Synthesis and selected reactions of hydrazides containing an imidazole moiety

Article abstract of DOI:10.1002/hlca.201100292

The preparation of two types of imidazole derivatives bearing a hydrazide group was achieved by treatment of the corresponding esters with NH ₂NH₂·H₂O in MeOH at room temperature. In the case of 4-(ethoxycarbonyl)-1H-imidazole 3-oxides 3, hydrazides of type 1 were formed with retention of the N-oxide structure (Scheme 1). Interestingly, due to a strong H-bonding, no deoxygenation of the N→O function could be achieved even by treatment of 3 with Raney-Ni. The second type, 2-[(1H-imidazol-2-yl)sulfanyl]acetohydrazides 2, was obtained from 1H-imidazole-2(3H)-thiones 4 in two steps via S-alkylation with methyl bromoacetate, followed by treatment with NH₂NH₂· H₂O (Scheme 2). An imidazole 7, containing both types of hydrazide groups, was prepared analogously from ethyl 2,3-dihydro-2-thioxo-1H-imidazole-4- carboxylate 4d (Scheme 4). Both types of hydrazides, 1 and 2, were transformed successfully to the corresponding acylhydrazones 8 and 9, respectively (Scheme 5). Furthermore, it has been shown that hydrazides of type 1 are useful starting materials for the synthesis of 1,2,4-triazole-3-thiones 11 and 1,3,4-thiadiazole-2-amines 12, bearing an imidazole 3-oxide moiety (Scheme 7). Copyright

Full text of DOI:10.1002/hlca.201100292

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Helvetica Chimica Acta – Vol. 94 (2011)
Synthesis and Selected Reactions of Hydrazides Containing an Imidazole
Moiety
by Grzegorz Mloston´*, Adam Marek Pieczonka1), and Ewelina Kowalczyk2)
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łodz
(phone: þ 48426355761; fax: þ 48426655162; e-mail: gmloston@uni.lodz.pl)
and Anthony Linden and Heinz Heimgartner*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
The preparation of two types of imidazole derivatives bearing a hydrazide group was achieved by
treatment of the corresponding esters with NH2NH2 · H2O in MeOH at room temperature. In the case of
4-(ethoxycarbonyl)-1H-imidazole 3-oxides 3, hydrazides of type 1 were formed with retention of the N-
oxide structure (Scheme 1). Interestingly, due to a strong H-bonding, no deoxygenation of the N ! O
function could be achieved even by treatment of 3 with Raney-Ni. The second type, 2-[(1H-imidazol-2-
yl)sulfanyl]acetohydrazides 2, was obtained from 1H-imidazole-2(3H)-thiones 4 in two steps via S-
alkylation with methyl bromoacetate, followed by treatment with NH2NH2 · H2O (Scheme 2). An
imidazole 7, containing both types of hydrazide groups, was prepared analogously from ethyl 2,3-dihydro-
2-thioxo-1H-imidazole-4-carboxylate 4d (Scheme 4). Both types of hydrazides, 1 and 2, were trans-
formed successfully to the corresponding acylhydrazones 8 and 9, respectively (Scheme 5). Furthermore,
it has been shown that hydrazides of type 1 are useful starting materials for the synthesis of 1,2,4-triazole-
3-thiones 11 and 1,3,4-thiadiazole-2-amines 12, bearing an imidazole 3-oxide moiety (Scheme 7).
1. Introduction. – In a series of our recent publications, various syntheses of
imidazole derivatives including optically active products were reported [1]. It is well-
documented that some imidazole derivatives such as imidazole N-oxides [2],
imidazole-2-thiones [3], or 2-sulfanylimidazoles [4] show diverse biological activities.
On the other hand, imidazole N-oxides were used for the preparation of more complex
N-heterocycles via Pd-catalyzed direct arylation [5], and, in the case of optically active
derivatives, they were applied as promising ligands for asymmetric allylation of
aromatic aldehydes [6].
Hydrazides were frequently reported as biologically active compounds, and similar
properties were shown for their derivatives, e.g., hydrazones, semicarbazones, and
thiosemicarbazones [7]. Furthermore, acyl hydrazides are privileged starting materials
for the preparation of various heterocycles such as 1,2,4-triazoles, 1,3,4-thiadiazoles,
1,3,4-oxadiazoles, etc. [8].
The aim of the present study was the synthesis of hydrazides containing differently
substituted imidazole moieties starting with the corresponding esters described in our
1
´
´
Part of the planned Ph.D. thesis of A. M. P., University of Łodz.
)
)
2
´
´
Part of the Diploma thesis of E. K., University of Łodz, 2003.
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
1765
recent publications. For the first time, hydrazides derived from 3-oxidoimidazole
carboxylic acids and the influence of the oxido function on the reactivity of the
hydrazide unit and vice versa will be reported. In addition, the synthesis of
corresponding hydrazones as representative derivatives is presented.
2. Results and Discussion. – For the synthesis of imidazole-containing hydrazides of
types 1 and 2, the typical protocol based on the treatment of the corresponding ethyl
carboxylates with NH2NH2 · H2O [9] was applied, and the expected products were
obtained in high yields.
The 1H-imidazole N-oxides 3 with an ester group at C(4) were easily available from
the reaction of 2-(hydroxyimino)-3-oxobutanoate with the corresponding primary
amine and CH2O [1g][10]. Treatment of 3a – 3c with NH2NH2 · H2O in MeOH at room
temperature led to the products 1a – 1c, respectively, which were obtained as crystalline
materials in good yields (Scheme 1). Their structures were determined on the basis of
their spectroscopic data. The presence of the N-oxido function was evidenced by the
diagnostic high-field shifted HꢀC(2) signal at 8.60 – 8.37 ppm.
Scheme 1
Finally, the structure of 1b was established by X-ray crystallography (Fig.). The
N(4)ꢀH group forms bifurcated H-bonds. One interaction is an intramolecular H-bond
with the adjacent oxide O(1)-atom to form a loop, which can be described by a graph
set motif [12] of S(6). The second interaction is an intermolecular H-bond with the
oxide O-atom of a neighboring molecule. This interaction links pairs of molecules
related by a center of inversion into dimers, and the motif thus formed can be described
by a graph set motif of R22(12). The same two molecules are also linked by a H-bond
between the NH2 group and the oxide O-atom. The motif in this case is R22(14). The
other H-atom of the NH2 group forms an intermolecular H-bond with the hydrazide
O(2)-atom of a different neighboring molecule. This interaction links these molecules
into centrosymmetric dimers and can be described by a graph set motif of R22(10). The
combination of all intermolecular H-bonds links the molecules into two-dimensional
layer networks which lie parallel to the (001) plane. The Ph rings from adjacent layers
interdigitate.
Interestingly, in contrast to the ester 3a, the attempted ꢃsulfur-transfer reactionꢄ [1a]
aimed at obtaining the corresponding 1H-imidazole-2-thione from the hydrazide 1a
was unsuccessful. Moreover, the typical thermal isomerization of 2-unsubstituted 1H-
imidazole N-oxide derivatives to the corresponding imidazol-2-ones was not achieved
even after heating of 1a in boiling toluene. Finally, the attempted deoxygenation with

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Figure. ORTEP Plot [11] of the molecular structure of 1b
(with 50% probability ellipsoids; arbitrary numbering of the
atoms)
Raney-Ni, which was performed smoothly in many other cases of 1H-imidazole N-
oxides [1c – 1e], did not afford the expected products. All these observations evidence
that the presence of the hydrazide function strongly influences the reactivity of the
oxido function, most likely as a result of a strong intramolecular H-bond between the
hydrazide NꢀH and the oxide O-atom.
The second type of hydrazides 2 presented in this study was obtained via S-
alkylation of 1H-imidazole-2-thiones 4 with methyl 2-bromoacetate and subsequent
conversion of the ester function (Scheme 2). A convenient access to the differently
Scheme 2

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1767
substituted starting materials 4 is the so-called ꢃsulfur-transfer reactionꢄ [1a][1e], in
which the 2-unsubstituted 1H-imidazole N-oxide is treated with a cycloaliphatic
thioketone. The crystalline hydrazides 2a – 2c were obtained in good yields.
Another method used for the incorporation of an ester group into the side chain of
imidazoles consists of the condensation of a-hydroxyimino ketones with CH2O and an
appropriate a-amino acid ester [1e]. In that case, the ester group is placed in the
a-position of the side chain at N(1). Unexpectedly, by treatment with NH2NH2 · H2O,
even under very mild conditions, the 1H-imidazole N-oxides 5a and 5b were converted
to the a-(1H-imidazol-1-yl)carboxylic acids 6a and 6b, respectively, in nearly
quantitative yields (Scheme 3). The preservation of the N-oxide function was
1
confirmed by the H-NMR spectra, which showed the typical absorption for HꢀC(2)
at 8.13 for 2a and 8.36 ppm for 2b.
Scheme 3
Starting with 2-thioxo-1H-imidazole-4-carboxylate 4d, which was obtained in
analogy to the corresponding N-Ph amide [1g] by the ꢃsulfur-transfer reactionꢄ with 3b,
subsequent alkylation with methyl 2-bromoacetate, and treatment with 2 equiv. of
NH2NH2 · H2O led to the bis-hydrazide 7 (Scheme 4). The latter represents an example
in which the structure elements of type 1 and type 2 are combined.
Scheme 4
Both types of easily available hydrazides, 1 and 2, are attractive starting materials
for further syntheses involving the hydrazide group. In the present study, they were
used for the formation of hydrazones with various aldehydes and ketones3). In the case
of hydrazides 1b and 1c, the reactions with benzaldehyde, adamantan-2-one, and
cyclohexanone, respectively, in MeOH occurred smoothly at room temperature and
yielded the expected hydrazones 8a – 8f in high yields (Scheme 5). The analogous
3
)
For some recent articles on synthesis and biological interest of acylhydrazones, see [7a][8a][13].

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reactions with acetophenone required acid catalysis (AcOH in EtOH, reflux) to give 8e
and 8f (Scheme 5), whereas with benzophenone no hydrazone was obtained.
A series of hydrazones of type 9 derived from hydrazides 2a – 2c was prepared by
using some of aromatic aldehydes and cyclohexanone. The reactions were carried out in
boiling EtOH in the presence of catalytic amounts of AcOH, and, in all cases, the
products were isolated as crystalline materials (Scheme 5).
Scheme 5
In contrast to hydazide 1a, which did not undergo the ꢃsulfur-transfer reactionꢄ upon
treatment with 2,2,4,4-tetramethylcyclobutane-1,3-dithione, the analogous reaction
with hydrazide 8c afforded, after 24 h at room temperature in CH2Cl2, the expected 1H-
imidazol-2-thione derivative 4e in 88% yield (Scheme 6). It is worth mentioning that
corresponding N-Me- and N-Ph-substituted 3-oxido-1H-imidazole-4-carboxamides
react under similar conditions [1g], whereas the transformation of 4-methyl- and 4-
phenyl-1H-imidazole 3-oxides is complete within ca. 30 min. This result confirms the
importance of the H-bonding between the amide and hydrazide function and the N !
O group for the tuning of the reactivity of imidazole N-oxide as a 1,3-dipole [1a].
Scheme 6
The reaction of hydrazides with isothiocyanates is a typical procedure applied for
the preparation of 1,3,4-thiadiazoles or 1,2,4-triazole-3-thiones [14]. The two-steep
reactions led initially to thiosemicarbazides, which subsequently undergo cyclocon-
densation under acidic or basic reaction conditions. Using these methods, hydrazide 1b

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was smoothly converted into triazole thione 11 by heating of thiosemicarbazide 10 in
aqueous NaOH solution, whereas, after stirring of a solution of 1b in concentrated
H2SO4 at room temperature, thiadiazole 12 was obtained in high yield (Scheme 7).
Scheme 7
3. Conclusions. – The presented results show that differently substituted imidazole
N-oxides containing an ester group can be easily transformed into the corresponding
hydrazides without loss of the N-oxide function. To the best of our knowledge, there are
no such examples of azaheterocyclic N-oxides reported to date. The presence of the
hydrazide function and the N-oxide group offer a unique opportunity for their
application in the synthesis of more complex heterocycles, which are potentially useful
building blocks for the preparation of the biologically active products. Some imidazole
derivatives containing hydrazide [15] or hydrazone moieties [16] were reported as
potential pharmaceuticals, as reflected by several patents, e.g., [17].
In addition, imidazole N-oxides can be transformed to imidazole-2-thiones, which
may be used for syntheses of another class of hydrazides containing the imidazole unit.
These products can also be considered as potentially useful starting materials for the
preparation of diverse polyheterocycles.
The authors thank PD Dr. L. Bigler (University of Zurich) for recording a series of HR mass spectra.
A. P. thanks for financial support within the project co-funded by the European Union under the
European Social Fund ꢀ HUMAN – BEST INVESTMENT!ꢄ.
Experimental Part
1. General. M.p.: Melt-Temp. II (Aldrich); uncorrected. Optical rotations: PERKIN-ELMER 241
MC polarimeter at l 589 nm. IR Spectra: NEXUS FT-IR spectrophotometer; in KBr; absorptions in
cmꢀ1. 1H- and 13C{1H}-NMR Spectra: Bruker Avance III 600 using solvent signal as reference; d in ppm;

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coupling constants J in Hz; assignments of signals in 13C-NMR spectra accomplished on the basis of
HMQC experiments. EI-HR-MS: Bruker Esquire LC spectrometer. ESI-HR-MS: Finnigan MAT-95
instrument.
2. Starting Materials. All solvents are commercially available and were used as received. Imidazole
N-oxides 3a – 3c and 5a and 5b, and 1H-imidazole-2-thiones 4a – 4c were prepared according to known
procedures [1a][1e]. 2,2,4,4-Tetramethylcyclobutane-1,3-dithione was prepared by thionation of 2,2,4,4-
tetramethylcyclobutane-1,3-dione using P2S5 as a thionating reagent [18].
3. General Procedure for the Synthesis of Hydrazides 1. To a soln. of freshly prepared 3-oxido-1H-
imidazole carboxylate 3 (10 mmol) in MeOH (5 ml) was added NH2NH2 · H2O (20 mmol). The mixture
was stirred for 16 h at r.t., the solvent was evaporated under vacuum, and the residue was crystallized
from MeOH.
1,5-Dimethyl-1H-imidazole-4-carbohydrazide 3-Oxide (1a). Yield: 1.02 g (65%). Colorless crystals.
M.p. 242 – 2468 (dec., MeOH). IR (KBr): 3309s, 3261s (NH), 1648vs (C¼O), 1601vs, 1530m, 603m.
1H-NMR ((D6)DMSO): 11.58 (br. s, NH); 8.37 (s, HꢀC(2)); 4.49 (br. s, NH2); 3.54 (s, MeN); 2.48 (s, Me).
13C-NMR ((D6)DMSO): 159.3 (C¼O); 133.3, 120.7 (C(4), C(5)); 126.6 (C(2)); 32.2 (MeN); 9.3 (Me).
HR-ESI-MS: 171.0874 ([M þ H]þ, C6H11N4Oþ2 ; calc. 171.0876).
1-Benzyl-5-methyl-1H-imidazole-4-carbohydrazide 3-Oxide (1b). Yield: 1.353 g (55%). Colorless
crystals. M.p. 228 – 2308 (dec., MeOH). IR (KBr): 3296vs (NH), 1661vs (C¼O), 1604vs, 1579m, 977m.
1H-NMR ((D6)DMSO): 11.57 (br. s, NH); 8.60 (s, HꢀC(2)); 7.40 – 7.21 (m, 5 arom. H); 5.21 (s, CH2); 4.51
(br. s, NH2); 2.42 (s, Me). 13C-NMR ((D6)DMSO): 159.2 (C¼O); 136.0, 121.3 (C(4), C(5)); 130.0 (1
arom. C); 129.4, 128.6, 127.6 (5 arom. CH); 126.6 (C(2)); 48.6 (CH2); 9.6 (Me). HR-ESI-MS: 247.1191
([M þ H]þ, C12H15N4Oþ2 ; calc. 247.1190).
1-Cyclohexyl-5-methyl-1H-imidazole-4-carbohydrazide 3-Oxide (1c). Yield: 1.428 g (60%). Color-
less crystals. M.p. 170 – 1728 (MeOH). IR (KBr): 3305s, 3271s (NH), 1655vs (C¼O), 1600vs, 1544m,
1416m, 1281m. 1H-NMR ((D6)DMSO): 11.63 (br. s, NH); 8.58 (s, HꢀC(2)); 4.49 (br. s, NH2); 4.09 – 4.00
(m, CH); 2.55 (s, Me); 1.96 – 1.76 (m, 4 cyclohexyl H); 1.70 – 1.57 (m, 3 cyclohexyl H); 1.46 – 1.35 (m, 2
cyclohexyl H); 1.22 – 1.11 (m, 1 cyclohexyl H). 13C-NMR ((D6)DMSO): 159.4 (C¼O); 129.2, 120.3 (C(4),
C(5)); 124.2 (C(2)); 55.0 (CH); 33.0, 25.4, 25.0 (5 cyclohexyl CH2); 9.33 (Me). HR-EI-MS: 239.1494
([M þ H]þ, C11H19N4Oþ2 ; calc. 239.1502).
Treatment of ethyl a-(3-oxido-1H-imidazol-1-yl) carboxylates 5 with NH2NH2 · H2O according to
the same procedure led to the corresponding carboxylic acids 6.
(2S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)propanoic Acid (6a). Yield: 1.656 g (90%). Yellow-
1
ish oil. [a]2D0 ¼ þ74 (c ¼ 1, MeOH). IR (film): 1683vs (C¼O), 1633m, 1568m, 1410m, 1337m. H-NMR
(CD3OD): 8.18 (s, HꢀC(2’)); 4.63 (q, J ¼ 7.2, CH); 2.16, 2.15 (2s, 2 Me); 1.68 (d, J ¼ 7.2, Me). 13C-NMR
(CD3OD): 174.8 (C¼O); 124.8, 122.7 (C(4’), C(5’)); 124.3 (C(2’)); 57.0 (CH); 17.2 (Me); 7.3, 5.6 (2
imidazole Me). HR-EI-MS: 185.0921 ([M þ H]þ, C8H13N2O3þ ; calc. 185.0927).
(2S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-3-methylbutanoic Acid (6b). Yield: 1.844 g (87%).
Yellowish oil. [a]D20 ¼ þ34 (c ¼ 1, MeOH). IR (film): 1671vs (br. C¼O), 1633m, 1558m, 1411m, 1333m.
1H-NMR (CD3OD): 8.36 (s, HꢀC(2’)); 4.21 (d, J ¼ 10.6, CHN); 2.42 – 2.35 (m, CH); 2.22, 2.15 (2s, 2 Me);
1.03 (d, J ¼ 6.5, Me); 0.83 (d, J ¼ 7.1, Me ) . 13C-NMR (CD3OD): 178.8 (C¼O); 125.2, 122.6 (C(4’), C(5’));
124.8 (C(2’)); 63.5 (CHN); 31.9 (CH); 17.9, 17.6 (2 Me); 7.4, 5.6 (2 imidazole Me). HR-EI-MS: 213.1232
([M þ H]þ, C10H17N2Oþ3 ; calc. 213.1240).
4. General Procedure for the Synthesis of Hydrazides 2. To a soln. of an 1H-imidazole-2-thione 4
(1 mmol) in CH2Cl2 (5 ml) was added methyl 2-bromoacetate (1 mmol). The mixture was stirred for 48 h
at r.t., then, the solvent was evaporated under vacuum, and the residue was used immediately without
further purification. The oily residue was dissolved in EtOH (5 ml), and NH2NH2 · H2O (2 mmol) was
added. The mixture was heated under reflux for 2 h, the solvent was evaporated under vacuum, and the
residue was crystallized from MeOH.
2-[(1-Benzyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]acetohydrazide (2a). Yield: 0.225 g (88%).
Colorless crystals. M.p. 127 – 1298 (MeOH). IR (KBr): 3321s (NH), 1671vs (C¼O), 1420m, 722m.
1H-NMR (CDCl3): 9.88 (br. s, NH); 7.26 – 6.91 (m, 5 arom. H); 4.99 (s, CH2N); 3.48 (s, CH2S); 2.10, 1.96
(2s, 2 Me). 13C-NMR (CDCl3): 170.2 (C¼O); 138.6 (C(2’)); 136.0, 134.6, 125.3 (1 arom. C, C(4’), C(5’));

Helvetica Chimica Acta – Vol. 94 (2011)
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129.0, 127.9, 126.2 (5 arom. CH); 47.9 (CH2N); 35.4 (CH2S); 12.7, 9.2 (2 Me). HR-EI-MS: 291.1275
([M þ H]þ, C14H19N4OSþ; calc. 291.1280).
2-[(1-Cyclohexyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]acetohydrazide (2b). Yield: 0.212 g
(75%). Colorless crystals. M.p. 117 – 1198 (MeOH). IR (KBr): 3314s, 3226s (br., NH), 1676vs (C¼O),
1615vs, 1523m, 1413m, 1003m. 1H-NMR (CDCl3): 10.0 (br. s, NH); 3.97 – 3.93 (m, CH); 3.63 (s, CH2S);
2.16, 2.11 (2s, 2 Me); 2.03 – 1.71 (m, 7 cyclohexyl H); 1.39 – 1.18 (m, 3 cyclohexyl H). 13C-NMR (CDCl3):
170.5 (C¼O); 137.9 (C(2’)); 134.2, 124.6 (C(4’), C(5’)); 57.2 (CH); 35.2 (CH2S); 31.7, 26.2, 25.2 (5
cyclohexyl CH2); 12.6, 10.6 (2 Me). HR-EI-MS: 283.1589 ([M þ H]þ, C13H23N4OSþ; calc. 283.1588).
2-[(1-Benzyl-4,5-diphenyl-1H-imidazol-2-yl)sulfanyl]acetohydrazide (2c). Yield: 0.323 g (76%).
Colorless crystals. M.p. 112 – 1158 (MeOH). IR (KBr): 3329s, 3276s (NH), 1673vs (C¼O), 1601vs,
1
1453m, 1436m, 701m. H-NMR (CDCl3): 9.96 (br. s, NH); 7.38 – 6.82 (m, 15 arom. H); 4.90 (s, CH2N);
3.67 (s, CH2N). 13C-NMR (CDCl3): 170.2 (C¼O); 142.3, 131.1, 129.2 (3 arom. C); 138.2, 133.5 (C(4’),
C(5’)); 136.0 (C(2’)); 131.0, 130.1, 129.1, 128.8, 128.6, 127.9, 126.8, 126.6, 126.4 (15 arom. CH); 48.1
(CH2N); 34.6 (CH2S). HR-EI-MS: 415.1583 ([M þ H]þ, C24H23N4OSþ; calc. 415.1588).
5. General Procedure for the Synthesis of 1H-Imidazole-2-thiones 4. To a magnetically stirred soln. of
1H-imidazole N-oxide (1 mmol) in CH2Cl2 (1 ml), a soln. of 2,2,4,4-tetramethylcyclobutane-1,3-dithione
[18][19] (0.6 mmol) in CH2Cl2 (1 ml) was added dropwise. The addition was complete after ca. 10 min,
and stirring was continued for 24 h, while a little precipitate was formed. Then, the solvent was removed
under reduced pressure, the resulting solid was washed with hexane, and filtered. The crude product was
recrystallized from MeOH.
Ethyl 1-Benzyl-2,3-dihydro-5-methyl-2-thioxo-1H-imidazole-4-carboxylate (4d). Yield: 0.146 g
(53%). Colorless crystals. M.p. 205 – 2078 (dec., MeOH). IR (KBr): 1706vs (C¼O), 1417vs, 1335m,
721m. 1H-NMR ((D6)DMSO): 12.87 (br. s, NH); 7.35 – 7.21 (m, 5 arom. H); 5.36 (s, CH2); 4.22 (q, J ¼ 7.1,
MeCH2O); 2.28 (s, Me); 1.26 (t, J ¼ 7.1, MeCH2O). 13C-NMR ((D6)DMSO): 164.3 (C¼S); 159.1 (C¼O);
136.6, 115.8 (C(4), C(5)); 135.4 (1 arom. C); 129.1, 127.9, 127.2 (5 arom. CH); 60.9 (MeCH2O); 47.0
(CH2); 14.5 (MeCH2O); 10.9 (Me). HR-EI-MS (70 eV): 276.0930 (Mþ, C14H16N2O2Sþ; calc. 276.0932).
1-Benzyl-2,3-dihydro-5-methyl-2-thioxo-N’-(tricyclo[3.3.1.13,7]dec-2-ylidene)-1H-imidazole-4-carbo-
hydrazide (4e). Yield: 0.345 g (88%). Colorless crystals. M.p. 284 – 2868 (dec., MeOH). IR (KBr): 3293s
1
(NH), 3140s, 3063s, 1616vs (C¼O), 1510m, 1496m, 1406m, 1365m. H-NMR (D6)DMSO): 12.78 (br. s,
NH); 9.99 (br. s, imidazol NH); 7.36 – 7.23 (m, 5 arom. H); 5.34 (s, CH2); 3.32, 2.55 (2 br. s, 2 adamantyl
CH); 2.28 (br. s, Me); 1.99 – 1.75 (m, 12 adamantyl H). 13C-NMR ((D6)DMSO): 162.5 (C¼O); 155.5
(C¼S); 136.8 (C¼N); 133.3, 117.9 (C(4), C(5)); 130.0 (1 arom. C); 129.1, 127.9, 127.3 (5 arom. CH); 46.9
(CH2); 39.1, 37.8, 36.3, 31.6, 27.6 (9 adamantyl C); 10.7 (Me). HR-ESI-MS: 395.1895 ([M þ H]þ,
C22H27N4O2Sþ; calc. 395.1900).
6. Synthesis of 1-Benzyl-2-[(2-hydrazinyl-2-oxoethyl)sulfanyl]-5-methyl-1H-imidazole-4-carbohy-
drazide (7). To a soln. of 4d (267 mg, 1 mmol) in CH2Cl2 (5 ml) was added methyl 2-bromoacetate
(153 mg, 1 mmol). The mixture was stirred for 48 h at r.t., the solvent was evaporated under vacuum, and
the residue was used for the following reaction without further purification. The oily residue was
dissolved in EtOH (5 ml), and NH2NH2 · H2O (2 mmol) was added. The mixture was stirred for 16 h at
r.t., the solvent was evaporated under vacuum, and the residue was crystallized from MeOH: 7 (0.293 g,
88%). Colorless crystals. M.p. 194 – 1988 (MeOH). IR (KBr): 3315vs (NH), 3203m, 1664vs (C¼O),
1612vs, 1594m, 1495m, 734m. 1H-NMR (CDCl3): 9.26, 8.99 (2 br. s, 2 NH); 7.36 – 7.05 (m, 5 arom. H); 5.15
(s, CH2N); 4.30 (br. s, 2 NH2); 3.73 (s, CH2S); 2.38 (s, Me). 13C-NMR (CDCl3): 167.3, 162.9 (2 C¼O);
140.3, 131.0 (C(4), C(5)); 136.6 (C(2)); 133.9 (1 arom. C); 129.3, 128.1, 126.9 (5 arom. CH); 47.2 (CH2N);
35.1 (CH2S); 10.0 (Me). HR-ESI-MS: 335.1286 ([M þ H]þ, C14H19N6O2Sþ; calc. 335.1285).
7. General Procedure for the Synthesis of 8a – 8f. To a stirred soln. of a hydrazide 1 (1 mmol) in
MeOH (4 ml) at 208, an equimolar quantity of the carbonyl component (bezaldehyde, adamantan-2-one,
cyclohexanone) was added slowly. The mixture was stirred for 16 h at r.t., the soln. was concentrated, the
resulting solid was treated with Et2O, filtered, and crystallized from MeOH.
1-Benzyl-5-methyl-N’-[(Z)-phenylmethylidene]-1H-imidazole-4-carbohydrazide 3-Oxide (8a).
Yield: 0.308 g (92%). Colorless crystals. M.p. 232 – 2348 (dec., MeOH). IR (KBr): 3086m, 1667vs
(C¼O), 1607vs, 1594m, 1558m, 1461m. 1H-NMR (CDCl3): 13.80 (br. s, NH); 8.20 (s, HꢀC¼N); 7.79 – 7.77
(m, 2 arom. H; HꢀC(2)); 7.41 – 7.15 (m, 8 arom. H); 5.07 (s, CH2); 2.67 (s, Me). 13C-NMR (CDCl3): 156.3

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(C¼O); 149.0 (C¼N); 134.1, 122.2 (C(4), C(5)); 133.0, 132.2 (2 arom. C); 130.3, 129.6, 129.3, 128.6, 127.8,
127.3 (10 arom. CH); 125.3 (C(2)); 49.6 (CH2); 9.8 (Me). HR-ESI-MS: 335.1503 ([M þ H]þ,
C19H19N4Oþ2 ; calc. 335.1503).
1-Cyclohexyl-5-methyl-N’-[(Z)-phenylmethylidene]-1H-imidazole-4-carbohydrazide 3-Oxide (8b).
Yield: 0.229 g (70%). Colorless crystals. M.p. 206 – 2088 (dec., MeOH). IR (KBr): 3109m, 1671vs (C¼O),
1608vs, 1592m, 1417m, 1270m. 1H-NMR (CDCl3): 13.89 (br. s, NH); 8.21 (s, HꢀC¼N); 7.85 (s, HꢀC(2));
7.80 – 7.78 (m, 2 arom. H); 7.39 – 7.37 (m, 3 arom. H); 3.98 – 3.93 (m, CHN); 2.70 (s, Me); 2.09 – 1.96 (m, 4
cyclohexyl H); 1.70 – 1.42 (m, 5 cyclohexyl H); 1.30 – 1.23 (m, 1 cyclohexyl H). 13C-NMR (CDCl3): 156.5
(C¼O); 148.8 (C¼N); 134.2 (1 arom. C); 131.2, 121.4 (C(4), C(5)); 130.2, 128.6, 127.8 (5 arom. CH); 122.6
(C(2)); 55.7 (CH); 33.7, 25.4, 24.9 (5 cyclohexyl CH2); 9.6 (Me). HR-ESI-MS: 327.1816 ([M þ H]þ,
C18H23N4Oþ2 ; calc. 327.1816).
1-Benzyl-5-methyl-N’-(tricyclo[3.3.1.13,7]dec-2-ylidene)-1H-imidazole-4-carbohydrazide 3-Oxide
(8c). Yield: 0.302 g (80%). Colorless crystals. M.p. 260 – 2628 (dec., MeOH). IR (KBr): 3181m (NH),
1
3042m, 1682vs (C¼O), 1602vs, 1547m, 1255m. H-NMR (CDCl3): 13.35 (br. s, NH); 7.76 (s, HꢀC(2));
7.41 – 7.38 (m, 3 arom. H); 7.13 – 7.12 (m, 2 arom. H); 5.07 (s, CH2); 3.23, 2.87 (2 br. s, 2 adamantyl CH);
2.64 (s, Me); 2.05 – 1.80 (m, 12 adamantyl H). 13C-NMR (CDCl3): 168.5 (C¼O); 156.1 (C¼N); 133.1,
122.7 (C(4), C(5)); 131.8 (1 arom. C); 129.6, 129.2, 127.1 (5 arom. CH); 125.0 (C(2)); 49.5 (CH2); 39.4,
39.1, 37.9, 36.4, 32.8, 27.8 (9 adamantyl C); 9.8 (Me). HR-ESI-MS: 379.2132 ([M þ H]þ, C22H27N4O2þ ;
calc. 379.2128).
1-Cyclohexyl-5-methyl-N’-(tricyclo[3.3.1.13,7]dec-2-ylidene)-1H-imidazole-4-carbohydrazide 3-Ox-
ide (8d). Yield: 0.260 g (70%). Colorless crystals. M.p. 226 – 2288 (dec., MeOH). IR (KBr): 3104w
(NH), 1679vs (C¼O), 1596vs, 1416m. 1H-NMR (CDCl3): 13.47 (br. s, NH); 7.77 (s, HꢀC(2)); 3.96 – 3.90
(m, CHN); 3.22, 2.85 (2 br. s, 2 adamantyl CH); 2.68 (s, Me); 2.09 – 2.02 (m, 2 cyclohexyl H); 2.01 – 1.82
(m, 12 adamantyl H, 1 cyclohexyl H); 1.81 – 1.75 (m, 2 cyclohexyl H); 1.57 – 1.38 (m, 4 cyclohexyl H);
1.30 – 1.21 (m, 1 cyclohexyl H). 13C-NMR (CDCl3): 168.1 (C¼O); 156.5 (C¼N); 130.7, 121.9 (C(4), C(5));
122.4 (C(2)); 55.6 (CHN); 39.4, 39.3, 39.1, 37.9, 36.4, 33.7, 32.7, 27.8, 25.4, 24.8 (9 adamantyl C, 5
cyclohexyl C); 9.5 (Me). HR-ESI-MS: 371.2441 ([M þ H]þ, C21H31N4O2þ ; calc. 371.2442).
1-Benzyl-N’-cyclohexylidene-5-methyl-1H-imidazole-4-carbohydrazide 3-Oxide (8e). Yield: 0.320 g
(98%). Colorless crystals. M.p. 220 – 2228 (dec., MeOH). IR (KBr): 3081s, 2930s, 1667vs (C¼O), 1602vs,
1559m, 1452m. 1H-NMR (CDCl3): 13.46 (br. s, NH); 7.77 (s, HꢀC(2)); 7.40 – 7.38 (m, 3 arom. H); 7.13 –
7.11 (m, 2 arom. H); 5.06 (s, CH2); 2.63 (s, Me); 2.63 – 2.43 (m, 4 cyclohexyl H); 1.73 – 1.67 (m, 4
cyclohexyl H); 1.64 – 1.60 (m, 2 cyclohexyl H). 13C-NMR (CDCl3): 161.8 (C¼O); 156.1 (C¼N); 133.1,
122.6 (C(4), C(5)); 131.8 (1 arom. C); 129.5, 129.2, 127.1 (5 arom. CH); 125.1 (C(2)); 49.5 (CH2); 35.4,
28.1, 27.0, 26.1, 25.7 (5 cyclohexyl C); 9.8 (Me). HR-ESI-MS: 327.1814 ([M þ H]þ, C18H23N4O2þ ; calc.
327.1816).
1-Cyclohexyl-N’-cyclohexylidene-5-methyl-1H-imidazole-4-carbohydrazide 3-Oxide (8f). Yield:
0.239 g (75%). Colorless crystals. M.p. 218 – 2208 (dec., MeOH). IR (KBr): 3084m, 2931vs, 1685vs
(C¼O), 1596vs, 1538m, 1416m, 1261m. 1H-NMR (CDCl3): 13.47 (br. s, NH); 7.82 (s, HꢀC(2)); 3.97 – 3.91
(m, CHN); 2.68 (s, Me); 2.46 – 2.43 (m, 4 cyclohexyl H); 2.07 – 2.05 (m, 2 cyclohexyl H); 1.97 – 1.95 (m, 2
cyclohexyl H); 1.78 – 1.66 (m, 5 cyclohexyl H); 1.65 – 1.60 (m, 2 cyclohexyl H); 1.58 – 1.39 (m, 4 cyclohexyl
H); 1.30 – 1.21 (m, 1 cyclohexyl H). 13C-NMR (CDCl3): 161.5 (C¼O); 156.3 (C¼N); 130.8, 121.8 (C(4),
C(5)); 122.5 (C(2)); 55.6 (CHN); 35.5, 33.7, 28.1, 27.0, 26.1, 25.7, 25.4, 24.8 (10 cyclohexyl C); 9.54 (Me).
HR-ESI-MS: 319.2129 ([M þ H]þ, C17H27N4O2þ ; calc. 319.2128).
8. General Procedure for the Synthesis of 8g, 8h, and 9a – 9g. A soln. of hydrazide 1 or 2 (1 mmol) in
EtOH (4 ml) and an equimolar amount of the carbonyl component (4-methoxy-, 4-(dimethylamino)-,
and 4-(methylsulfanyl)benzaldehyde, and cyclohexanone) and a cat. amount of AcOH was heated to
reflux for 4 h. After cooling to r.t., the solvent was evaporated under reduced pressure, the residue was
dissolved in CH2Cl2 and, after addition of NaHCO3, stirred for 0.5 h. The mixture was filtered, the solvent
was evaporated under reduced pressure, and the residue was purified by crystallization from MeOH.
1-Benzyl-5-methyl-N’-[(1Z)-1-phenylethylidene]-1H-imidazole-4-carbohydrazide 3-Oxide (8g).
Yield: 0.261 g (76%). Colorless crystals. M.p. 222 – 2268 (dec., MeOH). IR (KBr): 3061m, 2914m,
1678vs (C¼O), 1602vs, 1546m, 1269m, 705m. 1H-NMR (CDCl3): 13.71 (br. s, NH); 7.90 – 7.88 (m, 2 arom.
H); 7.82 (s, HꢀC(2)); 7.42 – 7.36 (m, 6 arom. H); 7.16 – 7.14 (m, 2 arom. H); 5.09 (s, CH2); 2.67 (s,

Helvetica Chimica Acta – Vol. 94 (2011)
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imidazole Me); 2.39 (s, MeC¼N). 13C-NMR (CDCl3): 156.2 (C¼O); 153.0 (C¼N); 138.1, 132.1 (2 arom.
C); 133.0, 122.6 (C(4), C(5)); 129.6, 129.4, 129.3, 128.2, 127.2, 126.8 (10 arom. CH); 125.2 (C(2)); 49.6
(CH2); 14.5 (MeC¼N); 9.8 (imidazole Me). HR-ESI-MS: 349.1664 ([M þ H]þ, C20H21N4O2þ ; calc.
349.1659).
1-Cyclohexyl-5-methyl-N’-[(1Z)-1-phenylethylidene]-1H-imidazole-4-carbohydrazide 3-Oxide (8h).
Yield: 0.238 g (70%). Colorless crystals. M.p. 264 – 2688 (dec., MeOH). IR (KBr): 3080m, 2937s 1675vs
1
(C¼O), 1601vs, 1553m, 1417m, 1273m. H-NMR (CDCl3): 13.67 (br. s, NH); 7.94 – 7.92 (m, 2 arom. H,
HꢀC(2)); 7.41 – 7.39 (m, 3 arom. H); 4.03 – 3.98 (m, CHN); 2.75 (s, imidazole Me); 2.43 (s, MeC¼N);
2.14 – 2.00 (m, 4 cyclohexyl H); 1.64 – 1.45 (m, 4 cyclohexyl H); 1.34 – 1.25 (m, 2 cyclohexyl H). 13C-NMR
(CDCl3): 156.2 (C¼O); 152.9 (C¼N); 138.1 (1 arom. C); 131.2, 121.8 (C(4), C(5)); 129.4, 128.2, 126.8 (5
arom. CH); 122.8 (C(2)); 55.8 (CHN); 33.7, 25.4, 24.8 (5 cyclohexyl C); 14.5 (MeC¼N); 9.6 (Me). HR-
ESI-MS: 341.1975 ([M þ H]þ, C19H25N4O2þ ; calc. 341.1972).
2-[(1-Benzyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]-N’-[(E)-(4-methoxyphenyl)methylidene]ace-
tohydrazide (9a). Yield: 0.237 g (57%). Colorless crystals. M.p. 130 – 1328 (MeOH). IR (KBr): 3186m
(br.), 3067m (br.), 1664vs (C¼O), 1606vs, 1407m, 1245m. 1H-NMR (CDCl3): 12.82 (br. s, NH); 8.12 (s,
HꢀC¼N); 7.72 – 6.89 (m, 9 arom. H); 5.08 (s, CH2N); 3.84 (s, MeO); 3.61 (s, CH2S); 2.24, 2.05 (2s, 2
imidazole Me). 13C-NMR (CDCl3): 166.0 (C¼O); 161.4 (C¼N); 147.8 (arom. CꢀO); 139.3 (C(2’)); 135.9,
125.5 (C(4’), C(5’)); 134.1(1 arom. C); 129.3, 129.0, 128.0, 126.6, 126.3, 114.1 (1 arom. C, 9 arom. CH);
55.4 (MeO); 48.1 (CH2N); 36.3 (CH2S); 12.7, 9.2 (2 imidazole Me). HR-ESI-MS: 409.1701 ([M þ H]þ,
C22H25N4O2Sþ; calc. 409.1694).
2-[(1-Benzyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]-N’-{(E)-[4-(dimethylamino)phenyl]methyli-
dene}acetohydrazide (9b). Yield: 0.337 (80%). Colorless crystals. M.p. 75 – 798 (MeOH). IR (KBr):
3203m (br.), 3023m (br.), 2917s (br.), 1679vs (C¼O), 1608vs, 1525m, 1360m, 1180m. 1H-NMR (CDCl3):
12.52 (br. s, NH); 8.05 (s, HꢀC¼N); 7.64 – 6.66 (m, 9 arom. H); 5.07 (s, CH2N); 3.60 (s, CH2S); 3.01 (s,
Me2N); 2.23, 2.04 (2s, 2 imidazole Me). 13C-NMR (CDCl3): 165.6 (C¼O); 151.9 (C¼N); 148.8 (arom.
CꢀN); 139.3 (C(2’)); 135.9 (1 arom. C); 134.2, 121.6 (C(4’), C(5’)); 129.2, 129.0, 127.9, 126.32, 126.29,
111.6 (1 arom. C, 9 arom. CH); 48.0 (CH2N); 40.2 (Me2N); 36.3 (CH2S); 12.7, 9.2 (2 imidazole Me). HR-
ESI-MS: 422.2009 ([M þ H]þ, C23H28N5OSþ; calc. 422.2010).
2-[(1-Benzyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]-N’-cyclohexylideneacetohydrazide (9c).
Yield: 0.322 g (87%). Colorless crystals. M.p. 124 – 1308 (MeOH). IR (KBr): 3207m (br., NH), 3061m
(br.), 1667vs (C¼O), 1406m, 718m. 1H-NMR (CDCl3): 11.81 (br. s, NH); 7.33 – 6.99 (m, 5 arom. H); 5.04
(s, CH2N); 3.61 (s, CH2S); 2.54 – 2.42 (m, 4 cyclohexyl H); 2.12, 2.03 (2s, 2 imidazole Me); 1.75 – 1.61 (m, 6
cyclohexyl H). 13C-NMR (CDCl3): 166.7 (C¼O); 160.9 (C¼N); 140.0 (C(2’)); 135.9 (1 arom. C); 134.1,
125.2 (C(4’), C(5’)); 129.0, 127.9, 126.2 (5 arom. CH); 48.0 (CH2N); 36.2 (CH2S); 35.4, 28.3, 27.0, 26.1,
25.7 (5 cyclohexyl CH2); 12.6, 9.2 (2 imidazole Me). HR-ESI-MS: 371.1879 ([M þ H]þ, C20H27N4OSþ;
calc. 371.1901).
2-[(1-Cyclohexyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]-N’-{(E)-[4-(methylsulfanyl)phenyl]me-
thylidene}acetohydrazide (9d). Yield: 0.152 g (37%). Colorless crystals. M.p. 76 – 788 (MeOH). IR
(KBr): 3296m, (br., NH), 3058m, 1667vs (C¼O), 1596vs, 1505m, 1363m. 1H-NMR (CDCl3): 13.11 (br. s,
NH); 8.05 (s, HꢀC¼N); 7.66 – 7.21 (m, 4 arom. H); 3.99 – 3.95 (m, CHN); 3.70 (s, CH2S); 2.49 (s, MeS);
2.19, 2.18 (2s, 2 imidazole Me); 2.05 – 1.72 (m, 7 cyclohexyl H); 1.42 – 1.18 (m, 3 cyclohexyl H). 13C-NMR
(CDCl3): 166.5 (C¼O); 147.2 (C¼N); 141.6 (C(2’)); 138.6, 130.6 (C(4’), C(5’)); 134.9 (1 arom. C); 128.0,
125.8, 124.8 (1 arom. C, 4 arom. CH); 57.4 (CHN); 36.2 (CH2S); 31.7, 26.2, 25.2 (5 cyclohexyl CH2); 15.2
(MeS); 12.7, 10.5 (2 imidazole Me). HR-ESI-MS: 417.1767 ([M þ H]þ, C21H29N4OS2þ ; calc. 417.1778).
2-[(1-Cyclohexyl-4,5-dimethyl-1H-imidazol-2-yl)sulfanyl]-N’-[(E)-(4-methoxyphenyl)methylide-
ne]acetohydrazide (9e). Yield: 0.288 g (72%). Colorless crystals. M.p. 96 – 1028 (MeOH). IR (KBr):
3203m (br., NH), 2917s (br.), 1664vs (C¼O), 1607vs, 1512m, 1418m, 1307m, 1250m. 1H-NMR (CDCl3):
12.96 (br. s, NH); 8.05 (s, HꢀC¼N); 7.69 – 6.86 (m, 4 arom. H); 3.99 – 3.96 (m, CHN); 3.83 (s, MeO); 3.70
(s, CH2S); 2.19, 2.18 (2s, 2 imidazole Me); 2.05 – 1.74 (m, 7 cyclohexyl H); 1.42 – 1.18 (m, 3 cyclohexyl H).
13C-NMR (CDCl3): 166.4 (C¼O); 161.4 (C¼N); 147.6 (1 arom. CꢀO); 141.6, 126.7 (C(4’), C(5’)); 138.6
(C(2’)); 129.3, 124.7, 114.1 (1 arom. C, 4 arom. CH); 57.4 (CHN); 55.3 (MeO); 36.2 (CH2S); 31.7, 26.2,
25.2 (5 cyclohexyl CH2); 12.6, 10.5 (2 imidazole Me). HR-ESI-MS: 401.1986 ([M þ H]þ, C21H29N4O2Sþ;
calc. 401.2007).

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2-[(1-Benzyl-4,5-diphenyl-1H-imidazol-2-yl)sulfanyl]-N’-{(E)-[4-(methylsulfanyl)phenyl]methyl-
idene}acetohydrazide (9f). Yield: 0.390 g (71%). Colorless crystals. M.p. 154 – 1568 (MeOH). IR (KBr):
1
3296m (br., NH), 3058m (br.), 1683vs (C¼O), 1596vs, 1433m, 702m. H-NMR (CDCl3): 12.90 (br. s,
NH); 7.87 (s, HꢀC¼N); 7.50 – 6.92 (m, 19 arom. H); 5.01 (s, CH2N); 3.83 (s, CH2S); 2.47 (s, MeS).
13C-NMR (CDCl3): 165.9 (C¼O); 148.1 (C¼N); 143.1, 141.7, 131.2, 129.7 (4 arom. C); 137.9, 133.6 (C(4’),
C(5’)); 135.8 (C(2’)); 130.9, 130.4, 129.3, 129.2, 128.9, 128.5, 128.01, 127.98, 127.1, 126.6, 126.5, 125.8 (1
arom. C, 19 arom. CH); 48.3 (CH2N); 35.6 (CH2S); 15.2 (MeS). HR-ESI-MS: 549.1770 ([M þ H]þ,
C32H29N4OSþ2 ; calc. 549.1778).
2-[(1-Benzyl-4,5-diphenyl-1H-imidazol-2-yl)sulfanyl]-N’-cyclohexylideneacetohydrazide (9g).
Yield: 0.329 g (67%). Colorless crystals. M.p. 166 – 1688 (MeOH). IR (KBr): 3321s (br., NH),
3026m,1679vs (C¼O), 1602vs, 1453m, 1433m, 701m. 1H-NMR (CDCl3): 11.38 (br. s, NH); 7.36 – 6.92 (m,
15 arom. H); 4.97 (s, CH2N); 3.93 (s, CH2S); 2.34 – 1.93 (m, 4 cyclohexyl H); 1.62 – 1.03 (6 cyclohexyl H).
13C-NMR (CDCl3): 166.3 (C¼O); 161.4 (C¼N); 143.6, 131.2 (C(4’), C(5’)); 135.7 (C(2’)); 131.0, 130.9,
129.7, 129.0, 128.8, 128.3, 128.2, 127.9, 126.9, 126.7, 126.6 (3 arom. C, 15 arom. CH); 48.3 (CH2N); 35.3
(CH2S); 34.6, 27.8, 26.7, 25.4, 25.3 (5 cyclohexyl CH2). HR-ESI-MS: 495.2207 ([M þ H]þ, C30H31N4OSþ;
calc. 495.2214).
9. Synthesis of 2-[(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)carbonyl]-N-methylhydrazinecar-
bothioamide (10). A mixture of 1b (247 mg, 1 mmol) and methyl isothiocyanate (80 mg, 1.1 mmol) in
EtOH (5 ml) was heated to reflux for 2 h. The formed product 10 was then filtered off, washed with Et2O,
and crystallized from MeOH. Yield: 0.257 g (90%). Colorless crystals. M.p. 224 – 2288 (MeOH). IR
(KBr): 3271vs (NH), 3097s (br.), 1682vs (C¼O), 1599vs, 1557m, 740m. 1H-NMR ((D6)DMSO): 12.39,
9.34 (2 br. s, 2 NH); 8.71 (s, HꢀC(2)); 8.00 (br. s, NH); 7.42 – 7.24 (m, 5 arom. H); 5.25 (s, CH2N); 2.85 (d,
J ¼ 4.3, Me); 2.43 (s, Me). 13C-NMR ((D6)DMSO): 182.6 (C¼O); 159.7 (C¼S); 135.8, 121.3 (C(4’),
C(5’)); 131.3 (1 arom. C); 129.5, 128.7, 127.7 (5 arom. CH); 126.8 (C(2’)); 48.7 (CH2N); 31.4 (MeN); 9.8
(Me). HR-ESI-MS: 320.1174 ([M þ H]þ, C14H18N5O2Sþ; calc. 320.1181).
10. Synthesis of 5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-2,4-dihydro-4-methyl-3H-1,2,4-tri-
azole-3-thione (11). A mixture of 10 (320 mg, 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: 11 (0.217 g, 72%). Colorless crystals. M.p. 244 – 2488 (MeOH). IR (KBr):
3161s (NH), 1564m, 1457m, 1341m, 698m. 1H-NMR ((D6)DMSO): 14.02 (br. s, NH); 8.58 (s, HꢀC(2));
7.43 – 7.29 (m, 5 arom. H); 5.23 (s, CH2N); 3.50 (s, MeN); 2.14 (s, Me). 13C-NMR ((D6)DMSO): 168.1
(C¼S); 142.6 (triazol C(3)); 136.1, 118.0 (imidazole C(4), C(5)); 129.5, 128.63, 127.8 (5 arom. CH);
128.60 (1 arom. C); 126.5 (imidazole C(2)); 49.2 (CH2N); 31.7 (MeN); 9.4 (Me). HR-ESI-MS: 302.1068
([M þ H]þ, C14H16N5OSþ; calc. 302.1076).
11. Synthesis of 5-(1-Benzyl-5-methyl-3-oxido-1H-imidazol-4-yl)-N-methyl-1,3,4-thiadiazol-2-amine
(12). A soln. of 10 (320 mg, 1 mmol; in 5 ml conc. H2SO4) 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: 12
(0.162 g, 54%). Yellowish crystals. M.p. 214 – 2168 (dec., MeOH). IR (KBr): 3201m (br.), 3127s, 2963s
1
(br.), 1517m, 1261m, 1096m, 1031m, 800m. H-NMR ((D6)DMSO): 8.57 (s, HꢀC(2)); 7.52 (br. s, NH);
7.41 – 7.26 (m, 5 arom. H); 5.24 (s, CH2N); 2.89 (d, J ¼ 4.8, MeN); 2.49 (s, Me). 13C-NMR ((D6)DMSO):
169.9, 144.7 (thiadiazol C(2), C(5)); 136.3, 123.0 (imidazole C(4), C(5)); 129.4, 128.5, 127.6 (5 arom.
CH); 125.3 (imidazole C(2)); 124.0 (1 arom. C); 48.9 (CH2N); 31.7 (MeN); 10.1 (Me). HR-ESI-MS:
302.1068 ([M þ H]þ, C14H16N5OSþ; calc. 302.1076).
12. X-Ray Crystal-Structure Determination of 1b (Table and Fig.)4). All measurements were made
on an Agilent Technologies SuperNova area-detector diffractometer [20] using MoKa radiation (l ¼
0.71073 ꢅ) from a micro-focus X-ray source and an Oxford Instruments Cryojet XL cooler. Data
reduction was performed with CrysAlisPro [20]. The intensities were corrected for Lorentz and
polarization effects, and an empirical absorption correction using spherical harmonics [20] was applied.
The space group was determined from packing considerations, a statistical analysis of intensity
4
)
CCDC-838434 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre, via www.ccdc.cam.ac.uk/
data_request/cif.

Helvetica Chimica Acta – Vol. 94 (2011)
1775
distribution, and the successful solution and refinement of the structure. Equivalent reflections were
merged. The data collection and refinement parameters are given in the Table. A view of the molecule is
shown in the Figure. The structure was solved by direct methods using SHELXS97 [21], which revealed
the positions of all non-H-atoms. The non-H-atoms were refined anisotropically. The hydrazide H-atoms
were placed in the positions indicated by a difference electron-density map, and their positions were
allowed to refine together with individual isotropic displacement parameters. All remaining H-atoms
were placed in geometrically calculated positions and refined by using a riding model where each H-atom
was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its parent C-atom
(1.5 Ueq for the Me group). The refinement of the structure was carried out on F2 by using full-matrix
least-squares procedures, which minimized the function Sw(F2o ꢀ Fc2 )2. The weighting scheme was based
on counting statistics and included a factor to downweight the intense reflections. A correction for
secondary extinction was applied. Neutral atom-scattering factors for non-H-atoms were taken from
[22a], and the scattering factors for H-atoms were taken from [23]. Anomalous dispersion effects were
Table. Crystallographic Data for Compound 1b
Crystallized from
MeOH
Empirical formula
Formula weight [g molꢀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C12H14N4O2
246.27
pale-yellow, prism
0.28 ꢁ 0.30 ꢁ 0.30
160(1)
]
Crystal system
Space group
triclinic
P1
ꢀ
Z
2
Reflections for cell determination
2q Range for cell determination [8]
7053
5 – 59
Unit cell parameters
a [ꢅ]
b [ꢅ]
c [ꢅ]
a [8]
b [8]
g [8]
6.8168(2)
7.6666(2)
11.7286(4)
97.379(3)
93.255(3)
101.516(3)
593.49(3)
1.378
V [ꢅ3]
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
0.0977
w
2q(max) [8]
58.5
Transmission factors (min; max)
Total reflections measured
Symmetry-independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
0.855; 1.000
10252
2815
2618
2815
177
Final
R(F) [I > 2s(I) reflections]
wR(F2) (all data)
0.0412
0.1054
Weights
w ¼ [s2(F2o ) þ (0.0466P)2 þ 0.2729P]ꢀ1
where P ¼ (F2o þ 2Fc2 )/3
1.038
Goodness-of-fit
Secondary extinction coefficient
Final Dmax/s
0.013(4)
0.001
0.33; ꢀ 0.41
D1 (max; min) [e ꢅꢀ3
]

1776
Helvetica Chimica Acta – Vol. 94 (2011)
included in Fc [24]; the values for f’ and f’’ were those of [22b]. The values of the mass attenuation
coefficients are those of [22c]. The SHELXL97 program [25] was used for all calculations.
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Received July 15, 2011