Reactions of 1,2,4-triazole derivatives with a Model thiirane

Article abstract of DOI:10.1134/S1070428010050155

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a model thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7- dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N ² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1- yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7- dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4- triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3] thiazolo-[2,3-f]purine-2,4(1H,3H)-dione. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010050155

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 685−688. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © E.E. Klen, F.A. Khaliullin , 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 5, pp. 694−697.
Reactions of 1,2,4-Triazole Derivatives with a “Model” Thiirane
E. E. Klen and F.A. Khaliullin
Bashkir State Medical University, Ufa, 450000, Russia
e-mail: khaliullin_ufa@yahoo.com
Received May 20, 2009
Abstract—Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-
7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N1and N2 of the triazole ring and
yield 7-(5-R-3-R'-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R'-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-
dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at
the position N1 forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-
[2,3-f]purine-2,4(1H,3H)-dione.
DOI: 10.1134/S1070428010050155
Reactions of 1,2,4-triazole derivatives with thiiranes
are virtually unstudied mainly due to the polymerization
proceeding at the reaction of thiiranes with nucleophilic
reagents [1].
The reactions of thiirane I with 1,2,4-triazole IIa–IIe
were carried out in the presence of KOH in boiling
ethanol over 3–5 h (Scheme 2).
The reaction of symmetric 3,5-dibromo-1H-1,2,4-tri-
azole (IIa) with thiirane I led to the formation of 7-[(3,5-
dibromo-1H-1,2,4-triazol-1-yl)methyl]-1,3-dimethyl-6,7-
dihydro[1,3]-thiazolo[2,3-f]purine-2,4(1H,3H)-dione (III)
(Scheme 2) in 77% yield.
1H NMR spectrum of compound III confirmed the
formation of the fused system of the dihydrothiazolo-
purine: characteristic multiplets appeared in the regions
4.62–4.74 and 4.96–5.06 ppm, corresponding to the protons
of NCH2 and SCH groups of the dihydrothiazole ring
respectively [5, 6].
The 13C NMR spectrum of compound III contained
the signals of carbon atoms of dihydrothiazolopurine [4,
5]. The signals at 132.11 and 139.54 ppm belonged to
atoms C5 and C3 of the triazole ring respectively. Their
magnetic nonequivalence showed that the reaction
occurred at the position N1 (N2) of triazole IIa.
We investigated the reactions of 3-mono- and 3,5-
disubstituted 1,2,4-triazoles with thiiranes by an example
of a “model” thiirane suggested by us [2], 8-bromo-1,3-
dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-
2,6-dione (I), whose application made it possible to obtain
monomer products in reactions with nucleophiles owing
to the intramolecular heterocyclization affording
derivatives of 6,7-dihydro[1,3]thiazolo[2,3-f]purine-
2,4(1H,3H)-dione (Scheme 1).
The reaction of 3-nitro-1,2,4-triazole with oxiranes is
known to proceed at the position N1 of the triazole [3],
whereas the 3-azido-1,2,4-triazole gave with oxiranes
a mixture of reaction products at positions N1 and N2
[4]. The products of reaction at the position N4 were not
mentioned in [3, 4]. We also did not found a product of
the reaction at the position N4 in treating with thiirane I
the unsubstituted 1,2,4-triazole [2].
Scheme 1.
O
O
O
Nu
N
N
_
N
N
N
N
Nu
NuH
H3CN
O
H3CN
O
S
Br
H3CN
O
S
S
Br
N
N
N
CH3
CH3
CH3
685

KLEN, KHALIULLIN
686
Scheme 2.
O
N
N
N
N
N
H3CN
S
N NH
R
R'
N
O
N
O
R
R'
CH3
N
IIa_IIe
III, IV, Va_VIIa
N
N
H3CN
O
S
Br
KOH
O
N
N
CH3
N
S
R
N
H3CN
O
R'
N
N
CH3
Va_VIIa
R = R' = Br (IIa, III); R = SO2CH3, R' = H (IIb, IV); R = SCH3, R' = H (IIc, Va, Vb); R = piperidin-1-yl, R' = Br (IId, VIa, VIb);
R = NHCH2C6H5, R' = Br (IIe, VIIa, VIIb).
of 3-methylsulfanyl isomer Va in a weaker field, at 8.62
ppm, in agreement with the published data [4].
In the 13C NMR spectrum of 5-methylsulfanyl isomer
Vb the signal at 155.02 ppm belonged to the atom C5 of
the triazole, and the upfield signal at 151.96 ppm, to atom
C3, also in agreement with the published data [7].
The reaction of thiirane I with unsymmetrical 3-
methylsulfonyl-1H-1,2,4-triazole (IIb) proceeded
regiospecifically at the position N1 of the triazole ring
(Scheme 2). 1,3-Dimethyl-7-[(3-methylsulfonyl-1H-1,2,4-
triazol-1-yl)methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-
2,4(1H,3H)-dione (IV) formed in 86% yield.
1
The H NMR spectrum of compound IV alongside
The reaction of 5-bromo-3-(piperidin-1-yl)-1H-1,2,4-
triazole (IId) with thiirane I also yielded two products
(Scheme 2). 7-[(5-Bromo-3-piperidin-1-yl-1H-1,2,4-
triazole-1-yl)methyl]-1,3-dimethyl-6,7-dihydro[1,3]-
thiazolo[2,3-f]purine-2,4(1H,3H)-dione (VIa) precipitated
in 54% yield. 5-Piperidinyl isomer VIb was isolated after
evaporation of the filtrate in 31% yield.
the signals of protons of the fused system of dihydro-
thiazolopurine and of 7-CH2 group contained a singlet
from the protons of the methylsulfonyl group at 3.34 ppm.
The singlet from the proton =CH of the triazole ring at
8.98 ppm confirmed the formation of 3-methylsulfonyl
isomer IV [4, 7].
The reaction of thiirane I with 3-methylsulfanyl-1H-
1,2,4-triazole (IIc) afforded two compounds (Scheme 2).
On cooling the reaction mixture 1,3-dimethyl-7-[(5-
methylsulfanyl-1H-1,2,4-triazol-1-yl)methyl]-6,7-dihydro-
[1,3]thiazolo[2,3-f]purine-2,4-(1H,3H)-dione (Vb)
precipitated in 32% yield. 3-Methylsulfanyl isomer (Va)
was isolated after evaporation of the filtrate also in 32%
yield.
Inasmuch as compounds VIa, VIb unlike compounds
Va, Vb do not contain protons in the triazole ring, their
assignment to the 3- and 5-piperidinyl isomers is difficult.
Therefore we performed an independent synthesis of
5-piperidinyltriazole VIb by reaction of triazole III with
piperidine (Scheme 3). As known, in the presence of
a substituent in the position of N1 of the 1,2,4-triazole the
nucleophilic substitution of bromine occurs in the position
C5 [8]. The reaction was carried out by boiling the
reagents in BuOH for 5 h to obtain compound Vb in 95%
yield.
In the 1H NMR spectra of compounds Va and Vb the
singlet of the proton =CH of the triazole ring of 5-methyl-
sulfanyl isomer Vb appeared at 7.88 ppm, and the singlet
Scheme 3.
O
O
N
N
N
N
HN
N
N
N
N
H3CN
O
H3CN
O
S
S
Br
Br
Br
N
N
N
N
N
CH3
CH3
VIb
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010
III

REACTIONS OF 1,2,4-TRIAZOLE DERIVATIVES WITH A “MODEL” THIIRANE
687
The mixed samples of compound Vb obtained in
different ways melted without depression of the melting
points, and their 1H NMR spectra were totally identical.
trometer Bruker AM-300 at operating frequency 300
and 75 MHz respectively. The signals of solvents served
as internal references. TLC was performed on Silufol
plates using as eluent ethanol or the mixture hexane–
ethanol, 3:2, development in the iodine vapor.
The 1H NMR spectra of compounds VIa, VIb contain-
ed the proton signals corresponding to the skeleton of
dihydrothiazolopurine, to the 7-CH2 group, and to the
piperidine fragment. The multiplet of the protons of
N(CH2)2 group from the piperidine residue of the
3-piperidinyl isomer VIa is shifted by 0.25 ppm downfield
compared with the analogous signal in the spectrum of
5-piperidinyl isomer VIb.
7-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-
1,3-dimethyl-6,7-dihydro[1,3]-thiazolo[2,3-f]purine-
2,4(1H,3H)-dione (III). A solution of 0.56 g (10 mmol)
of KOH, 2.26 g (10 mmol) of triazole (IIa), 1.66 g
(5 mmol) of thiirane I in 100 ml of ethanol was boiled for
2 h. On cooling the reaction mixture the separated
precipitate was filtered off and washed with a solution
of KOH and water. Yield 77%, mp 267–269°C (dioxane–
water). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.21 s
(3H, 3-CH3), 3.36 s (3H, 1-CH3), 4.48– 4.57 m (2H,
7-CH2), 4.62–4.74 m (2H, NCH2), 4.96–5.06 m (1H,
SCH). 13C NMR spectrum (DMSO-d6), δ, ppm: 27.47
(3-CH3), 29.57 (1-CH3), 48.76 (NCH2), 51.94 (7-CH2),
52.20 (SCH), 106.61 (C4a), 132.11 (C5triazole), 139.54
(C3triazole), 150.69 (C9a), 151.61 (C2), 152.79 (C4), 154.26
(C8a). Found, %: C 30.11; H 2.37; N 20.65.
C12H11Br2N7O2S. Calculated, %: C 30.21; H 2.32;
N 20.55.
The reaction of 3-benzylamino-5-bromo-1H-1,2,4-
triazole (IIe) with thiirane I also furnished two isomers
VIIa and VIIb (Scheme 2). 7-{[3-(Benzylamino)-5-
bromo-1H-1,2,4-triazol-1-yl]methyl}-1,3-dimethyl-6,7-
dihydro[1,3]thiazolo[2,3-f]purine-2,4(1H,3H)-dione
(VIIa) precipitated in 36% yield. 5-Benzylamino isomer
VIIb we failed to obtain in an individual state. The overall
yield of the reaction products was 83%.
1
In the H NMR spectrum of the mixture of com-
pounds VIIa and VIIb a double set of signals was
observed from the protons of NCH3 group of the purine
residue, of NHCH2 and NHCH2 protons of the benzyl-
amine fragment; therefore we were able to conclude on
the formatiom of 3- and 5-benzylamino isomers VIIa and
VIIb in a ratio 3:2 (according to the integral intensities
of the signals).
In the 1H NMR spectrum of compound VIIa the signal
of protons of NHCH2 of the benzylamine fragment
appears as a doublet at 4.42 ppm, in a weaker field as
compared with the similar signal of 5-benzylamino isomer
VIIb (at 4.34 ppm in the spectrum of the mixture),
indicating as in the event of compound VIa the formation
of 3-benzylamino isomer.
1,3-Dimethyl-7-[(3-methylsulfonyl-1H-1,2,4-
triazol-1-yl)methyl]-6,7-dihydro-[1,3]-thiazolo[2,3-
f]-purine-2,4(1H,3H)-dione (IV) was obtained
1
similarly. Yield 86%, mp 215–217°C (H2O). H NMR
spectrum (DMF-d7), δ, ppm: 3.23 s (3H, 3-CH3), 3.34 s
(3H, SO2CH3), 3.38 s (3H, 1-CH3), 4.63 d.d (1H, NCH2,
3
2
2J 11.9, J 7.5 Hz), 4.73 d.d (1H, NCH2, J 11.9,
3J 2.8 Hz), 4.98–5.12 m (2H, 7-CH2) 5.15–5.26 m
(1H, SCH), 8.98 s (1H, H5'). Found, %: C 39.41; H 3.62;
N 24.58. C13H15N7O4S2. Calculated, %: C 39.29; H 3.80;
N 24.67.
Thus the reactions of 1,2,4-triazoles with thiirane I
proceed nonselectively at positions N1 and N2except for
3-methylsulfonyl-1H-1,2,4-triazole (IIb) that reacts
regioselectively at the position N1. As a result form
isomeric 7-(5-R-3-R'-1,2,4-triazol-1-yl)methyl- Va–VIIa
and 7-(5-R'-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-
6,7-dihydro[1,3]thiazolo[2,3-f]purine-2,4(1H,3H)-diones
Vb–VIIb whose ratio depends on the character of
substituents in the positions C3 and C5 of the triazole ring.
From symmetric 3,5-dibromo-1H-1,2,4-triazole (IIa)
formed a single compound III, no reaction products at
the position N4 were detected.
1,3-Dimethyl-7-[(3-methylsulfanyl-1H-1,2,4-
triazol-1-yl)methyl]-6,7-dihydro-[1,3]thiazolo[2,3-f]-
purine-2,4(1H,3H)-dione (Va) and 1,3-dimethyl-7-
[(5-methylsulfanyl-1H-1,2,4-triazol-1-yl)methyl]-
6,7-dihydro[1,3]thiazolo[2,3-f]purine-2,4-(1H,3H)-
dione (Vb). A solution of 1.12 g (20 mmol) of KOH,
2.30 g (20 mmol) of triazole IIc, 3.31 g (10 mmol) of
thiirane I in 100 ml of ethanol was boiled for 4.5 h. On
cooling the reaction mixture the separated precipitate was
filtered off and washed with a solution of KOH and water.
We obtained compound Vb. Yield 32%, mp 229–230°C
1
(i-PrOH). H NMR spectrum (CDCl3), δ, ppm: 2.71 s
(3H, SCH3), 3.37 s (3H, 3-CH3), 3.54 s (3H, 1-CH3),
4.37–4.48 m [3H, NCH2 (1H), 7-CH2], 4.55 d.d (1H,
EXPERIMENTAL
2
3
1H and 13C NMR spectra were registered on a spec-
NCH2, J 11.9, J 3.4 Hz), 4.77–4.92 m (1H, SCH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

KLEN, KHALIULLIN
688
7.88 C (1H, H3'). 13C NMR spectrum (CDCl3), δ, ppm:
15.63 (SCH3), 27.92 (3-CH3), 29.93 (1-CH3), 48.95
(NCH2), 50.83 (7-CH2), 51.11 (SCH), 107.27 (C4a),
151.26 (C9a), 151.96 (C3triazole), 152.53 (C2), 153.56 (C4),
154.03 (C8a), 155.02 (C5triazole). Found, %: C 42.66;
H 4.18; N 26.78. C13H15N7O2S2. Calculated, %: C 42.73;
H 4.14; N 26.83.
and filtered off. Yield 95%, mp 223–225°C (BuOH).
Found, %: C 42.48; H 4.44; N 23.33. C17H21BrN8O2S.
Calculated, %: C 42.42; H 4.40; N 23.28.
7-{[3-(Benzylamino)-5-bromo-1H-1,2,4-triazol-1-
yl]methyl}-1,3-dimethyl-6,7-dihydro[1,3]thiazolo-
[2,3-f]purine-2,4(1H,3H)-dione (VIIa) and 7-{[5-
(benzylamino)-3-bromo-1H-1,2,4-triazol-1-yl]-
methyl}-1,3-dimethyl-6,7-dihydro[1,3]thiazolo-
[2,3-f]purine-2,4-(1H,3H)-dione (VIIb). A solution of
0.17 g (3 mmol) of KOH, 0.76 g (3 mmol) of triazole IIe,
0.50 g (1.5 mmol) of thiirane I in 25 ml of EtOH was
boiled for 3 h. The reaction mixture was evaporated in
a vacuum to dryness, the residue was washed with the
solution of KOH, water, and filtered off. Yield of the
The filtrate was evaporated in a vacuum to dryness,
the residue was washed with the solution of KOH, water,
and filtered off to obtain compound Va. Yield 32%, mp
177–178°C (toluene). 1H NMR spectrum (DMF-d7), δ,
ppm: 2.53 s (3H, SCH3), 3.23 s (3H, 3-CH3), 3.39 s (3H,
1-CH3), 4.47–4.72 m (2H, NCH2), 4.72–4.92 m (2H,
7-CH2), 5.03–5.23 m (1H, SCH), 8.62 s (1H, H5').
Found, %: C 42.63; H 4.21; N 26.91. C13H15N7O2S2.
Calculated, %: C 42.73; H 4.14; N 26.83.
1
mixture 83%, mp 128–144°C. H NMR spectrum
(CDCl3), δ, ppm: 3.18 s [3H, 3-CH3 (VIIb)], 3.30 s [3H,
1-CH3 (VIIb)], 3.39 s [3H, 3-CH3 (VIIa)], 3.55 C [3H,
1-CH3 (VIIa)], 4.28–4.62 m (6H, 2-CH2, NCH2,
NHCH2), 4.65 t [1H, NHCH2, 3J 6.0 Hz (VIIa)], 4.77–
7-[(5-Bromo-3-piperidin-1-yl-1H-1,2,4-triazol-1-
yl)methyl]-1,3-dimethyl-6,7-dihydro-[1,3]thiazolo-
[2,3-f]purine-2,4(1H,3H)-dione (VIa) and 7-[(3-
bromo-5-piperidin-1-yl-1H-1,2,4-triazole-1-yl)-
methyl]-1,3-dimethyl-6,7-dihydro[1,3]thiazolo-[2,3-
f]purine-2,4(1H,-3H)-dione (VIb). Asolution of 0.28 g
(5 mmol) of KOH, 1.16 g (5 mmol) triazole IId, 0.83 g
(2.5 mmol)of thiirane I in 25 ml of ethanol was boiled for
3 h. On cooling the reaction mixture the separated
precipitate was filtered off and washed with water to
obtain compound VIa. Yield 54%, mp 200–202°C
(BuOH). 1H NMR spectrum (CDCl3), δ, ppm: 1.52–
1.68 m [6H, (CH2)3], 3.25–3.45 m [4H, N(CH2)2], 3.39 s
(3H, 3-CH3), 3.55 s (3H, 1-CH3), 4.34 d (2H, 7-CH2,
3
4.93 m (1H, SCH), 5.57 t [1H, NHCH2, J 5.6 Hz
(VIIb)], 7.24–7.47 m (5H, 5CHarom). Found, %: C 45.27;
H 3.77; N 22.40. C19H19BrN8O2S. Calculated, %:
C 45.33; H 3.80; N 22.26.
Compound VIIa was obtained similarly to compound
1
VIa. Yield 36%, mp 177–179°C (i-PrOH). H NMR
spectrum (CDCl3), δ, ppm: 3.39 s (3H, 3-CH3), 3.55 s
3
(3H, 1-CH3), 4.34 d (2H, 7-CH2, J 7.1 Hz), 4.38–
4.48 m [3H, NHCH2, NCH2 (1H)], 4.60 d.d (1H, NCH2,
3
3
2J 12.1, J 3.7 Hz), 4.65 t (1H, NHCH2, J 6.0 Hz),
4.77–4.88 m (1H, SCH), 7.26–7.44 m (5H, 5CHarom).
Found, %: C 45.38; H 3.75; N 22.32. C19H19BrN8O2S.
Calculated, %: C 45.33; H 3.80; N 22.26.
2
3
3J 7.1 Hz), 4.44 d.d (1H, NCH2, J 12.0, J 7.4 Hz),
4.59 d.d (1H, NCH2, 2J 12.0, J 3.7 Hz), 4.76–4.90 m
3
(1H, SCH). Found, %: C 42.51; H 4.34; N 23.17.
C17H21BrN8O2S. Calculated, %: C 42.42; H 4.40;
N 23.28.
REFERENCES
1. Fokin,A.V. and Kolomiets,A.F., Khimiya tiiranov (Thiirane
Chemistry), Moscow: Nauka, 1978, p. 344.
2. Khaliullin, F.A. and Klen, E.E., Zh. Org. Khim., 2009, vol. 45,
1703.
3. Kofman, T.P. and Kartseva, G.Yu., Zh. Org. Khim., 2001,
vol. 37, 744.
4. Kofman, T.P. and Krasnov, K.N., Zh. Org. Khim., 2004,
vol. 40, 1699.
5. Khaliullin, F.A., Cand. Sci. (Farm.) Dissertation, Ufa., 1998,
428 p.
a. The filtrate was evaporated in a vacuum to dryness,
the residue was washed with the solution of KOH, water,
and filtered off to obtain compound VIb. Yield 31%, mp
1
221–223°C (dioxane–water). H NMR spectrum
(CDCl3), δ, ppm: 1.50–1.63 m [6H, (CH2)3], 3.02–
3.16 m [4H, N(CH2)2], 3.40 s (3H, 3-CH3), 3.54 s (3H,
3
1-CH3), 4.28 d (2H, 7-CH2, J 7.2 Hz), 4.46 d (2H,
NCH2, 3J 5.5 Hz), 4.86–4.97 m (1H, SCH). Found, %:
C 42.51; H 4.34; N 23.17. C17H21BrN8O2S. Calculated,
%: C 42.42; H 4.40; N 23.28.
6. Khaliullin, F.A., Strokin, Yu.V., and Kataev, V.A., Khim.
Geterotsikl. Soedin., 1991, p. 840.
b. A solution of 1.43 g (3 mmol) of triazole III and
1.27 g (15 mmol) of piperidine in 50 ml of BuOH was
boiled for 5 h. The reaction mixture was evaporated in a
vacuum to dryness, the residue was washed with water
7. Saraev, V.V., Kanakina, T.P., Pevzner, M.S., Golod, E.L., Ug-
rak, B.I., and Kachala, V.V., Khim. Geterotsikl. Soedin., 1996,
p. 1078.
8. Zumbrunn,A., Synthesis, 1998, p. 1357.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010