Phenothiazines from diphenylamines

A patent claims the preparation of A-substituted phenothiazines from the corresponding diphenylamines using SCI 2 in benzene as a thionating agent. There is no mention of chlorination as a side reaction, although with S2CI2, which is less reactive in this respect, chlorination seems to accompany the thionation (see Section V, A, l,d). 

Describe how would you synthesize ethopropazine hydrochioride—a phenothiazine analogue from diphenylamine. 

Some other inhibitors from the patent literature include hydroquinone [129], ionoP [130], and quinone [131]. Other inhibitors used to stabilize MMA include butylated hydroxy toluene (BHT), phenothiazine, methylene blue, hydroxy-diphenylamine and di-/jc/<3-napthol [132]. Several good reviews of inhibition and inhibitors have been written [133-136]. The mechanisms of inhibition are subtle and complicated. For example, it has been reported that highly purified benzo-quinone acts as a retarder rather than an inhibitor [137]. It has been proposed... 

Substituted diphenylamines react in the same way, and the formation of small amounts of 4-substituted phenothiazines is observed, a feature also encountered in other thionation reactions. Phenothiazine could be obtained neither from nitrodiphenylamines nor, surprisingly, from A -phenyltoluidines. Also surprising is the... 

These include amitraz (110), prepared from 54, a member of the form amidine class, active against mites and ticks, that have replaced organophosphorus compounds. Notably, amitraz is active against newer strains of pyrethroid-resistant ticks. The reaction of diphenylamine (8) with sulfur in the presence of iodine as catalyst yields the anthelmintic (worming agent) phenothiazone (phenothiazine) (111) (Scheme 24). It is too toxic for human use, though it is an intermediate in the production of antipsychotic drugs. 

N-substituted diphenylamines also yielded phenothiazines on treatment with SOCI2 (33GEP562268). In this way, A-acetyldiphenylamine was quantitatively converted into tetrachlorophenothiazine, while A-phenyldiphenylamine (triphenyla-mine) gave 3,7-dichloro-10-(4 -chlorophenyl)-phenothiazine in 91% yield. In the first case, the chlorine atoms in positions 1 and 9 promote the removal of the acyl group from position 10 in the second case, the bulky N-substituent prevents the replacements of hydrogen from positions 1 and 9 by chlorine. The behavior of A-methyl-diphenylamine is intermediate in this respect 3,7-dichloro-lO-methylphenothiazine was isolated in 7% yield, along with tetrachlorophenothiazine (68AHC325). 

Two patents claim the preparation of phenothiazine-sulfones from substituted diphenylamines (with at least one free position ortho to the amino group) using oleum with 60-70% SO3 at 80-125 °C (33GEP562268, 34BRP420444). 

The synthesis of SFs-substituted phenothiazine was disclosed in a patent from Smith, Kline French Laboratories (63USP3107242). 3-SFs-Acetanilide (120), prepared by acetylation of d-SFs-aniline (39) with acetic anhydride, was first condensed with bromobenzene under basic conditions, in the presence of Cul and copper-bronze powder, and after add hydrolysis provided 3-SFs-diphenylamine (121). This product was then fused with sulfur in the presence of a catalytic amount of iodine to give 2-SFs-phenothiazine (122) in unreported yield (Scheme 34). 

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