Thietanyl Protection in the Synthesis of 5-Aryloxy(sulfonyl)-3-bromo-1,2,4-triazoles

Article abstract of DOI:10.1134/S1070428018120242

Previously unknown 5-aryloxy- and 5-benzenesulfonyl-3-bromo-1H-1,2,4-triazoles have been synthesized starting from 3,5-dibromo-1,2,4-triazole by successive alkylation with 2-chloromethylthiirane, nucleophilic substitution of the 5-bromine atom by phenoxy

Full text of DOI:10.1134/S1070428018120242

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1856–1859. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © F.A. Khaliullin, E.E. Klen, N.N. Makarova, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 12,
pp. 1841–1844.
SHORT
COMMUNICATIONS
Thietanyl Protection in the Synthesis
of 5-Aryloxy(sulfonyl)-3-bromo-1,2,4-triazoles
F. A. Khaliullina, E. E. Klena,* and N. N. Makarovaa
a Bashkir State Medical University, ul. Lenina 3, Ufa, 450008 Bashkortostan, Russia
*e-mail: klen_elena@yahoo.com
Received May 8, 2018; revised October 10, 2018; accepted October 17, 2018
Abstract—Previously unknown 5-aryloxy- and 5-benzenesulfonyl-3-bromo-1H-1,2,4-triazoles have been
synthesized starting from 3,5-dibromo-1,2,4-triazole by successive alkylation with 2-chloromethylthiirane,
nucleophilic substitution of the 5-bromine atom by phenoxy or phenylsulfanyl group, oxidation of the thietane
sulfur atom with hydrogen peroxide, and removal of the thietanyl protecting group by treatment with sodium
ethoxide.
DOI: 10.1134/S1070428018120242
1,2,4-Triazole derivatives attract interest from both
theoretical and practical viewpoints. In particular,
these compounds are promising as pharmacologically
active substances since they inhibit cytochrom P450-
mediated processes [1] and synthesis of viral RNA and
virus-specific proteins [2], selectively inhibit aroma-
tase [3] and reuptake of serotonin at brain synapses,
and act as 5-HT2A/2C serotonin receptor antagonists [4].
1,2,4-Triazole ring is a structural unit of many medi-
cines used for the treatment of fungal and viral infec-
tions, malignant tumors, and psychic disorders [5].
Furthermore, 1,2,4-triazole derivatives are extensively
studied as potential antidepressants, analgesics, and
anti-inflammatory agents [6].
2-methoxypropan-2-yl [10], tetrahydrofuran-2-yl [11],
and cyanoethyl [12].
Herein, we propose to use a thietanyl protecting
group [13] for the synthesis of previously unknown
5-aryloxy(sulfonyl)-3-bromo-1H-1,2,4-triazoles. This
protecting group can be easily introduced by alkylation
of 3,5-dibromo-1H-1,2,4-triazole with 2-chloromethyl-
thiirane, it ensures subsequent reactions with nucleo-
philes, and is readily removed by treatment with
sodium alkoxide after oxidation of the sulfur atom.
5-Substituted 3-bromo-1H-1,2,4-triazoles were
synthesized in several steps. Initially, the reaction of
3,5-dibromo-1H-1,2,4-triazole with 2-chloromethyl-
thiirane gave 3,5-dibromo-1-(thietan-3-yl)-1H-1,2,4-
triazole (1) [14] which was treated with sodium
phenoxides and sodium benzenethiolate to obtain
5-aryloxy(sulfanyl)-3-bromo-1-(thietan-3-yl)-1H-
1,2,4-triazoles (Scheme 1) [15]. Compounds 2a–2g
were oxidized with hydrogen peroxides to the corre-
3,5-Disubstituted 1H-1,2,4-triazoles are convenient
building blocks for the creation of combinatorial
libraries of potential biologically active compounds;
these syntheses utilize various protecting groups such
as 3-oxobutyl [7], benzyl [8], diphenylmethyl [9],
Scheme 1.
O
S
S
S
O
RNa
H2O2
N
N
N
N
N
N
N
N
N
Br
Br
Br
Br
R
R
1
2a–2g
3a–3g
2, 3, R = PhO (a), 4-MeC6H4O (b), 3,4-Me2C6H3O (c), 2-i-Pr-5-MeC6H3O (d), 2,4-Cl2C6H3O (e), naphthalen-1-yloxy (f);
2g, R = PhS; 3g, R = PhSO2.
1856

THIETANYL PROTECTION IN THE SYNTHESIS OF 5-ARYLOXY(SULFONYL)-3-BROMO-...
1857
Scheme 2.
O
S
O
N
N
O
O
EtONa
NH
N
N
EtO
S
+
Br
N
Br
R
R
3a–3g
4a–4g
5
R = PhO (a), 4-MeC6H4O (b), 3,4-Me2C6H3O (c), 2-i-Pr-5-MeC6H3O (d), 2,4-Cl2C6H3O (e), naphthalen-1-yloxy (f), R = PhSO2 (g).
sponding thietane S,S-dioxides 3a–3g [16]. The oxida-
tion of the thietane sulfur atom in 2g was accompanied
by the transformation of the phenylsulfanyl group to
benzenesulfonyl.
correlations of aromatic protons only with carbon
atoms of the benzene ring and methyl group (Fig. 1).
Likewise, neither C3 nor C5 signal was detected
in the 13C NMR spectra of 4c in CD3COOD and
DMSO-d6. Only the 13C NMR spectrum of 4g in
DMSO-d6 showed signals at δC 134.08 and
161.67 ppm, which were assigned, respectively, to C3
and C5 of the triazole ring.
The thietanyl protection was readily removed by
treatment of 5-substituted 3-bromo-1-(1,1-dioxo-λ6-
thietan-3-yl)-1H-1,2,4-triazoles 3a–3g with sodium
ethoxide. We thus isolated 20–80% of 3-bromo-5-
aryloxy(benzenesulfonyl)-1H-1,2,4-triazoles 4a–4g
and 3-ethoxythietane 1,1-dioxide (5) (Scheme 2).
Thus, we have demonstrated the possibility of using
thietanyl protection for the synthesis of difficultly
accessible 5-aryloxy- and 5-benzenesulfonyl-3-bromo-
1H-1,2,4-triazoles.
The structure of the synthesized compounds was
confirmed by elemental analyses and NMR and IR
spectra, and their purity was checked by TLC. Unlike
compounds 3a–3g, the IR spectra of triazoles 4a–4g
contained an absorption band at 2642–3093 cm–1 due
to stretching vibrations of associated N–H group,
whereas no bands assignable to vibrations of sulfonyl
group were present; these data confirmed elimination
of the thietane dioxide ring with formation of 5-sub-
Compounds 4a–4g (general procedure). Metallic
sodium, 0.27 g (11.6 mmol), was added to 25 mL of
anhydrous ethanol, and the mixture was heated until
hydrogen no longer evolved. 5-Substituted 3-bromo-1-
(1,1-dioxo-λ6-thietan-3-yl)-1H-1,2,4-triazole 3a–3g,
9.7 mmol, was then added, and the mixture was
refluxed for 0.5 h. The solvent was distilled off under
reduced pressure, the residue was treated with 5 mL of
benzene and dissolved in 25 mL of water, and the
mixture was acidified to pH 3 with dilute sulfuric acid.
The precipitate was filtered off, washed with water,
dried, and purified by reprecipitation with sulfuric acid
from a solution in aqueous potassium hydroxide.
1
stituted 3-bromo-1H-1,2,4-triazoles. The H NMR
spectra of 4a–4g lacked proton signals typical of
thietane 1,1-dioxide fragment, while signals from
protons of the substituent on C5 were present. For
1
example, in the H NMR spectrum of 4g we observed
three aromatic proton signals, a multiplet at δ 7.62–
7.68 ppm, a triplet at δ 7.74 ppm, and a doublet at
δ 7.95 ppm, which indicated conservation of the ben-
zenesulfonyl group.
3-Bromo-5-phenoxy-1H-1,2,4-triazole (4a). Yield
0.84 g (36%), mp 95–97°C. IR spectrum, ν, cm–1:
3065, 3036, 2945, 2842 (N–H), 1600, 1571, 1541,
13
1
In keeping with the data of [17, 18], the C NMR
1487 (C=N, C=C). H NMR spectrum (CDCl3), δ,
spectra of 4a–4f in CDCl3 displayed only signals of the
aromatic substituent, whereas signals of C3 and C5 of
the triazole ring were not observed. Presumably, this is
due to fast tautomeric transformations of compounds
4a–4f in solution, which leads to considerable broad-
ening of the ring carbon signals. The two-dimensional
ppm: 7.20–7.27 m (3H, Harom), 7.36–7.41 m (2H,
7.16
7.11
H
H
N
NH
119.46
151.22
130.42
20.86
Br
N
O
CH3
1
1H–15N HSQC and H–15N HMBC spectra of 4b
2.32
130.42
showed no cross peaks between the NH proton (it
resonated as a broadened singlet at δ 10.39 ppm in the
1H NMR spectrum) and nitrogen atoms, which can
119.46
7.16 H
H7.11
1
also be explained by exchange processes. The H–13C
Fig. 1. Correlations in the H–13C HMBC spectrum of
3-bromo-5-(4-methylphenoxy)-1H-1,2,4-triazole (4b).
1
1
HMBC and H–13C HSQC spectra of 4b displayed
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

KHALIULLIN et al.
1858
Harom). 13C NMR spectrum (CDCl3), δ, ppm: 119.53
(C2′, C6′), 125.91 (C4′), 129.94 (C3′, C5′), 153.44 (C1′).
Found, %: C 39.62; H 2.50; N 18.02. C8H6BrN3O.
Calculated, %: C 40.03; H 2.52; N 17.50.
N 14.21. C12H14BrN3O. Calculated, %: C 48.67;
H 4.76; N 14.19.
3-Bromo-5-(2,4-dichlorophenoxy)-1H-1,2,4-tri-
azole (4e). Yield 1.17 g (39%), mp 126–128°C. IR
spectrum, ν, cm–1: 3093, 3068, 3021, 2962, 2853, 2737
(N–H), 1591, 1568, 1475 (C=N, C=C). 1H NMR spec-
trum (CDCl3), δ, ppm: 7.29 d (1H, 5′-H, J = 2.3 Hz),
7.31 s (1H, 3′-H), 7.45 d (1H, 6′-H, J = 2.2 Hz).
13C NMR spectrum (CDCl3), δC, ppm: 123.00 (C6′),
126.96 (C4′), 128.34 (C5′), 130.65 (C3′), 132.12 (C2′),
147.88 (C1′). Found, %: C 30.94; H 1.30; N 13.48.
C8H4BrCl2N3O. Calculated, %: C 31.10; H 1.31;
N 13.60.
3-Bromo-5-(4-methylphenoxy)-1H-1,2,4-triazole
(4b). Yield 1.16 g (47%), mp 120–122°C. IR spectrum,
ν, cm–1: 3030, 2926, 2853, 2820, 2743, 2653 (N–H),
1
1561, 1501, 1489 (C=N, C=C). H NMR spectrum
(CDCl3), δ, ppm: 2.32 s (3H, CH3), 7.11 d (2H, 3′-H,
5′-H, 3J = 8.5 Hz), 7.16 d (2H, 2′-H, 6′-H, 3J = 8.5 Hz),
13
10.39 br.s (1H, NH). C NMR spectrum (CDCl3), δC,
ppm: 20.86 (4′-CH3), 119.46 (C2′, C6′), 130.42 (C3′,
C5′), 135.80 (C4′), 151.22 (C1′). Found, %: C 42.87;
H 3.10; N 16.83. C9H8BrN3O. Calculated, %: C 42.54;
H 3.17; N 16.54.
3-Bromo-5-(naphthalen-1-yloxy)-1H-1,2,4-tri-
azole (4f). Yield 2.25 g (80%), mp 112–113°C. IR
spectrum, ν, cm–1: 3024, 2949, 2845, 2740, 2650
(N–H), 1582, 1557, 1489 (C=N, C=C). 1H NMR spec-
trum (CDCl3), δ, ppm: 7.32–7.52 m (4H, 2′-H, 3′-H,
6′-H, 7′-H), 7.70 d (1H, 4′-H, 3J = 8.1 Hz), 7.83 d (1H,
3-Bromo-5-(3,4-dimethylphenoxy)-1H-1,2,4-tri-
azole (4c). Yield 1.85 g (71%), mp 133–134°C. IR
spectrum, ν, cm–1: 3023, 2939, 2918, 2848, 2734, 2642
(N–H), 1569, 1551, 1498, 1488 (C=N, C=C). 1H NMR
spectrum, δ, ppm: in CDCl3: 2.22 s (3H, 4′-CH3),
3
3
8′-H, J = 8.0 Hz), 8.00 d (1H, 5′-H, J = 8.1 Hz).
13C NMR spectrum (CDCl3), δC, ppm: 115.41 (C8′),
120.99 (C4′), 125.42 (C7′), 125.89 (C9′), 126.05 (C3′),
126.73 (C5′), 126.85 (C2′), 127.95 (C6′), 134.82 (C10′),
149.23 (C1′). Found, %: C 49.79; H 2.86; N 14.40.
C12H8BrN3O. Calculated, %: C 49.68; H 2.78;
N 14.48.
3
4
2.24 s (3H, 3′-CH3), 6.95 d.d (1H, 6′-H, J = 8.2, J =
4
2.4 Hz), 6.99 d (1H, 2′-H, J = 2.2 Hz), 7.11 d (1H,
5′-H, 3J = 8.2 Hz); in CD3COOD: 2.24 s (3H, 4′-CH3),
3
4
2.25 s (3H, 3′-CH3), 6.98 d.d (1H, 6′-H, J = 8.2, J =
4
2.4 Hz), 7.05 d (1H, 2′-H, J = 2.1 Hz), 7.15 d (1H,
3
5′-H, J = 8.3 Hz); in DMSO-d6: 2.17 s (3H, 4′-CH3),
3
4
3-Bromo-5-benzenesulfonyl-1H-1,2,4-triazole
(4g). Yield 0.83 g (30%), mp 203–205°C. IR spectrum,
ν, cm–1: 3064, 2951, 2873, 2735, 2667 (N–H), 1421,
2.19 s (3H, 3′-CH3), 6.94 d.d (1H, 6′-H, J = 8.2, J =
4
2.1 Hz), 7.02 d (1H, 2′-H, J = 2.7 Hz), 7.14 d (1H,
3
5′-H, J = 8.2 Hz). 13C NMR spectrum, δC, ppm: in
1
CDCl3: 19.18 (4′-CH3), 19.98 (3′-CH3), 116.81 (C2′),
120.68 (C6′), 130.73 (C5′), 134.52 (C4′), 138.50 (C3′),
151.30 (C1′); in CD3COOD (125 MHz): 18.07
(4′-CH3), 18.77 (3′-CH3), 116.87 (C2′), 120.66 (C6′),
130.49 (C5′), 134.26 (C4′), 138.40 (C3′), 151.63 (C1′);
in DMSO-d6: 19.13 (4′-CH3), 19.87 (3′-CH3), 116.92
(C2′), 120.66 (C6′), 130.88 (C5′), 133.79 (C4′), 138.50
(C3′), 152.25 (C1′). Found, %: C 44.98; H 3.71;
N 15.80. C10H10BrN3O. Calculated, %: C 44.80;
H 3.76; N 15.67.
1373 (C=N, C=C), 1340, 1161 (SO2). H NMR spec-
trum (DMSO-d6), δ, ppm: 7.62–7.68 m (2H, 3′-H,
5′-H), 7.74 t (1H, 4′-H, 3J = 7.4 Hz), 7.95 d (2H, 2′-H,
6′-H, 3J = 7.2 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 127.80 (C2′, C6′), 129.62 (C3′, C5′), 134.08 (C3),
134.20 (C4′), 139.61 (C1′), 161.67 (C5). Found, %:
C 33.31; H 2.43; N 14.77. C8H6BrN3O2S. Calculated,
%: C 33.35; H 2.10; N 14.58.
The IR spectra were recorded in KBr on an Infra-
1
lyum FT-02 spectrometer. The H and 13C NMR
spectra were measured on a Bruker AV-500 instrument
at 500 and 125 MHz, respectively, relative to the
residual proton and carbon signals of the deuterated
solvent. The elemental analyses were obtained on
a Hekatech Euro 3000 CHNS analyzer. The melting
points were determined with a Stuart SMP30 melting
point apparatus.
3-Bromo-5-[5-methyl-2-(propan-2-yl)phenoxy)-
1H-1,2,4-triazole (4d). Yield 0.57 g (20%), mp 139–
140°C. IR spectrum, ν, cm–1: 2961, 2926, 2866, 2736,
1
2651 (N–H), 1567, 1491 (C=N, C=C). H NMR spec-
3
trum (CDCl3), δ, ppm: 1.20 d [6H, CH(CH3)2, J =
6.8 Hz], 2.32 s (3H, 5′-CH3), 3.10 d.d [1H, CH(CH3)2,
4
3J = 6.8 Hz], 6.99 d (1H, 6′-H, J = 2.4 Hz), 7.04 m
(1H, 4′-H, 3J = 8.4, 4J = 2.6 Hz), 7.23 d (1H, 3′-H, 3J =
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144.78 (C5′), 150.80 (C1′). Found, %: C 49.01; H 4.57;
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