Facile and selective synthesis of 4-methyl- and 4-phenylthiosemicarbazide (= N-methyl- and N-phenylhydrazinecarbothioamide) derivatives of benzil (= 1,2-Diphenylethane-1,2-dione)

Article abstract of DOI:10.1002/hlca.200790228

A selective synthesis of 4-methylthiosemicarbazide (= N- methylhydrazinecarbothioamide; 4a) derivatives by reaction with benzil (= 1,2-diphenylethane-1,2-dione; 3) is described. The reaction conditions determined the condensation product formed. The most

Full text of DOI:10.1002/hlca.200790228

Helvetica Chimica Acta – Vol. 90 (2007)
2201
Facile and Selective Synthesis of 4-Methyl- and
4-Phenylthiosemicarbazide (¼ N-Methyl- and
N-Phenylhydrazinecarbothioamide) Derivatives of Benzil
(¼1,2-Diphenylethane-1,2-dione)
by David G. Calatayud, Francisco J. Escolar, Elena Lo´pez-Torres, and M. Antonia Mendiola*
´
´
Departamento de Química Inorganica, Universidad Autonoma de Madrid, E-28049 Madrid
(phone: þ 34914944844; fax: þ 34914974833; e-mail: antonia.mendiola@uam.es)
A selective synthesis of 4-methylthiosemicarbazide (¼ N-methylhydrazinecarbothioamide; 4a)
derivatives by reaction with benzil (¼1,2-diphenylethane-1,2-dione; 3) is described. The reaction
conditions determined the condensation product formed. The most important factor was the acid used: in
the presence of conc. HCl solution, the open-chain 2 :1 compound 1a was exclusively obtained, whereas
in the presence of 2m HCl, the cyclic 1:1 condensation product 2a was formed. The alcohol used, the
presence of H2O, and the time of heating were additional crucial factors. The new cyclic compound 2a
with a MeO group was exclusively formed when working under high-dilution conditions. The reaction
with the 4-phenyl derivative 4b gave new cyclic compounds as the major products under all conditions
used (Scheme).
1. Introduction. – There is considerable current interest in the biological activity of
Schiff-base macroligands derived from thiosemicarbazides (¼ hydrazinecarbothio-
amides) and their complexes. Bis(thiosemicarbazones) (¼2,2’-(alkanediylidene)bis-
[hydrazinecarbothioamides]) of type 1 have been known for over fifty years, and they
have shown interesting biological activity as free ligands and as their metal complexes
[1]. Recently, it has become apparent that they may also provide a convenient way of
labeling biologically active molecules to act as imaging agents for both fluorescence
(M ¼ Zn) and positron emission tomography (PET) (M ¼ Cu) [2]. On the other hand,
in the last few years, a great deal of research has been aimed to design highly selective
and sensitive compounds to heavy-metal ions, from the point of view of chemical,
biological, and environmental processes [3]. Among the many different strategies
proposed, the preparation of electrochemical and fluorescent sensors should be
highlighted, and thiosemicarbazones (¼2-alkylidenehydrazinecarbothioamides) are
good candidates in this field. Although apparently simple, the synthesis of bis(thio-
semicarbazone) ligands from diketones with aryl substituents can be problematic due
to the formation of cyclic products [4]. In particular, reactions with 4-methylthiose-
micarbazide (¼ N-methylhydrazinecarbothioamide; 4a) in EtOH and in the presence
of H2SO4 gave a mixture of the open-chain and cyclic compounds [4a].
We have been interested in the preparation of carbohydrazones, thiocarbohydra-
zones, semicarbazones, and thiosemicarbazones derived from benzil (¼1,2-diphenyl-
ethane-1,2-dione; 3) and their coordination compounds to get potential modifiers of
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

2202
Helvetica Chimica Acta – Vol. 90 (2007)
standard electrodes [5]. Some of their complexes (Cu and Hg) have been used in the
preparation of potentiometric sensors for these metals, and the Cd and Hg complexes
of thiosemicarbazone have shown promising antibacterial properties [6]. In our
experience, the synthesis of semi- and thiosemicarbazone ligands is rarely straightfor-
ward, but we have reported selective procedures to obtain the open-chain and the cyclic
compounds. The optimum conditions to get the open-chain molecules vs. the
heterocycles depend on the diamine precursor. In particular, the open-chain product
formally derived from benzil/semicarbazide 1:2 was prepared in the presence of LiOH,
whereas the cyclic compound was obtained in acidic medium [5b]. However, in the case
of thiosemicarbazide (i.e., 4 with R ¼ H), derivatives of both types (i.e., 1 and 2 with
R ¼ H) were obtained in the presence of HCl. The cyclic compound was obtained pure
and in almost quantitative yield working under high-dilution conditions, but under all
the other conditions, the open-chain product was also formed [5b][7].
Our recent interest concerns the effect of the presence of an organic group at N(4)
of the starting thiosemicarbazide (i.e., 4-methyl- and 4-phenylthiosemicarbazide ¼ N-
methyl- and N-phenylhydrazinecarbothioamide; 4a and 4b, resp.) on the structure of
the condensation products with benzil (3). The structural characteristics of such
condensation products determine their properties, reactivity, and potential applications
for preparing sensors for toxic metals, and small structural changes like substitution of
an H-atom by a Me or Ph group can have strong effects on the biological properties.
The aim of this work was to find the reaction conditions yielding only a specific
compound (i.e., of type 1 or 2) and to elaborate the procedures permitting the selective
synthesis of the desired product. Here we present the selective routes, spectroscopic
characterization, and X-ray structure analysis of the compounds derived from 4-
substituted thiosemicarbazides 4a,b, including of those previously published by
alternative synthetic routes [8].
2. Results and Discussion. – Syntheses. From the reactions between benzil (3) and 4 -
methyl- or 4-phenylthiosemicarbazide (4a or 4b) as precursors, we isolated and
characterized the two open-chain molecules 1a and 1b and the five 1:1 condensation
products 2a – e (Scheme). Our results pointed out that the cyclic molecules were
formed easier than the open-chain products under all the conditions studied. Thus, the
substitution of an H-atom of a ꢁprimary-aminoꢂ group by a Me or a Ph group increased
the ease of obtaining the cyclic 1:1 products 2 and concomitantly increased the
difficulty to get pure 1:2 products 1 in high yield. This fact can be explained by the high
stability of the 4-methyl- or 4-phenyl-substituted 1,2,4-triazine rings of 2a – e, which
show a better charge delocalization than the triazine obtained from the unsubstituted
thiosemicarbazide. The Ph derivatives 2c – e are even more stable than the Me
analogues 2a,b, probably due to the aromatic ring at N(1)1) of the triazine ring, which
gives rise to a more extended electron delocalization.
We then confirmed that the reaction conditions can determine the structure of the
condensation products obtained from 4-methylthiosemicarbazide (4a) and benzil (3) as
precursors (Scheme). In the presence of AcOH, only a mixture of the reagents was
obtained, and with H2SO4, the 1:2 product 1a was isolated but contaminated with other
1
)
Arbitrary atom numbering.

Helvetica Chimica Acta – Vol. 90 (2007)
2203
Scheme. Best Synthetic Routes for the Synthesis of 4-Substituted Thiosemicarbazide Derivatives 1 and
1,2,4-Triazine-3(2H)-thiones 2
compounds, including the 1:1 product 2a. However, in the presence of HCl, both
condensation products could easily and selectively be synthesized, improving the
previous reaction conditions which led to a mixture 1a/2b (in EtOH) [4a]. The solvent
used also affected the results. In EtOH, only the 1:1 compound 2b was formed, but in
MeOH both types of compounds, 1a and 2a, were present. The crystal structure of the
EtO derivative 2b, obtained from the reaction of 4-ethylthiosemicarbazide with 1,2,8,9-
tetraphenyl-3,7-diazanona-1,9-dione in the presence of Cu(OAc)2, has been previously
published [8]. The pure 1:2 condensation product 1a was obtained as the major
compound if the reaction was carried out in dry MeOH with some drops of conc. HCl
solution. However, the reaction in 2m HCl and commercial MeOH yielded 1a and 2a;
the open-chain product 1a precipitated first, and the 1:1 product 2a was isolated from
the filtrate. The 1:1 molecule 2a was exclusively formed working under high-dilution
conditions in the presence of HCl. An additional factor was the time of heating:
Best results were achieved under anhydrous conditions by heating 45 min under re-
flux.
From 4-phenylthiosemicarbazide (4b) and following the same procedures as those
described for the Me derivatives 4a, also 1:1 and 1:2 products could be synthesized

2204
Helvetica Chimica Acta – Vol. 90 (2007)
(Scheme). The cyclic compounds 2c and 2d were formed in the presence AcOH but in a
very low yield and isolated together with the unreacted precursor 4b. In dry MeOH or
EtOH, even controlling the temperature and the heating time, 2c and 2d were always
obtained contaminated with the 1:2 product 1b. Again, 2c and 2d were isolated pure
and in almost quantitative yield under the high-dilution conditions. Unlike 1a, the 1:2
product 1b was only obtained when working in EtOH, but in a very poor yield (10%)
and together with the cyclic derivative 2d as the major product. In addition, the reaction
of benzil (3) and 4-phenylthiosemicarbazide (4b) gave, in the absence of any acid, a
new cyclic compound 2e containing an OH instead of the MeO or EtO group. It was not
possible to obtain such a compound from the 4-methylthiosemicarbazide (4a) under the
same conditions. However, the corresponding 5-hydroxy-4-methyl-1,2,4-triazine de-
rivative has been isolated as an unexpected product from the reaction between 4-
methylthiosemicarbazide (4a) and bis(benzil)-1,3-diiminopropane (¼ꢁ1,2,8,9-tetra-
phenyl-3,7-diazanona-2,7-diene-1,9-dioneꢂ [9] ¼2,2’-(propane-1,3-diyldinitrilobis[1,2-
diphenylethanone]) in the presence of copper(II) acetate [9].
Spectroscopy. The IR spectra of the compounds 1 and 2 show bands between 3450 –
3220 cmꢀ1 corresponding to the NꢀH stretching, as well as the bands related to the
thioamide groups (see Exper. Part).
The FAB-MS (positive mode) of 1a shows a peak at m/z 385.2 corresponding to the
molecular ion and a peak at m/z 769.6 corresponding to a dimer, suggesting the
presence of strong intermolecular interactions. Additional peaks assigned to different
fragments can also be observed. The FAB-MS of 1b shows a peak at m/z 509.3, which
corresponds to the proposed molecular mass.
The FAB-MS (positive mode) of 2a and 2b are very similar. Peaks at m/z 312.2 and
326.2 corresponding to the molecular ions are observed, as well as the interaction of
two molecules by H-bonds. Additional peaks at lower m/z are observed, the first,
corresponds to the loss of the MeO or EtO group. From this peak on, both spectra show
the same fragments. The FAB-MS (positive mode) of 2c and 2d are similar to those of
the Me derivatives, and the peaks at m/z 374.0 and 388.0 confirm the 1:1 condensation
products with one MeO or EtO group attached at C(2)1). The formation of 2e, with a
hydroxy group at C(2), is confirmed by a peak at m/z 360.0.
The 1H-NMR spectra of 1a (Fig. 1) show the presence of two kinds of NH groups at
low field with different multiplicities, a m for the H-atoms of the Ph groups, and a s
attributable to the Me groups. The 1H-NMR spectrum of 1b shows two s arising from
the NH groups and ms for the Ph groups. In both spectra, the integrals confirm the 1:2
condensation and suggest a symmetric structure in solution. The NH signals appear at
lower field in the case of the Ph derivative 1b than in the Me derivative 1a. The
13C-NMR spectra confirm the proposed structures.
The 1H-NMR spectra of the cyclic compounds 2a – e show one s for the NH group
and one m for the Ph groups. In 2a – d, peaks due to the MeO or EtO groups are
observed, while in 2e, these signals have disappeared. In addition, compounds 2a and 2b
also show one s corresponding to the Me group attached to N(4). The 13C-NMR spectra
in solution confirm the formation of the triazine rings, as well as the presence of an
MeO (2a and 2c) or EtO group (2b and 2d), and of the imino and thioamide moieties.
In 2e, the signal corresponding to the quaternary C-atom is shifted with respect to the
alkoxy derivatives.

Helvetica Chimica Acta – Vol. 90 (2007)
2205
Fig. 1. 1H-NMR Spectrum ((D6)-DMSO) of 1a
X-Ray Structure Determination. Compound 1a. The structure of 1a contains a
disordered molecule of DMSO of crystallization, which could not be satisfactorily
modelled. The contribution from this solvent molecule was removed from the observed
data by using SQUEEZE in the software program PLATON [10]. Compound 1a
crystallizes in the monoclinic system. This system, the space group, the cell parameters
of the crystal, and other data included in the Exper. Part are different from those
previously published for this compound [4a]. This fact is probably due to the different
solvent used for crystallization. The crystal structure (Fig. 2) shows that the molecule
exists in the thione form, supported by the presence of hydrazinic NꢀH and CꢀS bond
distances, the latter being much shorter than a single CꢀS bond. These data correspond
to a structure where the two 4-methylthiosemicarbazone moieties are on the same side
(cisoid) of the single bond C(2)ꢀC(3)1), which explains the deviation from the
previously published structure, in which the thiosemicarbazone moieties were in
transoid position [4a][5d]. This difference can be explained by the absence of H-bonds
in the bis(4-methylthiosemicarbazone) 1a recristallized from DMSO.
Both thiosemicarbazone moieties of 1a adopt an (E) configuration with respect to
the C¼N bond. Bond distances and angles of both thiosemicarbazone moieties are very
similar, and the molecular conformation of the S-atoms and the azomethine N-atoms
N(2) and N(3) are anti-periplanar with respect to the C(1)ꢀN(1) and C(4)ꢀN(4)
bonds1). The NꢀN distances are shorter than 1.44 Š (typical value for an NꢀN single
bond) and agree well with those of similar thiosemicarbazones [11]. The CꢀS bond
distances of 1.681(4) and 1.675(4) Š are intermediate between those of a single and
double bond (1.82 and 1.56, resp.) [12], showing the partial double-bond character

2206
Helvetica Chimica Acta – Vol. 90 (2007)
Fig. 2. Molecular structure of 1a1). Thermal ellipsoids at 50% probability. Selected bond distances [Š]:
C(1)ꢀN(5) 1.320(5), C(1)ꢀN(1) 1.378(4), C(1)ꢀS(1) 1.681(4), C(2)ꢀN(2) 1.302(4), C(2)ꢀC(3)
1.505(5), C(4)ꢀN(6) 1.348(5), C(4)ꢀS(2) 1.675(4), C(3)ꢀN(3) 1.287(5), N(1)ꢀN(2) 1.370, and
N(4)ꢀN(3) 1.354.
implied by the canonical structures usually considered for thiosemicarbazones. The
azomethine C¼N bond lengths are likewise short enough to imply a partial double
bond.
Compounds 2a – e. The crystal structures of 2a and 2b (Figs. 3 and 4) confirm the
formation of the 1,2,4-triazines. The data of 2b are similar to those previously published
for 2b obtained from other precursor molecules [8], and we have included them here
only for comparison purposes. The CꢀS distances of 2a and 2b (1.684(14) and
1.687(19) Š, resp.) are much shorter than a CꢀS single bond, which indicates that the
ligands are in the thione form. The same electron delocalization is present in the
triazine ring of all compounds 2; whereas the C(3)ꢀN(2) bond distances agree with the
predicted C¼N bond of 1.28 Š, both C(1)ꢀN(1) and C(1)ꢀN(3) are considerably
shorter than the single bond expected and thus have considerable double bond
character1). The C(2)ꢀN(1) distances are consistent with a CꢀN single bond, but the
C(2)ꢀC(3) distances are slightly shorter than the predicted 1.54Š for a single bond,
and the N(2)ꢀN(3) distances are significantly shorter than the expected NꢀN single-
bond distances. This delocalization is in accordance with an almost planar triazine
moiety of all compounds 2, some p-electron density is probably derived from the thione
bond, but it is in the range expected for a C¼S bond. The CꢀO bonds are slightly
shorter than predicted for a single bond. The C(2)ꢀC(3) bonds are longer than the
1.50 Š for a C(sp3)ꢀC(sp2) single bond. Thus, there is no strong evidence that the two
Ph substituents or the O-atom contribute to the p character of the triazine. Therefore,

Helvetica Chimica Acta – Vol. 90 (2007)
2207
Fig. 3. Molecular structure of 2a including the H-bonds1). Thermal ellipsoids at 50% probability.
Selected bond distances [Š]: C(1)ꢀS(1) 1.684(14), C(1)ꢀN(1) 1.347(17), C(1)ꢀN(3) 1.351(18),
C(2)ꢀO(1) 1.418(15), C(2)ꢀN(1) 1.470(17), C(2)ꢀC(3) 1.527(18), C(3)ꢀN(2) 1.287(17), and
N(2)ꢀN(3) 1.373(17).
the three N-atoms of the triazine ring of 2 must delocalize their non-bonding electrons
to give the ring its planarity even though there is formally only one double bond. Each
NH group forms a H-bond with the S-atom of a neighboring molecule (Fig. 3), and in
2a the molecules are linked together by p – p interactions with a distance of 3.569 Š.
The crystal structures fo 2c – e (Figs. 5 – 7) confirm their cyclic structures. The bond
distances and angles of these compounds are similar to those observed for the Me
derivatives 2a,b. In the alkoxy derivatives 2c and 2d, the molecules are linked by H-
bonds NHꢀS (Figs. 5 and 6). In addition, the molecules are linked together by p – p
interactions, at a distance of 3.422 and 3.443 Š, respectively. The presence of a
molecule of DMSO in the hydroxy derivative 2e causes H-bonds involving the O-atoms
of the solvent with the HꢀN(3) and with the H-atom of the OH group.
The lengths of the CꢀO bonds exhibit the most important differences among the
cyclic compounds 2. The shortest CꢀO length, close to that of the Me derivative
LMe(H)(OH) published by other authors [9], is observed for the hydroxy derivative 2e
and the largest for 2a. The CꢀO length in 2b is exactly the same as in the
thiosemicarbazide derivative (LH2(OMe)) previously published [5b]. The complete
sequence is 2e < LMe(H)(OH) [9] < 2d < 2b < 2c < 2a. This order can be explained
taking into account the small size of the H-atom, the planar structure of the benzene
ring, and the lesser steric requirements of the CH2 than of the Me groups.
3. Conclusions. – Our results show that substitution of an ꢁaminoꢂ H-atom by a Me
or a Ph group increased the ease and speed of formation of the cyclic molecules 2 from
benzil (3) and a thiosemicarbazide as compared to the formation of the open-chain
compounds which were thus more difficult to get pure and with high yield. We
established the optimum working conditions for the facile and selective synthesis of the

2208
Helvetica Chimica Acta – Vol. 90 (2007)
Fig. 4. Molecular structure of 2b1). Thermal ellipsoids at 50% probability. Selected bond distances [Š]:
C(1)ꢀS(1) 1.687(19), C(1)ꢀN(1) 1.345(2), C(1)ꢀN(3) 1.342(3), C(2)ꢀO(1) 1.410(2), C(2)ꢀN(1)
1.483(2), C(2)ꢀC(3) 1.526(3), C(3)ꢀN(2) 1.286(2), and N(2)ꢀN(3) 1.365(2).
open-chain benzil bis(4-methylthiosemicarbazone) (1a) and of the cyclic 4,5-dihydro-5-
methoxy-4-methyl-5,6-diphenyl-1,2,4-triazine-3(2H)-thione (2a) and 5-ethoxy-4,5-di-
hydro-4-methyl-5,6-diphenyl-1,2,4-triazine-3(2H)-thione (2b), i.e., both types of com-
pounds were selectively synthesized in the presence of HCl in MeOH or EtOH, the
cyclic molecules 2a and 2b in the presence of H2O, and the open-chain molecule 1a
under anhydrous conditions and with a controlled heating time. The results obtained
from the reactions with 4-phenylthiosemicarbazide (4b) were similar leading to the
corresponding compounds 1b, 2c, and 2d. A new cyclic compound, 2e, with an OH
instead of a MeO or EtO group was obtained working in EtOH and in the absence of
acid. Another difference was the low yield of the open-chain compound 1b, which is
probably due to the presence of four Ph groups in the molecule and the easier
formation of the cyclic molecule 2d.
These results respresent an important synthetic improvement and open new ways to
selectively prepare compounds of type 1 or 2 with different structures and specific
reactivity from particular precursor molecules.

Helvetica Chimica Acta – Vol. 90 (2007)
2209
Fig. 5. Molecular structure of 2c including the H-bonds1). Thermal ellipsoids at 50% probability.
Selected bond distances [Š]: C(1)ꢀS(1) 1.6851(15), C(1)ꢀN(1) 1.353(2), C(1)ꢀN(3) 1.350(2),
C(2)ꢀO(1) 1.4124(19), C(2)ꢀN(1) 1.4915(19), C(2)ꢀC(3) 1.526(2), C(3)ꢀN(2) 1.287(2), and
N(2)ꢀN(3) 1.3726(18).
´
We thank Cesar J. Pastor and Manuela E. Medina from the Servicio Interdepartamental de
´
´
Investigacion de la Universidad Autonoma de Madrid (SIDI) for the X-ray diffraction measurements.
We also thank DGICYT for financial support (project CT2005-07788/BQU) and the Universidad
´
Autonoma de Madrid for a grant to D. G. C.
Experimental Part
1. General. Commercially available reagents were used without further purification. Solvents were
dried, when necessary, by standard methods. IR Spectra: Jasco FT/IR-410 spectrophotometer; 4000 –
400 cmꢀ1 range; KBr pellets. 1H-and 13C-NMR Spectra: Bruker AMX-300 spectrometer; at r.t., in
CDCl3 or (D6)DMSO. MS: VG Auto-Spec instrument, with Cs as the fast atom and 3-nitrobenzyl alcohol

2210
Helvetica Chimica Acta – Vol. 90 (2007)
Fig. 6. Molecular structure of 2d including the H-bonds1). Thermal ellipsoids at 50% probability.
Selected bond distances [Š]: C(1)ꢀS(1) 1.6845(15), C(1)ꢀN(1) 1.3490(19), C(1)ꢀN(3) 1.3472(19),
C(2)ꢀO(1) 1.4086(16), C(2)ꢀN(1) 1.4999(17), C(2)ꢀC(3) 1.5286(18), C(3)ꢀN(2) 1.2830(19), and
N(2)ꢀN(3) 1.3677(17).
(3NBA) as the matrix for FAB; Bruker Reflex-III mass spectrometer equipped with a N2 laser emitting at
337 nm and dithranol as matrix for MALDI-TOF; in m/z (rel. %). Microanalyses: Perkin-Elmer 2400-II-
CHNS/O elemental analyzer.
2. Benzil Bis(4-methylthiosemicarbazone) (¼2,2’-(1,2-Diphenylethane-1,2-diylidene)bis[N-methyl-
hydrazinecarbothioamide]; 1a). A soln. of benzil (3; 1.503 g, 7.15 mmol) and conc. HCl soln. (10 drops) in
dry MeOH (75 ml) was added to a soln. of 4-methylthiosemicarbazide (4a; 1.504g, 14.30 mmol) in dry
MeOH (125 ml) and 1 ml of conc. HCl soln. (1 ml). The mixture was stirred under reflux for 45 min.
After cooling to r.t., the pale yellow precipitate was filtered off, washed (cold dry MeOH), and dried: 1a
(60%). Recrystallization from DMSO gave pale yellow crystals suitable for X-ray crystallography.
M.p. 2248. IR (KBr): 3435s and 3335s (NH), 1601w (CN), 1546s (thioamide II), 845w (thioamide IV).
1H-NMR ((D6)DMSO): 9.85 (s, 2 NH); 8.89 (q, J ¼ 4.6, 2 NHMe); 7.72 (m, 4arom. H); 7.38 ( m, 6 arom.
H); 3.01 (d, J ¼ 4.6, 2 Me). 1H-NMR (CDCl3): 8.52 (s, 2 NH); 7.81 (q, J ¼ 4.6, 2 NHMe); 7.74( m, 4arom.

Helvetica Chimica Acta – Vol. 90 (2007)
2211
Fig. 7. Molecular structure of 2e1). Thermal ellipsoids at 50% probability. Selected bond distances [Š]:
C(1)ꢀS(1) 1.680(3), C(1)ꢀN(1) 1.351(4), C(1)ꢀN(3) 1.350(4), C(2)ꢀO(1) 1.404(4), C(2)ꢀN(1)
1.503(4), C(2)ꢀC(3) 1.533(4), C(3)ꢀN(2) 1.298(4), and N(2)ꢀN(3) 1.365(4).
H); 7.32 (m, 6 arom. H); 3.31 (d, J ¼ 4.6, 2 Me). 13C-NMR ((D6)DMSO): 178.6 (C¼S); 140.4 (C¼N);
133.2 – 126.8 (Ph); 31.5 (Me). FAB-MS (pos.): 769.6 (10, [2M þ 1]þ), 385.2 (80, [M þ 1]þ). Anal. calc. for
C18H20N6S2 (384.52): C 56.22, H 5.17, N 21.86, S 16.68; found: C 55.90, H 5.24, N 21.71, S 16.49.
A soln. of 3 (0.105 g, 0.50 mmol) in MeOH (5 ml) was added to a soln. of 4a (0.150 g, 1 mmol) in
MeOH (10 ml) and AcOH (5 drops) or H2SO4 (3 drops). The mixture was stirred under reflux for 8 h
and then concentrated until a solid was formed: 3/4a (AcOH) or 1a/2a/unknown compounds (H2SO4).
A soln. of 3 (0.210 g, 1.00 mmol) in EtOH (20 ml) was added to a soln. of 4a (0.210 g, 2.00 mmol) in
EtOH (20 ml). The mixture was stirred under reflux for 3 h. Then, the solvent was partially evaporated,
and the mixture kept cold during two days. The precipitate formed was filtered off and dried. The solid
contains at least two compounds: a crystalline yellow compound, i.e., 3, and a white one, i.e., 4a.
3. 4,5-Dihydro-5-methoxy-4-methyl-5,6-diphenyl-1,2,4-triazine-3(2H)-thione (2a). A soln. of
3
(0.210 g, 1.00 mmol) and conc. HCl soln. (2 drops) in MeOH (13 ml) was added to a soln. of 4a
(0.210 g, 2.00 mmol) in MeOH (12 ml), conc. HCl soln. (1 ml), and 2m HCl (10 ml). The mixture was
stirred under reflux for 3 h. After cooling to r.t., the pale yellow precipitated 1a was filtered off, washed
with MeOH, dried, and characterized (see above). From the filtrate, a white solid was collected: 2a
(40%). White crystals suitable for X-ray crystallography were formed by slow evaporation of the mother
liquor. White-solid data: M.p. 1368. IR (KBr): 3229s (NH), 1612w (CN), 1511s (thioamide II), 846w
(CS). 1H-NMR ((D6)DMSO): 12.26 (s, NH); 7.52 – 7.21 (m, 2 Ph); 3.18 (s, MeO); 2.93 (s, MeN).
1H-NMR (CDCl3): 9.50 (s, NH); 7.61 – 7.13 (m, 2 Ph); 3.43 (s, MeO); 3.10 (s, MeN). 13C-NMR
((D6)DMSO): 171.7 (C¼S); 141.4 (C¼N); 139.9 – 126.4(Ph); 87.1 (MeO C); 51.10 (MeO); 33.3 (Me).
FAB-MS (pos.): 622.5 (10, 2Mþ), 312.2 (100, [M þ 1]þ), 280.2 (13, C16H14N3Sþ), 118.1 (8, C7H6Nþ2 ), 105.1
(20, [C7H6N þ 1]þ), 77.0 (9, Phþ). Anal. calc. for C17H17N3OS (311.40): C 65.56, H 5.50, N 13.50, S 10.30;
found: C 65.62, H 5.51, N 13.51, S 10.17.

2212
Helvetica Chimica Acta – Vol. 90 (2007)
A soln. of 4a (1.05 g, 10.00 mml) in MeOH/2m HCl 1:1 (48 ml) and conc. HCl soln. (1 ml), and a
soln. of 3 (2.10 g, 10.00 mmol) in MeOH (200 ml) were each added dropwise and slowly with strong
stirring to MeOH (150 ml). After completion of the addition of all the reagents, the mixture was stirred
for 24h. The soln. was concentrated, and a crystalline white solid formed. The precipitate was filtered off
and dried: 2a (85%). Spectroscopic data: see above.
4. 5-Ethoxy-4,5-dihydro-4-methyl-5,6-diphenyl-1,2,4-triazine-3(2H)-thione (2b). A soln. of
3
(0.105 g, 0.50 mmol) and conc. HCl soln. (1 drop) in EtOH (6 ml) was added to a soln. of 4a (0.105 g,
1.00 mmol) in EtOH (6 ml), conc. HCl soln. (2 drops), and 2m HCl (5 ml). The mixture was stirred under
reflux for 3 h. After cooling at 58 for 24h, a white solid was obtained, which was filtered and dried: 2b
(77%). White crystals suitable for X-ray crystallography were formed by slow evaporation of the mother
liquor. M.p. 1858. IR (KBr): 3278s (NH), 1618w (CN), 1511s (thioamide II), 885w (CS). 1H-NMR
1
((D6)DMSO): 12.22 (s, NH); 7.58 – 7.21 (m, 2 Ph); 2.94( s, MeN); 1.35 (t, J ¼ 7.0, MeCH2O). H-NMR
(CDCl3): 9.596 (s, NH); 7.60 – 7.08 (m, 2 Ph); 3.52 (q, J ¼ 7.0, MeCH2O); 3.07 (s, MeN, 3 H); 1.34( t,
J ¼ 7.0, MeCH2O). 13C-NMR ((D6)DMSO): 171.5 (C¼S); 141.8 (C¼N); 140.0 – 126.3 (Ph); 86.3
(EtOC); 59.4(Me CH2O); 33.3 (MeN); 14.6 (MeCH2O). FAB-MS (pos.): 650.5 (10, 2Mþ), 326.2 (100,
[M þ 1]þ), 280.2 (8, C16H14N3Sþ), 118.1 (4, C7H6N2þ ), 105.1 (33, [C7H6N þ 1]þ), 77.0 (11, Phþ). Anal. calc.
for C18H19N3OS (325.43): C 66.43, H 5.89, N 12.92, S 9.85; found: C 66.02, H 5.93, N 12.96, S 9.75.
5. 4,5-Dihydro-5-methoxy-4,5,6-triphenyl-1,2,4-triazine-3(2H)-thione (2c). The reaction was carried
out following the second procedure described for 2a, but with 4b (1.05 g, 10.00 mmol): 2c (95%).
M.p. 2478. IR (KBr): 3229s (NH), 1612w (CN), 1511s (thioamide II), 845w (CS). 1H-NMR
((D6)DMSO): 12.55 (s, NH); 7.57 – 6.90 (m, 13 arom. H); 6.31 (d, 2 arom. H); 3.57 (s, MeO).
1H-NMR (CDCl3): 9.80 (s, NH); 7.65 – 6.92 (m, 13 arom. H); 6.32 (d, J ¼ 7.9, 2 arom. H); 3.54( s, MeO).
13C-NMR ((D6)DMSO): 172.3 (C¼S); 142.6 (C¼N); 139.3 – 126.9 (Ph); 87.5 (MeOC); 51.2 (MeO).
FAB-MS (pos.): 746.9 (2, 2Mþ), 374.0 (100, [M þ 1]þ), 105.1 (25, [C7H6N þ 1]þ), 77.0 (35, Phþ). Anal.
calc. for C22H19N3OS (373.47): C 70.80, H 5.09, N 11.26, S 8.58, found: C 70.69, H 5.10, N 11.36, S 8.61.
A soln. of 3 (0.105 g, 0.50 mmol) and conc. HCl (2 drops) in MeOH (13 ml) was added to a soln. of
4b (0.167 g, 1.00 mmol) in MeOH (12 ml), conc. HCl soln. (1 ml), and 2m HCl (10 ml). The mixture was
stirred under reflux for 3 h. After cooling to r.t., the precipitate formed was filtered off, washed with
MeOH, and dried: 2c/unknown compound. 1H-NMR ((D6)DMSO): 12.55 (s, 1 H, NH); 10.51 (s, 0.37 H,
NH); 10.38 (s, 0.37 H, NH); 9.80 (s, 0.8 H, NH); 7.72 – 6.69 (m, 18 H, Ph); 6.32 (d, J ¼ 7.9, 2 H, Ph); 3.64
(s, 3 H, MeO). FAB-MS (pos.): 509.0 (40, [C28H24N6S2 þ 1]þ), 374(100, [C 22H19N3OS þ 1]þ), 105.1 (25,
[C7H6N þ 1]þ), 77.0 (35, Phþ).
A soln. of 3 (2.10 g, 10.00 mmol) and conc. HCl soln. (10 drops) in dry MeOH (75 ml) was added to a
soln. of 4b (1.05 g, 10.00 mmol) in dry MeOH (125 ml) conc. HCl soln. (1 ml). The mixture was stirred at
r.t. for 8 h. The white solid formed was filtered off and dried in vacuum: 2c. White crystals suitable for X-
ray crystallography were formed by slow evaporation of the mother liquor. Spectroscopic data: see
above.
A soln. of 3 (2.10 g, 10.00 mmol) and conc. HCl soln. (10 drops) in dry MeOH (75 ml) was added to a
hot soln. of 4b (1.05 g, 10 mmol) in dry MeOH (125 ml) and conc. HCl soln. (10 ml). Immediately, a solid
was formed. The mixture was heated under reflux for 45 min. The yellow solid (impure 2c) was filtered
off and dried.
A soln. of 3 (0.105 g, 0.50 mmol) in MeOH (5 ml) was added to a soln. of 4b (0.167 g, 1 mmol) in
MeOH (10 ml) and AcOH (5 drops). The mixture was stirred under reflux for 8 h and then concentrated
until a solid formed: 2c (1%). The reagent 4b was recovered from the filtrate.
6. Benzil Bis(4-phenylthiosemicarbazone) (¼2,2’-(1,2-Diphenylethane-1,2-diylidene)bis[N-phenyl-
hydrazinecarbothioamide]; 1b) and 5-Ethoxy-4,5-dihydro-5,6-triphenyl-1,2,4-triazine-3(2H)-thione (2d).
A soln. of 3 (0.105 g, 0.5 mmol) and conc. HCl soln. (1 drop) in EtOH (20 ml) was added to a soln. of 4b
(0.161 g, 1 mmol) in EtOH (30 ml), conc. HCl soln. (2 drops), and 2m HCl (5 ml). The mixture was
stirred under reflux for 3 h. After cooling to r.t., yellowish white solid 1b was obtained (5%), which was
filtered off and dried. From the filtrate white solid 2d was isolated.
Data of 1b: M.p. 2238. IR (KBr): 3340s, 3266s (NH), 1616w (CN), 1593s (thioamide II), 871w
(thioamide IV). 1H-NMR ((D6)DMSO): 10.52 (s, 2 NH); 10.40 (s, 2 NH); 7.87 (m, 4arom. H); 7.72 – 7.20
(m, 16 arom. H). 13C-NMR ((D6)DMSO): 171.3 (C¼S); 141.6 (C¼N); 139.0 – 125.7 (Ph). FAB-MS

Helvetica Chimica Acta – Vol. 90 (2007)
2213
(pos.): 509.3 (5, [M þ 1]þ), 388.2 (45, C18H21N3Sþ). MALDI-TOF-MS: 509.1 (2100 a.i., [M þ 1]þ), 388.1
(1700 a.i., C18H21N3Sþ). Anal. calc. for C28H24N6S2 (509.04): C 66.14, H 4.72, N 16.53, S 12.59; found: C
66.11, H 4.90, N 16.35, S 12.38.
Data of 2d: M.p. 2058. IR (KBr): 3162s (NH), 1594w (CN), 1505s (thioamide II), 812w (CS).
1H-NMR ((D6)DMSO): 12.53 (s, NH); 7.58 – 6.30 (m, 3 Ph); 3.48 (q, J ¼ 7.0, MeCH2O); 1.39 (t, J ¼ 7.0,
MeCH2O). 13C-NMR ((D6)DMSO): 172.5 (C¼S); 143.3 (C¼N); 139.6 – 126.6 (Ph); 86.9 (EtOC); 59.34
(MeCH2O); 14.6 (MeCH2O). FAB-MS (pos.): 775.1 (5, [2M þ 1]þ), 388.0 (100, [M þ 1]þ), 105.0 (40,
[C7H6N þ 1]þ) 77.0 (21, Phþ). Anal. calc. for C23H21N3OS (387.50): C 71.03, H 5.40, N 10.80, S 8.30; found:
C 70.72, H 5.30, N 10.90, S 8.31.
A soln. of 3 (0.105 g, 0.5 mmol) and conc. HCl soln. (1 drop), in abs. EtOH (30 ml) was added to a
soln. of 4b (0.161 g, 1.0 mmol) in abs. EtOH (20 ml) and conc. HCl soln. (2 drops). The mixture was
stirred at r.t. for 3 h, then the yellowish solid formed was filtered and dried: 1b (10%). From the filtrate, a
white solid was isolated: 2d. Spectroscopic data: see above.
A soln. of 4b (1.67 g, 10.00 mml) in EtOH/2m HCl 1:1 (80 ml) and conc. HCl soln. (1 ml), and a soln.
of 3 (2.10 g, 10.00 mmol) in EtOH (200 ml) were added alternatively dropwise and slowly with strong
stirring to EtOH (150 ml). After completion of the addition of all the reagents, the mixture was stirred
for 4days. The soln. was concentrated, and the crystalline white solid was filtered off and dried: 2d
(82%). Crystals suitable for X-ray studies were grown by keeping the concentrated mother liquor int the
fridge.
7. 4,5-Dihydro-5-hydroxy-4,5,6-triphenyl-1,2,4-triazine-3(2H)-thione (2e). A soln. of 3 (0.210 g,
1.00 mmol) in EtOH (20 ml) was added to a soln. of 4b (0.322 g, 2.00 mmol) in EtOH (20 ml). The
mixture was stirred under reflux for 3 h. Then the white solid formed was filtered and dried: 2e (40%).
Crystals suitable for X-ray diffraction studies were formed by slow evaporation of a DMSO soln.
M.p. 1938. IR (KBr): 3230s (NH), 1615w (CN), 1498s (thioamide II), 872w (CS). 1H-NMR
((D6)DMSO): 8.43 (s, NH); 7.61 – 6.89 (m, 3 Ph); 6.09 (d, J ¼ 8.0, OH). 13C-NMR ((D6)DMSO): 170.9
(C¼S); 146.4 (C¼N); 141.1 – 126.6 (Ph); 82.3 (OHꢀC). FAB-MS (pos.): 719.0 (5, [2M þ 1]þ), 360.0 (35,
[M þ 1]þ). Anal. calc. for C21H17N3OS (359.44): C 70.19, H 4.73, N 11.69, S 8.91; found: C 69.96, H 4.79, N
11.69, S 8.88.
8. Crystal-Structure Determinations. Crystallographic data of compounds are summarized in the
Table. Crystals of compounds were mounted on a glass fiber and transferred to a Bruker SMART-6K-
CCD area-detector three-circle diffractometer with a rotating anode (CuKa radiation, l 1.54178 Š)
generator from MAC Science Co., Ltd., equipped with Goebel mirrors at settings of 45 kV and 110 mA.
X-Ray data were collected at 100 K, with a combination of six runs at different f and 2q angles, 3600
frames. The data were collected by using 0.38 wide w scans with a crystal-to-detector distance of 4.0 cm.
The substantial redundancy in data allowed empirical absorption corrections (SADABS) [13] to be
applied by using multiple measurements of symmetry-equivalent reflections (ratio of minimum to
maximum apparent transmission: 0.560366 for 1a, 0.769374for 2a, 0.607923 for 2b, 0.824277 for 2c,
0.616163 for 2d, and 0.490640 for 2e. The unit cell parameters were obtained by full-matrix least-squares
refinements of 4228 reflections for 1a, 7400 for 2a, 5854for 2b, 3955 for 2c, 5195 for 2d, and 5701 for 2e.
The raw intensity data frames were integrated with the SAINT [14] program, which also applied
corrections for Lorentz and polarization effects. The software package SHELXTL [15] version 6.10 was
used for space-group determination, structure solution, and refinement. The space-group determination
was based on a check of the Laue symmetry and systematic absences and was confirmed by using the
structure solution. The structure was solved by direct methods (SHELXS-90) [16], completed with
difference Fourier syntheses, and refined with full-matrix least squares by using SHELXL-97 [17]
2
minimizing w(Fo ꢀ Fc2)2. Weighted R factors (Rw) and all goodness of fit S are based on F2; conventional
R factors (R) are based on F. All non-H-atoms were refined with anisotropic displacement parameters.
All scattering factors and anomalous dispersion factors are contained in the SHELXTL 6.10 program
library. The high quality of the data set allowed that all H-atoms were located by difference maps and
refined isotropically in all compounds, except for some H-atoms of 1a and 2e.
Supplementary crystallographic data have been deposited as CCDC-624595 for 2b, -624596 for 1a,
-624597 for 2a, -624598 for 2d, -624599 for 2e · DMSO, and -624600 for 2c with the Cambridge

2214
Helvetica Chimica Acta – Vol. 90 (2007)

Helvetica Chimica Acta – Vol. 90 (2007)
2215
Crystallographic Data Centre. These data can be obtained free of charge via www.ccdc.cam.ad.uk/
data_request/cif.
REFERENCES
[1] D. X. West, A. E. Liberta, S. B. Padhye, R. C. Chikate, P. B. Sonawane, A. S. Kumbhar, R. G.
Yeranda, Coord. Chem. Rev. 1993, 123, 49 and refs. cit. therein; A. E. Liberta, D. X. West, Biometals
1992, 5, 121; D. X. West, S. B. Padhye, P. B. Sonawane, Struct. Bonding 1991, 76, 1; ꢁInternational
Encyclopedia of Pharmacology and Therapeuticsꢂ, Eds. J. G. Cory and A. H. Cory, Pergamon Press,
´
´
New York, 1989; R. Pedrido, M. R. Bermejo, M. J. Romero, M. Vazquez, A. M. Gonzalez-Noya, M.
´
Maneiro, M. J. Rodríguez, M. I. Fernandez, Dalton Trans. 2005, 572; I. H. Hall, K. G. Rajendran,
D. X. West, A. E. Liberta, Anticancer Drugs 1993, 4, 231; M. Belicchi-Ferrari, F. Bisceglie, C. Casoli,
S. Durot, I. Morgenstern-Baradau, G. Pelosi, E. Piloti, S. Pinelli, P. Tarasconi, Med. Chem. 2005, 48,
1671; H. Beraldo, D. Cambino, Mini-Rev. Med. Chem. 2004, 4, 31; A. G. Quiroga, C. N. Ranninger,
Coord. Chem. Rev. 2004, 248, 119; N. C. Kasuga, K. Onodera, S. Nakano, K. Hayashi, K. Nomiya, J.
Inorg. Biochem. 2006, 100, 1176.
[2] A. R. Cowley, J. Davis, J. R. Dilworth, P. S. Donnelly, R. Dobson, A. Mightingale, J. M. Peach, B.
Shore, D. Ker, L. Seymour, Chem Commun. 2005, 7, 845; J. P. Holland, J. C. Green, J. R. Dilworth,
Dalton Trans. 2006, 783; A. R. Cowley, J. R. Dilworth, P. S. Donnelly, J. M. White, Inorg. Chem.
2006, 45, 496.
[3] M. M. Reinoso García, W. Verboom, D. N. Reinhoudt, E. Malinowska, M. Pietrzak, D.
Wojciechowska, Tetrahedron 2004, 60, 11299; G. E. Tumambac, M. Rosencrance, C. Wolf,
Tetrahedron 2004, 60, 11293; S.-M. Cheung, W.-H. Chan, Tetrahedron 2006, 62, 8379.
[4] a) L. Alsop, A. R. Cowley, J. R. Dilworth, P. S. Donnelly, J. M. Peach, J. T. Rider, Inorg. Chim. Acta
2005, 358, 2770; b) M. Christlieb, J. R. Dilworth, Chem.–Eur. J. 2006, 12, 6194; c) M. Christlieb, H. J.
Claughton, A. R. Cowley, J. M. Heslop, J. R. Dilworth, Transition Met. Chem. 2006, 31, 88.
´
´
[5] a) P. Souza, M. A. Mendiola, A. Arquero, V. Fernandez, E. Gutierrez-Puebla, C. Ruíz-Valero, Z.
˜
Naturforsch, B 1994, 49, 263; b) A. Arquero, M. Canadas, M. Martinez-Ripoll, M. A. Mendiola, A.
´
Rodriguez, Tetrahedron 1998, 54, 11271; c) M. A. Blanco, E. Lopez-Torres, M. A. Mendiola, E.
´
Brunet, M. T. Sevilla, Tetrahedron 2002, 58, 1525; d) E. Lopez-Torres, M. A. Mendiola, C. J. Pastor,
´
´
B. Souto Perez, Inorg. Chem. 2004, 43, 5222 and refs. cit. therein; e) E. Lopez-Torres, M. A.
´
Mendiola, C. J. Pastor, Inorg. Chem. 2006, 45, 3103 and refs. cit. therein; f) E. Lopez-Torres, M. A.
Mendiola, C. J. Pastor, Polyhedron 2006, 25, 1464.
[6] M. J. Gismera, M. A. Mendiola, J. Rodríguez-Procopio, M. T. Sevilla, Anal. Chim. Acta 1999, 385,
´
´
143; J. Ruiperez, M. A. Mendiola, M. T. Sevilla, J. Rodríguez-Procopio, L. Hernandez, Electro-
analysis 2002, 14, 532; M. Colilla, M. A. Mendiola, J. R. Procopio, M. T. Sevilla, Electroanalysis 2005,
´
17, 933; F. Zani, D. G. Calatayud, E. Lopez-Torres, M. A. Mendiola, J. R. Procopio, ꢁEUROBIC 8
Conference bookꢂ, ISBN 989-20-0305-5, Aveiro, Portugal, 2006, p. 153.
´
[7] E. Franco, E. Lopez-Torres, M. A. Mendiola, M. T. Sevilla, Polyhedron 2000, 19, 4 4 1.
[8] E. Bermejo, A. Castin˜eiras, D. X. West, J. Mol. Struct. 2003, 650, 93.
˜
[9] A. Castineiras, E. Bermejo, D. X. West, J. Mol. Struct. 1999, 478, 73.
[10] A. L. Spek, PLATON, The University of Utrecht, Utrecht, 2004.
[11] E. Bermejo, A. Castin˜eiras, R. Dominguez, R. Carballo, C. Maiche-Mçssmer, J. Strꢃhle, D. X. West,
Z. Anorg. Allg. Chem. 1999, 625, 961.
[12] E. Sutton, ꢁTables of Interatomic Distances and Configuration in Molecules and Ions (Suplement)ꢂ,
The Chemical Society, London, 1965.
[13] G. M. Sheldrick, SADABS version 2.03, Program for Empirical Absorption Corrections, Universitꢃt
Gçttingen, Gçttingen, 1997 – 2001.
[14] G. M. Sheldrick, SAINTþ NT (version 6.04) SAX, Area-Detector Integration Program, Bruker
AXS, Madison, WI, 1997 – 2001.
[15] Bruker AXS SHELXTL (version 6.10), Structure Determination Package, Bruker AXS, Madison,
WI, 2000.

2216
Helvetica Chimica Acta – Vol. 90 (2007)
[16] G. M. Sheldrick, SHELXS-90, Program for Structure Solution: Direct Methods, Acta Crystallogr.
Sect. A 1990, 46, 467.
[17] G. M. Sheldrick, SHELXL-97, Program for Crystal Structure Refinement, Universitꢃt Gçttingen,
Gçttingen, 1997.
Received May 30, 2007