10- phenothiazine, reaction with

In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 25. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine. Alkylation with the familiar halide (3) affords dimethothiazine (18). ... 

Ullmann condensation of the sodium salt of p-chlorothiophe-nol (31) with 2-iodobenzoic (32) acid gives 33. Cyclization by means of sulfuric acid affords the thioxanthone, 34. Reaction with the Grignard reagent from 3-dimethylaminopropyl chloride affords the tertiary carbinol (35). Dehydration by means of acetic anhydride affords chlorprothixene as a mixture of geometric isomers, 36. (Subsequent work showed the Z isomer-chlorine and amine on the same side—to be the more potent compound.) Chlorprothixene is said to cause less sedation than the phenothiazines. ... 

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... 

Reaction of the benzotriazole-linked phenothiazine 444 with 2,3-dihydrofuran and zinc bromide yields the peri-fused furopyridophenothiazine 445 (Equation 193) <1999JHC473>. 

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

Substitution of an additional nitrogen atom onto the three-carbon side chain also serves to suppress tranquilizing activity at the expense of antispasmodic activity. Reaction of phenothiazine with epichlorohydrin by means of sodium hydride gives the epoxide 121. It should be noted that, even if initial attack in this reaction is on the epoxide, the alkoxide ion that would result from this nucleophilic addition can readily displace the adjacent chlorine to give the observed product. Opening of the oxirane with dimethylamine proceeds at the terminal position to afford the amino alcohol, 122. The amino alcohol is then converted to the halide (123). A displacement reaction with dimethylamine gives aminopromazine (124). ... 

Chlorpromazine and other phenothiazines can be identified by their reactions with benzene-, toluene-o-, and toluene /j-stilbinic acids, and with p-hydroxy-, m-nitro-, w-amino-, and p-nitrobenzene stilbinic acids in an HCl medium. The reaction products are initially colorless masses but rapidly oxidize to yield colored products [32]. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Heterocyclic substrates in SET processes have been widely studied, including the reactions of dihydronicotinamide,116 pyridine, and quinoline117 and also phenoxazine and phenothiazines.118 Phenothiazine has also been shown by ESR analysis to undergo an electron-transfer reaction with its radical cation with an appreciable 15N/14N isotope effect.119 The reaction of phenazine di-iV-oxide radical cations with hydrocarbons shows evidence of non-radical processes.120... 

Dithiazepine 127 upon reaction with phenothiazine or chlorophenothiazine 128 in dimethylformamide (DMF) in the presence of sodium hydroxide gave the 1,2,5-dithiazepine 129 (Scheme 30) <2001BML1859>. 

Benzophenone (BP) sensitized photooxidation of phenothiazine leads mainly to the formation of products A and B (17). In view of the many data available from the literature and from our own experiments the published interpretation needs, however, some revision provided 3H-phenothiazine-3-ones are not products of a singlet oxygen reaction with ground state phenothiazine (c.f. methylphenothiazine), formation of products A and B implies two different oxidation mechanisms. Since singlet oxygen sensitization by benzophenone (Equations 10 to 12) is known to be very inefficient, reaction sequence (10), (13), (14), and (9)... 

Casey, J. E, Lasky, J. J., Klett, C. J., Hollister, L. E. 1960b, Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital, Am.].Psychiatry, vol. 117, pp. 97-105. 

Eberson and co-workers have recently discussed the probability that the interaction of ion-radicals with nucleophiles and electrophiles is subject to orbital symmetry constraints.31,32 This follows the observation that with perylene the cation-radical (18) the preferred course of reaction with halide ions is electron transfer rather than nucleophilic addition, whereas with the phenothiazine cation-radical (19) nucleophilic attack by Cl" and Br occurs. 

Phenothiazine substitution reactions have been much studied in recent years. This work was stimulated by the search for new phenothiazine derivatives with useful pharmacological properties and by the commercial availability of unsubstituted phenothiazine. 

---