)].
1,5-Dimethyl-4-mercaptoimidazole4a.Trimethylsilyltrifluoro-
methanesulfonate (12.2 g, 54.8 mmol) was added dropwise
over 30 min to a solution of the thioamide 3a (2.0 g, 13.7 mmol)
and triethylamine (8.32 g, 82.3 mmol) in CH2Cl2 (140 cm3) at
(Ϫ10 ЊC to Ϫ5 ЊC). After 2 h at (Ϫ5 ЊC to 0 ЊC) the mixture was
washed with water, dried and evaporated in vacuo. The residue
was flash-chromatographed on silica gel (solvent system:
CH2Cl2–MeOH, 80:20) to yield 4a as a brown oil. Recrystal-
lization of this from ethyl acetate afforded the pure imidazole as
a yellow oil (0.79 g, 45%) (Found: C, 46.9; H, 6.3; N, 21.8; S,
25.1. C5H8N2S requires C, 46.8; H, 6.3; N, 21.8; S, 25.0%);
νmax(KBr)/cmϪ1 3120, 1260, 1150 and 1030; λmax(H2O)/nm 196
and 264; δH(CDCl3) 2.31 (3 H, s, 1-CH3), 3.68 (3 H, s, 5-CH3)
and 8.45 (1 H, s, 2-H); m/z (EI), 128 (Mϩ, 100), 100 (15), 68 (18),
56 (91) and 42 (22).
1-Methyl-2-(2-chlorophenyl)-4-mercaptoimidazole 4g. Flash
chromatography (solvent system: CH2Cl2–MeOH, 95:5) and
recrystallization from AcOEt–CH2Cl2, 70:30) gave a beige solid
(25%), mp 175–176 ЊC (Found: C, 53.5; H, 4.1; N, 12.4; S, 14.2.
C10H9ClN2S requires C, 53.4; H, 4.0; N, 12.5; S, 14.3%);
νmax(KBr)/cmϪ1 3140, 2890, 2790, 2650, 1610 and 1480;
λmax(H2O)/nm 199 and 276; δH(CDCl3) 2.00 (1 H, br s, SH), 3.50
(3 H, s, 1-CH3), 6.88 (1 H, s, 5-H) and 7.35–7.50 (4 H, m, ArH);
m/z (EI) 224 (Mϩ, 80) and 86 (100).
Oxidized form: disappearance of the SH proton at 2.00 ppm
and shift of the 5-H signal from 6.88 to 7.30 ppm.
1-Methyl-2-(2-trifluoromethylphenyl)-4-mercaptoimidazole
4h. Flash chromatography (solvent system: CH2Cl2–MeOH,
90:10) and recrystallization from AcOEt gave a red solid (20%),
mp 176–178 ЊC (Found: C, 51.4; H, 3.5; N, 11.0; S, 12.5.
C11H9F3N2S requires C, 51.2; H, 3.5; N, 10.9; S, 12.4%);
νmax(KBr)/cmϪ1 3110, 2910–2720, 1590 and 1480; λmax(H2O)/nm
197 and 280; δH(CDCl3) 2.10 (1 H, br s, SH), 3.75 (3 H, s,
1-CH3), 6.98 (1 H, s, 5-H) and 7.55–7.90 (4 H, m, ArH); m/z
(EI) 258 (Mϩ, 100), 86 (60) and 45 (9).
1-(3,4-Dimethoxyphenyl)-4-mercaptoimidazole
4b.
The
thioamide 3b was treated in the same way as 3a. Flash chrom-
atography of the residue (solvent system: CH2Cl2–MeOH, 95:5)
and recrystallization from CH2Cl2–MeOH, 97:3, gave 4b as a
brown solid (22%), mp 148–150 ЊC (Found: C, 55.9; H, 5.2;
N, 11.8; S, 13.4. C11H12N2O2S requires C, 55.9; H, 5.1; N, 11.9;
S, 13.6%); νmax(KBr)/cmϪ1 3100, 3000–2820, 1600 and 1500;
λmax(H2O)/nm 199 and 244; δH(CDCl3) 1.95 (1 H, br s, SH),
3.90, 3.95 (6 H, 2 s, 2 OCH3), 6.80–6.95 (3 H, m, ArH), 7.47 (1
H, s, 2-H) and 7.75 (1 H, s, 5-H); m/z (EI) 236 (Mϩ, 100), 208
(13), 164 (22), 79 (12) and 51 (15).
Flash chromatography allowed isolation of the disulfide
which differs in its NMR spectrum from the reduced form by
the absence of the SH proton together with an important shift
of the 5-H signal from 7.75 to 9.00 ppm.
1-(4-Methoxyphenyl)-4-mercaptoimidazole 4c. This com-
pound was obtained by recrystallization of the crude product
from ethyl acetate as a beige solid (39%), mp 144–145 ЊC
(Found: C, 58.3; H, 4.8; N, 13.7; S, 15.6. C10H10N2OS requires
C, 58.2; H, 4.9; N, 13.6; S, 15.6%); νmax(KBr)/cmϪ1 3110, 2980–
Oxidized form: disappearance of the SH proton at 2.10 ppm
and shift of the 5-H signal from 6.98 to 7.30 ppm.
1-Methyl-2-(3-trifluoromethylphenyl)-4-mercaptoimidazole 4i.
Flash chromatography (solvent system: CH2Cl2–MeOH, 95:5)
gave an orange solid (40%), mp 190–192 ЊC (Found: C, 51.3; H,
3.6; N, 10.9; S, 12.4. C11H9F3N2S requires C, 51.2; H, 3.4; N,
10.8; S, 12.4%); νmax(KBr)/cmϪ1 3090, 2900–2710, 1585 and
1490; λmax(H2O)/nm 197 and 269; δH(CDCl3) 2.10 (1 H, br s,
SH), 3.75 (3 H, s, 1-CH3), 7.32 (1 H, s, 5-H) and 7.53–7.94 (4 H,
m, ArH); m/z (EI) 258 (Mϩ, 100), 173 (33), 145 (17), 86 (98) and
45 (25).
1-Methyl-5-(2-trifluoromethylphenyl)-4-mercaptoimidazole 4j.
The crude product was washed with water, dried (Na2SO4)
and concentrated in vacuo to afford 4j as a white solid (21%);
mp 174–176 ЊC (Found: C, 51.4; H, 3.4; N, 11.0; S, 12.3.
C11H9G3N2S requires C, 51.2; H, 3.5; N, 10.9; S, 12.4%);
νmax(KBr)/cmϪ1 3150–2600, 1540 and 1315; λmax(H2O)/nm 200;
δH(CDCl3) 2.08 (1 H, br s, SH), 3.35 (3 H, s, 1-CH3), 7.34 (1 H,
J. Chem. Soc., Perkin Trans. 1, 1997
2987

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6 R. Schreck, K. Albermann and P. A. Baeuerle, Free Rad. Res.
Commun., 1992, 17, 221.
s, 2-H), 7.52–7.68 (3 H, m, ArH) and 7.82 (1 H, m, ArH); m/z
(MALDI-TOF) 258.9 (MHϩ, 75).
7 M. B. Toledano and W. J. Leonard, Proc. Natl. Acad. Sci. USA,
1991, 88, 4328.
8 F. Müller, Free Rad. Biol. Med., 1992, 13, 651.
9 M. Roederer, S. W. Ela, F. J. Staal and L. A. Herzenberg, AIDS Res.
Hum. Retrovir., 1992, 8, 209.
10 Y. J. Suzuki and L. Packer, Biochem. Biophys. Res. Commun., 1993,
193, 277.
11 N. I. Krinsky, Free Rad. Biol. Med., 1993, 7, 617.
12 R. A. Axford-Gutley and G. J. Wilson, Cardiovasc. Res, 1991, 25, 89.
13 B. Hennig, C. Enoch and C. K. Chew, Nutr. Res., 1987, 7, 1242.
14 S. Partharanthy, S. G. Young. J. L. Witzum, R. G. Pittman and
D. Steinberg, J. Clin. Invest., 1986, 7, 641.
15 S. V. Jovanovic, S. Steeken, M. Tosic, B. Marjanovic and M. G.
Simic, J. Am. Chem. Soc., 1994, 116, 4846.
16 N. Cotelle, J. L. Bernier, J. P. Hénichart, J. P. Catteau, E. Gaydou
and J. C. Wallet, Free Rad. Biol. Med., 1992, 13, 211.
17 P. M. Mehta, K. Przyklenk and R. A. Kloner, Eur. Heart J., 1990,
11, 94.
18 I. A. Cotgreave and P. Moldeus, Bull. Eur. Physiopathol. Respir.,
1987, 23, 275.
19 B. Amor, C. Mercy and A. Degery, Arthritis, 1982, 25, 698.
20 E. Turner, R. Klevit, L. J. Hager and B. M. Shapiro, Biochemistry,
1987, 26, 4028.
1-Methyl-5-(2-chlorophenyl)-4-mercaptoimidazole 4k. The
crude product was washed with water, dried (Na2SO4) and con-
centrated in vacuo to afford 4k as a white solid (21%), mp 170–
171 ЊC (Found: C, 53.7; H, 3.8; N, 12.5; S, 14.5. C10H9ClN2S
requires C, 53.5; H, 4.0; N, 12.5; S, 14.3%); νmax(KBr)/cmϪ1
3155–2600, 1540 and 1485; λmax(H2O)/nm 201 and 255;
δH(CDCl3) 2.07 (1 H, br s, SH), 3.49 (3 H, s, 1-CH3), 7.34 (1 H,
s, 2-H) and 7.38–7.60 (4 H, m, ArH); m/z (MALDI-TOF) 225
(Mϩ, 56).
1-Methyl-5-(4-chlorophenyl)-4-mercaptoimidazole 4l. The
crude product was washed with water, dried (Na2SO4) and
concentrated in vacuo to afford 4l as a white solid (30%), mp
179–182 ЊC (Found: C, 53.6; H, 4.1; N, 12.7; S, 14.1. C10H9-
ClN2S requires C, 53.5; H, 4.0; N, 12.5; S, 14.3%); νmax(KBr)/
cmϪ1 3160–2600, 1540 and 1495; λmax(H2O)/nm 198 and 260;
δH(CDCl3) 3.46 (3 H, s, 1-CH3), 7.35 (1 H, s, 2-H), 7.37–7.43 (2
H, d, J 7.0, ArH) and 7.51–7.56 (2 H, d, J 7.0, ArH); m/z
(MALDI-TOF) 225.2 (Mϩ, 40).
1-Methyl-5-(4-methoxyphenyl)-4-mercaptoimidazole 4m. The
crude product was washed with water, dried (Na2SO4) and con-
centrated in vacuo to afford 4m as a white solid (63%), mp 141–
144 ЊC (Found: C, 60.2; H, 5.5; N, 12.8; S, 14.4. C11H12N2OS
requires C, 60.0; H, 5.5; N, 12.7; S, 14.6%); νmax(KBr)/cmϪ1
3120, 2950, 1610 and 1580; λmax(H2O)/nm 199 and 245;
δH(CDCl3) 1.80 (1 H, br s, SH), 3.50 (3 H, s, 1-CH3), 3.83 (3 H,
s, OCH3), 6.90 (2 H, d, J 8.7, ArH), 7.15 (2 H, d, J 8.7, ArH)
and 7.43 (1 H, s, 2-H); m/z (MALDI-TOF) 221 (MHϩ, 31).
1-Methyl-2-trifluoromethyl-5-(2-methoxyphenyl)-4-mercapto-
imidazole 4n. Flash chromatography (solvent system: CH2Cl2–
MeOH, 95:5) and recrystallization from ethyl acetate gave 4n
as a yellow solid (13%), mp 85–87 ЊC (Found: C, 50.1; H, 4.0;
N, 9.7; S, 11.3. C12H11F3N2OS requires C, 50.0; H, 3.9; N, 9.7; S,
11.1%); νmax(KBr)/cmϪ1 3100–2810, 1610 and 1480; λmax(H2O)/
nm 200; δH(CDCl3) 1.65 (1 H, br s, SH), 3.50 (3 H, s, 1-CH3),
3.80 (3 H, s, OCH3), 7.00–7.13 (2 H, m, ArH), 7.23 (1 H, s,
ArH) and 7.42–7.56 (1 H, m, ArH); m/z (MALDI-TOF) 289
(Mϩ, 34).
21 E. Turner, L. J. Hager and B. M. Shapiro, Science, 1988, 252, 939.
22 B. M. Shapiro, Science, 1991, 252, 533.
23 J. W. Heinecke and B. M. Shapiro, J. Biol. Chem., 1992, 267, 7959.
24 K. H. Weaver and D. L. Rabenstein, J. Org. Chem., 1995, 60, 1904.
25 T. P. Holler and P. B. Hopkins, J. Am. Chem. Soc., 1988, 110, 4837.
26 T. P. Holler and P. B. Hopkins, Biochemistry, 1990, 29, 1953.
27 H. G. Viehe, R. Merenyi, L. Stella and Z. Janousek, Angew. Chem.,
Int. Ed. Engl., 1979, 18, 917.
28 H. G. Viehe, Z. Janousek, R. Merenyi and L. Stella, Acc. Chem.
Res., 1985, 18, 148.
29 C. Bienarz and M. J. Cornwell, Tetrahedron Lett., 1993, 34, 939.
30 F. Asinger, A. Sans, H. Offermanns, P. Krings and H. Andree,
Justus Liebigs Ann. Chem., 1971, 744, 51.
31 F. Asinger, A. Sans and H. D. Hahn, Justus Liebigs Ann. Chem.,
1966, 691, 92.
32 J. C. Caille, S. Didierlaurent, D. Lefrançois, M. H. Lelièvre, C. Sury
and J. Aszodi, Synthesis, 1995, 6, 635.
33 A. Spaltenstein, T. P. Holler and P. B. Hopkins, J. Org. Chem., 1987,
52, 2977.
34 V. S. Zyabrev, V. V. Kiselev, E. O. Romanenko and B. S. Drach, Zh.
Org. Khim., 1994, 5, 715.
35 H. Zimmer, D. C. Lankin and S. W. Morgan, Chem. Rev., 1971, 71,
229.
36 M. S. Blois, Nature, 1958, 181, 1199.
References
1 H. Sies, Angew. Chem., Int. Ed. Engl., 1986, 25, 1058.
2 C. A. Rice-Evans and A. T. Diplock, Free Rad. Biol. Med., 1993, 15,
77.
37 H. J. Ha, G. S. Nam and K. P. Park, Synth. Commun., 1991, 21, 155.
38 K. Takahashi, T. Masuda, K. Ogura and H. Iida, Synthesis, 1983,
12, 1043.
3 B. Halliwell and J. M. C. Gutteridge, in Free radicals in biology and
medicine, Oxford University Press, Oxford, 1989.
4 M. Fontecave and J. L. Pierre, Bull. Soc. Chim. Fr., 1991, 128, 505.
5 R. H. Schirmer, J. G. Müller and R. L. Krauth-Siegel, Agnew.
Chem., Int. Ed. Engl., 1995, 34, 141.
Paper 7/03741D
Received 29th May 1997
Accepted 21st July 1997
2988
J. Chem. Soc., Perkin Trans. 1, 1997