From 2-Aminobenzenethiols

In 1880, Hofmann reported the first preparation of benzothiazole from 2-aminobenzenethiol and formamide. Hofmann stated that benzothiazoles were formed by the interaction of 2-aminobenzenethiol and aldehydes. Bogert et al. later confirmed the same as part of their own studies on the derivatives of thiazoles,during which they synthesized 6-chloro-2-phenyl-benzothiazole. Hofmann had noted only formation of 2- anilinobenzothiazole from the reaction of 2-aminothiophenol and phenyl isothiocyanate. 

Variations of this reaction have been applied over the years, typically involving the condensation of 2-aminothiophenols with substituted carboxylic acids, acyl chlorides, aldehydes, and nitriles. Initially, the reaction involves the formation of an imine that cyclizes spontaneously and then oxidation to form benzothiazole. An application of this chemistry has been showcased in the synthesis of 2-(4-aminophenyl)benzothiazoles and the evaluation of their in vitro and in vivo activities against breast cancer cell lines, with compound a exhibiting the most potent growth inhibition. Unfortunately, there are limitations due to the difficulties met during the syntheses of readily oxidizable o-aminothiophenol-bearing substituents. 

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Early reports that 2-substituted dihydro-1,4-benzothiazines (39) could be prepared from 2-aminobenzenethiol with epoxides84,85 were later shown incorrect.86-88 The actual product is the amino alcohol 40. Fujii88 claimed, however, that heating the hydrochloride salt of 40 (R = H) did produce 3,4-dihydro-1,4-benzothiazine (39, R = H), and more recently it has been shown that benzothiazines can be obtained by reaction of perfluoroepoxides with 2-aminobenzenethiol.89... 

Miyano et al. observed an interesting cyclization of the vinylogous thiol ester (59), prepared from 2-aminobenzenethiol and 3-chloro-5,5-dimethylcyclohex-2-enone. On heating in DMSO, 59 gave benzothiazine 60. A... 

Important variants for the synthesis of benzimidazoles allow the use of aldehydes, rather than acids ytterbium triflate (best for aliphatic aldehydes) or scandium triflate catalyse the condensation and the subsequent air oxidation of the dihydrobenzimidazole immediate product. Incorporating nitrobenzene in the reaction mixture as the oxidant can also be used. orf/to-Nitroanilines can be used by incorporating a reducing agent in the reaction mixture - e.g. hydrogen over palladium or sodium dithionite - for in situ generation of the orffto-phenylenediamine. 2-Aryl-benzothiazoles can be made from 2-aminobenzenethiol, aromatic aldehydes and air, in the presence of activated carbon. ... 

Scheme 16. Konig benzothiazolium synthesis from 2-aminobenzenethiol...

A direct synthesis of quaternary salts (e.g. alkylsulfates, iodides, bromides, perchlorates) of benzothiazole from 2-aminobenzenethiol has been narrated in Uteratue by Kiptrianov and Pazenko. Fry and Kendall synthesized quaternary salts of 2-alkylsulfanylbenzothiazole and used them in the synthesis of thiacyanine dyes (Fry Kendall 1951). Similar type of synthesis of 2-haloalkylsufanyl benzothiazolium salts was carried out by Knott in 1955 (Knott 1955). Brooker (1951) prepared benzothiazolium salts from substituted benzothiazoline and p-toluensulfonate for further conversion to cyanine dyes (Brooker et al 1951). 

Both oxidation and fluorodediazoniation with sodium nitrite and hydrogen fluoride/pyridine mixtures have been used advantageously in the synthesis of fluorinated aryl disulfides from aminobenzenethiols.98 In this case, too, the global yield is dependent on the hydrogen fluoride/ pyridine ratio (e.g., fluorodediazoniation yield = 65% with 20 wt % pyridine, 90% with 30 wt % pyridine, 93 % with 40 wt % pyridine and 10 % with 50 wt % pyridine for the formation of 4-fluorobenzenethiol).98... 

Based on the reaction displayed in Scheme 22, one could expect that the phenothiazine ring could be prepared from aminobenzenethiols and 1,2-dihalogeno-benzenes. However, the low reactivity of halogen atoms attached to the benzene ring makes this method difficult. 

Appropriate 2-aminobenzenethiol 1 (2 mmol) and /(-kctocstcr or /(-di ketone 2 (2 mmol) were introduced in a beaker (100 mL) and dissolved in chloroform (5 mL). Basic alumina (S.D. Fine Chemicals Pvt. Ltd., 5 g) was then added and swirled for a while followed by removal of solvent under gentle vacuum. The dry powder thus obtained was irradiated in a microwave oven at power output of 520 W for an appropriate time (monitored by TLC). The inorganic support (which can be reused 3-4 times without any loss of activity) was separated by filtration after eluting the product with acetone (5x20 mL). The filtrate was dried over sodium sulfate and the product, obtained after removal of solvent, was recrystallized from methanol as colored crystals in good yields. 

The pyrilium salt 30a was obtained from benzo-9-crown-3 in 29% yield in two steps by formylation with hexamine in the presence of CF3CO2H, followed by reaction with 2 equiv of acetophenone in the presence of POCI3 <2002JOC2065>. In the same manner, the Vilsmeier formylation of the /V-phenyl dithiazonine and the subsequent condensation reaction with 2-aminobenzenethiol resulted in substituted benzothiazole 43 in 38% yield < 1999J(P2)1273>. Benzo-9-crown-3 ether trimerizes in the presence of fed and aqueous sulfuric acid to produce tris-(9-crown-3)-triphenylene 28 in 25% yield <2001CJC195>. 

Stephens WD, Field L (1959) A seven-membered heterocycle from o-aminobenzenethiol and chalcone. J Org Chem 24 1576... 

Chelate amino complexes (V Y = NH, Z = 0,S) were obtained from [7T-C5H5Co(CO)l2] with o-aminophenols and o-aminobenzenethiols (255). Related complexes are obtained from [Rh(CO)2Cl]2 with the latter ligands... 

Fe3(CO)[2 reacts with o-aminobenzenethiol in boiling cyclohexane to form the nitrogen- and sulfur-bridged complex (XII), through loss of hydrogen from both the sulfur and nitrogen atoms (338). 

Coordination complexes of CpTiCl3 with N2S2 and S202 ligands derived from n-aminobenzenethiol have been synthesized.4... 

Synthesis. - From oviho-Aminobenzenethiols (Type A S-C 4 N + C). The cyclization between RNC and 0-NH2C6H4SH gives a 2-substituted benzothiazole. ... 

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