Synthesis of 5-aminomethyl-substituted 2-bromo-5,6-dihydrothiazolo[3,2-b]- 1,2,4-triazoles

Article abstract of DOI:10.1134/S1070428011020126

By the reaction of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with aliphatic and aromatic amines 5-aminomethyl-substituted 2-bromo-5,6- dihydrothiazolo[3,2-b]-1,2,4-triazoles were obtained.

Full text of DOI:10.1134/S1070428011020126

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 2, pp. 236238. Pleiades Publishing, Ltd., 2011.
Original Russian Text  E.E. Klen, F.A. Khaliullin, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 2, pp. 244246.
Synthesis of 5-Aminomethyl-Substituted
2-Bromo-5,6-dihydrothiazolo[3,2-b]-1,2,4-triazoles
E.E. Klen and F.A. Khaliullin
Bashkir State Medical University, Ufa, 450000 Russia
e-mail: khaliullin_ufa@yahoo.com
Received September 7, 2009
Abstract—By the reaction of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with aliphatic and aromatic amines
5-aminomethyl-substituted 2-bromo-5,6-dihydrothiazolo[3,2-b]-1,2,4-triazoles were obtained.
DOI: 10.1134/S1070428011020126
46–98% yield (Scheme 1).
5,6-Dihydrothiazolo[3,2-b]-1,2,4-triazoles are
promising compounds for testing for biological activity
[1]. They can be prepared by various methods where
the main procedure is the alkylation of 3(5)-mercapto-
1,2,4-triazoles with 1,2-dibromoethane [2, 3] and the
cycclization of 3-allylsulfanyl-1,2,4-triazole with iodine
[4]. We have demonstrated that the reactions of 3,5-di-
bromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with certain
nucleophiles also lead to the formation of 5-substituted
2-bromo-5,6-dihydro-thiazolo[3,2-b]-1,2,4-triazoles [5].
The investigation of reactions of thiirane I with
aromatic amines, in particular, with aniline, showed that
the latter under the conditions used with the aliphatic
amines reacted slowly (~7.5 h) evidently due to the low
nucleophilicity of aniline. The performance of the reac-
tion in DMF reduced the reaction time to 2 h. 2-Bromo-5-
(phenylamino)methyl-5,6-dihydrothiazolo[3,2-b]-1,2,4-
triazole (IIf) formed in 96 and 74% yields respectively
(Scheme 1).
The reaction of thiirane I with ethyl p-aminobenzoate
was carried out by boiling the reagents in DMF over 3 h.
2-Bromo-5-(4-ethoxycarbonylphenylamino)methyl-5,6-
dihydrothiazolo[3,2-b]-1,2,4-triazole (IIg) formed in 37%
yield (Scheme 1).
In this study the reactions of 3,5-dibromo-1-(thiiran-
2-ylmethyl)-1,2,4-triazole (I) were investigated with
primary and secondary aliphatic amines, and also with
primary aromatic amines.
The reactions of thiirane I with the 3-fold molar excess
of primary or secondary aliphatic amines were carried
out at boiling in ethanol over 3 h. The reaction with the
volatile diethylamine was performed in a pressure reac-
tor at 100°С. 5-Amino-methyl-substituted 2-bromo-5,6-
dihydrothiazolo[3,2-b]-1,2,4-triazoles IIа–IIe formed in
The composition and the structure of the synthesized
compounds IIа–IIg were confirmed by the elemental
analysis, 1Н and 13С NMR spectra, and by the indepen-
dent synthesis.
The unsymmetrically substituted thiiranes open
Scheme 1.
N
N
NRR'
N N
N
N N
N
HNRR'
NRR'
S
Br
SH
Br
Br
Br
S
Br
N
IIa_IIg
I
NRR’ = NHBn (а), NHC6H11 (b), N(Et)2 (c), piperidino (d), azepan-1-yl (e), NHPh (f), NHC6H4COOEt-4 (g).
236

SYNTHESIS OF 5-AMINOMETHYL-SUBSTITUTED...
237
Scheme 2.
N
N N
N
N NH
N
S
N
S
KOH
Br
Br
Br
IId
under treatment with amines from the side of smaller
steric hindrances, i.e., at the more hydrogenised carbon
atom [6]. The independent synthesis of 2-bromo-5-
piperidinomethyl-5,6-dihydrothiazolo-[3,2-b]-1,2,4-
triazole (IId) from 3,5-dibromo-1,2,4-triazole and
1-(thiiran-2-ylmethyl)piperidine (Scheme 2) confirmed
the opening of the thiirane ring in keeping with Krasusky
rule. The samples of compounds IId obtained by different
methods did not provide the melting temperature depres-
sion of the mixed probe, and their 1Н NMR spectra were
completely identical.
1Н NMR spectra of compounds IIа–IIg prove the for-
mation of the fused system of the dihydrothiazolotriazole:
The characteristic multiplets are observed in the range
4.21–4.41 and 4.42–4.73 ppm belonging to the protons
of NCH2 and SCH groups of the dihydrothiazole ring
respectively. In the spectra the signals of the protons of
the 5-СН2 group and of the fragments of the correspond-
ing amines also appeared.
hexane–ethanol, 1:4, development in iodine vapor).
1-(Thiiran-2-ylmethyl)piperidine was obtained by
procedure [7].
5 - ( B e n z y l a m i n o ) m e t h y l - 2 - b ro m o - 5 , 6 -
dihydrothiazolo[3,2-b]-1,2,4-triazole (IIa). A solution
of 0.29 g (1.0 mmol) of thiirane I and 0.32 g (3.0 mmol)
of benzylamine in 15 ml of ethanol was boiled for 3 h,
then it was evaporated in a vacuum. Water was added to
the residue, and the precipitate was filtered off. Yield 0.23
1
g (73%), mp 87.5–89°С (hexane–ethanol), Rf 0.62. Н
NMR spectrum, δ, ppm: 3.00 d.d (1Н, 5-CH2, 3J 7.3, 2J
12.7 Hz), 3.08 d.d (1Н, 5-CH2, 3J 6.3, 2J 12.7 Hz), 4.26
d.d (1Н, N-CH2, 3J 5.9, 2J 10.9 Hz), 4.36 d.d (1Н, N-CH2,
3J 8.0, 2J 10.9 Hz), 4.42–4.53 m (1Н, SCН), 7.25–7.39
m (5Н, Нarom). Found, %: С 44.52; Н 3.89; N 17.03.
С12H13BrN4S. Calculated, %: С 44.32; Н 4.03; N 17.23.
2-Bromo-5-(cyclohexylamino)methyl-5,6-
dihydrothiazolo[3,2-b]-1,2,4-triazole (IIb) was
similarly obtained. Yield 0.17 g (53%), mp 80.5–81.5°С
Inthe13СNMRspectrumof5-piperidinomethyldihydro-
thiazolotriazoleа (IId) signals of carbon atoms located at
54.68 (NСН2) and 50.11 (SСН) ppm confirm the presence
of the dihydrothiazole ring. The signal of the carbon atom
of the 5-СН2 group is observed at 50.45 ppm. The spec-
trum also contains the carbon signals from the triazole
and piperidine fragments.
1
(ethanol–water), Rf 0.53. Н NMR spectrum, δ, ppm:
0.98–1.34 m [6Н, (СН2)3], 1.55–1.92 m [4Н, СН(СН2)2],
2.39–2.50 m (1Н, СН), 2.96–3.13 m (2Н, 5-CH2), 4.26
3
2
d.d (1Н, NCH2, J 5.7, J 10.8 Hz), 4.33–4.52 m (1Н,
NCH2 + 1Н, SCН). Found, %: С 41.45; Н 5.51; N 17.82.
С11H17BrN4S. Calculated, %: С 41.65; Н 5.40; N 17.66.
2-Bromo-5-(diethylamino)methyl-5, 6-
dihydrothiazolo[3,2-b]-1,2,4-triazole (IIc). A solution
of 0.29 g (1.0 mmol) of thiirane I and 0.22 g (3.0 mmol)
of diethylamine in 10 ml of ethanol was heated over 2
h in a pressure reactor at 100°С, then the solvent was
evaporated in a vacuum. Water was added to the residue,
and the precipitate was filtered off. Yield 0.13 g (46%),
Thus the reactions of thiirane I with aliphatic and
aromatic amines led to the formation of 5-aminomethyl-
substituted 2-bromo-5,6-dihydro-thiazolo[3,2-b]-1,2,4-
triazoles proving the opening of the thiirane ring at the
more hydrogenised carbon atom in keeping with Krasusky
rule.
1
mp 61–62°С (hexane), Rf 0.48. Н NMR spectrum, δ,
3
ppm: 1.03 t (6Н, 2СН3, J 7.1 Hz), 2.59 q (4Н, 2СН2,
EXPERIMENTAL
3J 7.1 Hz), 2.81 d (2Н, 5-CH2, 3J 7.8 Hz), 4.22 d.d (1Н,
NCH2,3J 6.7, 2J 11.0 Hz), 4.35 d.d (1Н, NCH2, 3J 7.9, 2J
11.0 Hz), 4.49–4.59 m (1Н, SCН). Found, %: С 39.92;
Н 5.27; N 19.04. С9H15BrN4S. Calculated, %: С 37.12;
Н 5.19; N 19.24.
1Н and 13С NMR spectra were registered on a spec-
trometer BrukerAM-300 at operating frequencies 300 and
75 MHz respectively. The signals of CDCl3 solvent served
as internal references. The homogeneity of compounds
synthesized was checked by TLC Silufol plates (eluent
2-Bromo-5-piperidinomethyl-5,6-dihydrothiazolo-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011

KLEN, KHALIULLIN
238
[3,2-b]-1,2,4-triazole (IId). а. It was prepared like
compound IIa. Yield 0.25 g (83%), mp 127–127.5°С
(hexane), Rf 0.63. 1Н NMR spectrum, δ, ppm: 1.32–1.50
m (1Н, СН2), 1.50–1.68 m (4Н, 2СН2), 2.35–2.55 m [4Н,
N(СН2)2], 2.70 d (2Н, 5-CH2, 3J 7.7 Hz), 4.21 d.d (1Н,
NCH2, 3J 6.8, 2J 11.0 Hz), 4.35 d.d (1Н, NCH2, 3J 7.9,
2J 11.0 Hz), 4.52–4.68 m (1Н, SCН). 13С NMR spectrum,
δ, ppm: 23.99 (С4 piperidine), 57.79 (С3, С5 piperidine),
50.11 (SCH), 50.45 (5-СН2), 54.68 (NCH2), 62.13 (С2,
С6 piperidine), 142.32 (С3а), 140.82 (С2). Found, %:
С 39.71; Н 5.06; N 18.35. С10H15BrN4S. Calculated, %:
С 39.61; Н 4.99; N 18.48.
0.48 g (5.2 mmol) of aniline in 10 ml of DMF was boiled
for 2 h, then evaporated in a vacuum. The residue was
dissolved in ethanol, poured into water, and the formed
precipitate was filtered off. Yield 0.30 g (74%), mp 113–
114.5°С (ethanol), Rf 0.73. 1Н NMR spectrum, δ, ppm:
3.50–3.66 m (2Н, 5-CH2), 4.13 br.s (1Н, NH), 4.28 d.d
(1Н, NCH2, J 4.7, J 11.3 Hz), 4.41 d.d (1Н, NCH2,
3J 7.8, 2J 11.3 Hz), 4.61–4.73 m (1Н, SCН), 6.65 d (2Н,
СН2',6'arom, 3J 7.8 Hz), 6.82 t (1Н, СН4'arom, 3J 7.3 Hz),
7.23 t (2Н, СН3',5'arom, 3J 7.8 Hz). Found, %: С 42.36;
Н 3.62; N 17.96. С11H11BrN4S. Calculated, %: С 42.45;
Н 3.56; N 18.00.
3
2
2-Bromo-5-(4-ethoxycarbonylphenylamino)
methyl-5,6-dihydrothiazolo[3,2-b]-1,2,4-triazole (IIg)
was prepared like compound IIf (method b) from 0.29 g
(1.0 mmol) of thiirane I and 0.50 g (3.0 mmol) of ethyl
p-aminobenzoate. The reaction mixture was poured into
water, and the formed oily residue was ground with ether.
Yield 0.14 g (37%), mp 141–142°С (2-propanol–water),
b.Asolution of 1.59 g (7 mmol) of 3,5-dibromo-1,2,4-
triazole, 0.39 g (7 mmol) of KОН, and 1.10 g (7 mmol)
of 1-(thiiran-2-yl-methyl)piperidine in 15 ml of DMF was
boiled over 3 h. The reaction mixture was cooled, diluted
with water, the precipitate was filtered off. Yield 1.40 g
(66%), mp 125–127°С (2-propanol), Rf 0.63. Found, %:
С 39.58; Н 4.87; N 18.40. С10H15BrN4S. Calculated, %:
С 39.61; Н 4.99; N 18.48.
1
Rf 0.56. Н NMR spectrum, δ, ppm: 1.38 t (3Н, СН3,
3J 7.1 Hz), 3.56–3.74 m (2Н, 5-CH2), 4.25–4.50 m (4Н,
N-CH2,ОСН2,), 4.58–4.72 m (2Н, SCН, NH), 6.65 d (2Н,
СН2',6'arom, 3J 8.7 Hz), 7.92 d (2Н, СН3',5'arom, 3J 8.7 Hz).
Found, %: С 43.94; Н 3.86; N 14.55. С14H15BrN4О2S.
Calculated, %: С 43.87; Н 3.94; N 14.62.
5-(Azepan-1-yl)methyl-2-bromo-5,6-dihydrot-
hiazolo[3,2-b]-1,2,4-triazole (IIe) was prepared like
compound IIa from 0.29 g (1.0 mmol) of thiirane I
and 0.30 g (3.0 mmol) of hexamethyleneimine. The
reaction mixture was poured into water, and the formed
precipitate was filtered off. Yield 0.31 g (98%), mp
88–90°С (hexane), Rf 0.79. 1Н NMR spectrum, δ, ppm:
1.50–1.62 m (8Н, 4СН2), 2.67–2.81 m [4Н, N(СН2)2],
REFERENCES
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3
2.81–2.97 m (2Н, 5-CH2), 4.22 d.d (1Н, NCH2, J 6.7,
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3
2
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N 17.74. С11H17BrN4S. Calculated, %: С 41.64; Н 5.40;
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2-Bromo-5-(phenylamino)methyl-5,6-dihydro-
thiazolo[3,2-b]-1,2,4-triazole (IIf). а. It was prepared
like compound IIa from 0.39 g (1.3 mmol) of thiirane I
and 0.36 g (3.9 mmol) of aniline. The reaction mixture
was boiled for 7.5 h, poured into water, and the formed
precipitate was filtered off. Yield 0.39 g (96%), mp
112.5–114.5°С (ethanol), Rf 0.73.
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b. A solution of 0.39 g (1.3 mmol) of thiirane I and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 2 2011