Phenothiazines, Smiles rearrangement

Chloro-5-nitrobenzaldehyde, -acetophenone, or -benzophenone derivatives treated with 2-aminothiophenol under alkaline conditions provided good yields of the corresponding dibenzo[(3,/][l,4]thiepins. Similar treatment of 2-chloro-3,5-dinitrobenzophenone (318) provided 58% of dibenzo[(3,/][l,4]thiepin 321 and 20% of phenothiazine 323. Its formation can be easily explain by the Smiles rearrangement of the initially formed intermediate 320 into diphenylamine derivative 322, followed by denitrocyclization reaction leading to the corresponding product of denitrocyclization 323 (Scheme 49). When the reaction was done in pyridine, only this product was isolated in 50% yield (57JCS3818). 

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... 

Synthesis of a new dipyrido-l,4-thiazine 328 has been described involving a Smiles rearrangement, and A -alkylation, arylation and heteroarylation of 328 have been repotted as well as its promising anti-tumor activity <2007H(71)1347>. Phenothiazine derivatives such as 329 and 330 have been developed for use in dye-sensitized solar cells <2007CC3741>. 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

The synthesis of phenothiazines starting with o-amino-o -halogeno-diphenyl sulfides has been a controversial problem, inasmuch as compounds like 8 may undergo an Ulmann-type cyclization to 2,8-disubstituted phenothiazines (9), or, through a Smiles rearrangement, may give 2,7-disubstituted phenothiazines (10). 

Warburton et al. (57AJC502) have tried the synthesis of 1,4-benzothiazino[2, 3-Z ]phenothiazine from 4,6-Z A[(2-acetamido-4-chlorophenyl)thio]-1,3-dinitroben-zene 11 by a double Smiles rearrangement. Unfortunately, the reaction stops after the first rearrangement to yield phenothiazine derivative 12 (Scheme 11). 

Other syntheses of phenothiazines via Smiles rearrangements fall into the next sections. 

The Smiles rearrangement of the sulfide 47 in the presence of potassium hydroxide in ethanol under reflux for 2.5 h flmiished the phenothiazines 48. The sulfide 47, in turn, was obtained from the reaction of aminothiophenol 44 and 2,5-dichloronitrobenzene 45 followed by formylation. ... 

Phenothiazines 178 were obtained from the Smiles rearrangement of sulfides 176 which were, in turn, prepared from the reaction of aminothiophenol 174 and nitrobenzene 175. ... 

Traditional routes to phenoxazines include the thermolysis of 2-aminophenol and catechol, the latter acting as an acid catalyst, or catechol and ammonia. Phenothiazines are prepared similarly by heating diphenylamines with sulfur (Scheme 10) (B-78MI22701). 2-Hydroxy- (or mercapto-) 2, 4 -dini-trodiphenylamines cyclize to phenoxazines (or phenothiazines) in base by elimination of nitrous acid. This reaction is complicated by Smiles-type rearrangement so that mixtures of isomeric products are obtained (Scheme 11). 

Among the more recent approaches to phenoxazines and phenothiazines the reductive cyclization of 2-nitrodiphenyl ethers and sulfides with trialkyl phosphites is the most interesting. Here too a spiro intermediate is involved, produced by attack of an initially formed aryl nitrene on the second aromatic ring. The sulfide (252), for example, reacts with triethyl phosphite to yield 1-methylphenothiazine (253) and it is clear that in this case ring opening of the spiro intermediate also proceeds with a rearrangement of the Smiles type (Scheme 113) (75JCS(P1)2396). 

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