Hydrazones derived from thiooxamohydrazides and 3-formyl-4-hydroxycoumarin: Synthesis, structures, and fragmentation

Article abstract of DOI:10.1007/s11172-012-0325-x

Novel hydrazones were obtained from thiooxamohydrazides and 3-3-formyl-4-hydroxycoumarin. According to data from NMR spectroscopy and X-ray diffraction, the coumarin fragment in the compounds obtained exists as 4-hydroxycoumarin or chromane-2,4-dione. When dissolved in dimethyl sulfoxide, these hydrazones undergo fragmentation into derivatives of 1,3,4-thiadiazole and 4-hydroxycoumarin.

Full text of DOI:10.1007/s11172-012-0325-x

Russian Chemical Bulletin, International Edition, Vol. 61, No. 12, pp. 2311—2321, December, 2012
2311
Hydrazones derived from thiooxamohydrazides and
3ꢀformylꢀ4ꢀhydroxycoumarin: synthesis, structures, and fragmentation
B. G. Milevsky,a N. P. Solov´eva,a T. A. Chibisova,a V. N. Yarovenko,b E. S. Zayakin,b
V. V. Chernyshev,c,d M. M. Krayushkin,b and V. F. Travena
aD. I. Mendeleyev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (495) 609 2964. Eꢀmail: traven@muctr.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119991 Moscow, Russian Federation
dA. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation
Novel hydrazones were obtained from thiooxamohydrazides and 3ꢀformylꢀ4ꢀhydroxycouꢀ
marin. According to data from NMR spectroscopy and Xꢀray diffraction, the coumarin fragꢀ
ment in the compounds obtained exists as 4ꢀhydroxycoumarin or chromaneꢀ2,4ꢀdione. When
dissolved in dimethyl sulfoxide, these hydrazones undergo fragmentation into derivatives of
1,3,4ꢀthiadiazole and 4ꢀhydroxycoumarin.
Key words: 3ꢀformylꢀ4ꢀhydroxycoumarin, oxamic acids, thiohydrazides, 1,3,4ꢀthiadiazole,
tautomerism, NMR spectroscopy, Xꢀray diffraction.
Hydrazones, amides, and hydrazides, which are derivꢀ
atives of aldehydes and carboxylic acids, exhibit high bioꢀ
logical activity.1—3 Hydrazones synthesized by reactions
of benzohydrazide and pyridineꢀ3ꢀcarbohydrazide with
salicylaldehyde affect the virulence system of pathogenic
bacteria.4 To treat malaria infection, deferoxamine (1) is
used in clinical practice. Its therapeutic activity against
the infection is due to the ability to bind free iron(III) ions
that abound in infected red blood cells.5
formations (including tautomerization) characteristic of
this class of compounds can affect their tendency toward
complex formation as well as the character of their biologꢀ
ical activity.9
In this respect, hydrazones of thiooxamohydrazides
containing the 3ꢀformylꢀ4ꢀhydroxycoumarin fragment (3)
are of undoubted interest.
Aroylhydrazones of salicylaldehyde and its analogs are
chelators of iron(III) ions that are comparable in efficiency
with deferoxamine.6,7 Hydrazones of thiooxamohydrazides
with fluorineꢀcontaining substituents (2) possess low toxꢀ
icity and a pronounced inhibitive effect on acute chlamyꢀ
dia infection.8 It is significant that isomerizational transꢀ
For instance, hydrazone derivatives (thiazolidinones 4
and thiadiazoles 5) containing the coumarin fragment are
known to exhibit antioxidant and antifungal effects, reꢀ
spectively,10,11 and natural and synthetic coumarin derivꢀ
atives generally show high biological activity.12
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2290—2300, December, 2012.
1066ꢀ5285/12/6112ꢀ2311 © 2012 Springer Science+Business Media, Inc.

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Milevsky et al.
All the tautomeric forms depicted in Scheme 2 can be
identified in the NMR spectra of hydrazones 3a—g. In the
1H NMR spectra of their freshly prepared solutions in
DMSOꢀd6 and DMSOꢀd6—CDCl3, the signals for the
H(9) proton differ in multiplicity. In the spectrum of comꢀ
pound 3a, this proton is manifested as two doublets at
 8.68 (3JH(9),N(10)H = 13.4 Hz) and 8.85 (3JH(9),N(10)H
=
= 12.5 Hz), with an intensity ratio of 7 : 3. The lowꢀfield
region of the spectrum shows doublets for the N(10)H
protons at  14.23 (3JH(9),N(10)H = 13.4 Hz) and 13.20
(3JH(9),N(10)H = 12.5 Hz), which correspond to chromaneꢀ
2,4ꢀdione structures B1 and B2.
In the spectra of compounds 3b and 3f in DMSOꢀd6—
CDCl3, a singlet for the H(9) proton appears at  9.17 (3b)
and 9.21 (3f). These spectra contain strongly broadened
lowꢀfield signals at  14.80 (3b) and 14.71 (3f), which
correspond to the OH group of the coumarin ring in tautoꢀ
mer A1.
In our continued search for novel biologically active
compounds, we obtained a number of hydrazones 3 from
thiohydrazides and 3ꢀformylꢀ4ꢀhydroxycoumarin 6
(Scheme 1)8 and examined their structures by NMR specꢀ
troscopy and Xꢀray diffraction analysis.
The presence of the coumarin and thiohydrazide fragꢀ
ments in hydrazones 3 allows them to exist in several tautoꢀ
meric forms.
Scheme 2 displays four tautomers of compounds
3a—g: two of them contain the 4ꢀhydroxycoumarin
fragment (structures A1 and A2) and the other two conꢀ
tain the chromaneꢀ2,4ꢀdione fragment (geometric isoꢀ
mers B1 and B2 stabilized by intramolecular hydrogen
bonds). Earlier, in the study of the ratio of the isoꢀ
mers of arylimines of compound 6, we have found13
that keto enamines of the type B1 with a stronger intraꢀ
molecular hydrogen bond between the N(10)H group
and the fragment C(4)=O of coumarin predominate
in mixtures with the corresponding keto enamines of
the type B2.
The 1H NMR spectrum of a freshly prepared solution
of compound 3c in DMSOꢀd6 exhibits a singlet at  8.71
for the H(9) proton and a strongly broadened signal at
 14.29 for the proton of the OH group of the coumarin
fragment; these signals belong to the major tautomer A1
(60%). The minor tautomer B1 (40%) in this spectrum is
characterized by a doublet at  8.85 (H(9), 3JH(9),N(10)H
= 12.8 Hz) and a doublet at  13.20 (N(10)H).
=
A similar spectral pattern is observed for compound 3d.
The major isomer (4ꢀhydroxycoumarin A1, 60%) is repreꢀ
sented by a singlet at  8.70 for the H(9) proton and
a strongly broadened signal at  14.80 for the proton of the
OH group of the coumarin fragment. For the minor tautoꢀ
Scheme 1
R = H (a), 4ꢀF (b), 4ꢀBr (c), 4ꢀNO2 (d), 4ꢀOCH3 (e), 2ꢀCF3 (f), 3ꢀCF3 (g)

4ꢀHydroxycoumarinꢀ3ꢀcarbaldehyde hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
2313
Scheme 2
mer (chromaneꢀ2,4ꢀdione B1, 40%), doublet signals apꢀ
3
pear at  8.86 (H(9), JH(9),N(10)H = 12.0 Hz) and 13.20
(N(10)H).
a
C(10)
S(16)
C(18)
C(26)
C(24)
The spectrum of compound 3g is most complicated.
The spectrum of a freshly prepared solution of this comꢀ
pound in DMSOꢀd6 shows signals for its four tautomers,
B1 and B2 being dominant. The signals for the H(9) proꢀ
ton and the corresponding signals for the N(10)H proton
appear as doublets. For B1 (50%):  8.77 (d, H(9),
3JH(9),N(10)H = 12.0 Hz) and 14.23 (N(10)H); for B2 (25%):
C(9)
O(17)
C(21)
N(20)
C(25)
C(5)
N(14)
C(4)
C(12)
C(7)
C(8)
C(23)
C(6)
O(1)
C(22)
N(13)
C(3)
C(15)
O(19)
C(2)
O(11)
3
 8.92 (d, H(9), JH(9),N(10)H = 12.0 Hz) and 13.20
b
(N(10)H). The minor tautomers A1 and A2 are manifested
by singlets for the H(9) protons at  9.00 and 9.04 with
a total relative intensity of 25%.
S(16)
O(17)
The proposed signal assignment to the tautomers of
compounds 3a—g is confirmed by the 13C NMR spectra.
For instance, the 13C NMR spectrum of compound 3a in
DMSOꢀd6—CDCl3 contains signals for the C(4)=O atoms
at  177.1 and 177.4, which correspond to tautomers B1
and B2, respectively. The 13C NMR spectrum of comꢀ
pound 3f shows no signals for the C(4)=O atom in this
region; instead, signals for the C(4)—OH atom appear at
 161.5 and 161.8 (tautomers A1 and A2, respectively).
In contrast to solutions containing, in some or other
amount, all the four isomers of hydrazones 3a—g depicted
in Scheme 2, these compounds in the solid state exist as
chromaneꢀ2,4ꢀdione B1 only, which was confirmed by
Xꢀray powder diffraction data14—16 for compounds 3a and
3f. The geometrical parameters of the molecules in the
crystal structures 3a(I) and 3a(II) (these are two polyꢀ
morphs of hydrazone 3a) and 3f (Fig. 1) have typical valꢀ
ues in agreement with tautomeric structures B; they are
O(19)
O(1)
O(11)
c
F(28)
C(27)
F(30)
F(29)
S(16)
O(17)
O(1)
O(19)
O(11)
Fig. 1. Molecular structures of compounds 3a(I) (a), 3a(II) (b),
and 3f (c) with atomic numbering. The unnumbered atoms in
structures 3a(II) and 3f correspond to the numbered ones in
structure 3a(I). The nonꢀhydrogen atoms are depicted as atomic
displacement spheres (p = 50%).

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Milevsky et al.
also comparable with the parameters of related compounds
retrieved from the Cambridge Structural Database.17
In structures 3a(I) and 3a(II), the plane of the phenyl
ring is nearly parallel to the meanꢀsquare plane of the
coumarin fragment: the angle between them is 2(2) and
4(2) in 3a(I) and 3a(II), respectively. In structure 3f, the
corresponding angle is 14(2).
The crystal packing in all the structures consists of
centrosymmetric dimers formed by intermolecular hydroꢀ
...
gen bonds N(14)—H(14) O(11) (Table 1). A centrosymꢀ
metric dimer in the crystal structure of compound 3f is
shown in Fig. 2. The formation of these dimers in comꢀ
pounds 3a(II) and 3f is also contributed by nonclassic
Fig. 2. Centrosymmetric dimer formed by intermolecular hyꢀ
drogen bonds N—H O (indicated with dashed lines) in the crysꢀ
...
...
hydrogen bonds C(12)—H(12) O(11) (see Table 1). In
talline structure of compound 3f. Intramolecular hydrogen bonds
N—HѕO are indicated with dotted lines.
polymorphic crystals of 3a(I) and 3a(II), weak interꢀ
molecular interactions C(9)—H(9) S(16) (see Table 1)
...
play an important role by uniting the centrosymmetric
dimers into ribbons along the crystallographic axes [110]
and [120], respectively.
Scheme 3
Earlier,8,18 cyclic tautomers of hydrazones derived from
thiohydrazides, apart from their linear tautomers, have
been detected. The predominance of linear (A) or cyclic
(C) tautomers (Scheme 3) in an equilibrium mixture
in solution depends on both the mutual effects of subꢀ
stituents in the aldehyde and thiohydrazide moieties and
the polarity of the medium. It has been noted that an
increase in the bulkiness and electronegativity of subꢀ
stituent R (see Scheme 3) stabilizes thiadiazoline strucꢀ
ture C, while the presence of electronꢀdonating and bulky
substituents R1 in the aldehyde moiety favors hydrazone
structure A.
For thiobenzoylhydrazones of cyclic ꢀoxo esters, the
major tautomer is thiadiazoline C in a mixture with the
ene hydrazine tautomer;19 for thiobenzoylhydrazones of
aroylacetones and aroylacetaldehydes, three tautomers
(ene hydrazine, 1,3,4ꢀthiadiazoline, and 5ꢀhydroxypyrꢀ
azoline) are in equilibrium.20
1
When analyzing the H NMR spectra of hydrazones
3a—g, we identified signals for cyclic tautomer C (Scheme 4)
in compounds 3f and 3g soluble in acetoneꢀd6: a singlet
Table 1. Hydrogen bond parameters in the tautomeric structures 3a(I), 3a(II), and 3f*
Comꢀ
pound
D—H…A
D—H
H…A
D…A
D—H…A
/deg
Å
3a(I) B
N(13)—H(13)…O(17)
N(14)—H(14)…O(11)a
C(9)—H(9)…S(16)b
N(13)—H(13)…O(17)
N(14)—H(14)…O(11)c
C(12)–H(12)…O(11)c
C(9)—H(9)…S(16)d
N(13)—H(13)…O(17)
N(14)—H(14)…O(11)b
C(12)—H(12)…O(11)b
0.86
0.86
0.93
0.86
0.86
0.93
0.93
0.86
0.86
0.93
1.82
2.09
2.68
1.87
2.24
2.28
2.73
1.85
2.09
2.01
2.534 (15)
2.882 (14)
3.511 (15)
2.54 (2)
3.01 (3)
3.08 (3)
139
152
149
133
149
145
157
132
148
147
3a(II) B
3.60 (2)
3f B
2.515 (12)
2.851 (13)
2.833 (15)
c
* The symmetry operation codes are a –x, –y, 1 – z; b 2 – x, 1 – y, 1 – z; –x, 2 – y, 1 – z; d 1 – x,
2 – y, 1 – z.

4ꢀHydroxycoumarinꢀ3ꢀcarbaldehyde hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
2315
Scheme 4
for the methine proton of the thiadiazoline ring apꢀ
pears at  6.66 (3f) and 6.58 (3g), which agrees with the
literature data ( 6.50—7.10).8,18 The lowꢀfield spectra
contain signals for the NHC(O) proton of the cyclic
tautomer. The content of the cyclic tautomer is ~10 (3f)
and 20% (3g).
this assignment was proved by analyzing the 1H NMR
spectra of both individual solutions of compounds 3b and
10 and their mixture (Fig. 4).
To prove the fragmentation of hydrazone 3b into comꢀ
pounds 10 and 11 (Scheme 5), we carried out a NOE
experiment and recorded a 13C NMR spectrum of the
mixture under study. According to the NOE data, the
signals at  5.58 (H(3)) and 12.14 (OH); 7.24 (H(6,8))
and 7.52 (H(7)); 7.24 (H(6,8)) and 7.78 (H(5)) for
4ꢀhydroxycoumarin (10) as well as the signals at  11.10
(NH) and 7.84 (H(8´), H(12´)); 7.06 (H(9´), H(11´)) and
7.84 (H(8´), H(12´)) for compound (11b) show clear corꢀ
relations. In the 13C NMR spectrum, we identified the
signals for 4ꢀhydroxycoumarin (163.9 (C(2)), 160.5 (C(4)),
154.2 (C(8a)), 130.5 (C(7)), 121.8 (C(6))*, 121.4 (C(5))*,
114.4 (C(8)), 114.2 (C(4a)), 89.3 (C(3))) and Nꢀ(4ꢀfluoroꢀ
phenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (164.0 (C(6´)),
Cyclic tautomer C is not abundant and could be deꢀ
tected only in acetoneꢀd6 solutions. However, the cyclic
tautomer of hydrazones derived from thiohydrazides and
3ꢀformylꢀ4ꢀhydroxycoumarin seems to play a considerꢀ
able role in their structural transformations. Analysis of
1
the H NMR spectra revealed that the hydrazones under
study are unstable in DMSOꢀd6 and DMSOꢀd6—CDCl3.
Even the spectra of freshly prepared solutions of all hydrꢀ
azones, except for 3a (R = H) and 3g (R = 3ꢀCF3), show
distinct lowꢀintensity signals (10%): singlets at  5.60
and 9.66—9.91, broadened signals at  10.08—11.10, and
strongly broadened signals at  12.20—12.55, all these signꢀ
als being of equal intensity.
We studied in detail the behavior of hydrazone 3b,
which exists as 4ꢀhydroxyꢀ2ꢀchromanone A in a freshly
prepared solution in DMSOꢀd6—CDCl3. In the 1H NMR
spectra of this compound (Fig. 3), the signals for the
N(14)H ( 10.15) and H(9) protons ( 9.15) gradually
become less intense with time and finally vanish. Simultaꢀ
neously, the originally minor signals (the singlets at  5.60
and 9.65 and the broadened signals at  11.10 and 12.20)
become more intense and are predominant 48 h after the
preparation of the solution. In about 15 days, these signals
remain the only ones in the spectra.
157.3 (1J13 = 242.8 Hz, C(10´)), 155.8 (1J13C,H = 214.3
C,F
Hz, C(5´)), 151.8 (C(2´)), 132.2 (4J13C,F = 2.7 Hz, C(7´)),
120.8 (3J13
= 8.0 Hz, C(8´), C(12´)), 113.4 (2J13
=
C,F
C,F
22.2 Hz, C(9´), C(11´))), which confirms the above fragꢀ
mentation of compound 3b. The presence of the signal for
the C(5´) atom at  155.8 with the characteristic coupling
constant 1J13C,H = 214.3 Hz is conclusive evidence for the
correctness of structure 11b. 1,3,4ꢀThiadiazoles 11b,f were
isolated from the reaction mixtures and characterized by
1H NMR and mass spectra.
Fragmentation of hydrazones 3c,d,e into 4ꢀhydroxyꢀ
coumarin and the corresponding Nꢀarylꢀ1,3,4ꢀthiadiazoleꢀ
2ꢀcarboxamides was proved by 1H NMR spectroscopy
without isolation of the amides. At the same time, hydrꢀ
The singlet at  5.60 (1J13C,H = 167.0 Hz) and the
strongly broadened signal at  12.20 were assigned to the
H(3) proton and the proton of the C(4)—OH group, reꢀ
spectively, in 4ꢀhydroxycoumarin (10). The correctness of
* The signals at  121.8 (C(5)) and 121.4 (C(6)) may be interꢀ
changeable.

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Milevsky et al.
a
*
3b (NH)
3b (H(9))
10 (H(3))
10 (H(3))
11b (H(5´))
*
b
c
11b (H(5´))
10 (OH)
11b (NH)
3b (NH)
3b (H(9))
11b (H(5´))
10 (H(3))
11b (NH)
*
10 (OH)
12.5 12.0 11.5 11.0 10.5 10.0
9.5
9.0 8.5
8.0
7.5
7.0
6.5
6.0
5.5

1
Fig. 3. H NMR spectra of solutions of compounds 3b, 10, and 11b in DMSOꢀd6—CDCl3: freshly prepared (a); after 48 h (b); after
15 days (c) (the signals of the solvent are asterisked; the structures of compounds 10 and 11b are discussed in text).
azones 3a and 3g keep fairly stable in DMSO. No signals
azone 3a even upon prolonged storage of its solution. The
fragmentation of compound 3g in DMSO proceeds very
slowly (for more than three months).
for 4ꢀhydroxycoumarin and 1,3,4ꢀthiadiazoleꢀ2ꢀcarboxꢀ
1
anilide were detected in the H NMR spectrum of hydrꢀ
a
10 (H(3))
*
b
10 (H(3))
11b (H(5´))
*
c
10 (H(3))
11b (H(5´))
*
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5

Fig. 4. 1H NMR spectra of solutions of 4ꢀhydroxycoumarin 10 (a), compound 3b (b), and their mixture (c) in DMSOꢀd6—CDCl3
(the signals of the solvent are asterisked).

4ꢀHydroxycoumarinꢀ3ꢀcarbaldehyde hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
2317
Scheme 5
R = 4ꢀF (b), 4ꢀBr (c), 4ꢀNO2 (d), 4ꢀOMe (e), 2ꢀCF3 (f)
Scheme 6
R´ = 4ꢀFꢀC6H4 (b); 4ꢀBrꢀC6H4 (c), 4ꢀNO2ꢀC6H4 (d), 4ꢀOCH3ꢀC6H4 (e), 2ꢀCF3ꢀC6H4 (f)
It should be noted that fragmentation of hydrazones
derived from thiooxamohydrazides according to the patꢀ
Experimental
tern described above for compounds 3b—f has not been
1
H NMR spectra were recorded on Bruker WPꢀ200ꢀSY
and Varian Unity+ 400 spectrometers in DMSOꢀd6, CDCl3—
DMSOꢀd6, and acetoneꢀd6. The signals of the residual protons
reported hitherto.8,18 A possible sequence of transformaꢀ
tions of compound 3b in DMSO is shown in Scheme 6. It
is not improbable that this fragmentation is due to the
domination of tautomer A (4ꢀhydroxyꢀ2ꢀchromanone),
which is characteristic of compounds 3b—f.
of the solvent ( 2.50 for DMSOꢀd6 and CDCl3—DMSOꢀd6
and  2.05 for acetoneꢀd6 with reference to Me4Si) served as
H
H
the internal standards. 13C NMR spectra were recorded on a
Bruker Avance spectrometer (600 MHz) in CDCl3—DMSOꢀd6.
The signal for 13C in DMSOꢀd6 (C 39.8 with reference to Me4Si)
was used as the internal standard. Lowꢀresolution mass spectra
were measured with a Kratos MSꢀ30 instrument (UK) (EI, 70 eV,
direct inlet probe, 200 C). Highꢀresolution mass spectra were
recorded on a Bruker micrOTOF II instrument (ESI).21 Meaꢀ
surements were performed in the positive ion (capillary voltage
4500 V) or negative ion modes (capillary voltage 3200 V); m/z
In contrast, the stability of hydrazones 3a and 3g is
probably due to the fact that these compounds both exist
in solution either entirely as chromaneꢀ2,4ꢀdione B1 (3a)
or with substantial domination of this tautomer. Apparꢀ
ently, strong intramolecular hydrogen bonding characꢀ
teristic of tautomers B1 and B2 prevents fragmentation of
these compounds.

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Milevsky et al.
scan range was 50—3000 Da. The instrument was calibrated
internally or externally using an Electrospray Calibrant Solution
(Fluka). An analyte dissolved in methanol was syringed into the
mass spectrometer at a flow rate of 3 L min–1. Nitrogen was
employed as a spray gas (4 L min–1); the interface temperature
was 180 C. Elemental analysis was carried out on a Euro Eleꢀ
mental analyzer.
3ꢀFormylꢀ4ꢀhydroxycoumarin13 and thiohydrazides 9a—g
(see Ref. 8) were prepared as described earlier. Hydrazone samꢀ
ples for Xꢀray powder diffraction were additionally purified by
repeated recrystallization from different solvents.
Synthesis of hydrazones 3a—g (general procedure). A soluꢀ
tion of an appropriate thiohydrazide 9a—g (1.1 mmol) in DMF
(1—2.5 mL) was mixed with a solution of 3ꢀformylꢀ4ꢀhydroxyꢀ
coumarin (6) (1.1 mmol) in DMF (2.5 mL). Methanol was addꢀ
ed with stirring to the resulting mixture until a precipitate of
hydrazone was formed. The precipitate was filtered off, washed
on the filter with nꢀhexane, and dried with P2O5 in vacuo at
78 C. The hydrazones obtained were analyzed without further
purification.
2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀDioxoꢀ2Hꢀchromenꢀ3(4H)ꢀyl)methylidꢀ
ene]hydrazino}ꢀ2ꢀthioxoacetanilide (3a). Yield 93%, m.p. 290 C
(decomp.). 1H NMR (200 MHz, DMSOꢀd6), : 14.23 (d, 0.7 H,
N(10)H (B1), 3J = 13.4 Hz); 13.20 (d, 0.3 H, N(10)H (B2),
3J = 12.5 Hz); 10.17 (br.s, 1 H, NHCO); 8.85 (d, 0.3 H, H(9)
(B2), 3J = 12.5 Hz); 8.68 (d, 0.7 H, H(9) (B1), 3J = 13.4 Hz);
7.99 (d, 1 H, H(5), 3J = 7.4 Hz); 7.58—7.80 (m, 3 H, H(7),
H(2´), H(6´)); 7.24—7.40 (m, 4 H, H(6), H(8), H(3´), H(5´));
7.06 (t, 1 H, H(4´), 3J = 7.3 Hz). MS (EI, 70 eV), m/z (Irel (%)):
276 [M – C6H5N]+ (5), 173 [M – C8H8N3SO]+ (22), 163
[M – C10H8O3N2]+ (6), 162 [M – C9H7N3SO]+ (43), 119
[M – C11H8O3N2S]+ (89), 92 [M – C12H7O4N2S]+ (100).
HRMS. Found: m/z 366.0543 [M – H]–. C18H13N3O4S. Calcuꢀ
lated: M – H = 366.0543.
Nꢀ(4ꢀFluorophenyl)ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀchromenꢀ
3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide (3b). Yield
32%, m.p. 170—173.5 C. 1H NMR (400 MHz, DMSOꢀd6),
: 14.80 (br.s, 1 H, OH); 10.20 (br.s, 1 H, NHCO); 9.18 (s, 1 H,
H(9)); 8.00 (d, 1 H, H(5), 3J = 8.1 Hz); 7.67—7.74 (m, 2 H,
H(2´), H(6´)); 7.56 (t, 1 H, H(7), 3J = 7.9 Hz); 7.17—7.29
(m, 2 H, H(6), H(8)); 6.97—7.05 (m, 2 H, H(3´), H(5´)). MS
(EI, 70 eV), m/z (Irel (%)): 385 [M]+ (4), 223 [M – C9H6O3]+
(49), 203 [M – C8H5FNOS]+ (39), 181 [M – C10H8N2O3]+
(39), 162 [M – C9H6FN3OS]+ (60), 137 [M – C11H8N2O3S]+
(100), 121 [M – C9H6FN3OS – C2HO]+ (56), 110 [M –
–C12H7N2O4S]+ (29). HRMS. Found: m/z 384.0457. [M – H]–.
C18H12FN3O4S. Calculated: M – H = 384.0449.
Nꢀ(4ꢀBromophenyl)ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀchromenꢀ
3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide (3c). Yield
33%, m.p. 208—209 C. 1H NMR (200 MHz, DMSOꢀd6),
: 14.29 (br.s, 0.6 H, OH); 13.20 (br.s, 0.4 H, N(10)H); 10.27
(br.s, 1 H, NHCO); 8.85 (d, 0.4 H, H(9), 3J = 12.8 Hz); 8.71
(s, 0.6 H, H(9)); 7.99 (d, 1 H, H(5), 3J = 7.9 Hz); 7.24—7.88
(m, 7 H, H(6), H(7), H(8), H(2´), H(3´), H(5´), H(6´)).
MS (EI, 70 eV), m/z (Irel (%)): 447 [M{Br81}]+ (2), 445
[M{Br79}]+ (2), 285 [M{Br81} – C6H4OC(O)CHC(OH)]+ (63),
283 [M{Br79} – C6H4OC(O)CHC(OH)]+ (60), 243 [M{Br81} –
– C10H7O3N2 – H]+ (30), 241 [M{Br79} – C10H7O3N2 – H]+
(33), 204 [M
– } –
C8H4NSOBr]+ (91), 199 [M{Br81
– C11H7O3N2S – H]+ (93), 197 [M{Br79} – C11H7O3N2S – H]+
(95), 189 [M – C8H5N2SOBr]+ (14), 173 [M – C8H7N3OBr]+
(23), 162 [M – C9H6N3OSBr]+ (100). HRMS. Found: m/z
443.9659. [M – H]–. C18H12BrN3O4S. Calculated: M – H =
= 443.9648.
Table 2. Crystallographic parameters and the data collection statistics for compounds 3a(I), 3a(II), and 3f
Parameter
3a(I)
3a(II)
3f
Molecular formula
Crystal system
C18H13N3O4S
Monoclinic
C18H13N3O4S
Monoclinic
C19H12F3N3O4S
Monoclinic
Space group
a/Å
b/Å
P21/c
5.1035(17)
10.238(2)
32.196(4)
90.925(18)
1682.0(7)
27
P21/c
10.081(4)
5.070(3)
32.505(5)
91.29(4)
1660.9(12)
32
P21/c
4.8391(18)
20.620(3)
18.978(3)
95.27(2)
1885.7(8)
32
c/Å
/deg
3
V/Å
M20
*
F30
Z

*
32 (0.009, 53)
4
25 (0.011, 63)
4
37 (0.008, 54)
4
calc/g cm–3
1.451
1.469
1.534
Radiation
CuꢀK ( = 1.5406 Å)
1
Scan range:
3.00—80.00
3.00—70.00
4.00—80.00
(2min—2max)/deg
Scan step/deg
0.01
0.01
0.01
*
Rp
Rwp
Rexp
2*
0.0270
0.0345
0.0164
3.990
0.0215
0.0271
0.0174
2.309
0.0214
0.0323
0.0116
7.102
*
*

2
* The figures of merit M20 (see Ref. 32) and F30 (see Ref. 33) were defined earlier; Rp, Rwp, Rexp, and 
were calculated by the formulas cited in Ref. 34.

4ꢀHydroxycoumarinꢀ3ꢀcarbaldehyde hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
2319
Nꢀ(4ꢀNitrophenyl)ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀchromenꢀ
3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide (3d). Yield
31%, m.p. 218—219 C. 1H NMR (200 MHz, DMSOꢀd6),
: 14.80 (br.s, 0.6 H, OH); 13.20 (d, 0.4 H, N(10)H, 3J = 12.0 Hz);
10.68 (s, 1 H, NHCO); 8.86 (d, 0.4 H, H(9), 3J = 12.0 Hz); 8.70
(s, 0.6 H, H(9)); 8.14—8.30 (m, 2 H, H(3´), H(5´)); 7.91—8.09
(m, 3 H, H(2´), H(6´), H(5)); 7.66 (t, 1 H, H(7), 3J = 7.7 Hz);
7.25—7.40 (m, 2 H, H(6), H(8)). MS (EI, 70 eV), m/z (Irel (%)):
412 [M]+ (2), 395 [M – OH]+ (6), 250 [M – C9H6O3]+ (42),
208 [M – C10H8O3N2]+ (35), 204 [M – C8H4N2O3S]+ (30), 162
[M – C9H6O3N4S]+ (100). HRMS. Found: m/z 411.0405.
[M – H]–. C18H12N4O6S. Calculated: M – H = 411.0394.
Nꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀchromꢀ
enꢀ3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide (3e).
Yield 38%, m.p. 181—182 C. 1H NMR (200 MHz, DMSOꢀd6),
: 10.09 (s, 1 H, NHCO); 8.76 (br.s, 1 H, H(9)); 7.92—8.04
(m, 1 H, H(5)); 7.59—7.81 (m, 3 H, H(7), H(2´), H(6´)); 7.27—7.45
(m, 2 H, H(6), H(8)); 6.85—7.02 (m, 2 H, H(3´), H(5´)).
MS (EI, 70 eV), m/z (Irel (%)): 235 [M – C9H6O3]+ (23), 162
[M – C10H9N3O2S]+ (42), 149 [M – C11H8N2O3S]+ (97), 134
[M – C11H8N2O3S – CH3]+ (100), 121 [M – C10H9N3O2S –
– C2HO]+ (78), 108 [M – C12H7N3O4S]+ (52). Found (%):
C, 57.47; H, 3.88; N, 10.36; S, 7.93. C19H15N3O5S. Calculatꢀ
ed (%): C, 57.43; H, 3.78; N, 10.58; S, 8.06.
I/(rel. units)
a
80000
40000
×5
1
2
0
20
40
60
2/deg
I/(rel. units)
30000
b
×5
15000
Nꢀ[2ꢀ(Trifluoromethyl)phenyl]ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀ
chromenꢀ3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide
(3f). Yield 84%, m.p. 242—244 C. 1H NMR (200 MHz,
DMSOꢀd6—CDCl3), : 14.71 (br.s, 1 H, OH); 10.40 (br.s, 1 H,
NHCO); 9.21 (s, 1 H, H(9)); 8.27 (d, 1 H, H(6´), 3J = 8.3 Hz);
8.00 (d, 1 H, H(5), 3J = 7.4 Hz); 7.51—7.69 (m, 3 H, H(7),
H(3´), H(5´)); 7.30—7.50 (m, 3 H, H(6), H(8), H(4´)).
Found (%): C, 52.07; H, 2.46; N, 9.54. C19H12F3N3O4S. Calcuꢀ
lated (%): C, 52.41; H, 2.76; N, 9.65.
1
2
0
20
40
60
2/deg
Nꢀ[3ꢀ(Trifluoromethyl)phenyl]ꢀ2ꢀ{2ꢀ[(E/Z)ꢀ(2,4ꢀdioxoꢀ2Hꢀ
chromenꢀ3(4H)ꢀyl)methylidene]hydrazino}ꢀ2ꢀthioxoacetamide
(3g). Yield 78%, m.p. 310—312 C. 1H NMR (200 MHz,
DMSOꢀd6), : 14.23 (d, 0.5 H, N(10)H (B1), 3J = 12.0 Hz);
I/(rel. units)
c
60000
30000
0
3
13.20 (d, 0.25 H, N(10)H (B2), J = 12.0 Hz); 10.48 (br.s, 1 H,
NHCO); 9.04, 9.00 (both s, 0.25 H, H(9), (A2, A1)); 8.92
(d, 0.25 H, H(9) (B2), 3J = 12.0 Hz); 8.77 (d, 0.5 H, H(9)
(B1), 3J = 12.0 Hz); 8.27 (br.s, 1 H, H(2´)); 7.91—8.08 (m, 2 H,
H(5), H(6´)); 7.50—7.75 (m, 2 H, H(7), H(5´)); 7.20—7.50
(m, 3 H, H(6), H(8), H(4´)). Found (%): C, 52.06; H, 2.54;
N, 10.00. C19H12F3N3O4S. Calculated (%): C, 52.41; H, 2.76;
N, 9.65.
Transformations of hydrazones 3b,f into thiadiazoles 11b,f.
Hydrazone 3b or 3f (0.2 mmol) was dissolved in DMSO
(2—3 mL). The resulting solution was kept at ~20 C until the
starting compound was completely consumed (TLC, Silufol UV
254 plates, chloroform—acetone—methanol (30 : 5 : 2)) and two
new spots appeared; one of them (Rf 0.5) corresponds to 4ꢀhydrꢀ
oxycoumarin. Then the reaction mixture was poured into
a 20ꢀfold volume of water and the product was extracted with
ethyl acetate (5×10 mL). The combined extracts were dried with
MgSO4, concentrated in vacuo, and separated into components
by preparative TLC on Silufol UV 254 plates with chloroꢀ
form—acetone—methanol (30 : 5 : 2) as an eluent. The bands
with Rf 0.7—0.9 were cut out and cut into small pieces; the
product was extracted with ethyl acetate. The solvent was reꢀ
moved to give a crystalline precipitate.
×5
1
2
20
40
60
2/deg
Fig. 5. The Rietveld refinement of the crystal structure of
polymorph 3a(I) (a), polymorph 3a(II) (b), and compound 3f
(c): (1) the experimental curve and (2) the difference between
the experimental curve and the calculated profile upon the
refinement; the highꢀangle range (2 > 35) is shown with
a 5x magnification. The calculated positions of the reflections
are indicated with vertical strokes. For twoꢀphase refineꢀ
ment (b), the upper and lower rows of the vertical strokes correꢀ
spond to the reflections from polymorphs 3a(I) and 3a(II), reꢀ
spectively.

2320
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
Milevsky et al.
Nꢀ(4ꢀFluorophenyl)ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxamide (11b).
Yield 13%, m.p. 181.5—184 C. H NMR (400 MHz, CDCl3),
the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
1
: 9.34 (s, 1 H, H(5´); 9.23 (br.s, 1 H, NH); 7.66—7.73 (m, 2 H,
H(8´), H(12´)); 7.07—7.16 (m, 2 H, H(9´), H(11´)). The
1H NMR spectrum agrees with the literature data.22 MS (EI,
70 eV), m/z (Irel (%)): 223 [M]+ (50), 203 [M – HF]+ (27), 137
[M – C2H2N2S]+ (100).
Nꢀ[2ꢀ(Trifluoromethyl)phenyl]ꢀ1,3,4ꢀthiadiazoleꢀ2ꢀcarboxꢀ
amide (11f). Yield 9%, m.p. 88—90 C. 1H NMR (200 MHz,
DMSOꢀd6), : 7.54—7.85 (m, 4 H, H(9´), H(10´), H(11´),
H(12´); 9.88 (s, 1 H, H(5´)); 10.89 (br.s, 1 H, NH). HRMS.
Found: m/z 296.0071. [M + Na]+. C10H6N3F3OS. Calculated:
M + Na = 296.0076.
We are grateful to V. I. Pol´shakov and E. A. Batuev
for recording the 13C NMR spectra at the Laboratory of
Magnetic Tomography and Spectroscopy of the Faculty
of Fundamental Medicine of the M. V. Lomonosov Mosꢀ
cow State University.
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3a(II), and 3f. The crystal structures of samples 3a(I), 3a(II),
and 3f were examined by Xꢀray powder diffraction14—16 in
a Guinier—Huber G670 camera with a curved germanium monoꢀ
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4ꢀHydroxycoumarinꢀ3ꢀcarbaldehyde hydrazones
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Received August 28, 2012;
in revised form November 16, 2012