New 1,3,4-thiadiazole derivatives from 1-benzylidenethiocarbonohydrazides and 3-Bromo-1-phenylprop-2-yn-1-one

Article abstract of DOI:10.1134/S1070428008060158

3-Bromo-1-phenylprop-2-yn-1-one reacted with 1- benzylidenethiocarbonohydrazones in acetic acid or acetonitrile at room temperature (reaction time 3 h) to give in good yields the corresponding benzaldehyde N′-(5-benzoylmethyl-1,3,4-thiadiazol-2-yl)hydrazo

Full text of DOI:10.1134/S1070428008060158

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 6, pp. 866–869. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © T.E. Glotova, M.Yu. Dvorko, V.G. Samoilov, I.A. Ushakov, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 6,
pp. 875–878.
New 1,3,4-Thiadiazole Derivatives from 1-Benzylidene-
thiocarbonohydrazides and 3-Bromo-1-phenylprop-2-yn-1-one
T. E. Glotova, M. Yu. Dvorko, V. G. Samoilov, and I. A. Ushakov
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: glotova@irioch.irk.ru
Received November 6, 2007
Abstract—3-Bromo-1-phenylprop-2-yn-1-one reacted with 1-benzylidenethiocarbonohydrazones in acetic acid
or acetonitrile at room temperature (reaction time 3 h) to give in good yields the corresponding benzaldehyde
N′-(5-benzoylmethyl-1,3,4-thiadiazol-2-yl)hydrazone hydrobromides which were converted into the free bases
by treatment with aqueous ammonia.
DOI: 10.1134/S1070428008060158
Depending on the substrate structure and condi-
tions, reactions of bielectrophilic α-acetylenic ketones
with multident N,S-centered nucleophiles could take
different paths, giving rise to N,S-containing hetero-
cycles possessing a broad spectrum of useful prop-
erties. From this viewpoint, the most interesting are
thiocarbonohydrazones derived from aromatic and ali-
phatic aldehydes and ketones, which were found to
exhibit strong biological activity (antituberculostatic,
antitumor, antiviral, and fungicidal) [1–5] and act as
quite efficient complexing agents [3–8].
N′-(5-benzoylmethyl-1,3,4-thiadiazol-2-yl)hydrazone
hydrobromides IIIa–IIId in 73–84% yield (Scheme 1).
Compounds IIIa–IIId were also obtained when the
reaction was carried out in acetonitrile (20–23°C, 3 h),
but their yields were slightly lower (63–70%).
Scheme 1.
S
Ph
R
N
NH2
+
Br
N
H
N
H
O
I
IIa–IId
H
N
Aromatic aldehyde thiocarbonohydrazones were
reported to react with terminal α-acetylenic ketones
exclusively at the triple bond to give, depending on the
reactant ratio, 2-(2-acylvinyl)- or 2,2-bis(2-acylvinyl)-
thiocarbonohydrazones [9]. The reactions of benzal-
dehyde thiocarbonohydrazone with 1-benzoyl- and
1-(2-thenoyl)-2-phenylacetylenes involved both the
triple bond and the carbonyl group in the latter, yield-
ing functionally substituted dihydropyrazoles [10].
S
AcOH, 20–23°C
CHR
Ph
N
·HBr
N
N
O
IIIa–IIId
R = Ph (a), 4-ClC6H4 (b), 4-O2NC6H4 (c), 4-Me2NC6H4 (d).
Presumably, the reaction involves nucleophilic re-
placement of the bromine atom at the triple-bonded
carbon atom with intermediate formation of benzoyl-
ethynyl sulfides A [11] (Scheme 2) and intramolecular
With the goal of further studying reactions of
α-acetylenic ketones with thiocarbonohydrazones and
extending synthetic potential of these reactions, in the
present work we examined reactions of 1-bromo-2-
benzoylacetylene (I) with thiocarbonohydrazones IIa–
IId derived from benzaldehyde, 4-chlorobenzaldehyde,
4-nitrobenzaldehyde, and 4-dimethylaminobenzalde-
hyde. Acetylenic ketone I reacted with an equimolar
amount of compounds IIa–IId in acetic acid at 20–
23°C to give in 3 h the corresponding benzaldehyde
Scheme 2.
Ph
S
·HBr
I
+ IIa–IId
O
NH
··
H2N
N
N
CHR
A
IIIa–IIId
866

NEW 1,3,4-THIADIAZOLE DERIVATIVES
867
cyclization of the latter via addition of the NH2 group
at the electron-deficient β-carbon atom at the triple
bond leads to N′-(5-benzoylmethyl-1,3,4-thiadiazol-2-
yl)hydrazones IIIa–IIId. By treatment of hydro-
bromides IIIa–IIId with 12% aqueous ammonia we
obtained the corresponding free bases IVa–IVd in 89–
93% yield (Scheme 3).
centers, so that thiadiazoles III and IV are promising
as multidentate ligands in the synthesis of metal com-
plexes with different coordination modes [19–22].
EXPERIMENTAL
The IR spectra were recorded in KBr on a Specord
75-IR spectrometer. The 1H and 13C NMR spectra were
measured from solutions in DMSO-d6 on a Bruker
Scheme 3.
1
DPX 400 spectrometer (400.13 MHz for H and
H
S
100.61 MHz for 13C) using hexamethyldisiloxane as
internal reference.
N
Aq. NH3
CHR
Ph
N
IIIa–IIId
–NH4Br
N
N
O
Substituted benzaldehyde N′-(5-benzoylmethyl-
1,3,4-thiadiazol-2-yl)hydrazone hydrobromides
IIIa–IIId (general procedure). Thiocarbonohydrazone
IIa–IId, 2.5 mmol, was added in portions to a solution
of 2.5 mmol of 3-bromo-1-phenylprop-2-yn-1-one (I)
in 10 ml of acetic acid, and the mixture was stirred for
3 h at 20–23°C. The precipitate was filtered off,
washed with 40 ml of anhydrous diethyl ether, and
dried under reduced pressure. The reaction in acetoni-
trile was carried out in a similar way. Compounds
IIIa–IIId were thus isolated as analytically pure
substances.
IVa–IVd
R = Ph (a), 4-ClC6H4 (b), 4-O2NC6H4 (c), 4-Me2NC6H4 (d).
The structure of compounds IIIa–IIId and IVa–
IVd was proved by their elemental analyses and IR
and H and 13C spectra. The IR spectra of hydro-
1
bromides IIIa–IIId and free bases IVa–IVd contained
absorption bands arising from stretching vibrations of
the NH group (3158–3284 cm–1), unconjugated car-
bonyl group (1668–1694 cm–1), and C=C and C=N
bonds (1508–1622 cm–1); in addition, hydrobromides
IIIa–IIId displayed in the IR spectra broadened bands
due to NH+ group in the region 2739–3002 cm–1.
Benzaldehyde N′-(5-benzoylmethyl-1,3,4-thiadi-
azol-2-yl)hydrazone hydrobromide (IIIa). Yield
0.81 g (80%, in AcOH), 70% (in MeCN); mp 191–
194°C. IR spectrum, ν, cm–1: 3230, 2749–3002, 1670,
1
In the H NMR spectra of IIIa–IIId and IVa–IVd
we observed singlets from protons of the CH2 group
(δ 4.78–4.92 ppm) and CH=N group (δ 8.05–8.14 ppm)
and multiplets from aromatic protons in the region
δ 6.71–8.29 ppm. In the spectra of hydrobromides
IIIa–IIId, signals from the NH and NH+ protons ap-
peared as strongly broadened singlets in the region
δ 9–10 ppm. The 13C NMR spectra were consistent
with the assumed structure of compounds IIIa–IIId
and IVa–IVd as 1,3,4-thiadiazole derivatives. Signals
in the 13C NMR spectra were assigned using two-di-
mensional HSQC [12] and HMBC techniques [13].
1
1553–1619. H NMR spectrum, δ, ppm: 4.92 s (2H,
CH2), 7.40–7.95 m (10H, Harom), 8.13 s (1H, CH=N).
13C NMR spectrum, δC, ppm: 41.42 (CH2); 126.62,
127.03, 128.53, 128.98, 130.28, 133.68, 134.07, 135.48
(Carom); 146.30 (CH=N); 153.43 (C5); 169.52 (C2);
194.89 (C=O). Found, %: C 50.98; H 3.65; Br 19.58;
N 13.94; S 7.72. C17H14N4OS·HBr. Calculated, %:
C 50.63; H 3.75; Br 19.81; N 13.89; S 7.95.
4-Chlorobenzaldehyde N′-(5-benzoylmethyl-
1,3,4-thiadiazol-2-yl)hydrazone hydrobromide
(IIIb). Yield 0.80 g (73%, in AcOH), 66% (in MeCN);
mp 178–181°C. IR spectrum, ν, cm–1: 3212, 2747–
We previously reported that 1-bromo-2-acylacet-
ylenes react with thiobenzohydrazide [14] and thio-
semicarbazides [15] to give 2-acylmethyl-1,3,4-thia-
diazole derivatives. Therefore, reactions of 1-bromo-
2-acylacetylenes with multicenter N,S-nucleophiles
possessing a thiocarbonohydrazine fragment may be
regarded as a general synthetic route to functionally
substituted 1,3,4-thiadizoles.
1
3001, 1672, 1552–1619. H NMR spectrum, δ, ppm:
4.88 s (2H, CH2), 7.49–8.11 m (9H, Harom), 8.14 s (1H,
CH=N). 13C NMR spectrum, δC, ppm: 39.53 (CH2);
128.57, 128.68, 129.11, 129.21, 133.06, 134.19,
134.51, 135.69 (Carom); 144.13 (CH=N); 153.35 (C5);
170.19 (C2); 195.17 (C=O). Found, %: C 46.22; H 3.32;
Br 18.06; Cl 8.36; N 12.65; S 7.29. C17H13ClN4OS·
HBr. Calculated, %: C 46.64; H 3.22; Br 18.25;
Cl 8.10; N 12.80; S 7.33.
Compounds III and IV are new highly functional-
ized representatives of pharmacophoric 1,3,4-thiadia-
zoles [16–18]; they can be used as precursors of drugs
of new generation. In addition, their molecules possess
a set of potential O-, N-, and S-electron-donating
4-Nitrobenzaldehyde N′-(5-benzoylmethyl-1,3,4-
thiadiazol-2-yl)hydrazone hydrobromide (IIIc).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

GLOTOVA et al.
868
Yield 0.94 g (84%, in AcOH), 63% (in MeCN);
Found, %: C 57.04; H 3.53; Cl 9.67; N 15.98; S 8.68.
C17H13ClN4OS. Calculated, %: C 57.22; H 3.67;
Cl 9.94; N 15.70; S 8.99.
mp 192–194°C. IR spectrum, ν, cm–1: 3161, 2739–
1
3001, 1671, 1517–1622. H NMR spectrum, δ, ppm:
4.87 s (2H, CH2), 7.47–8.29 m (10H, Harom, CH=N).
13C NMR spectrum, δC, ppm: 39.70 (CH2); 124.65,
127.74, 128.94, 129.18, 134.40, 136.11, 147.84, 142.01
(Carom); 141.10 (CH=N); 153.69 (C5); 171.15 (C2);
195.52 (C=O). Found, %: C 45.35; H 3.28; Br 17.48;
N 15.92; S 7.26. C17H13N5O3S·HBr. Calculated, %:
C 45.55; H 3.15; Br 17.82; N 15.62; S 7.15.
4-Nitrobenzaldehyde N′-(5-benzoylmethyl-1,3,4-
thiadiazol-2-yl)hydrazone (IVc). Yield 0.33 g (89%),
mp 176–178°C. IR spectrum, ν, cm–1: 3158, 1688,
1
1508–1592. H NMR spectrum, δ, ppm: 4.87 s (2H,
CH2), 7.47–8.29 m (10H, Harom, CH=N), 11.72 s (1H,
NH). 13C NMR spectrum, δC, ppm: 40.14 (CH2);
123.70, 127.13, 128.12, 128.84, 133.85, 135.58,
140.86, 147.41 (Carom); 139.25 (CH=N); 153.40 (C5);
175.70 (C2); 194.99 (C=O). Found, %: C 55.74;
H 3.42; N 19.14; S 8.40. C17H13N5O3S. Calculated, %:
C 55.58; H 3.57; N 19.06; S 8.73.
4-Dimethylaminobenzaldehyde N′-(5-benzoyl-
methyl-1,3,4-thiadiazol-2-yl)hydrazone hydro-
bromide (IIId). Yield 0.87 g (78%, in AcOH), 66% (in
MeCN); mp 191–193°C. IR spectrum, ν, cm–1: 3216,
1
2750–2996, 1668, 1537–1612. H NMR spectrum, δ,
4-Dimethylaminobenzaldehyde N′-(5-benzoyl-
methyl-1,3,4-thiadiazol-2-yl)hydrazone (IVd). Yield
0.33 g (90%), mp 162–164°C. IR spectrum, ν, cm–1:
ppm: 3.00 s (6H, Me), 4.87 s (2H, CH2), 6.88–8.04 m
(9H, Harom), 8.08 s (1H, CH=N). 13C NMR spectrum,
δC, ppm: 39.55 (CH2); 39.80 (Me); 112.76, 128.02,
128.38, 128.81, 133.83, 135.52, 150.56 (Carom); 145.66
(CH=N); 152.16 (C5); 171.91 (C2); 194.95 (C=O).
Found, %: C 51.23; H 4.78; Br 17.44; N 15.37; S 7.02.
C19H19N5OS·HBr. Calculated, %: C 51.12; H 4.52;
Br 17.90; N 15.69; S 7.18.
1
3197, 1691, 1524–1607. H NMR spectrum, δ, ppm:
2.93 s (6H, Me), 4.78 s (2H, CH2), 6.71–7.93 m (9H,
H
arom), 8.05 s (1H, CH=N), 11.96 s (1H, NH).
13C NMR spectrum, δC, ppm: 39.85 (Me); 39.95 (CH2);
111.84, 121.61, 127.66, 128.36, 128.78, 133.71,
135.65, 151.11 (Carom); 144.50 (CH=N); 151.71 (C5);
170.57 (C2); 195.09 (C=O). Found, %: C 62.78;
H 5.09; N 19.08; S 8.53. C19H19N5OS. Calculated, %:
C 62.44; H 5.24; N 19.16; S 8.77.
Substituted benzaldehyde N′-(5-benzoylmethyl-
1,3,4-thiadiazol-2-yl)hydrazones IVa–IVd (general
procedure). Hydrobromide IIIa–IIId, 1 mmol, was
added in portions to 30 ml of 12% aqueous ammonia,
and the mixture was stirred for 1 h at 20–23°C. The
precipitate was filtered, washed with distilled water,
dried over CaCl2 under reduced pressure, and recrys-
tallized from ethanol or acetonitrile.
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13
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1
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