Isothiazole
In isothiazole (1,2-thiazole), the pyridine-like N-atom is bonded to the S-atom. This cr-bond is also the weakest link in the molecule and is cleaved by ring-opening reactions.
The isothiazole molecule is planar; its ionization energy amounts to 9.42 eV and its dipole moment to 2.4 D. Isothiazole absorbs at longer wavelengths than isoxazole and thiazole, due to a tt-> n transition:
g Isothiazole is aromatic. The NMR spectra confirm a largely undisturbed derealization of the n- electrons. In consequence, the aromaticity of isothiazole is greater than that of isoxazole, just as the aromaticity of thiophene is greater than that of furan. From the calculated ^--electron densities, it follows by analogy to isoxazole (see p 138) that electrophilic substitution should occur at the 4-position, while nucleophiles should attack the 3-position. The most important reactions of isothiazoles can be summarized as follows:
Salt formation
Isothiazoles are weak bases with a pKa value of -0.51. Protonation occurs on the N-atom. Liquid isothiazoles can be characterized by their crystalline Perchlorates, e.g.:
Metalation
Isothiazoles unsubstituted in the 5-position are metalated by «-butyllithium [95]. 5-Lithioisothiazoles react with electrophilic reagents, e.g. with haloalkanes to give 5-alkylisothiazoles.
Reactions with electrophilic reagents
Isothiazoles are quaternized by iodoalkanes, dialkyl sulfate, trialkyloxonium tetrafluoroborate or dia-zomethane.
Electrophilic substitutions, e.g. halogenation, nitration and sulfonation, take place regioselectively at the 4-position. The pyridine-like N-atom again impairs electrophilic substitution. For this reason, isothiazole reacts more slowly than thiophene, but faster than benzene.
Reactions with nucleophilic reagents
Isothiazoles react more slowly with nucleophiles than isoxazoles. They are not affected by alkali hydroxides or alkoxides. 2-Alkylisothiazolium salts are more reactive. By the action of aqueous alkali hydroxide, ring-opening occurs with formation of polymeric products. Carbanions cause ring-opening by nucleophilic attack on the S-atom [109], e.g.:
EtOOC-CHo—COOK -EtOOC-CH2 K
NHPh
COOEt
The (ethyloxycarbonyl)methanide ion is produced in the reaction mixture from the potassium salt of the monoethyl ester of the malonic acid. Ring opening by cleavage of the N-S bond is followed by cyclization and /^-elimination. This results in a ring transformation to give substituted thiophenes.
Oxidation
Trisubstituted isothiazoles are oxidized by peroxy acids to 1-oxides and further to 1,1-dioxides. Isothi-azoles, unsubstituted in the 3-position, yield isothiazol-3(2//)-one-1,1 -dioxide with H202 in acetic acid at 80°C [110].
The synthesis of isothiazoles is usually carried out by one of the two methods:
(1) The oxidation of /?-imino thiones with iodine or hydrogen peroxide gives 3,5-disubstituted isothiazoles 1:
- 2
The /?-imino thione is isomeric with its thiol form. Cyclization occurs by a nucleophilic substitution on the S-atom via 2. The reaction can tolerate wide variations in R1 and R2. For instance, p-imino thioamides (R1 = NH2) yield 5-aminoisothiazoles.
(2) The cyclocondensation of /?-chlorovinyl aldehydes (see p 76) with two equivalents of ammonium thiocyanate produces 4,5-disubstituted isothiazoles 3 [110]:
+ nh4scn
- nh4ci
NH4SCN
Vi iNHiscN.
- X
First, an isolable 3-thiocyanatopropenal 4 is formed. It reacts with ammonium thiocyanate to an imine 5, which forms the isothiazole 3 by nucleophilic substitution at the S-atom.
jy Isothiazole is a colourless liquid with a pyridine-like odour, bp 113°C, and sparingly soluble in - water.
The isothiazole moiety is very rarely found in natural products. The fungicidal Brassilexin 6 was isolated from the leaves of the cruciferous plant Brassica juncea. This compound is a derivative of isothi-azoloindole [111]:
Many synthetic isothiazoles are biologically active. For instance, the 5-acetylisothiazolothiosemicarba-zone 7 has a virostatic action and 2-octylisothiazol-3(2//)-one 8 is fungicidal and algicidal.
Saccharin 9, the earliest synthetic sweetening agent (1879), is derived from 1,2-benzothiazole. Saccharin is produced from 2-methylbenzenesulfonyl chloride as follows:
Oxidation of 2-methylbenzenesulfonamide yields the corresponding carboxylic acid, which is transformed into saccharin by cyclodehydration.
Saccharin is a crystalline, virtually water-insoluble compound of mp 244°C. As its water-soluble sodium salt, it is used as a sweetening agent [112]. It is 300 to 500 times as sweet as saccharose, but has a bitter-metallic aftertaste.
Like 7V-bromosuccinimide, TV-bromosaccharin can be used as a brominating or oxidizing agent. —-J TV-Acylsaccharins serve as acylating agents for tertiary alcohols and convert amino alcohols selectively into Af-acyl derivatives.
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