Synthesis of bis-heterocyclic 1H-imidazole 3-oxides from 3-oxido-1H-imidazole-4-carbohydrazides

Article abstract of DOI:10.1002/hlca.201100470

The reaction of 1H-imidazole-4-carbohydrazides 1, which are conveniently accessible by treatment of the corresponding esters with NH₂NH ₂·H₂O, with isothiocyanates in refluxing EtOH led to thiosemicarbazides (=hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling aqueous NaOH yielded 2,4-dihydro-3H-1,2,4-triazole-3- thiones 5, the reaction in concentrated H₂SO₄ at room temperature gave 1,3,4-thiadiazol-2-amines 6. Similarly, the reaction of 1 with butyl isocyanate led to semicarbazides 7, which, under basic conditions, undergo cyclization to give 2,4-dihydro-3H-1,2,4-triazol-3-ones 8 (Scheme 3). Treatment of 1 with Ac₂O yielded the diacylhydrazine derivatives 9 exclusively, and the alternative isomerization of 1 to imidazol-2-ones was not observed (Scheme 4). It is important to note that, in all these transformations, the imidazole N-oxide residue is retained. Furthermore, it was shown that imidazole N-oxides bearing a 1,2,4-triazole-3-thione or 1,3,4-thiadiazol-2-amine moiety undergo the S-transfer reaction to give bis-heterocyclic 1H-imidazole-2-thiones 11 by treatment with 2,2,4,4-tetramethylcyclobutane-1,3- dithione (Scheme 5). Copyright

Full text of DOI:10.1002/hlca.201100470

404
Helvetica Chimica Acta – Vol. 95 (2012)
Synthesis of Bis-Heterocyclic 1H-Imidazole 3-Oxides from 3-Oxido-1H-
imidazole-4-carbohydrazides
by Adam Marek Pieczonka1), Grzegorz Mloston´*
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łodz
(phone: þ 48 42 6355761; fax: þ 48 42 6655162; e-mail: gmloston@uni.lodz.pl)
and Heinz Heimgartner*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41 44 6354282; fax: þ 41 44 6356812; e-mail: heimgart@oci.uzh.ch)
The reaction of 1H-imidazole-4-carbohydrazides 1, which are conveniently accessible by treatment
of the corresponding esters with NH2NH2 · H2O, with isothiocyanates in refluxing EtOH led to
thiosemicarbazides (¼ hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling
aqueous NaOH yielded 2,4-dihydro-3H-1,2,4-triazole-3-thiones 5, the reaction in concentrated H2SO4 at
room temperature gave 1,3,4-thiadiazol-2-amines 6. Similarly, the reaction of 1 with butyl isocyanate led
to semicarbazides 7, which, under basic conditions, undergo cyclization to give 2,4-dihydro-3H-1,2,4-
triazol-3-ones 8 (Scheme 3). Treatment of 1 with Ac2O yielded the diacylhydrazine derivatives 9
exclusively, and the alternative isomerization of 1 to imidazol-2-ones was not observed (Scheme 4). It is
important to note that, in all these transformations, the imidazole N-oxide residue is retained.
Furthermore, it was shown that imidazole N-oxides bearing a 1,2,4-triazole-3-thione or 1,3,4-thiadiazol-2-
amine moiety undergo the S-transfer reaction to give bis-heterocyclic 1H-imidazole-2-thiones 11 by
treatment with 2,2,4,4-tetramethylcyclobutane-1,3-dithione (Scheme 5).
1. Introduction. – Acid hydrazides (carbohydrazides) and the corresponding
hydrazones are well known as a class of compounds with diverse biological activities
[1]. Particularly important are derivatives bearing a heterocycle, and one of the best-
known examples is isoniazid (isonicotinohydrazide) [2]. Imidazole-derived hydrazides
were also reported to exhibit biological activities [3], and the majority of reports is
restricted to patents (e.g., [4]). However, in most cases, N,N-disubstituted hydrazides
were described, which are of limited interest with respect to their use as building blocks
for new heterocyclic systems.
The N-unsubstituted carbohydrazides are widely applied as unique building blocks
for the synthesis of diverse five- and six-membered heterocycles such as pyrroles,
pyrazoles, thiazolidines, 1,2,4-triazoles, phthalazines, pyrimidines, etc. [5]. A typical
procedure for the preparation of unsubstituted hydrazides is the treatment of the
corresponding carboxylate with NH2NH2 · H2O [1][5]. Recently, we have reported on
the application of this method for the preparation of diverse types of unsubstituted
hydrazides containing the imidazole ring in their structure [6]. The precursors of 1H-
1
´
´
)
Part of the planned Ph.D. thesis of A. M. P., University of Łodz.
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
405
imidazole-4-carbohydrazides 1 were the corresponding esters 2, available via con-
densation of ethyl 2-(hydroxyimino)-3-oxobutanoate (3), a primary amine, and
formaldehyde [7] (Scheme 1).
Scheme 1
In earlier reports, we presented the synthetic potential of the ꢃnitrone-likeꢄ fragment
of 2-unsubstituted 1H-imidazole 3-oxides [8]. The aim of the present study was the
synthesis of new bis-heterocycles with the preserved 1H-imidazole 3-oxide moiety by
investigating of the reactivity of the carbohydrazido group in compounds 1. In
preliminary experiments, it was shown that 1 can be used for the preparation of bis-
heterocycles [6]. To the best of our knowledge, there are no other bis-heterocycles with
the reactive N-oxide function known to date (cf. [6]).
Results and Discussion. – As described earlier, 1H-imidazole 3-oxides 1 with the
hydrazinocarbonyl moiety at C(4) are stable, colorless, crystalline materials [6]. In
contrast to the corresponding esters, they did not undergo the thermal isomerization to
imidazol-2-ones. Even more surprisingly, they could neither be converted to the
corresponding imidazole-2-thiones via the ꢃS-transfer reactionꢄ [8a] nor reduced to the
parent system by treatment with Raney-Ni [8c].
It seems likely that this diminished reactivity of the N ! O function is the result of a
strong intramolecular H-bond [6][8d]. On the other hand, reactions with aldehydes
and aliphatic ketones proceeded smoothly to yield the expected hydrazones [6]. In
addition, a preliminary experiment revealed that thiosemicarbazide 4a obtained from
1a (R ¼ PhCH2) and methyl isothiocyanate underwent the cyclocondensation to give,
depending on the reaction conditions, bis-heterocycles 5a or 6a. In analogy to 1a,
derivatives 1b and 1c were also reacted with other isothiocyanates (R2 ¼ Bu, Ph), and
the thiosemicarbazides (¼ hydrazinecarbothioamides) 4 were heated in a 2% aqueous
solution of NaOH to give the triazole-3-thiones 5 (Scheme 2). In addition, the sterically
crowded tert-butyl isothiocyanate was used for the reaction with 1a, and the expected
thiosemicarbazide 4d was obtained in good yield as a crystalline material. However, the
attempted cyclization of 4d under basic conditions was unsuccessful, and the starting
material was recovered in nearly quantitative yield. Apparently, in this case, steric
t
hindrance resulting from the presence of the bulky Bu group at the N-atom does not
allow the system to undergo the cyclization.

406
Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2
The structure of the triazole-3-thiones 5 was indicated by the C¼S absorption in the
13C-NMR spectra at 168 – 169 ppm. In addition, the unchanged N-oxide structure of the
imidazole was confirmed by the characteristic 1H-NMR absorption of HꢀC(2) at 8.6 –
8.1 ppm.
The alternative course of the cyclocondensation was observed when thiosemicar-
bazides of type 4 were stirred in conc. H2SO4 at room temperature for 1 d. Under these
conditions, the only products formed were 5-amino-1,3,4-thiadiazol-2-yl-carrying 1H-
imidazole 3-oxides 6 (Scheme 2). Unexpectedly, the reactions carried out under these
conditions with 4b and 4i, which were derived from phenyl isothiocyanate, yielded 6b
and 6e, respectively, bearing a 4-phenylsulfonic acid moiety (R2 ¼ 4-(HOSO2)ꢀC6H4).
It is very likely that these products result from the sulfonation of the intermediate 5-
(phenylamino)-1,3,4-thiadiazole derivatives formed after the initial cyclocondensation
step2). Based on the comparison of the chemical shifts of HꢀC(2) in 6b, and in the
2
)
The sulfonation of aniline with conc. H2SO4 at elevated temperatures is a well known process [9]
and has been studied in detail by Khelevin [10]. A study of the thermolysis of diphenylammonium
hydrogen sulfate leading to 4-(phenylamino)benzenesulfonic acid has bee published recently [11].

Helvetica Chimica Acta – Vol. 95 (2012)
407
analogous MeN and BuN derivatives 6a and 6c, respectively, a zwitterionic structure
can be postulated for both arylsulfonic acids 6b and 6e (see Scheme 5). To the best of
our knowledge, secondary sulfonation of 5-(phenylamino)-1,3,4-thiadiazoles obtained
from corresponding thiosemicarbazides in the presence of H2SO4 under similar
reaction conditions (room temperature) has not been reported so far [12][13].
Similarly to the reactions with isothiocyanates, carbohydrazides 1a and 1b reacted
with butyl isocyanate in refluxing EtOH to yield semicarbazides 7a and 7b, respectively,
as crystalline materials in high yields (Scheme 3). After isolation and purification, they
were used for the synthesis of bis-heterocyclic 1,2,4-triazol-3-ones 8a and 8b,
respectively, under basic conditions. Both products 7 and 8 were obtained with the
preserved N-oxide function.
Scheme 3
Transformation of carbohydrazides to 3-alkyl-1,3,4-oxadiazoles can be performed
via cyclization of their N-acyl derivatives under acidic conditions [5]. In the case of 1a
and 1c, the acetylation performed with a slight excess of Ac2O in boiling EtOH
afforded the expected N-Ac derivatives 9 (Scheme 4). Apparently, this conversion is
much faster than the alternative isomerization to the corresponding imidazol-2-ones
reported as a typical reaction of 2-unsubstituted imidazole N-oxides by treatment with
Ac2O [8b]. However, the attempted cyclocondensations of products 9 under acidic
conditions (H2SO4, room temperature) were unsuccessful.
Scheme 4
In a series of reports, we demonstrated that the treatment of 2-unsubstituted 1H-
imidazole 3-oxides with a cycloaliphatic thioketone, e.g., 2,2,4,4-tetramethylcyclobu-
tane-1,3-dithione (10), opens an easy access to imidazole-2-thiones [8a][8c][8e][8f].
On the other hand, we found recently that the presence of a carbohydrazide moiety at

408
Helvetica Chimica Acta – Vol. 95 (2012)
C(4) inhibits the S-transfer reaction [6]. Having in hand bis-heterocyclic imdazole N-
oxides of type 5 and 6, the S-transfer with 10 was tested. In both cases, i.e., 5g and 6e, the
desired imidazole-2-thiones were smoothly formed at room temperature (Scheme 5).
Scheme 5
This result evidences the influence of the intramolecular H-bond on the ꢃnitrone-
likeꢄ reactivity of the imidazole N-oxides 1. Whereas the strong H-bond in the
hydrazides [6] causes reduced reactivity, there is no such H-bond present in the bis-
heterocyclic imidazole N-oxides 5 and 6, which easily enter a [2 þ 3] cycloaddition with
10.
Conclusions. – The present study reveals that imidazole-carbohydrazides of type 1,
containing a N-oxide function, react with isothiocyanates, isocyanates, and Ac2O in a
typical manner to yield the corresponding thiosemicarbazides 4, semicarbazides 7, and
N-Ac derivatives 9, respectively, in high yields. In the case of thiosemicarbazides,
cyclizations to 1,2,4-triazole-3-thiones 5 and 2-amino-1,3,4-thiadiazoles 6 were per-
formed under corresponding basic and acidic conditions. Similarly, semicarbazides 7
were converted to 1,2,4-triazole-3-ones 8 in aqueous NaOH solution. In all these
reactions, the N-oxide function in the imidazole ring was preserved. However,
attempted acid-catalyzed cyclizations of 7 and 9 to the corresponding 3-amino- and 3-
methyl-1,3,4-oxadiazoles, respectively, were unsuccessful.
In contrast to carbohydrazides 1, which do not undergo the S-transfer reaction upon
treatment with the dithione 10 under standard conditions [6], bis-heterocyclic
imidazole N-oxides of type 5 and 6 smoothly undergo this reaction.

Helvetica Chimica Acta – Vol. 95 (2012)
409
To the best of our knowledge, the elaborated protocol offers a unique route for the
synthesis of bis-heterocyclic N-oxides, which cannot be prepared by an oxidative
approach. This novel type of N-oxides may be of interest as a new group of ligands for
coordination chemistry. Moreover, in a recent study, derivatives of 5-amino-1,3,4-
thiadiazoles obtained from 5-methylimidazole-4-carbohydrazide according to the
general method described in the present paper, displayed high anti-Toxoplasma gondi
and antimicrobial activities [13].
The authors thank PD Dr. L. Bigler, University of Zurich, for recording of the HR-ESI mass spectra.
A. M. P. is grateful for financial support within the project European Social Fund ꢀ HUMAN – BEST
INVESTMENT!ꢁ, co-funded by the European Union.
Experimental Part
1. General. M.p.: STUART SMP30; uncorrected. IR Spectra: NEXUS FT-IR spectrophotometer; in
1
KBr; absorptions in cmꢀ1. H- and 13C{1H}-NMR Spectra: Bruker Avance III 600, in (D6)DMSO, using
solvent signals as reference; d in ppm; coupling constants J in Hz; assignments of signals in 13C-NMR
spectra accomplished by HMQC experiments. HR-ESI-MS: Finnigan MAT-95. HR-EI-MS: Bruker
Esquire LC spectrometer.
2. Starting Materials. All solvents are commercially available and used as received. Carbohydrazides
1a – 1c were prepared from the corresponding esters by treatment with NH2NH2 · H2O according to the
protocol described in [6].
3. Synthesis of Thiosemicarbazides 4a – 4j and Semicarbazides 7a and 7b. General Procedure. A
mixture of 1 (1 mmol) and the corresponding isothiocyanate (1.1 mmol) or isocyanate (1.1 mmol) in
EtOH (5 ml) was heated to reflux for 2 h. Then, the product formed was filtered off, washed with Et2O,
and crystallized from MeOH.
2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-methylhydrazinecarbothioamide (4a).
See [6].
2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-phenylhydrazinecarbothioamide (4b).
Yield: 0.347 g (91%). Colorless crystals. M.p. 200 – 2048 (dec., MeOH). IR (KBr): 3295s (NH), 3127s,
1663vs (C¼O), 1599vs, 1497m, 708m. 1H-NMR ((D6)DMSO): 9.80 (br. s, NH); 8.72 (s, HꢀC(2’)); 7.48 –
7.12 (m, 10 arom. H); 5.26 (s, CH2); 2.45 (s, Me); two NH absorptions missing. 13C-NMR ((D6)DMSO):
178.2 (C¼O); 159.2 (C¼S); 139.7, 135.9, 131.2, 121.3 (2 arom. C, C(4’), C(5’)); 126.7 (C(2’)); 129.5, 128.7,
128.6, 127.7, 127.6, 125.3 (10 arom. CH); 48.7 (CH2); 9.8 (Me). HR-ESI-MS: 404.1149 ([M þ Na]þ,
C19H19N5NaO2Sþ; calc. 404.1152), 382.1329 ([M þ H]þ, C19H20N5O2Sþ; calc. 382.1332).
2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-butylhydrazinecarbothioamide (4c).
Yield: 0.343 g (95%). Colorless crystals. M.p. 204 – 2078 (MeOH). IR (KBr): 3243m (NH), 2955s,
1661vs (C¼O), 1598vs, 1552m, 1456m, 737m. 1H-NMR ((D6)DMSO): 12.41, 9.31 (2 br. s, 2 NH); 8.72 (s,
HꢀC(2’)); 8.03 (br. s, NH); 7.42 – 7.25 (m, 5 arom. H); 5.25 (s, CH2); 3.40 (q, J ¼ 6.6, CH2N); 2.43 (s, Me);
1.49 – 1.44, 1.28 – 1.22 (2m, 2 CH2); 0.86 (t, J ¼ 7.2, Me). 13C-NMR ((D6)DMSO): 181.7 (C¼O); 159.6
(C¼S); 135.9, 131.2, 121.3 (1 arom. C, C(4’), C(5’)); 126.7 (C(2’)); 129.5, 128.7, 127.7 (5 arom. CH); 48.7
(PhCH2); 43.9 (CH2N); 31.3, 19.9 (2 CH2); 14.2 (Me); 9.8 (MeꢀC(5’)). HR-ESI-MS: 384.1467 ([M þ
Na]þ, C17H23N5NaO2Sþ; calc. 384.1465), 362.1643 ([M þ H]þ, C17H24N5O2Sþ; calc. 362.1645).
2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-(tert-butyl)hydrazinecarbothioamide
(4d). Yield: 0.235 g (65%). Colorless crystals. M.p. 201 – 2038 (MeOH). IR (KBr): 3235m (NH), 3088s,
1668vs (C¼O), 1599vs, 1541m, 1362m, 709m. 1H-NMR ((D6)DMSO): 9.51 (br. s, NH); 8.67 (s, HꢀC(2’));
t
7.41 – 7.25 (m, 5 arom. H); 5.24 (s, CH2); 2.43 (s, Me); 1.44 (s, Bu); two NH absorptions missing.
13C-NMR ((D6)DMSO): 178.9 (C¼O); 159.8 (C¼S); 135.8, 131.1, 120.9 (1 arom. C, C(4’), C(5’)); 126.7
(C(2’)); 129.4, 128.6, 127.7 (5 arom. CH); 53.2 (Me3C); 48.7 (CH2); 29.1 (Me3C); 9.8 (MeꢀC(5’)). HR-
ESI-MS: 384.1469 ([M þ Na]þ, C17H23N5NaO2Sþ; calc. 384.1465), 362.1646 ([M þ H]þ, C17H24N5O2Sþ;
calc. 362.1645).

410
Helvetica Chimica Acta – Vol. 95 (2012)
2-[(1,5-Dimethyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-methylhydrazinecarbothioamide (4e).
Yield: 0.173 g (71%). Colorless crystals. M.p. 229 – 2318 (MeOH). IR (KBr): 3160s, 2974s, 1638vs
(C¼O), 1602vs, 1485s, 1285m, 606m. 1H-NMR ((D6)DMSO): 9.35 (br. s, NH); 8.48 (s, HꢀC(2’)); 8.01 (br.
s, NH); 3.58 (s, imidazole Me); 2.85 (d, J ¼ 4.1, MeN); 2.48 (s, Me); one NH absorption missing.
13C-NMR ((D6)DMSO): 182.6 (C¼O); 159.8 (C¼S); 131.8, 120.7 (C(4’), C(5’)); 126.8 (C(2’)); 32.4
(MeN(1’)); 31.4 (MeN); 9.5 (MeꢀC(5’)). HR-ESI-MS: 266.0682 ([M þ Na]þ, C8H13N5NaO2Sþ; calc.
266.0682), 244.0859 ([M þ H]þ, C8H14N5O2Sþ; calc. 244.0863).
2-[(1,5-Dimethyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-phenylhydrazinecarbothioamide (4f).
Yield: 0.262 g (86%). Colorless crystals. M.p. 223 – 2258 (MeOH). IR (KBr): 3245m (NH), 3093s,
3036s, 1667vs (C¼O), 1600vs, 1497s, 1321s, 760m. 1H-NMR ((D6)DMSO): 9.79 (br. s, NH); 8.48 (s,
HꢀC(2’)); 7.50 – 7.11 (m, 5 arom. H); 3.58 (s, MeN); 2.50 (s, Me; overlaps with DMSO signal); two NH
absorptions missing. 13C-NMR ((D6)DMSO): 179.0 (C¼O); 160.8 (C¼S); 139.8, 131.6, 120.7 (1 arom. C,
C(4’), C(5’)); 128.8, 128.6, 125.1 (5 arom. CH); 126.8 (C(2’)); 32.4 (MeN); 9.5 (MeꢀC(5’)). HR-ESI-MS:
328.0835 ([M þ Na]þ, C13H15N5NaO2Sþ; calc. 328.0839), 306.1013 ([M þ H]þ, C13H16N5O2Sþ; calc.
306.1019).
N-Butyl-2-[(1,5-dimethyl-3-oxido-1H-imidazol-4-yl)carbonyl]hydrazinecarbothioamide (4g). Yield:
0.262 g (92%). Colorless crystals. M.p. 208 – 2108 (MeOH). IR (KBr): 3189s, 2957s, 1640vs (C¼O),
1599vs, 1483s, 1277m, 616m. 1H-NMR ((D6)DMSO): 12.44, 9.30 (2 br. s, 2 NH); 8.47 (s, HꢀC(2’)); 8.01
(br. s, NH); 3.58 (s, MeN); 3.40 (q, J ¼ 6.6, CH2N); 2.48 (s, Me); 1.49 – 1.44, 1.29 – 1.22 (2m, 2 CH2); 0.87
(t, J ¼ 7.2, Me). 13C-NMR ((D6)DMSO): 181.7 (C¼O); 159.5 (C¼S); 131.7, 120.7 (C(4’), C(5’)); 126.8
(C(2’)); 43.9 (CH2N); 31.4 (MeN); 31.3, 19.9 (2 CH2); 14.2 (Me); 9.5 (MeꢀC(5’)). HR-ESI-MS: 308.1151
([M þ Na]þ, C11H19N5NaO2Sþ; calc. 308.1152), 286.1329 ([M þ H]þ, C11H20N5O2Sþ; calc. 286.1332).
2-[(1-Cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-methylhydrazinecarbothioamide
(4h). Yield: 0.258 g (83%). Colorless crystals. M.p. 207 – 2118 (MeOH). IR (KBr): 3250s (NH), 3139s,
1664vs (C¼O), 1596vs, 1552m, 1495m, 1259m. 1H-NMR ((D6)DMSO): 12.45, 9.35 (2 br. s, 2 NH); 8.72 (s,
HꢀC(2’)); 8.00 (br. s, NH); 4.12 – 4.07 (m, CH); 2.85 (d, J ¼ 4.4, MeN); 2.55 (s, Me); 1.92 – 1.79 (m, 4
cyclohexyl H); 1.67 – 1.60 (m, 3 cyclohexyl H); 1.44 – 1.38 (m, 2 cyclohexyl H); 1.21 – 1.13 (m, 1 cyclohexyl
H). 13C-NMR ((D6)DMSO): 182.6 (C¼O); 159.9 (C¼S); 130.7, 120.3 (C(4’), C(5’)); 124.5 (C(2’)); 55.1
(CH); 33.0, 25.3, 25.0 (5 cyclohexyl CH2); 31.4 (MeN); 9.5 (MeꢀC(5’)). HR-ESI-MS: 334.1306 ([M þ
Na]þ, C13H21N5NaO2Sþ; calc. 334.1308), 312.1488 ([M þ H]þ, C13H22N5O2Sþ; calc. 312.1489).
2-[(1-Cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-phenylhydrazinecarbothioamide
(4i). Yield: 0.332 g (89%). Colorless crystals. M.p. 174 – 1768 (MeOH). IR (KBr): 3231s (NH), 3139s,
2934s, 1675vs (C¼O), 1600vs, 1497m, 1257m. 1H-NMR ((D6)DMSO): 9.81 (br. s, NH); 8.73 (s, HꢀC(2’));
7.50 – 7.12 (m, 5 arom. H); 4.12 – 4.07 (m, CH); 2.57 (s, Me); 1.93 – 1.80 (m, 4 cyclohexyl H); 1.67 – 1.61
(m, 3 cyclohexyl H); 1.45 – 1.38 (m, 2 cyclohexyl H); 1.22 – 1.14 (m, 1 cyclohexyl H); two NH absorptions
missing. 13C-NMR ((D6)DMSO): 172.4 (C¼O); 156.2 (C¼S); 139.7, 130.6, 120.3 (1 arom. C, C(4’), C(5’));
129.4, 129.1, 128.6 (5 arom. CH); 124.4 (C(2’)); 55.1 (CH); 33.0, 25.4, 25.0 (5 cyclohexyl CH2); 9.5
(MeC(5’)). HR-ESI-MS: 396.1469 ([M þ Na]þ, C18H23N5NaO2Sþ; calc. 396.1465), 374.1649 ([M þ H]þ,
C18H24N5O2Sþ; calc. 374.1645).
N-Butyl-2-[(1-cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]hydrazinecarbothioamide
(4j). Yield: 0.318 g (90%). Colorless crystals. M.p. 176 – 1808 (MeOH). IR (KBr): 3302s (NH), 3143s,
2934s, 1681vs (C¼O), 1604vs, 1545m, 1265m. 1H-NMR ((D6)DMSO): 12.48, 9.26 (2 br. s, 2 NH); 8.72 (s,
HꢀC(2’)); 8.02 (br. s, NH); 4.11 – 4.07 (m, CH); 3.43 – 3.38 (m, CH2N); 2.55 (s, Me); 1.92 – 1.79 (m, 4
cyclohexyl H); 1.67 – 1.60 (m, 3 cyclohexyl H); 1.49 – 1.38 (m, 2 cyclohexyl H, Bu CH2); 1.28 – 1.15 (m, 1
cyclohexyl H, Bu CH2); 0.87 (t, J ¼ 7.6, Me). 13C-NMR ((D6)DMSO): 181.7 (C¼O); 159.8 (C¼S); 130.6,
120.3 (C(4’), C(5’)); 124.4 (C(2’)); 55.0 (CH); 43.9 (CH2N); 33.0, 25.3, 25.0 (5 cyclohexyl CH2); 31.3, 19.9
(2 Bu CH2); 14.2 (Me); 9.5 (MeꢀC(5’)). HR-ESI-MS: 376.1777 ([M þ Na]þ, C16H27N5NaO2Sþ; calc.
376.1778), 354.1955 ([M þ H]þ, C16H28N5O2Sþ; calc. 354.1958).
2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-butylhydrazinecarboxamide (7a).
Yield: 0.338 g (98%). Colorless crystals. M.p. 201 – 2058 (MeOH). IR (KBr): 3304s (NH), 3105m,
2960m, 1656vs (C¼O), 1603s, 1544m. 1H-NMR ((D6)DMSO): 12.08 (br. s, NH); 8.67 (s, HꢀC(2’)); 7.41 –
7.23 (m, 5 arom. H); 7.94, 6.42 (2 br. s, 2 NH); 5.24 (s, CH2); 3.01 (q, J ¼ 7.0, CH2N); 2.42 (s, Me); 1.38 –
1.34, 1.29 – 1.22 (2m, 2 CH2); 0.86 (t, J ¼ 7.0, Me). 13C-NMR ((D6)DMSO): 159.5, 158.0 (2 C¼O); 135.9,

Helvetica Chimica Acta – Vol. 95 (2012)
411
131.0, 121.3 (1 arom. C, C(4’), C(5’)); 126.8 (C(2’)); 129.4, 128.6, 127.6 (5 arom. CH); 48.7 (PhCH2); 39.4
(CH2N); 32.4, 19.9 (2 CH2); 14.2 (Me); 9.7 (MeꢀC(5’)). HR-ESI-MS: 368.1697 ([M þ Na]þ,
C17H23N5NaO3þ ; calc. 368.1693), 346.1875 ([M þ H]þ, C17H24N5Oþ3 ; calc. 346.1874).
N-Butyl-2-[(1,5-dimethyl-3-oxido-1H-imidazol-4-yl)carbonyl]hydrazinecarboxamide (7b). Yield:
0.256 g (95%). Colorless crystals. M.p. 190 – 1938 (MeOH). IR (KBr): 3308vs, 3132m, 2957s, 1644vs
1
(C¼O), 1602s, 1534s, 1254m, 608m. H-NMR ((D6)DMSO): 12.10 (br. s, NH); 8.44 (s, HꢀC(2’)); 7.93,
6.39 (2 br. s, 2 NH); 3.56 (s, MeN); 3.00 (q, J ¼ 5.8, CH2N); 2.47 (s, Me); 1.39 – 1.34, 1.29 – 1.23 (2m, 2
CH2); 0.87 (t, J ¼ 7.0, Me). 13C-NMR ((D6)DMSO): 159.5, 158.0 (2 C¼O); 131.4, 120.7 (C(4’), C(5’));
126.8 (C(2’)); 39.4 (CH2N); 32.4 (MeN); 32.3, 19.9 (2 CH2); 14.2 (Me); 9.4 (MeꢀC(5’)). HR-ESI-MS:
292.1383 ([M þ Na]þ, C11H19N5NaO3þ ; calc. 292.1380), 270.1560 ([M þ H]þ, C11H20N5Oþ3 ; calc.
270.1561).
4. Synthesis of 1,2,4-Triazole-3-thiones 5. General Procedure. A mixture of 4 (1 mmol) and a 2% aq.
soln. of NaOH (5 ml) was heated to reflux for 2 h. Then, the soln. was neutralized with AcOH, and the
formed precipitate was filtered off and crystallized from MeOH.
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione
(5a). See [6].
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-phenyl-3H-1,2,4-triazole-3-thione
(5b). Yield: 0.192 g (53%). Colorless crystals. M.p. 262 – 2648 (dec. MeOH). IR (KBr): 3110s, 3044m,
1497s, 1319m, 688m. 1H-NMR ((D6)DMSO): 8.35 (s, HꢀC(2’)); 7.47 – 7.28 (m, 10 arom. H); 5.11 (s,
CH2N); 1.92 (s, Me); NH absorption missing. 13C-NMR ((D6)DMSO): 168.8 (C¼S); 141.4 (triazole
C(3)); 134.3, 128.8, 136.2, 117.6 (2 arom. C, imidazole C(4), C(5)); 129.3, 129.2, 128.4, 127.7, 127.2, 126.8
(10 arom. CH); 126.2 (imidazole C(2)); 48.8 (CH2N); 8.9 (Me). HR-ESI-MS: 386.1041 ([M þ Na]þ,
C19H17N5NaOSþ; calc. 386.1046), 364.1221 ([M þ H]þ, C19H18N5OSþ; calc. 364.1227).
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-4-butyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
(5c). Yield: 0.240 g (70%). Colorless crystals. M.p. 256 – 2588 (MeOH). IR (KBr): 3129m, 2930m,
1455m, 1294m, 730m. 1H-NMR ((D6)DMSO): 8.60 (s, HꢀC(2’)); 7.41 – 7.25 (m, 5 arom. H); 5.26 (s,
CH2N); 4.12 (t, J ¼ 6.8, CH2N); 2.08 (s, Me); 1.45 – 1.40 (m, CH2); 1.04 – 0.98 (m, CH2); 0.67 (t, J ¼ 6.8,
Me); NH absorption missing. 13C-NMR ((D6)DMSO): 167.9 (C¼S); 141.7 (C(3)); 136.1, 128.4, 118.5 (1
arom. C, imidazole C(4), C(5)); 129.4, 128.6, 127.6 (5 arom. CH); 126.7 (imidazole C(2)); 49.2 (CH2N);
44.0 (Bu CH2N); 30.1, 19.4 (2 Bu CH2); 13.7 (Bu Me); 9.1 (Me). HR-ESI-MS: 366.1359 ([M þ Na]þ,
C17H21N5NaOSþ; calc. 366.1359), 344.1537 ([M þ H]þ, C17H22N5OSþ; calc. 344.1540).
5-(1,5-Dimethyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (5d).
Yield: 0.144 g (64%). Colorless crystals. M.p. 321 – 3238 (MeOH). IR (KBr): 3147vs (NH), 1515m,
1455m, 1329m, 929m. 1H-NMR ((D6)DMSO): 8.31 (s, HꢀC(2’)); 3.58, 3.44 (2s, 2 MeN); 2.17 (s, Me); NH
absorption missing. 13C-NMR ((D6)DMSO): 168.2 (C¼S); 142.3 (C(3)); 128.1, 118.7 (imidazole C(4),
C(5)); 126.2 (imidazole C(2)); 32.7, 31.4 (2 MeN); 9.1 (Me). HR-ESI-MS: 248.0574 ([M þ Na]þ,
C8H11N5NaOSþ; calc. 248.0577), 226.0755 ([M þ H]þ, C8H12N5OSþ; calc. 226.0757).
5-(1,5-Dimethyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-phenyl-3H-1,2,4-triazole-3-thione (5e).
Yield: 0.155 g (54%). Colorless crystals. M.p. 270 – 2748 (dec. MeOH). IR (KBr): 3156vs (NH),
1506m, 1497s, 1326m, 694m. 1H-NMR ((D6)DMSO): 8.14 (s, HꢀC(2’)); 7.51 – 7.38 (m, 5 arom. H); 3.45 (s,
MeN); 2.09 (s, Me); NH absorption missing. 13C-NMR ((D6)DMSO): 169.0 (C¼S); 141.7 (C(3)); 136.9,
128.9, 117.1 (1 arom. C, imidazole C(4), C(5)); 129.4, 129.1, 127.8 (5 arom. CH); 126.2 (imidazole C(2));
32.6 (MeN); 8.7 (Me). HR-ESI-MS: 310.0733 ([M þ Na]þ, C13H13N5NaOSþ; calc. 310.0733), 288.0911
([M þ H]þ, C13H14N5OSþ; calc. 288.0914).
4-Butyl-5-(1,5-dimethyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5f).
Yield: 0.143 g (50%). Colorless crystals. M.p. 240 – 2428 (MeOH). IR (KBr): 3162s (NH), 2953s,
1570m, 1449m, 1348m, 1295m, 926m. 1H-NMR ((D6)DMSO): 8.38 (s, HꢀC(2’)); 4.14 (t, J ¼ 7.7, CH2N);
3.59 (s, MeN); 2.17 (s, Me); 1.51 – 1.46, 1.12 – 1.05 (2m, 2 CH2); 0.74 (t, J ¼ 7.7, Me); NH absorption
missing. 13C-NMR ((D6)DMSO): 167.9 (C¼S); 142.2 (C(3)); 128.8, 117.5 (imidazole C(4), C(5)); 126.7
(imidazole C(2)); 44.1 (CH2N); 32.8 (MeN); 30.0, 19.5 (2 CH2); 13.7, 8.9 (2 Me). HR-ESI-MS: 290.1042
([M þ Na]þ, C11H17N5NaOSþ; calc. 290.1046), 268.1225 ([M þ H]þ, C11H18N5OSþ; calc. 268.1227).
5-(1-Cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thi-
one (5g). Yield: 0.240 g (82%). Colorless crystals. M.p. 212 – 2168 (MeOH). IR (KBr): 3115s (NH),

412
Helvetica Chimica Acta – Vol. 95 (2012)
1
2941s, 1559m, 1418m, 1324m. H-NMR ((D6)DMSO): 8.49 (s, HꢀC(2’)); 4.05 – 4.00 (m, CH); 3.42 (s,
MeN); 2.20 (s, Me); 1.97 – 1.80 (m, 4 cyclohexyl H); 1.69 – 1.62 (m, 3 cyclohexyl H); 1.45 – 1.38 (m, 2
cyclohexyl H); 1.23 – 1.14 (m, 1 cyclohexyl H); NH absorption missing. 13C-NMR ((D6)DMSO): 168.3
(C¼S); 142.1 (C(3)); 126.7, 118.7 (imidazole C(4), C(5)); 123.6 (imidazole C(2)); 55.5 (CH); 33.2
(MeN); 31.4, 25.4, 23.1 (5 cyclohexyl CH2); 9.2 (Me). HR-ESI-MS: 316.1200 ([M þ Na]þ,
C13H19N5NaOSþ; calc. 316.1203), 294.1379 ([M þ H]þ, C13H20N5OSþ; calc. 294.1383).
5-(1-Cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-phenyl-3H-1,2,4-triazole-3-thi-
one (5h). Yield: 0.185 g (52%). Colorless crystals. M.p. 282 – 2848 (MeOH). IR (KBr): 3231m (NH),
1
2936m, 1601m, 1497m, 1320m. H-NMR ((D6)DMSO): 8.34 (s, HꢀC(2’)); 7.45 – 7.37 (m, 5 arom. H);
3.92 – 3.85 (m, CH); 2.07 (s, Me); 1.79 – 1.74 (m, 4 cyclohexyl H); 1.62 – 1.49 (m, 3 cyclohexyl H); 1.37 –
1.30 (m, 2 cyclohexyl H); 1.15 – 1.12 (m, 1 cyclohexyl H); NH absorption missing. 13C-NMR
((D6)DMSO): 168.9 (C¼S); 141.6 (C(3)); 134.1, 126.1, 118.4 (1 arom. C, imidazole C(4), C(5)); 129.3,
129.0, 127.7 (5 arom. CH); 123.6 (imidazole C(2)); 55.4 (CH); 33.0, 25.3, 24.9 (5 cyclohexyl CH2); 8.9
(Me). HR-ESI-MS: 378.1361 ([M þ Na]þ, C18H21N5NaOSþ; calc. 378.1359), 356.1541 ([M þ H]þ,
C18H22N5OSþ; calc. 356.1540).
4-Butyl-5-(1-cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
(5i). Yield: 0.251 g (75%). Colorless crystals. M.p. 248 – 2508 (MeOH). IR (KBr): 3066m, 2936m, 1356m,
1
1295m. H-NMR ((D6)DMSO): 8.55 (s, HꢀC(2’)); 4.12 (t, J ¼ 6.8, CH2N); 4.07 – 4.02 (m, CH); 2.20 (s,
Me); 1.95 – 1.81 (m, 4 cyclohexyl H); 1.69 – 1.62 (m, 3 cyclohexyl H); 1.48 – 1.38 (m, 2 cyclohexyl H, Bu
CH2); 1.22 – 1.17 (m, 1 cyclohexyl H); 1.07 – 1.01 (m, Bu CH2); 0.69 (t, J ¼ 6.8, Me); NH absorption
missing. 13C-NMR ((D6)DMSO): 167.9 (C¼S); 141.9 (C(3)); 123.1, 118.4 (imidazole C(4), C(5)); 123.9
(imidazole C(2)); 55.6 (CH); 43.7 (CH2N); 33.2, 25.4, 25.0 (5 cyclohexyl CH2); 30.0, 19.3 (2 Bu CH2);
13.6, 9.0 (2 Me). HR-ESI-MS: 358.1677 ([M þ Na]þ, C16H25N5NaOSþ; calc. 358.1672), 336.1856 ([M þ
H]þ, C16H26N5OSþ; calc. 336.1853).
5. Synthesis of 1,3,4-Thiadiazoles 6. General Procedure. A soln. of 4 (1 mmol) in conc. H2SO4 (5 ml)
was kept at r.t. for 1 d. After neutralization of the soln. with dil. NH4OH, the solid product was filtered
off, dried, and crystallized from MeOH.
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-N-methyl-1,3,4-thiadiazol-2-amine (6a). See [6].
4-{[5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-1,3,4-thiadiazol-2-yl]amino}benzenesulfonic
Acid (6b). Yield: 0.211 g (58%). Yellowish crystals. M.p. 300 – 3038 (dec., MeOH). IR (KBr): 3400 –
2800m (br.), 3124m, 3064m, 1509s, 1176m (br.), 1034m, 708m. 1H-NMR ((D6)DMSO): 10.34 (br. s,
NH); 8.66 (s, HꢀC(2’)); 7.60, 7.57 (AA’BB’, JAB ¼ 8.4, 4 arom. H); 7.42 – 7.28 (m, 5 arom. H); 5.29 (s, CH2);
2.56 (s, Me). 13C-NMR ((D6)DMSO): 164.4, 146.4 (thiadiazole C(2), C(5)); 142.1, 141.4, 136.1, 122.7,
116.6 (3 arom. C, imidazole C(4), C(5)); 129.4, 128.6, 127.7, 127.0, 125.0 (9 arom. CH); 125.6 (imidazole
C(2)); 49.0 (CH2); 10.2 (Me). HR-ESI-MS: 488.0432 ([M ꢀ 1 þ 2 Na]þ, C19H16N5Na2O4S2þ ; calc.
488.0434), 466.0610 ([M þ Na]þ, C19H17N5NaO4S2þ ; calc. 466.0614), 444.0791 ([M þ H]þ, C19H18N5O4Sþ2 ;
calc. 444.0795).
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-N-butyl-1,3,4-thiadiazol-2-amine (6c). Yield:
0.209 g (61%). Yellowish crystals. M.p. 206 – 2088 (dec., MeOH). IR (KBr): 3185m, 3068m, 2958s,
1576s, 1454m, 748m. 1H-NMR ((D6)DMSO): 8.57 (s, HꢀC(2’)); 7.58 (br. s, NH); 7.41 – 7.26 (m, 5 arom.
H); 5.24 (s, PhCH2); 3.34 – 3.23 (m, CH2N); 2.49 (s, Me); 1.59 – 1.54 (m, CH2); 1.39 – 1.33 (m, CH2); 0.90
(t, J ¼ 7.6, Me). 13C-NMR ((D6)DMSO): 169.2, 144.4 (C(2), C(5)); 136.3, 124.0, 123.0 (1 arom. C,
imidazole C(4), C(5)); 129.4, 128.5, 127.6 (5 arom. CH); 125.3 (imidazole C(2)); 48.9 (PhCH2); 44.9
(CH2N); 31.2, 20.1 (2 CH2); 14.1, 10.1 (2 Me). HR-ESI-MS: 366.1361 ([M þ Na]þ, C17H21N5NaOSþ; calc.
366.1359), 344.1541 ([M þ H]þ, C17H22N5OSþ; calc. 344.1540).
5-(1,5-Dimethyl-3-oxido-1H-imidazol-4-yl)-N-methyl-1,3,4-thiadiazol-2-amine (6d). Yield: 0.207 g
(92%). Yellowish crystals. M.p. 228 – 2308 (dec., MeOH). IR (KBr): 3375s (NH), 3120s, 2941s, 1541m,
1404m, 1097m, 1033m, 604m. 1H-NMR ((D6)DMSO): 8.37 (s, HꢀC(2’)); 7.55 (br. s, NH); 3.59 (s,
imidazole MeN); 2.89 (br. s, MeN); 2.54 (s, Me). 13C-NMR ((D6)DMSO): 169.8, 144.8 (C(2), C(5));
125.4 (imidazole C(2)); 124.5, 122.3 (imidazole C(4), C(5)); 32.5, 31.6 (2 MeN); 9.8 (Me). HR-ESI-MS:
248.0578 ([M þ Na]þ, C8H11N5NaOSþ; calc. 248.0577), 226.0760 ([M þ H]þ, C8H12N5OSþ; calc.
226.0757).

Helvetica Chimica Acta – Vol. 95 (2012)
413
4-{[5-(1-Cyclohexyl-5-methyl-3-oxido-1H-imidazol-4-yl)-1,3,4-thiadiazol-2-yl]amino}benzenesul-
fonic Acid (6e). Yield: 0.249 g (70%). Colorless crystals. M.p. 310 – 3128 (dec., MeOH). IR (KBr):
1
3400 – 2650m (br.), 3385s (NH), 3227s, 3038s, 1420s (br.), 1090s (br.), 613m. H-NMR ((D6)DMSO):
10.29 (br. s, NH); 8.65 (s, HꢀC(2’)); 7.60, 7.56 (AA’BB’, JAB ¼ 8.4, 4 arom. H); 4.14 – 4.09 (m, CH); 2.68 (s,
Me); 1.99 – 1.81 (m, 4 cyclohexyl H); 1.68 – 1.63 (m, 3 cyclohexyl H); 1.47 – 1.41 (m, 2 cyclohexyl H);
1.24 – 1.21 (m, 1 cyclohexyl H). 13C-NMR ((D6)DMSO): 164.4, 146.7 (thiadiazole C(2), C(5)); 142.2,
116.6 (2 arom. C); 141.4, 127.0 (4 arom. CH); 124.2 (imidazole C(2)); 123.1, 121.6 (imidazole C(4), C(5));
55.3 (CH); 33.1, 25.4, 25.0 (5 cyclohexyl CH2); 9.9 (Me). HR-ESI-MS: 458.0926 ([M þ Na]þ,
C18H21N5NaO4S2þ ; calc. 458.0927), 436.1110 ([M þ H]þ, C18H22N5O4Sþ2 ; calc. 436.1108).
6. Synthesis of 1,2,4-Triazole-3-ones 8. General Procedure. A mixture of 7 (1 mmol) and a 2% aq.
soln. of NaOH (5 ml) was heated to reflux for 8 h. Then, the soln. was neutralized with AcOH, and the
formed precipitate was filtered off and crystallized from MeOH.
5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-4-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (8a).
Yield: 0.216 g (66%). Colorless crystals. M.p. 224 – 2288 (MeOH). IR (KBr): 3115m, 2938m, 1705vs
(C¼O), 1558m, 1416m, 734m. 1H-NMR ((D6)DMSO): 8.55 (s, HꢀC(2’)); 7.41 – 7.24 (m, 5 arom. H); 5.23
(s, PhCH2); 3.73 (t, J ¼ 6.8, CH2N); 2.08 (s, Me); 1.58 (br. s, NH); 1.37 – 1.32, 1.06 – 1.00 (2m, 2 CH2); 0.68
(t, J ¼ 7.7, Me ) . 13C-NMR ((D6)DMSO): 155.4 (C¼O); 137.4, 136.3, 127.8, 119.8 (1 arom. C, C(3),
imidazole C(4), C(5)); 129.4, 128.6, 127.6 (5 arom. CH); 126.3 (imidazole C(2)); 49.1 (PhCH2); 41.0
(CH2N); 30.7, 19.4 (2 CH2); 13.6, 9.1 (2 Me). HR-ESI-MS: 350.1589 ([M þ Na]þ, C17H21N5NaO2þ ; calc.
350.1588), 328.1771 ([M þ H]þ, C17H22N5O2þ ; calc. 328.1768).
4-Butyl-5-(1,5-dimethyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8b). Yield:
0.176 g (70%). Colorless crystals. M.p. 214 – 2168 (MeOH). IR (KBr): 3409vs (NH), 1698vs (C¼O),
1
1559vs, 1410s, 649m. H-NMR ((D6)DMSO): 8.33 (s, HꢀC(2’)); 3.71 (q, J ¼ 7.0, CH2N); 3.58 (s, MeN);
2.16 (s, Me); 1.64 (br. s, NH); 1.39 – 1.35, 1.10 – 1.06 (2m, 2 CH2); 0.74 (t, J ¼ 7.4, Me). 13C-NMR
((D6)DMSO): 155.6 (C¼O); 137.4, 128.2, 118.8 (C(3), imidazole C(4), C(5)); 126.4 (imidazole C(2));
41.1 (CH2N); 32.7 (MeN); 32.7, 19.5 (2 CH2); 13.7, 8.9 (2 Me). HR-ESI-MS: 290.1012 ([M þ K]þ,
C11H17KN5Oþ2 ; calc. 290.1014), 274.1273 ([M þ Na]þ, C11H17N5NaO2þ ; calc. 274.1275), 252.1451 ([M þ
H]þ, C11H18N5Oþ2 ; calc. 252.1455).
7. Synthesis of N-Acetylcarbohydrazides 9. General Procedure. A mixture of 1 (1 mmol) and Ac2O
(1.1 mmol) in EtOH (5 ml) was heated to reflux for 2 h. The product formed was then filtered off, washed
with Et2O, and crystallized from MeOH.
4-[(2-Acetylhydrazinyl)carbonyl]-1-benzyl-5-methyl-1H-imidazol-1-ium 3-Oxide (9a). Yield:
1.251 g (87%). Colorless crystals. M.p. 164 – 1668 (MeOH). IR (KBr): 3119s, 1663vs (C¼O), 1601vs,
1
1497m, 709m. H-NMR ((D6)DMSO): 12.65, 10.26 (2 br. s, 2 NH); 8.68 (s, HꢀC(2)); 7.41 – 7.23 (m, 5
arom. H); 5.24 (s, CH2); 2.42, 1.90 (2s, 2 Me). 13C-NMR ((D6)DMSO): 167.3, 159.7 (2 C¼O); 135.6, 131.2,
120.8 (1 arom. C, C(4), C(5)); 129.5, 128.6, 127.6 (5 arom. CH); 126.9 (C(2)); 48.7 (CH2); 20.9, 9.6 (2
Me). HR-ESI-MS: 311.1118 ([M þ Na]þ, C14H16N4NaOþ3 ; calc. 311.1115), 289.1297 ([M þ H]þ,
C14H17N4Oþ3 ; calc. 289.1295).
4-[(2-Acetylhydrazinyl)carbonyl]-1-cyclohexyl-5-methyl-1H-imidazol-1-ium 3-Oxide (9b). Yield:
0.246 g (88%). Colorless crystals. M.p. 184 – 1888 (MeOH). IR (KBr): 3247s (NH), 2937s, 1654vs
1
(C¼O), 1601vs, 1418m, 1047m. H-NMR ((D6)DMSO): 12.61 (br. s, NH); 8.68 (s, HꢀC(2)); 4.10 – 4.03
(m, CH); 2.55 (s, Me); 1.93 – 1.78 (m, 4 cyclohexyl H, Me); 1.66 – 1.59 (m, 3 cyclohexyl H); 1.43 – 1.36 (m,
2 cyclohexyl H); 1.20 – 1.13 (m, 1 cyclohexyl H). 13C-NMR ((D6)DMSO): 168.6, 158.0 (2 C¼O); 130.7,
119.8 (C(4), C(5)); 124.5 (C(2)); 55.1 (CH); 33.0, 25.3, 24.9 (5 cyclohexyl CH2); 20.9, 9.4 (2 Me). HR-
ESI-MS: 303.1427 ([M þ Na]þ, C13H20N4NaOþ3 ; calc. 303.1428), 281.1607 ([M þ H]þ, C13H21N4Oþ3 ; calc.
281.1608).
8. Synthesis of Compounds 11. General Procedure. To a magnetically stirred soln. of 5g or 6e
(1 mmol) in CH2Cl2 (1 ml), a soln. of 2,2,4,4-tetramethylcyclobutane-1,3-dithione (10, 0.6 mmol) in
CH2Cl2 (1 ml) was added dropwise. The addition was complete after ca. 10 min, and stirring was
continued for 48 h, while a precipitate was formed. Then, the solvent was removed under reduced
pressure, and the resulting solid was washed with hexane and filtered. The crude product was
recrystallized from MeOH.

414
Helvetica Chimica Acta – Vol. 95 (2012)
5-(1-Cyclohexyl-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-4-methyl-2,4-dihydro-3H-1,2,4-
triazole-3-thione (11a). Yield: 0.250 g (81%). Colorless crystals. M.p. 276 – 2788 (MeOH). IR (KBr):
3092s, 2935s, 1560m, 1500m, 1416m, 1348m. 1H-NMR ((D6)DMSO): 3.72 (s, MeN); 3.35 – 3.29 (m, CH);
2.33 (s, Me); 1.83 – 1.64 (m, 6 cyclohexyl H); 1.36 – 1.16 (m, 4 cyclohexyl H); NH absorption missing.
13C-NMR ((D6)DMSO): 171.6, 163.2 (2 C¼S); 141.2 (C(3)); 126.3, 116.5 (imidazole C(4), C(5)); 55.4
(CH); 31.7 (MeN); 26.3, 25.8, 21.9 (5 cyclohexyl CH2); 11.9 (Me). HR-ESI-MS: 332.0973 ([M þ Na]þ,
C13H19N5NaS2þ ; calc. 332.0974), 310.1150 ([M þ H]þ, C13H20N5Sþ2 ; calc. 310.1155).
4-{[5-(1-Cyclohexyl-2,3-dihydro-5-methyl-2-thioxo-1H-imidazol-4-yl)-1,3,4-thiadiazol-2-yl]amino}-
benzenesulfonic Acid (11b). Yield: 0.338 g (91%). Colorless crystals. M.p. 314 – 3168 (dec., MeOH). IR
(KBr): 3400 – 2700m (br.), 3178s, 2935s, 1405s (br.), 1122s (br.), 616m. 1H-NMR ((D6)DMSO): 7.57 (br.
s, 4 arom. H); 3.36 – 3.29 (m, CH); 2.57 (s, Me); 1.94 – 1.63 (m, 6 cyclohexyl H); 1.37 – 1.21 (m, 4
cyclohexyl H); NH absorption missing. 13C-NMR ((D6)DMSO): 163.9, 147.3 (thiadiazole C(2), C(5));
162.9 (C¼S); 142.9, 123.0, 120.2, 116.8 (2 arom. C, imidazole C(4), C(5)); 140.1, 127.1 (4 arom. CH); 57.1
(CH); 26.3, 25.3, 21.2 (5 cyclohexyl CH2); 11.9 (Me). HR-ESI-MS: 474.0695 ([M þ Na]þ,
C18H21N5NaO3S3þ ; calc. 474.0699), 452.0877 ([M þ H]þ, C18H22N5O3Sþ3 ; calc. 452.0879).
REFERENCES
[1] C. A. M. Fraga, E. J. Barreiro, Curr. Med. Chem. 2006, 13, 167; S. Rollas, S¸. G. KꢁÅꢁkgꢁzel,
Molecules 2007, 12, 1910; B. Narasimhan, P. Kumar, D. Sharma, Acta Pharm. Sci. 2010, 52, 169.
[2] T. P. Sycheva, T. N. Pavlova, M. N. Shchukina, Pharm. Chem. J. 1972, 6, 696.
[3] J. H. M. Lange, H. H. van Stuivenberg, H. K. A. C. Coolen, T. J. P. Adolfs, A. C. McCreary, H. G.
Keizer, H. C. Wals, W. Veerman, A. J. M. Borst, W. de Looff, P. C. Verveer, C. G. Kruse, J. Med.
Chem. 2005, 48, 1823.
[4] Takeda Chemical Industries, Ltd., 1998, US 1998/5753664 A1; Solvay Pharmaceuticals B. V., 2005,
US 2005/54679 A1; Astrazeneca UK Ltd., 2007, WO 2007/31721 A1.
[5] A. A. Hassan, A. M. Shawky, J. Heterocycl. Chem. 2010, 47, 745.
´
[6] G. Mloston, A. M. Pieczonka, E. Kowalczyk, A. Linden, H. Heimgartner, Helv. Chim. Acta 2011, 94,
1764.
´
´
´
[7] M. Jasinski, G. Mloston, A. Linden, H. Heimgartner, Helv. Chim. Acta 2008, 91, 1916; M. Jasinski, G.
´
Mloston, Collect. Czech. Chem. Commun. 2010, 75, 871.
´
´
[8] a) G. Mloston, T. Gendek, H. Heimgartner, Helv. Chim. Acta 1998, 81, 1585; b) G. Mloston, M.
Celeda, G. K. S. Prakash, G. A. Olah, H. Heimgartner, Helv. Chim. Acta 2000, 83, 728; c) G.
´
´
´
Mloston, J. Romanski, M. Jasinski, H. Heimgartner, Tetrahedron: Asymmetry 2009, 20, 1073; d) G.
´
´
´
Mloston, M. Jasinski, H. Heimgartner, Eur. J. Org. Chem. 2011, 2542; e) G. Mloston, M. Jasinski, D.
´
´
Rygielska, H. Heimgartner, Heterocycles 2011, 83, 765; f) G. Mloston, D. Rygielska, M. Jasinski, H.
Heimgartner, Tetrahedron: Asymmetry 2011, 22, 669.
[9] S. Hauptmann, Organische Chemie, 2. Aufl., VEB Deutscher Verlag fꢁr Grundstoffindustrie,
Leipzig, 1985, p. 511.
[10] R. N. Khelevin, Zh. Org. Khim. 1984, 20, 379 (Russ. J. Org. Chem. 1984, 20, 339); R. N. Khelevin, Zh.
Org. Khim. 1984, 20, 1290 (Russ. J. Org. Chem. 1984, 20, 1173); R. N. Khelevin, Zh. Obsh. Khim.
1986, 56, 202 (J. Gen. Chem. USSR 1986, 56, 179).
[11] I. P. Singh Kapoor, M. Kapoor, G. Singh, J. Therm. Anal. Calorim. 2010, 102, 723.
[12] X. J. Zou, G. Y. Jin, Z. X. Zhang, J. Agricul. Food Chem. 2002, 50, 1451; A. Maliszewska-Guz, M.
´
Wujec, M. Pitucha, M. Dobosz, A. Chodkowska, E. Jagiełło-Wojtowicz, L. Mazur, A. E. Kozioł,
Collect. Czech. Chem. Commun. 2005, 70, 51.
´
[13] A. P. Liesen, T. M. de Aquino, C. S. Carvalho, V. T. Lima, J. M. de Araujo, J. G. de Lima, A. R.
´
de Faria, E. J. T. de Melo, A. J. Alves, E. W. Alves, A. Q. Alves, A. J. S. Goes, Eur. J. Med. Chem.
2010, 45, 3685.
Received November 25, 2011