Dioxothietanylation of Heterocycles 1. N-(1,1-Dioxothietan-3-yl)-1,2,4- triazoles

Article abstract of DOI:10.1007/s10593-013-1159-7

3,5-Substituted 1-(1,1-dioxothietan-3-yl)-1,2,4-triazoles have been prepared by treating NH-1,2,4-tri-azole sodium salts with 3,5-dibromo-1-(1,1- dioxothietan-3-yl)-1,2,4-triazole (a novel dioxothietanylating reagent). The reactions occur regioselectively at the position 2 for 5-bromo-1,2,4-triazoles containing ethoxy-, isopropoxy-, or phenoxy groups at the position 3 and at position 1 for 3-methylsulfanyl-1,2,4-tri-azole. The reaction occurs nonselectively at positions 1 and 2 in the case of 3-methylsulfonyl-1,2,4-tri- azole and 5-bromo-3-(piperidin-1-yl)-1,2,4-triazole, to give the isomeric 3-R-5-R¹- and 5-R-3-R¹-1-(1,1-di-oxothietan-3-yl)-1,2,4- triazoles.

Full text of DOI:10.1007/s10593-013-1159-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
DIOXOTHIETANYLATION OF HETEROCYCLES
1. N-(1,1-DIOXOTHIETAN-3-YL)-1,2,4-TRIAZOLES
E. E. Klen1*, N. N. Makarova1, and F. A. Khaliullin1
3,5-Substituted 1-(1,1-dioxothietan-3-yl)-1,2,4-triazoles have been prepared by treating NH-1,2,4-tri-
azole sodium salts with 3,5-dibromo-1-(1,1-dioxothietan-3-yl)-1,2,4-triazole (a novel dioxothietanylating
reagent). The reactions occur regioselectively at the position 2 for 5-bromo-1,2,4-triazoles containing
ethoxy-, isopropoxy-, or phenoxy groups at the position 3 and at position 1 for 3-methylsulfanyl-1,2,4-tri-
azole. The reaction occurs nonselectively at positions 1 and 2 in the case of 3-methylsulfonyl-1,2,4-tri-
azole and 5-bromo-3-(piperidin-1-yl)-1,2,4-triazole, to give the isomeric 3-R-5-R1- and 5-R-3-R1-1-(1,1-di-
oxothietan-3-yl)-1,2,4-triazoles.
Keywords: thietane 1,1-dioxide, 1,2,4-triazole, dioxothietanylation.
Methods have been reported in the literature for the preparation of N-(1,1-dioxothietan-3-yl)-
1,2,4-triazoles by oxidative reactions of N-(thietan-3-yl)- and N-(1-oxothietan-3-yl)-1,2,4-triazoles [1], inferring
a preliminary alkylation of 1,2,4-triazoles by 2-chloromethylthiirane and subsequent nucleophilic substitution
[2-4].
In continuation of our studies [5], we propose a novel method for the introduction of a thietane-
1,1-dioxide ring into 3,5-substituted NH-1,2,4-triazoles, which is based on the use of 3,5-dibromo-1-(1,1-dioxo-
thietan-3-yl)-1,2,4-triazole (1) as the dioxothietanylating reagent [6].
It was found that reaction of the NH-1,2,4-triazoles 2a-g with compound 1 in tert-butanol in the
presence of sodium tert-butoxide gave the N-dioxothietanylation products N-(1,1-dioxothietan-3-yl)-
1,2,4-triazoles 3-9 in 39-64% yields. Evidently the reaction of the 3,5-dibromo-1-(1,1-dioxothietan-3-yl)-
1,2,4-triazole (1) with sodium tert-butoxide occurs with elimination of thietane 1,1-dioxide, which takes part in a
Michael addition of the NH-1,2,4-triazoles. It is known that thietane 1,1-dioxides are used as Michael acceptors
and readily add ethanol, hydrogen sulfide, thiophenol and amines in the presence of bases to give high yields of
3-substituted thietane 1,1-dioxides [7].
The composition and structure of compounds 3-9 were confirmed from elemental analysis data, IR and
1H NMR spectroscopy, and also by a counter synthesis.
The reactions of compound 1 with the sodium salts of unsymmetrical 1,2,4-triazoles can occur at the
positions 1, 2, and 4 of the triazole ring. In the reaction of 3,5-dibromo-1-(1,1-dioxothietan-3-yl)-1,2,4-triazole
(1) with the unsubstituted 1,2,4-triazole (2a), addition occurs at the N-1 atom to give 1-(1,1-dioxothietan-3-yl)-
1,2,4-triazole (3). The product of dioxothietanylation at the N-4 atom was not observed [5].
_______
*To whom correspondence should be addressed, e-mail: khaliullin_ufa@yahoo.com.
1Bashkir State Medical University, 3 Lenin St., Ufa 450000, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1583-1586, October, 2012.
Original article submitted January 19, 2012.
0009-3122/13/4810-1473©2013 Springer Science+Business Media New York
1473

O
O
S
t-BuONa
t-BuOH
Na+
Br
O
S
N
N
N
N
O
+
Br
N
10
Br
Br
N
1
O
O
H
N
N
O
O
S
S
R1
R
N
2a–g
+
N
N
N
N
R1
R1
4, 5, 6, 8b, 9b
R
R
N
N
3, 7, 8a, 9a
2a, 3 R = R1 = H; 2b, 4 R = OEt, R1 = Br; 2c, 5 R = O(Pr-i), R1 = Br; 2d, 6 R = OPh, R1 = Br;
2e, 7 R = SMe, R1 = H; 2f, 8a,b R = SO2Me, R1 = H; 2g, 9a,b R = piperidin-1-yl, R1 = Br
In the case of the 5-bromo-3-ethoxy- (2b), 5-bromo-3-isopropoxy- (2c), and 5-bromo-3-phenoxy-
1,2,4-triazoles (2d) reactions occur regioselectively at the position 2, giving the 3-bromo-1-(1,1-dioxothietan-
3-yl)-5-ethoxy- (4), 3-bromo-1-(1,1-dioxothietan-3-yl)-5-isopropoxy- (5), and 3-bromo-1-(1,1-dioxothietan-
3-yl)-5-phenoxy-1,2,4-triazoles (6), respectively. Compounds 4-6 did not depress the melting points when
mixed with those samples obtained by known methods [1, 4] via oxidation of 3-bromo-1-(thietan-3-yl)-
5-ethoxy-, 3-bromo-5-isopropoxy-1-(thietan-3-yl)- and 3-bromo-1-(thietan-3-yl)-5-phenoxy-1,2,4-triazoles.
Their IR spectra were also in full agreement.
Reaction of compound 1 with 3-methylsulfanyl-1,2,4-triazole (2e) gave only the 1-(1,1-dioxothietan-
3-yl)-3-methylsulfanyl-1,2,4-triazole (7) in 63% yield. The 1H NMR spectrum of compound 7 showed signals in
the regions typical for the thietanedioxide ring [8] and methylsulfanyl residue protons. The singlet for the =CH
proton of the triazole ring was observed at 8.16 ppm, confirming the formation of the 3-methylsulfanyl isomer
[9].
Dioxothietanylation of the 3-methylsulfonyl-1,2,4-triazole (2f) gave a mixture of two compounds:
1-(1,1-dioxothietan-3-yl)-3-methylsulfonyl- (8a) and 1-(1,1-dioxothietan-3-yl)-5-methylsulfonyl-1,2,4-triazoles
(8b). In the 1H NMR spectrum of the isomer mixture the 5-methylsulfonyl isomer has triazole ring =CH proton
singlet at 9.05 ppm, while the singlet for the 3-methylsulfonyl isomer is found at lower field at 9.65 ppm, which
is in agreement with literature data [9, 10]. The ratio of 3-methylsulfonyl- and 5-methylsulfonyl isomers 8a and
8b was judged to be 1:2 from the integrated intensities of the NCH group proton signals.
The reaction of compound 1 with 5-bromo-3-(piperidin-1-yl)-1,2,4-triazole (2g) leads to a mixture of
isomeric 5-bromo-1-(1,1-dioxothietan-3-yl)-3-(piperidin-1-yl)- (9a) and 3-bromo-1-(1,1-dioxothietan-3-yl)-
1
5-piperidin-1-yl)-1,2,4-triazoles (9b). Doubling of the H NMR signals for the thietanedioxide ring and the
piperidine residue in the mixture of compounds 9a and 9b led us to conclude that they are formed in a 2:1 ratio
(according to the integrated intensities). The assignment of the proton signals to the 3- and 5-isomers was made
1
on the basis of H NMR spectrum of the 5-piperidinyl isomer 9b synthesized earlier by treating 3,5-dibromo-
1-(1,1-dioxothietan-3-yl)-1,2,4-triazole with piperidine [1, 9].
Hence the dioxothietanylation occurs regioselectively at the position 2 for the 5-bromo-1,2,4-triazoles
containing ethoxy-, isopropoxy- or phenoxy groups in position 3, but at position 1 of the triazole ring for the
3-methylsulfanyl-1,2,4-triazole. Reactions of 3-methylsulfonyl-1,2,4-triazole and 5-bromo-3-(piperidin-1-yl)-
1,2,4-triazole with 3,5-dibromo-1-(1,1-dioxothietan-3-yl)-1,2,4-triazole occur nonselectively at the positions 1
and 2, to yield the isomeric 3-R-5-R1- and 5-R-3-R1-1-(1,1-dioxothietan-3-yl)-1,2,4-triazoles. The ratio of
isomers depends on the nature of the substituents at positions 3 and 5 of the triazole ring.
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EXPERIMENTAL
1
IR spectra were recorded on an Infralum FT-02 instrument for KBr pellets. H NMR spectra were
recorded on a Bruker AM-300 instrument (300 MHz) with the residual solvent signals as standard (7.26 ppm for
CDCl3 and 2.50 ppm for DMSO-d6). Elemental analysis was performed on a Euro3000 Hekatech CHNS-
analyzer. Melting points were determined on a PTP instrument.
3,5-Dibromo-1-(1,1-dioxothietan-3-yl)-1H-1,2,4-triazole (1) was prepared by method [1] and 1-(1,1-di-
oxothietan-3-yl)-1H-1,2,4-triazole (3) by method [5].
Preparation of Compounds 4-7, 9a,b (General Method). Sodium metal (0.08 g, 3.3 mmol) was added
to t-BuOH (30 ml) and heated until evolution of gas bubbles ceased. Compound 2a-g (3.0 mmol) and
3,5-dibromo-1-(1,1-dioxothietan-3-yl)-1H-1,2,4-triazole (1) (0.99 g, 3.0 mmol) were then added. The reaction
mixture was refluxed for 2 h, the solvent was evaporated to dryness in vacuo, and water was added to the
residue. The precipitate was filtered off and dried.
3-Bromo-1-(1,1-dioxothietan-3-yl)-5-ethoxy-1H-1,2,4-triazole (4). Yield 0.57 g (64%); mp
169-170ºC (EtOH) (mp 166-167ºC [1]). The spectroscopic data agreed with the literature [1].
3-Bromo-1-(1,1-dioxothietan-3-yl)-5-isopropoxy-1H-1,2,4-triazole (5). Yield 0.36 g (39%), mp
154-155ºC (EtOH) (mp 150-151.5ºC [1]). IR spectrum, , cm-1: 1295, 1493, 1551 (C=N), 1143, 1342 (SO2). 1H
NMR spectrum (CDCl3), , ppm (J, Hz): 1.41 (6H, d, J = 6.2, CH(CH3)2); 4.40-4.58 (2H, m) and 4.64-4.81 (2H,
m, CH2SCH2); 4.96-5.20 (2H, m, OCH, NCH).
3-Bromo-1-(1,1-dioxothietan-3-yl)-5-phenoxy-1H-1,2,4-triazole (6). A. Yield 0.48 g (46%); mp
1
246-248ºC (n-BuOH). IR spectrum, , cm-1: 1292, 1487, 1528 (C=N, C=C), 1142, 1323 (SO2). H NMR
spectrum (DMSO-d6), , ppm (J, Hz): 4.69-4.89 (4H, m, CH2SCH2); 5.35-5.47 (1H, m, NCH); 7.28-7.35 (1H,
m, H Ph); 7.38-7.43 (2H, m, H Ph), 7.45-7.51 (2H, m, H Ph). Found, %: C 38.45; H 2.81; N 12.18.
C11H10BrN3O3S. Calculated, %: C 38.39; H 2.93; N 12.21.
B. A 37% solution of H2O2 (2.76 g, 30 mmol) was added to a solution of the 3-bromo-1-(thietan-3-yl)-
5-phenoxy-1,2,4-triazole [4] (0.94 g, 3.3 mmol) in glacial acetic acid (7 ml). The reaction mixture was refluxed
for 2 hours and then cooled. The precipitate formed was filtered off and dried. Yield 0.65 g (57%), mp
249-250ºC (n-BuOH). The spectroscopic data agreed with that for compound 6 prepared by method A.
1-(1,1-Dioxothietan-3-yl)-3-methylsulfanyl-1H-1,2,4-triazole (7). Yield 0.41 g (63%); mp 147-148ºC
1
(EtOH). H NMR spectrum (CDCl3), , ppm: 2.62 (3H, s, SCH3); 4.56-4.66 (2H, m) and 4.74-4.83 (2H, m,
CH2SCH2); 5.15-5.25 (1H, m, NCH); 8.16 (1H, s, H-5). Found, %: C 32.87; H 4.19; N 19.33. C6H9N3O2S2.
Calculated, %: C 32.86; H 4.14; N 19.16.
5-Bromo-1-(1,1-dioxothietan-3-yl)-3-(piperidin-1-yl)-1H-1,2,4-triazole (9a) and 3-Bromo-1-(1,1-di-
oxothietan-3-yl)-5-(piperidin-1-yl)-1H-1,2,4-triazole (9b). Yield 0.53 g (53%) as a mixture of compounds 9a
and 9b (isomer ratio 2:1); mp 160-162ºC (EtOH). 1H NMR spectrum (CDCl3), , ppm: 1.55-1.78 (6H, m, 3,4,5-CH2
piperidine (9a+9b)); 3.01-3.12 (1.32H, m, 2,6-CH2 piperidine (9b)); 3.32-3.45 (2.68H, m, 2,6-CH2 piperidine
(9a)); 4.41-4.55 (2H, m) and 4.75-4.91 (2H, m, CH2SCH2 (9a+9b)); 4.96-5.06 (0.33H, m, NCH (9b)); 5.10-
5.21 (0.67H, m, NCH (9a)). Found, %: C 35.90; H 4.55; N 16.69. C10H15BrN4O2S. Calculated, %: C 35.83; H
4.51; N 16.71.
1-(1,1-Dioxothietan-3-yl)-3-methylsulfonyl-1H-1,2,4-triazole (8a) and 1-(1,1-Dioxothietan-3-yl)-
5-methylsulfonyl-1H-1,2,4-triazole (8b). Sodium metal (0.08 g, 3.3 mmol) was added to t-BuOH (40 ml) and
heated until evolution of gas bubbles ceased. 3-Methylsulfonyl-1H-1,2,4-triazole (2f) (0.44 g, 3 mmol),
3,5-dibromo-1-(1,1-dioxothietan-3-yl)-1H-1,2,4-triazole (1) (0.99 g, 3 mmol) and DMF (25 ml) were added,
and the mixture was refluxed for 2 h. The solution was evaporated to dryness in vacuo, and the residue was
treated with water. The precipitate was filtered off and dried. Yield 0.34 g (45%) as a mixture of compounds 8a
1
and 8b (isomer ratio 1:2); mp 163-167ºC (n-BuOH). H NMR spectrum (DMSO-d6), , ppm: 3.38 (0.67H, s,
SO2CH3 (8b)); 3.55 (0.33H, s, SO2CH3 (8a)); 4.65-4.94 (4H, m, CH2SCH2 (8a+8b)); 5.40-5.51 (0.33H, m, NCH
1475

(8a)); 5.51-5.63 (0.67H, m, NCH (8b)); 9.05 (0.67H, s, H-3 (8b)); 9.65 (0.33H, s, H-5 (8a)). Found, %:
C 28.62; H 3.65; N 16.67. C6H9N3O4S2. Calculated, %: C 28.68; H 3.61; N 16.72.
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