Phenothiazine derivatives synthesis

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>. 

Figure 2.3.5 shows a series of tricyclic xanthene-, phenoxazine- and phenothiazine-derived templates that have been shown to stabilise p-tum conformations in attached peptides for n=2 and 4.24 These templates were also successfully employed for the synthesis of larger loop mimetics (n S 14). 

A first retrosynthetic approach disconnects the C-N bond yielding a diphenyl sulfide that can remake the initial phenothiazine via cyclization (Scheme 2). Sulfides that could produce phenothiazines by cyclization can be prepared as described in Section II.B. This is a relatively general pathway that allows for the synthesis of a large number of phenothiazine derivatives. 

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). 

An efficient palladium-catalyzed multicomponent system that combines two N-arylations with an S-arylation was developed for the synthesis of phenothiazine derivatives [47], The one-pot reaction of primary amines, 2-bromothiophenol, and substituted l-bromo-2-iodobenzenes, catalyzed by Pd2(dba)3 and ferrocene ligands, affords the phenothiazines 37 in good yields (Scheme 3.25). 

Phenothiazine derivatives, Friedel-Crafts ketone synthesis 17, 879 Phenoxazine ring 17, 328 Phenoxazines via formamides 17, 564... 

The synthesis of phenothiazine derivatives has been achieved through a palladium-catalyzed three-component reaction (Scheme 5.23) [37], The catalyst system comprised of Pdjldbalj and dppf was the most effective combination for the reaction. Some of the other phosphine ligands screened such as XPhos and BINAP generated significant amounts of an acyclic amine product. The reaction was typically carried out in two stages with the first... 

SCHEME 5.23 Synthesis of phenothiazine derivatives based upon a three-component coupling reaction [37],... 

Formation of 1,3-dinitro- and 1,3,6-trinitroselenazine derivatives by a method analogous to the synthesis of phenothiazines have been also described (14CB1873). 

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. 

Naphthoquinone Derivatives, These dyes are generally not very colorfast and sometimes also fade. Anthraquinone derivatives have better properties (see Dyes, ANTHRAQUINONE). New developments are based on compounds that combine the chemical structure of phenothiazine or phenoselenazine derivatives with benzoquinone or naphthoquinone units (16). These dyes show good chemical stability. Naphthoquinone derivatives have yet to find a practical application as dyes in WORM disks because of the high expenditure for synthesis due to low yields. 

Synthesis of pyrido[3,2,l-/r/]-l,4-phenothiazine, quino[8,l-hc]-l,4-ben-zothiazepine, and their derivatives 92JHC675. 

This method has been used for the synthesis of 1-aryl and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine as well as indoline. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A, albeit in very low yield (Scheme 8). 

The first synthesis of phenothiazine was reported by Bernthsen about 80 years ago. In the evolution of the chemistry of this heterocycle, three periods can be discerned. First, phenothiazine was of interest owing to its quinonoid derivatives—an important chapter in sulfur dye chemistry. Research work in the field of phenothiazine was then stimulated by the discovery of the anthelmintic action of unsubstituted and of some C -substituted phenothiazines. During the last two decades, the exceptional pharmacological properties of some A-substituted phenothiazines, e.g., the antihistaminic activity of promethazine, 10-(2-dimethylamino-l-propyl)phenothiazine, and particularly the psychotherapeutic action of chlorpromazine, 2-chloro-10-(3-dimethylamino-1 -propyl )phenothiazine, focused interest mainly on the synthesis and testing of a great number of compounds of this type. The phenothiazine drugs now play a very important part in chemotherapy. 

A-Acylation is, of course, rendered more difficult by the presence of substituents in positions 1 and 9, owing to steric effects. Massie and Kadaba observed that 1-substituted derivatives may be acetylated with acetic anhydride in pyridine, but the use of anhydrous solvents throughout the synthesis and purification is required, since the products are very readily hydrolyzed. 1-Chloro-lO-acetylpheno-thiazine, for example, loses its acyl group even on pouring the reaction mixture into water. Isopropenyl acetate has been recommended by the same authors as an acetylating agent which is able to overcome the steric hindrance in 1-substituted phenothiazines. 

Lithiation of both A/-phenyl- and 0-phenyl-urethanes has been reported. The ortho lithiadon of /V-r-bu-toxycaibonylaniline and subsequent addition to carbonyls, nitriles and several other electrophiles was first reported by Muchowski in 1980. In some cases the adduct cyclized by attacking the urethane carbonyl. Typical examples are shown in Scheme 17. Lithiation of an /V-r-butoxycarbonylaniline derivative served as one of two directed lithiation steps in Snieckus synthesis of anthramycin (17 Scheme 18). Treatment of phenothiazines with 2 equiv. of butyllithium affords an A(,o-dilithium species, but reaction with electrophiles occurs at both sites. Katritzky has shown that the sequence of N-lithiadon, car-bonation and o-lithiation protects the nitrogen from alkylation (Scheme 19). ... 

Phenothiazine (I), the synthesis of which was reported in 1883 by Bemthsen, was the first 1,4-thiazine derivative to be described. Its chemistry, which has been extensively investigated, has been the subject of both com-... 

An alternate synthesis was developed by Etablis-sements Clin-Byla which is based on the decarboxylation by heating of the aminoalkyl ester of the N-carboxy-phenothiazine, Specifically, 2-propionylphenothiazine is converted into its N-carbonyl chloride derivative by reacting with phosgene. Reaction of the chloride with 2-dimethylamino-l-propanol yields the ester hydrochloride, which is decarboxylated by heating (See Figure 7). 

The synthesis and pharmacology of a series of 2-hyd gxy and 2-alkoxy thioxanthene derivatives has been described. Additional phenothiazines related to 15f substituted with an alkypiperidyl group were jlso prepared and reported to have CNS depressant activity. 

Vigante and co-workers used the Hantzsch synthesis to prepare a series of novel symmetrical and unsymmetrical 1,4-dihydropyridine analogs to evaluate their antioxidant ability and therapeutic potential for the treatment of cancer. Reaction of P-unsaturated ketone 278 with p-aminocrotonate derivatives 214 and 210 in refluxing acetic acid gave the corresponding 1,4-dihydropyridine derivatives 279 and 280 in 70% and 65% yield, respectively. This method proved more effective than traditional Hantzsch syntheses involving phenothiazine and either 2 equiv methyl acetoacetate (37%) or P-... 

Andrieux, C. P., Audebert, R, and Saveant, J. M., Studies of modified electrodes starting from pyrrole monomers derivated by anthraquinone, phenothiazine or anthracene moieties on the nitrogen or in the 3-position, synthesis, cyclic voltammetry and a study of charge-transfer reactions, Synth. Metals, 35, 155-158 (1990). 

Downard et al. [123] reported the synthesis of thin films based on the oxidative electropolymerization of substituted pyrroles. The films contained redox couples involving pyrrole derivatives of either the chromophore [Ru(2,2 -bipyridine>3], the electron transfer acceptor paraquat, or the electron transfer donor phenothiazine. 

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