Sulfuric acid: A mild catalyst for the regioselective synthesis of 2-substituted [1,2,4]triazolo[5,1- b][1,3]thiazin-7-ones

Article abstract of DOI:10.1007/s007060170037

A facile and regioselective synthesis of 2-substituted [1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones by action of sulfuric acid on (4H-[1,2,4]triazol-3-ylsulfanyl)-acrylic acids is described.

Full text of DOI:10.1007/s007060170037

Monatshefte fuÈr Chemie 132, 1225±1228 (2001)
Sulfuric Acid: A Mild Catalyst for the
Regioselective Synthesis of 2-Substituted
[1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones
Majid M. Heravi1;2;Ã, Nasser Montazeri1, Mohammad Rahimizadeh1,
Mehdi Bakavoli1, and Mitra Ghassemzadeh3
1
Department of Chemistry, School of Sciences, Ferdowsi University, Mashhad, Iran
2
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
3
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
Summary. A facile and regioselective synthesis of 2-substituted [1,2,4]triazolo[5,1-b][1,3]thiazin-7-
ones by action of sulfuric acid on (4H-[1,2,4]triazol-3-ylsulfanyl)-acrylic acids is described.
Keywords. Sulfuric acid; Triazolothiazine; Regioselective cyclization.
Introduction
[1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones (4) have been ®rst prepared by Peter et al.
[1] by cyclization of 1,2,4-triazole-3-thiols (1) with diethyl ethoxy-methylenema-
lonate in fair to good yields. In the same year, Heindel et al. [2] have synthesized this
heterocyclic system by condensation of 3-mercapto-1,2,4-triazole-4-amines (2) with
methyl propionate, hydrolysis of the resulting S-acrylic esters to the corresponding
S-acrylic acids (3), and subsequent cyclization to 4 or 5 [2]. The cyclization of 3 to
4 or 5 using thionyl chloride has also been reported as an independent synthesis [2].
Here we report a simple and ef®cient synthesis of 3 and the regioselective
cyclization of the latter to give 4 in good to high yields.
Results and Discussion
Earlier studies which made triazoles 1 available in large quantities [3] and our
continuing interest in the synthetic application of acetylenenic esters [4] prompted
us to investigate the condensation of 1 with propiolic acid. A Michael-type addition
of equimolar quantites of 1a±c and propiolic acid in re¯uxing anhydrous methanol
afforded 1:1 adducts identi®ed as the S-substituted acrylic acids 3a±c in good
yields. 1H NMR spectra showed a broad, D2O exchangeable signal at about 14 ppm
and, in addition, two doublets at ca. 6 and 8 ppm, respectively.
Ã
Corresponding author. E-mail: mmheravi@azzahra.ac.ir

1226
M. M. Heravi et al.
Scheme 1
The adducts 3a±c exhibit (Z)-con®guration, re¯ecting a trans addition of the SH
group to the acetylenic bond. The two ole®nic protons show coupling constant of
10 Hz as has been reported for similar (Z)-con®gured adducts of methylpropiolate
and thioamides [5].
It has been reported that formation of (Z)-con®gured adducts (J ˆ 10:0 Hz)
predominates over that of the (E)-con®gured counterparts (J ˆ 15:5 Hz) in such
additions [5]. In spite of the (Z)-con®guration, which might favour a cyclization
pathway, cyclization was not observed under a variety of reaction conditions
(re¯uxing in solvents of high boiling point and using sodium alkoxide or sodium
hydroxide as catalyst). For the cyclization of 3a via its acid chloride, phosphorus
oxychloride was used; 4a was obtained in moderate yield (53%).
In a recent publication [6] we have demonstrated the utility of sulfuric acid
for the resioselective cyclization of propynylmercapto heterocycles to condensed
thiazoles. Thus, 3a was treated with conc. H2SO4 at 50ꢀC. Subsequent aqueous
work-up afforded a single compound (TLC). Its 1H NMR spectra showed signals at
7.0 (d, J ˆ 10Hz, 1H), 8.4 (s, 1H), and 8.6 (d, J ˆ 10Hz, 1H) ppm which con®rmed
a cyclized product. Fusion of the triazole and the thiazine moieties could be affected
in two different ways as represented by 4 and 5. Two further S-acrylic acid
derivatives (3b,c) were cyclized in order to obtain more spectroscopic information
and to establish the generality of the method. The data of the corresponding
products were in accordance with those of the products obtained from 3a. To
distinguish between structures 4 and 5, one should take into account that cyclization
of the acrylic acid side chain to the ring nitrogen adjacent to the substituent at C-5
of the triazolo ring would yield a carbonyl group in the peri position to that
attachment; in the case of a methyl group at this location, one would expect a
considerable anisotropic effect [2].
1
The H NMR spectra of 3b and its cyclization product show the ring methyl
signal at ꢀ ˆ 2:65 and 2.75 ppm, indicating almost no down®eld shift. Thus, the
cyclization product is assigned structure 4b, and, accordingly, 4a and 4c are
assigned to the cyclization products from 3a and 3c. In the case of 2,3-dimethyl-5H-

Regioselective Synthesis of [1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones
1227
imidazolo[2,1-b][1,3]thiazin-5-one, the methyl group signal has been found at
ca. 2.10 ppm [2].
In conclusion, sulfuric acid has been shown to smoothly catalyze the cyclization
of S-acrylic acid derivatives of triazole thiols. The present method to obtain
condensed 1,3-thiazines is superior to others which show drawbacks originating
from an indirect route [2], low yield [1], low regioselectivity [7], and toxic reagents
such as SOCl2 [2].
Experimental
[1,2,4]Triazole-3-thioles (1) were prepared according to a known procedure [1]. Unless otherwise
stated, melting points were determined on a Reichert apparatus and are uncorrected. IR spectra were
1
recorded on a Shimatsu spectrometer using KBr discs, H NMR spectra on a Bruker instrument at
100 MHz. Mass spectra were obtained on a Varian CH-7 spectrometer at 70 eV.
Preparation of 3a±c (general procedure)
[1,2,4]Triazole-3-thioles (0.01 mol) and 0.01 mol propiolic acid were re¯uxed in 25 cm3 CH3OH for
5 h. The solvent was evaporated to dryness under reduced pressure, and the crude product was
crystallized from H2O to afford 3a±c.
3-(4H-[1,2,4]triazol-3-ylsulfanyl)-acrylic acid (3a; C5H5N3SO2)
Yield: 78%; mp.: 209±210ꢀC; 1H NMR (DMSO-d6, ꢀ, 100 MHz): 6.15 (d, J ˆ 10 Hz, 1H, CH), 8.00
(d, J ˆ 10 Hz, 1H, CH), 8.6 (s, 1H, CH), 14.3 (s, br, exchangeable with D2O, 1H, COOH) ppm; IR
‡
(KBr disc): ꢁ ˆ 3500, 3110, 1650, 1330, 980cm 1; MS: m=z ˆ 171 (M ).
5-Methyl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-acrylic acid (3b; C6H7N3SO2)
Yield: 82%; mp.: 215±216ꢀC; 1H NMR (DMSO-d6, ꢀ, 100 MHz): 2.45 (s, 3H, Me), 6.1 (d, J ˆ 10 Hz,
1H, CH), 8.00 (d, J ˆ 10 Hz, CH), 13.8 (s, br, exchangeable with D2O, 1H, COOH) ppm; IR (KBr
‡
disc): ꢁ ˆ 3100, 1680, 1580, 1420, 1350, 900, 790 cm 1; MS: m=z ˆ 185 (M ).
5-Phenyl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-acrylic acid (3c; C11H9N3SO2)
Yield: 81%; mp.: 244±245ꢀC; 1H NMR (DMSO-d6, ꢀ, 100 MHz): 6.2 (d, J ˆ 10 Hz, 1H CH), 7.5 (s,
3H, aromatic), 7.9 (s, 2H, aromatic), 8.1 (d, J ˆ 10 Hz, 1H, CH), 14.7 (s, br, exchangeable with D2O,
1H, COOH) ppm; IR (KBr disc): ꢁ ˆ 3550, 3110, 1680, 1590, 1320, 1210, 790 cm 1; MS:
‡
m=z ˆ 247 (M ).
Preparation of 4a±c (general procedure)
Compounds 3a±c (0.005 mol) were dissolved in 5 cm3 conc. H2SO4, and the reaction mixture was
stirred at 50ꢀC for 2 h. After addition of crushed ice, solution was neutralized with NaOH. The
precipitated solid was ®ltered off, washed with 5 cm3 H2O, and crystallized from H2O to afford 4a±c.
[1,2,4]Triazolo[5,1-b][1,3]thiazin-7-one (4a; C4H3N3SO)
Yield: 68%; mp.: 230±232ꢀC; 1H NMR (DMSO-d6, ꢀ, 100 MHz): 7.0 (d, J ˆ 10 Hz, 1H, CH), 8.4 (d,
J ˆ 10 Hz, 1H, CH), 8.65 (s, 1H, CH) ppm; IR (KBr disc): ꢁ ˆ 3450, 3010, 1700, 1500, 1280,
‡
810 cm 1; MS: m=z ˆ 153 (M ).

1228
M. M. Heravi et al.: Regioselective Synthesis of [1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones
2-Methyl-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one (4b; C5H5N3SO)
1
Yield: 73%; mp.: 196±197ꢀC (Ref. [2]: 196±197ꢀC); H NMR (DMSO-d6, ꢀ, 100 MHz): 2.8 (s, 3H,
Me), 6.7 (d, J ˆ 10 Hz, 1H, CH), 8.3 (d, J ˆ 10 Hz, 1H, CH) ppm; IR (KBr disc): ꢁ ˆ 3400, 3050,
‡
1680, 1450, 1000, 1210, 810cm 1; MS: m=z ˆ 167 (M ).
2-Phenyl-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-one (4c; C10H7N3SO)
Yield: 80%; mp.: 264±265ꢀC; 1H NMR (DMSO-d6, ꢀ, 100 MHz): 7.0 (d, J ˆ 10 Hz, 1H, CH), 7.6 (m,
3H, aromatic), 8.3 (m, 2H, aromatic), 8.4 (d, J ˆ 10 Hz, 1H, CH) ppm; IR (KBr disc): ꢁ ˆ 3550,
1
‡
3110, 1680, 1590, 1320, 1210, 790cm ; MS: m=z ˆ 247 (M ).
References
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Received January 23, 2001. Accepted (revised) May 7, 2001