Phenothiazine formation sulfuration

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

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]. 

Sulfonylurea formation, isocyanate, 65, 66 Sulfuration, see also Lawesson benzoxazine, 471 lithio thiophene, 586 phenothiazine, 532, 533 Suzuki reaction, see Coupling Swem oxidation, 18... 

Formation of S" " is revealed by an orange coloration of the solutions when phenothiazine is electrochemically oxidized in acetonitrile and by a golden color when sulfuric acid is used as an oxidant. Characteristic absorption maxima located at 271, 437 and 515 my. were assigned to this species.The same spectrum is recorded when equivalent quantities of phenothiazine and phenothiazine-5-oxide are dissolved in 66% perchloric acid, " the sulfoxide being first converted by the acid into T+ (see Scheme 2, Section IV,B,2), then reduced to S" " by phenothiazine (R) as shown by Eq. (3) (Section IV,B,1). 

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... 

Several years ago. Shine and co-workers reported on reactions whereby sulfuric acid treatment of phenothiazine sulfoxides results in the formation of cation-radicals which are in a lower level of oxidation than the starting materials (i.e., Z47 249 see Section VI,B,3,a). Similar formation... 

PHENOTHIAZINE (92-84-2) Combustible solid. Mixture with acids or acid fumes causes decomposition and formation of sulfur dioxide and nitrogen oxides. Incompatible with aldehydes, cellulose nitrate (of high surface area), organic anhydrides, isocyanates, nitrates. 

Modifications of the palladium-phenothiazine derivative complex procedure of Ryan ° have been applied to the quantitative analysis of propiomazine hydrochloride successfully. j The colorimetric procedure is based on the reaction of palladium with propiomazine in an aqueous solution buffered at about pH 3 to form a colored complex which is spectrophotometrically measured at U65 m/u. Since this complex formation is based on an electron transfer from the sulfur moiety to the palladium ions, the procedure provides a method to assay propiomazine in the presence of its corresponding sulfoxide oxidative decomposition product. 

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