MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2007; 45: 667–673
Published online 11 June 2007 in Wiley InterScience
Spectral Assignments and Reference Data
1H, 13C, 15N and 19F NMR study of
acetylation products of heterocyclic
thiosemicarbazones
RESULTS AND DISCUSSION
The acetylation of thiosemicarbazones of 4-methoxybenzaldehyde
(1a), pyridine-4-aldehyde (1b), pyridine-3-aldehyde (1c), pyridine-
2-aldehyde (1d), thiophene-2-aldehyde (1e), furan-2-aldehyde (1f),
indole-3-aldehyde (1g), and isatine (1h) by acetic anhydride (2) has
been investigated in the present work in order to prepare promising
biologically active compounds. The reactions involved the cycle
closure (addition of mercapto group across the CH N bond) and
simultaneous acetylation across the NH group of the ring and
the NH2 group of the open chain to give 2-acetylamino-4-acetyl-5-
aryl(heteryl)-1,3,4-thiadiazolines (3a–h) (Scheme 1):
Lyudmila I. Larina,∗ Valentina N. Elokhina,
Tatyana I. Yaroshenko, Anatolii S. Nakhmanovich and
Gennadii V. Dolgushin
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian
Academy of Sciences, Russia
The reaction of pyridine-4-aldehyde thiosemicarbazone (1b),
°
with acetic anhydride at 100 C for 2 h resulted in a mixture
Received 11 December 2006; revised 13 March 2007; accepted 15 March 2007
of 2-acetylamino-4-acetyl-5-(pyridyl-4)-1,3,4-thiadiazoline (3b) (37%
yield) and 2-acetylamino-5(pyridyl-4)-1,3,4-thiadiazole (4a) (25%
Novel 2-acetylamino-4-acetyl-5-aryl(heteryl)-1,3,4-thiadia-
zolines, 2-acetylamino-5-aryl(heteryl)-1,3,4-thiadiazoles,
and some of their salts were prepared and stud-
ied by multinuclear 1H, 13C, 15N, 19F and 2D NMR
spectroscopy. The acetylation of thiosemicarbazones is
accompanied by ring closure to form the correspond-
ing 1,3,4-thiadiazolines and 1,3,4-thiadiazoles. 15N NMR
spectroscopy is a unique method for the identification
of thiadiazole pyridinium salts. Copyright 2007 John
Wiley & Sons, Ltd.
°
yield). The reaction at a temperature of 120 C for 5 h led to only one
product (4a) in 63% yield.
The cyclization of thiosemicarbazones 1a, 1c, 1d, 1e, and 1f
°
with acetic anhydride under heating (75–80 C) for 3–4 h gave
2-acetylamino-4-acetyl-5-aryl(heteryl)-1,3,4-thiazolines (3a, 3c–f) in
98–40% yields. The reaction did not involve the formation of
1,3,4-thiadiazoles (4). The reaction of indole-3-aldehyde thiosemi-
°
carbazone (1g) with acetic anhydride under heating (80 C) for 3 h
resulted in 2-acetylamino-4-acetyl-5-(3-indolyl)-1,3,4-thiadiazoline
(3g) in 90% yield. The product decomposed under long heating
at higher temperatures to give both 2-acetylamino-1,3,4-thiadiazole
(5) and an unidentified product.
Supplementary electronic material for this paper is available
jpages/0749-1581/suppmat/
The heating of 3-isatine thiosemicarbazone (1h) with acetic
°
anhydride at 115–120 C for 4 h led to the cyclization and the
formation of the intermediate A. The latter was acetylated across
the NH and NH2 groups to give spiro[2-acetylamino-4-acetyl-1,3,4-
thiadiazole-5,30-N-acetylindol-2-one] (3h) in 74% yield (Scheme 2).
The IR spectra of all compounds showed absorption bands of C–S
bonds, (690–695 cmꢀ1), C N (1580–1590 cmꢀ1), C O (1630–1640,
1690–1710 cmꢀ1), and NH (3150–3210 cmꢀ1).
KEYWORDS: 1,3,4-thiadiazolines; 1,3,4-thiadiazoles;
heterocyclization; acetylation; NMR spectroscopy;
B3LYP/6-311GC method
INTRODUCTION
In the 1H NMR spectrum of thiadiazole 5 (Table 1), the low-
field signal (9.13 ppm) is related to a proton in the position 5,
whereas in the 13C NMR spectrum without proton decoupling there
is a significant C-5 signal splitting characteristic of these cyclics
(1JC–H D 212 Hz).
Acetylation of thiosemicarbazones of the aromatic and hetero-
cyclic series by acetic anhydride has been investigated with
the aim of preparing new heterocyclic compounds of the thia-
diazole series. The unremitting interest in substituted thiadia-
zoles is caused by their remarkable biological properties such
as antitubercular, antifungal, antibacterial and hypoglycemic
activity.1–4
As seen from Table 1, the signal of methyl protons in the
NHCOCH3-fragment is in a high-frequency region (2.1–2.3 ppm)
compared to that of the acetyl group protons (2.0–2.10 ppm) and
does not depend much on the substituent in the thiadiazolyl fragment
at position 5. The chemical shifts of the NH group proton in both
thiadiazolines (3) and thiadiazoles (4) are hardly sensitive to the
effect of the heterocyclic substituent in the position 5 (Table 1). The
position of resonance signals of H-5 and C-5 in the proton and
carbon spectra of the thiadiazolyl (3) series changes insignificantly
depending on the substituent in this position (υ D 0.4 and 6 ppm,
respectively), whereas in the heteroaromatic system 4, the effect of
substituent is much higher (υ C-5 D 12 ppm, Table 1). Thus, the
chemical shifts of the heterocycle nuclei in the thiadiazoles are more
sensitive to substituent effects than those in thiadiazolines.
There are some known methods for the synthesis of substi-
tuted 1,3,4-thiadiazolines and 1,3,4-thiadiazoles based on thiosemi-
carbazones and thiobenzohydrazine.4–11 Some 1,3,4-thiadiazolines
were obtained from diaryl and aryl cycloalkyl ketones via the corre-
sponding thiosemicarbazones.4 2,4-Substituted 5,5-pentamethylene-
4,5-dihydro-1,3,4-thiadiazole was prepared by the reaction of cyclo-
hexanone thiosemicarbazone with acetic anhydride in the pres-
ence of acetyl chloride by heating in pyridine.5,6 1,4-Diphenyl-
thiosemicarbazide under long storage with formaldehyde in dioxane
afforded 4-phenyl-2-phenylamino-1,3,4-thiadiazoline.7 Substituted
4-carbamoyl-2-ureido-4,5-dihydro-1,3,4-thiadiazoles were prepared
by the cyclization reaction of thiosemicarbazones of benzaldehyde,
furan-2-aldehyde, acetone, cyclopentanone, and cyclohexanone with
isocyanates under heating.8 Thiobenzoylhydrazones were cyclized
under prolonged heating in chloroform to give 2,5-substituted
1,3,4-thiadiazoles.9 The reaction of thiosemicarbazones of benzalde-
hyde, formaldehyde, acetone, and acetophenone with acetic anhy-
The heterocyclic ring in the position 5 poorly influences the
15N screening constant of the thiadiazoline ring nitrogen atoms 3.
The position of the resonance signals of pyridinic nitrogen atom
N-3 is changed from ꢀ113 to ꢀ117 ppm region, whereas the signals
of pyrrolic type nitrogen atoms N-4 (from ꢀ192 to ꢀ199 ppm) are
shifted to lower frequencies by ¾80 ppm (Table 1), which is a well-
known fact in 15N NMR.13 Because of serious structural changes,
quite adifferentpicture isobservedin15NNMR spectraingoing from
thiadiazolines to thiadiazoles: the ring nitrogen atom signals show a
dramatic high-frequency shift (by more than 100 ppm). Disruption
of the aromaticity in the thiadiazolines decreases the screening of
15N nucleus of cyclic nitrogen atoms. Since both these nitrogen atoms
in the thiadiazoles are the ‘pyridine’ nitrogen atoms, a problem of
assigning their signals appears. As known from the literature,13 the
υ 5N value of nitrogen atoms of unsubstituted thiadiazole is ꢀ10 ppm
and depends much on the presence of the substituent in the positions
2 and 5 (Scheme 3):
2
°
dride under heating (100 C) led to 4-acetyl-2-acetylamino- -1,3,4-
thiadiazolines and 4-acetyl-2-amino-2-1,3,4-thiadiazolines.10 Sub-
stituted 2,3-dihydro-1,3,4-thiadiazoles were synthesized in benzene
by the reaction of N0-phenylthiobenzoylhydrazine with aliphatic,
aromatic, and heterocyclic aldehydes and ketones in the presence
of trimethylsilylchloride in benzene.11 Some data on the acetyla-
tion reaction of thiosemicarbazones have been reported in ashort
communication.12
ŁCorrespondence to: Lyudmila I. Larina, A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky St.,
664033, Irkutsk, Russian Federation, Russia.
15N NMR signals of the compounds studied were measured by
2D HMBC 1H–15N method or direct method of accumulation. The
E-mail: larina@irioch.irk.ru
Copyright 2007 John Wiley & Sons, Ltd.