Phenothiazines bromination

Mechanisms involving glycol bond fission have been proposed for the oxidation of vicinal diols, and hydride transfer for other diols in the oxidation of diols by bromine in acid solution.The kinetics of oxidation of some five-ring heterocyclic aldehydes by acidic bromate have been studied. The reaction of phenothiazin-5-ium 3-amino-7-dimethylamino-2-methyl chloride (toluidine blue) with acidic bromate has been studied. Kinetic studies revealed an initial induction period before the rapid consumption of substrate and this is accounted for by a mechanism in which bromide ion is converted into the active bromate and hyperbromous acid during induction and the substrate is converted into the demethylated sulfoxide. 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

Even the comparatively unreactive phenoxazine and phenothiazine systems undergo halogenation and nitration with ease and it is normal to prepare monosubstituted derivatives by stepwise procedures rather than by direct electrophilic attack. Indeed, the nitration of phenoxazine is uncontrollable and even N-acylphenoxazines afford a mixture of di- and tetra-nitro products (03CB475). Similarly phenothiazine and nitric acid produce a complex mixture of nitrated sulfoxides and sulfones. Chlorine in DMSO at 40 °C reacts with phenothiazine to yield 3,7-dichlorophenothiazine, whereas cupric chloride gives the 1,7-isomer (76JPR353). Direct bromination of phenoxazine produces a mixture of 3-bromo- and 3,7-dibromo-phenoxazines, while thionyl chloride affords the 1,3,7,9-tetrachloro derivative (60ZOB1893). 

Seven phenothiazines have been titrated with electrogenerated bromine in the range 0.1-3 mg with an average error of less than 1% [43]. The assay utilizes the oxidation of the phenothiazine in two one-electron steps to a cation-free radical and sulfoxide, respectively. 

To a hot solution 199.3 g (0.1 mol) of phenothiazine in 2 L of dry benzene was added a little quantity of bromine and then were added dropwise 136 g (0.1 mol) of chloroacetyle chloride. Then a mixture was refluxed for 5 hours. After cooling the mixture was concentrated in vacuo. Product was dissolved at reflux in ethanol absolute and filtered. At room temperature was crystallized chloracetyl-10-phenothiazine with 123°C yield 242 g. 

The existence of the ion radical S " has been directly demonstrated by ESR " and it has been shown that this species represents an obligatory step in the oxidation of phenothiazine to phenazathionium salts. This is a definitive confirmation of the results obtained as early as 1941 by Michaelis et who found evidence by potentiometric titration for the stage corresponding to the removal of only one electron in the oxidation of phenothiazine with bromine or lead tetraacetate in acetic acid. 

A particular instance of reductive bromination has been reported by Bodea and Terdic. They brominated phenothiazine-5-oxide with elementary bromine and found that bromophenothiazines are formed, containing one bromine atom more than expected on the basis of the utilized molar ratio. Thus, starting with phenothiazine-5-oxide, on treatment with 1 mole of bromine one obtains 3,7-dibromophenothiazine, with 2 moles of bromine 1,3,7-tribromopheno-thiazine, and with 3 moles of bromine 1,3,7,9-tetrabromophenothia-zine. It was therefore assumed that the first step consists of an electrophilic substitution, leading to 3-bromophenothiazine-5-oxide (54), which immediately undergoes reductive bromination with the hydrobromic acid formed in the first reaction to give 3,7-dibromo-phenothiazine (55). If more bromine is used, 55 is further brominated to the tri- or tetrabromo derivative. 

In earlier literature there are reports of the formation of perhalides on treatment of phenothiazine with bromine and iodine these are now considered to be charge-transfer complexes. The phenothiazine component normally acts as a donor and the electronegative halogens as acceptors, but here total transfer of electrons occurs and the phenothiazine is oxidized. Phenothiazine and 3,7-dimethylpheno-thiazine behave similarly in the presence of strong organic acceptors, like dicyanobenzoquinone and dichlorodicyanobenzoquinone. ... 

Although the reaction of chlorine and bromine with phenothiazine has been long investigated, reproducible methods leading to well-defined halogenated derivatives were described only within the last 15 years. Even for products like 1,3,7,9-tetrachlorophenothiazine which were characterized in the earlier literature, the definitive demonstration of the positions occupied by the chlorine atoms was performed only recently, and the methods of preparation have been substantially improved. 

Chlorinated, brominated, and iodinated derivatives have been prepared by halogenation of phenothiazine. Direct fluorination is unknown. All fluorinated phenothiazines (see, for example. Roe and Little ) have been made by ring closure. Thiocyanation of phenothiazine has also been reported. 

The action of chlorine on phenothiazine-6,5-dioxide in acetic acid or in nitrobenzene at room temperature yields 1,3,7-trichloro-phenothiazine-5,5-dioxide. The lowering of the reactivity in electrophilic substitutions by oxidation at the sulfur bridge is also shown by the fact that 1,3,7,9-tetrachlorophenothiazine-5,5-dioxide is the final product of chlorination even in nitrobenzene at 100°. Direct chlorination was also used with some substituted phenothia-zines. Bromophenothiazines are chlorinated in nitrobenzene to octahalophenazathionium perhalides, as mentioned in Section IV,H,2. There are also reports on the chlorination of some nitro-phenothiazines. Thus, if chlorine is bubbled through the reaction mixture prepared on treating phenothiazine with nitric acid, chloronitrophenothiazine-5-oxides of unknown orientation were obtained. When chlorination of nitrophenothiazines is carried out in nitrobenzene, chlorine replaces the nitrogroups e.g., 3-nitro-lO-methylphenothiazine was converted into octachlorophenothiazine. b. Bromination with Elementary Bromine. The formation of phenazathionium perbromide (66) by the action of bromine on... 

The bromination of phenothiazine-5-oxide probably proceeds via the phenazathionium cation and was therefore discussed in Section IV, G, 4. 

In boiling glacial acetic acid the bromination of phenothiazine-5, 5-dioxide (72) yields only a 3,7-dibromo derivative (71), unlike chlorination, where at room temperature a trichloro derivative was formed (Section V,A,l,a). l,3,7-Tribromophenothiazine-5,5-dioxide... 

Unlike phenothiazine, the 10-methyl derivative can be monobromi-nated in the 3-position. Ring bromination in glacial acetic acid occurs here at room temperature. With 2 moles of bromine, also at room temperature, 3,7-dibromo-lO-methylphenothiazine was prepared. The action of 3 moles of bromine did not lead to a tribromo derivative but to 1,3,7,9-tetrabromophenothiazine (69), the methyl group being removed. Steric considerations are not entirely sufficient to explain this behavior, since bromination of 3-nitro-7-chloro-10-... 

Brominations mth S Br and PBr. The cyclization of 4,4 -dichlorodiphenylamine (57) with S2Br2 to l,9-dibromo-3,7-dichloro-phenothiazine (59) was already mentioned in Section V,A,l,a. In this reaction cyclization probably takes place before bromination. 

The preparation of some 2-ohloro-3,7-bis(3-carbamoyl-l-pyridyl)-phenothiazines by the action of nicotinamide upon the products of bromination of 2-chlorophenothiazine and of its iV-substituted derivatives is described in a patent. ... 

A polyadduct formed from aniline, phenothiazine, oxirane and 2,3-epoxypropane [145] was proposed as a component for the synthesis of a light stable PUR. A polyadduct of 4,4 -isopropylidenebisphenol with 2-hydroxy-4-(2,3-epoxypropyl)-benzophenone [131], polymeric HALS 115 formed from bis(2,3-epoxypropyl)ani-line and 4-amino-2,2,6,6-tetramethylpiperidine [146] or a brominated oligomer 116 used in combination with antimony trioxide as FR for PET [147] are other examples of polyaddition stabilizers. 

The reaction of phenothiazine with halogens is a complex subject certainly radicals are involved. Alcais and Rau showed that the first step of interaction between phenothiazines without an V-substituent and bromine, in a variety of solvents, is irreversible electron transfer to give the... 

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