Synthesis and transformations of hydrazine substituted 6-fluoro derivatives of 1,3,4-thiadiazolo[3,2-a]pyrimidine

Article abstract of DOI:10.1002/jhet.773

2-Alkyl and 2-arylhydrazine derivatives of 5H-2-R-6-fluoro-7-methyl-1,3,4- thiadiazolo[3,2-a]pyrimidin-5-one were prepared by reaction of 5H-2-bromo-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one with hydrazine derivatives. A convenient procedu

Full text of DOI:10.1002/jhet.773

1404
Synthesis and Transformations of Hydrazine Substituted 6-Fluoro
Derivatives of 1,3,4-Thiadiazolo[3,2-a]pyrimidine
Vol 48
a
Muhamadsho A. Kukaniev and Cyril Parkanyi *
b
´
´
aLaboratory of Heterocyclic Compounds, V.I.Nikitin Institute of Chemistry of the Academy of
Sciences of the Republic of Tajikistan, 734063 Dushanbe, Tajikistan
bDepartment of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton,
Florida 33431-0991
*E-mail: parkanyi@fau.edu
Received July 27, 2010
DOI 10.1002/jhet.773
Published online 4 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
2-Alkyl and 2-arylhydrazine derivatives of 5H-2-R-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimi-
din-5-one were prepared by reaction of 5H-2-bromo-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimi-
din-5-one with hydrazine derivatives. A convenient procedure was developed for the preparation of new
hydrazine derivatives of 5H-2-R-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one.
J. Heterocyclic Chem., 48, 1404 (2011).
INTRODUCTION
1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one were carried out
in methanol at room temperature. Upon addition of the
hydrazino derivatives, the reaction mixture became warm
and, because of this, the addition was carried out drop-
wise. The yield of the reaction products was from 70 to
90%. The reaction yielded selectively 3a–c (a ¼ H, b ¼
CH3, c ¼ C6H5; Scheme 1).
Hydrazine derivatives are widely used in the synthesis
of different heterocyclic systems [1–3]. There are only
four published papers devoted to the synthesis and
chemical conversion of hydrazine derivatives of 1,3,4-
thiadiazolo[3,2-a]pyrimidine [4–7]. It is well known that
bromine in the 2-position of 1,3,4-thiazolo[3,2-a]pyrimi-
dine can easily undergo substitution by different nucleo-
philes [8–11].
According to the refs. 12–14, the reaction of hydra-
zine derivatives of nitrogen-containing heterocyclic
compounds, in which the hydrazine group is in the ortho
position with respect to the ring nitrogen, with carbox-
ylic acids under various conditions affords triazolo
derivatives. However, the reaction of hydrazines 2 with
formic acid and acetic acid produced only hydrazine
derivatives but not the cyclization products (Scheme 2).
The reaction of hydrazines 2 with acetic anhydride
resulted in acylation products of the hydrazines but did
not give any condensation products.
RESULTS AND DISCUSSION
In this work, we studied the possibility of the synthe-
sis of various derivatives of 5H-1,3,4-thiadiazolo[3,2-
a]pyrimidin-5-one containing the hydrazine fragment in
the position 2 and fluorine in the position 6.
We have initially investigated reactions of different
hydrazine derivatives with 5H-2-bromo-6-fluoro-7-methyl-
1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one. Reactions of hy-
drazine derivatives with 5H-2-bromo-6-fluoro-7-methyl-
Condensation of hydrazine 3a with acetone yielded
7a. Heating of 3a in acetone afforded hydrazino deriva-
tives of 3a in a high yield (Scheme 3). 3a reacted with
C
V
2011 HeteroCorporation

November 2011 Synthesis and Transformations of Hydrazine Substituted 6-Fluoro Derivatives of
1,3,4-Thiadiazolo[3,2-a]pyrimidine
1405
Scheme 1
Scheme 3
benzaldehyde in anhydrous dimethyl formamide to give
7b. Also, a 3-h reaction of 3a with acetylacetone in
PPA at 100ꢀC afforded the pyrazole 8 (Scheme 3). The
bromination of 8 with bromine in acetic acid gives 9.
The structures of resulting compounds were con-
firmed by elemental analysis and 1H-NMR and mass
1
spectroscopy. In the H-NMR spectrum of 9, the signal
trap mass spectrometer fitted with an electrospray ionization
(ESI) source. The m/z range was 100–1000 Da. Elemental
analyses were performed by Desert Analytics, Tucson, AZ.
5H-2-Bromo-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimi-
din-5-one was obtained according to the ref. 15.
General procedure for the preparation of 2H-2R-hydr-
azino-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-
ones (3a–c). Compound 1a (2.64 g, 10.0 mmol) was dissolved
in methanol (25 mL) and then the appropriate hydrazine (10.0
mmol) dissolved in methanol (5 mL) was added at room tem-
perature with stirring. The reaction mixture was stirred at
room temperature for 2 h. The reaction mixture was poured
into ice/water (100 mL), and the precipitated products (3a–c)
were filtered off and washed with water.
5H-2-Hydrazino-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-a]-
pyrimidine-5-one (3a). Yield 2.05 g (95%), m.p. 288ꢀC; 1H-
NMR (dimethylformamide-d7): 2.24 ppm (d, 3H from CH3),
5.65 ppm (s, 2H from NH2), 9.65 ppm (s, H from NH); ESI
ms: m/z (%), 216.07(100). Anal. Calcd.for C6H6FN5OS: C,
33.49; H, 2.81; N, 32.54; S, 14.90. Found: C, 33.69; H, 2.80;
N, 32.48; S, 14.89.
for the proton in the position 4 of the pyrazole ring is
absent. The 1H-NMR spectra of the compounds 3–9
display a doublet for the methyl protons at 2.20–2.30
ppm with a spin-spin coupling constant of 3.73 Hz,
which reflects the interaction between the fluorine atom
and the methyl group.
CONCLUSIONS
In the interaction of 5H-2-bromo-6-fluoro-7-methyl-
1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one with the deriva-
tives of hydrazine, the substituted bromine atom is
located in the position 2 of the ring and the fluorine atom
in the position 6 is not replaced. 5H-2-hydrazino-6-flu-
oro-7-methyl-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one in
the reaction with organic acids and anhydrides formed
acylation products but no ring closure took place.
5H-2-(N0-Methylhydrazino)-6-fluoro-7-methyl-1,3,4-thiadia-
zolo[3,2-a]pyrimidin-5-one (3b). Yield 2.08 g (90.8%), m.p.
269ꢀC; 1H-NMR (dimethyl sulfoxide-d6): 2.22 ppm (d, 3H
from CH3), 3.22 ppm (s, 3H from CH3), 5.56 ppm (s, 2H from
2 NH), ESI ms: m/z (%) 230.07 (100). Anal. Calcd. for
C7H8FN5OS: C, 36.68; H, 3.52; N, 30.55; F 8.29. Found: C,
36.28; H, 3.41; N, 30.02; F, 8.02.
EXPERIMENTAL
Melting points were determined on a Fisher-Johns melting
1
point apparatus and are uncorrected. H spectra were measured
on a Varian Mercury 400 instrument. Mass spectra were
obtained on a Thermo Electron LCQ Deca (San Jose, CA) ion
5H-2-(N0-Phenylhydrazino)-6-fluoro-7-methyl-1,3,4-thiadia-
zolo[3,2-a]pyrimidin-5-one (3c). Yield 2.14 g (73%), m.p.
274ꢀC; 1H-NMR (dimethyl sulfoxide-d6): 2.24 ppm (d, 3H
from CH3), 6.95 ppm (m, 3H from Ph-H), 7.25 ppm (m, 2H
from Ph-H), 8.78 ppm (s, H from NH), 10.48 ppm (s, H from
NH); ESI ms: m/z (%) 292.13 (100). Anal. Calcd. for
C12H10FN3OS: C, 49.48; H, 3.46; N, 24.04. Found; C, 49.40;
H, 3.39; N, 23.98.
Scheme 2
General procedure for the preparation of 5H-2R-N0-(6-
fluoro-7-methyl-5-oxo-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)-
hydrazines (4a,b). The solution of 3a (2.15 g, 10.0 mmol) in
a carboxylic acid (25 mL) was refluxed for 5 h and then
poured into ice/water. The precipitate was collected by filtra-
tion, dried, and crystallized from methanol.
5H-N0-Formyl-(6-fluoro-7-methyl-5-oxo-1,3,4-thiadiazolo-
[3,2-a]pyrimidin-2-yl)-hydrazine (4a). Yield 1.50 g (61.70%),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´ ´
M. A. Kukaniev and C. Parkanyi
1406
Vol 48
m.p. 275ꢀC. 1H-NMR (dimethyl sulfoxide-d6): 2.25 ppm (d,
3H from CH3), 8.19 ppm (s, 3H from CH), 10.40 ppm (s, H
from NH), 10.64 ppm (s, H from NH); ESI ms: m/z (%)
244.07 (100). Anal. Calcd. for C7H6FN5O2S: C, 34.57; H,
2.49; N, 28.79. Found: C, 34.48; H, 2.45; N, 28.66.
5H-N0Acetyl-(6-fluoro-7-methyl-5-oxo-1,3,4-thiadiazolo[3,2-
a]pyrimidin-2-yl)hydrazine (4b). Yield 2.20 g (85.60%), mp
318ꢀC. 1H-NMR (dimethyl sulfoxide-d6): 1.94 ppm (s, 3H
from CH3), 2.27 ppm (d, 3H from CH3), 10.30 ppm (s, H
from NH), 10.49 ppm (s, H from NH); ESI ms: m/z (%)
258.07 (100). Anal. Calcd. for C8H8FN5O2S: C, 37.35; H,
3.13; N, 27.22. Found: C, 37.43; H, 3.15; N, 27.20.
5H-N0,N00,N00-Triacetyl-(6-fluoro-7-methyl-5-oxo-1,3,4-thia-
diazolo[3,2-a]pyrimidin-2-yl)hydrazine (5). A solution of 3a
(2.15 g, 10.0 mmol) in acetic anhydride (25 mL) was refluxed
for 6 h and then poured into ice/water. The precipitate was
collected by filtration, dried, and crystallized from methanol.
Yield 2.04 g (59.82%), m.p. 197ꢀC. 1H-NMR (dimethyl sulf-
oxide-d6): 2.29 ppm (d, 3H from CH3), 2.33 ppm (s, 3H from
CH3), 2.47 ppm (s, 3H from CH3), 2.49 ppm (s, 3H from
CH3); ESI ms: m/z (%) 342.07 (100). Anal. Calcd. for
C12H12FN5O4S: C, 42.23; H, 3.54; N, 20.52. Found; C, 42.33
H, 3.48; N, 20.38.
ppm (d, 3H from CH3), 6.38 ppm (s, broad, H from CH); ESI
ms: m/z (%) 280.27 (100). Anal. Calcd. for C11H10FN5OS: C,
47.31; H, 3.61; N, 25.07. Found: C, 47.32; H, 3.35; N, 24.80.
5H-2-(4-Bromo-3,5-dimethyl-pyrazol-1-yl)-6-fluoro-7-methyl-
1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (9). To 2.79 g (10.0
mmol) of 5H-2-(3,5-dimethylpyrazol-1-yl)-6-fluoro-7-methyl-
1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one dissolved in acetic
acid (10 mL), 1.59 g (10.0 mmol) bromine, dissolved in acetic
acid (5 mL), was added dropwise at ambient temperature
within 10 min. The reaction mixture was stirred for 2 h. A sat-
urated aqueous solution of sodium acetate (0.82 g, 10.0 mmol)
was slowly added under cooling. The formed precipitate was
collected by filtration and washed with water (4 ꢁ 15 mL).
Recrystallization from dioxane yielded 9 (3.43 g, 95.8%), m.p.
217ꢀC. 1H-NMR (dimethyl sulfoxide-d6): 2.24 ppm (s, 3H
from CH3), 2.31 ppm (d, 3H from CH3), 2.64 ppm (s, 3H
from CH3); ESI ms: m/z (%) 358.13 (75), 360.13 (100). Anal.
Calcd. for C11H9 BrFN5OS: C, 36.89; H, 2.53; N, 19.55.
Found: C, 36.93; H, 2.47; N, 19.39.
Acknowledgment. The authors are grateful to the Fulbright
Foundation for a grant provided to M. A. Kukaniev.
5H-6-Fluoro-2-(N0-isopropylidene-hydrazino)-7-methyl-1,3,4-
thiadiazolo[3,2-a]pyrimidin-5-one (7a). A solution of 3a (2.15
g, 10 mmol) in acetone (25 mL) was refluxed for 5h and then
poured into ice/water. The precipitate was collected by filtra-
tion, dried, and crystallized from methanol. Yield 2.21 g
(81.75%); mp 288ꢀC; 1H-NMR (dimethyl sulfoxide-d6): 1.92
ppm (s, 3H from CH3), 1.95 ppm (s, 3H from CH3), 2.26 ppm
(d, 3H from CH3), 11.88 ppm (s, H from NH); ESI ms: m/z
(%) 256.07 (100). Anal. Calcd. for C9H10FN5OS: C, 42.35; H,
3.95; N, 27.43. Found: C, 42.43; H, 3.58; N, 27.24.
5H-2-(N0-Benzylidene-hydrazino)-6-fluoro-7-methyl-1,3,4-
thiadiazolo[3,2-a]pyrimidin-5-one (7b). A hydrazine 3a (2.15
g, 10.0 mmol) was dissolved in dimethylformamide (15 mL)
at room temperature and to this solution benzaldehyde (1.06 g,
10.0 mmol) was added. The mixture was stirred for 5 h at
room temperature and then poured into ice-water. The precipi-
tate was collected by filtration, dried, and crystallized from
dimethylformamide-dioxane (4:1). Yield 2.14 g (73%), mp
274ꢀC; ESI ms: m/z (%) 304.07 (100). Anal. Calcd. for
C13H10FN5OS: C, 51.48; H, 3.32; N, 23.09. Found: C, 51.55;
H, 3.39; N, 23.02.
REFERENCES AND NOTES
[1] Hipparagi, S. M.; Majunder, U. K.; Nargund, L. V. G.;
Vinaykumar, R. Indian J Heterocycl Chem 2007, 16, 401.
[2] Katz, L. (Schenley Industries, Inc.). U.S. Pat. 2659730
19531117, 1953; Chem Abstr 1955, 49, 12325.
[3] Bijev, A. T.; Prodanova, P. Chem Heterocycl Compd 2007,
43, 306.
[4] Shukurov, S.; Artykova, D. A.; Nasyrov, I. M.; Zakharov,
K. S.; Karakhanov, R. A. Izv Akad Nauk Ser Khim 1993, 219.
[5] Shukurov, S. Sh.; Artykova, D. A.; Zakharov, K. S.; Kuka-
niev, M. A.; Osimov, D. M. Khim Geterotsikl Soedin 1994, 560.
[6] Shukurov, S. Sh.; Artykova, D. A.; Dzhalolov, S. S.;
Nasyrov, I. M.; Zakharov, K. S. Izv Vyssh Ucheb Zaved Khim Khim
Tekhnol 1993, 36, 29.
[7] Okabe, T.; Taniguchi, E.; Maekawa, K. Bull Chem Soc Jpn
1974, 47, 2813.
[8] Kukaniev, M. A.; Salimov, T. M.; Murvatulloeva, M. S.;
Imatshoev, I. Kh. Pharm Chem J 2006, 40, 421.
[9] Shukurov, S. S.; Kukaniev, M. A.; Nasyrov, I. M.;
Zakharov, K. S.; Karakhanov, R. A. Izv Akad Nauk Ser Khim 1993,
1957.
5H-2-(3,5-Dimethylpyrazol-1-yl)-6-fluoro-7-methyl-1,3,4-
thiadiazolo[3,2-a]pyrimidin-5-one (8). A mixture of PPA (10
g) and 5H-2-hydrazino-6-fluoro-7-methyl-1,3,4-thiadiazolo[3,2-
a]pyrimidin-5-one (2.15 g, 10.0 mmol) was placed in a flask
and acetylacetone (1.0 g, 10.0 mmol) was added. The reaction
mixture was stirred for 3 h at 100ꢀC, cooled, and poured into
100 mL of ice/cold water. The precipitate was separated by fil-
tration, washed on the filter with 50 mL of ice/cold water, and
dried on air for 12 h. Recrystallization from methanol gave 2.5
[10] Kukaniev, M. A.; Shukurov, S. Sh.; Nasyrov, I. M.;
Zakharov, K. S. Dokl Akad Nauk Tadzhik SSR 1990, 33, 821.
[11] Kukaniev, M. A.; Nurov, U.; Shukurov, S. Sh.; Khodzhi-
baev, Yu. Russ Chem Bull (Translation of Izv Akad Nauk Ser Khim)
1999, 48, 1143.
[12] Beyer, H.; Stehwen, D. Arch Pharm 1953, 286, 13.
[13] Efros, I. S.; Davidenkov, L. R. Zh Obshch Khim 1951, 21,
2046.
[14] Druer, J.; Ringier, B. H. Helv Chem Acta 1951, 34, 195.
´ ´
[15] Kukaniev, M. A., Parkanyi, C. J Heterocycl Chem, to
1
g (89.6%) of 8, m.p. 215ꢀC; H-NMR (dimethyl sulfoxide-d6):
2.15 ppm (s, 3H from CH3), 2.31 ppm (d, 3H from CH3), 262
appear.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet