Phenothiazine Sulfides

Coordination-driven self-assembly of homologous bis-phenothiazine sulfide, sulfoxide, and sulfone ligand syntones 393-395 by... 

The phenothiazine sulfides were obtained from West Chemical Company. Their preparation has been described by Nodiff and Cantor, Their structures, and that of chlorpromazine hydrochloride (CPZ.HCl), are shown in Fig. 2. 

We wish to thank Dr. Cantor for his generous gift of phenothiazine sulfides ... 

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). ... 

An alternative synthesis of 4-nitrodibenzothiophene involves heating 2-amino-2 -nitrodiphenyl sulfide in a sealed tube at 190° (20%). The reaction probably proceeds via homolytic cleavage of the derived diazonium ion which could have been formed from nitrous acid liberated during the formation of phenothiazines, which were also detected. Similarly, 2-methyl-4-nitrodibenzothiophene is formed from 2-amino-2 -nitro-4 -methyldiphenyl sulfide (10%), and in this case the intermediacy of the diazonium ion was further indicated in that the same material was obtained by pyrolysis of the separately prepared diazonium salt of the sulfide. Although yields are poor in this reaction, it nevertheless represents the only route to substituted dibenzothiophenes containing a nitro substituent in the 4-position and as such is worthy of further attention. 

Deoxygenation of the diaryl sulfide (56) with triethyl phosphite gives the phenothiazine (58) in good yield via formation and rearrangement of the spiro intermediate (57). 

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). 

Examples of multifunctional sulfides which bond to platinum(II) via the sulfide sulfur are phenoxathiin (184) and the phenothiazine drugs (185).1732,1733... 

However, no recombination products according Equation 25 have been looked for and, thus, sulfoxide production due to sulfide oxidation by an intermediate 10-methyl-phenothiazine-3-hydroperoxide cannot be excluded. 

Among the many toxicants that cause convulsions are chlorinated hydrocarbons, amphetamines, lead, organophosphates, and strychnine. There are several levels of coma, the term used to describe a lowered level of consciousness. At level 0, the subject may be awakened and will respond to questions. At level 1, withdrawal from painful stimuli is observed and all reflexes function. A subject at level 2 does not withdraw from painful stimuli, although most reflexes still function. Levels 3 and 4 are characterized by the absence of reflexes at level 4, respiratory action is depressed and the cardiovascular system fails. Among the many toxicants that cause coma are narcotic analgesics, alcohols, organophosphates, carbamates, lead, hydrocarbons, hydrogen sulfide, benzodiazepines, tricyclic antidepressants, isoniazid, phenothiazines, and opiates. 

Some new variants of the thionation of diphenylamines and of the cyclization of suitably substituted diphenyl sulfides—the two well-known principal routes to the phenothiazine ring—have recently been developed. 

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). 

Hrutford and Bunnett obtained phenothiazine in 35% yield on treatment of o-amino-o -bromodiphenyl sulfide (11) with KNHg in liquid ammonia and assumed that a benzyne system 12 was an intermediate in the reaction. 

Cadogan et al. performed a reductive cyclization of o-nitro-diphenyl sulfide (14) to phenothiazines (9) using triethyl phosphite. In the case of unsubstituted phenothiazine, the yield was 54%. 

Dialkyl sulfides and aluminum chloride are reported to introduce alkylthio groups in position 3 of the phenothiazine molecule. Attempts to introduce the —SCCI3 group into the molecule of 10-methylphenothiazine failed. ... 

A sulfur moiety introduces a hydroperoxide deactivating effect into the stabilizer molecule. Moreover, the condensation of low molecular weight compounds with halides of sulfur represents an easy synthetic approach to the increase of the molecular weight and consequently to the improvement of the physical persistency of stabilizers. Efficient AO were prepared by this way from alkylphenols, aromatic amines or phenothiazine [21,174]. Most of them contain two active units connected with a sulfide/disulfide bridge and should be listed rather among high molecular weight stabilizers. Antioxidant 136 (n > m), prepared from pyrocatechol and... 

Source C. Aubert, R. Durand, P. Geneste, and C. Moreau, Hydroprocessing of Diben-zothiophene, Phenothiazine, Phenoxanthlin, Thianthrene, and Thioxanthene on a Sulfided i() Mot) Jy AllJournal of Catalysis 97 169—176 (1986). With permission. 

Phenoxazines and phenothiazines 32 and 33 are also made by reductive cyclization of o-nitrodiphenyl ethers or o-nitrodiphenyl sulfides, respectively, with triethyl phosphite. 

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