Phenothiazines halogenation

Halogen-metal exchange reactions provide the main route to 3-lithiated derivatives of phenothiazine and phenoxazine and examples of metalated compounds formed by the use of such exchange reactions include the... 

The nitrogen of phenothiazine 16 can be deprotonated and alkylated, for example, with a palladium catalyst <1985AXC1804>. When an excess of butyllithium was used for 188, an additional halogen-metal exchange occurred and the compound could be doubly silylated (Scheme 14) <20020L623>. 

Even the comparatively unreactive phenoxazine and phenothiazine systems undergo halogenation and nitration with ease and it is normal to prepare monosubstituted derivatives by stepwise procedures rather than by direct electrophilic attack. Indeed, the nitration of phenoxazine is uncontrollable and even N-acylphenoxazines afford a mixture of di- and tetra-nitro products (03CB475). Similarly phenothiazine and nitric acid produce a complex mixture of nitrated sulfoxides and sulfones. Chlorine in DMSO at 40 °C reacts with phenothiazine to yield 3,7-dichlorophenothiazine, whereas cupric chloride gives the 1,7-isomer (76JPR353). Direct bromination of phenoxazine produces a mixture of 3-bromo- and 3,7-dibromo-phenoxazines, while thionyl chloride affords the 1,3,7,9-tetrachloro derivative (60ZOB1893). 

Phenothiazine is readily oxidized when irradiated in solution with chlorinated hydrocarbones (8). The reaction has been shown to be an electron transfer generating the phenothiazine (PTH) radical cation (PTH+ ) and the halogen anion as shown in equation 1. hv. ... 

Physicochemical characterization of the oxidized species was primarily made working with chemically generated ones. Usually, only parameters characterizing the main absorption maximum of the colored products obtained by the action of sulfuric acid were reported. In the case of halogenated phenothiazines, systematic determinations were carried out by Rupprecht and the dependence of the position of the absorption maximum upon the amount and nature of the halogen atoms may be obtained from the data in Table IV. 

S ", obtained on treatment of di-, tetra-, and octachloro- and -bromo-phenothiazines with sulfuric acid was investigated by Bodea and Silberg. Precise g value measurements revealed a stepwise diminution of the relative influence of the halogen atoms on the ESR signal with increasing number of halogens. This was explained on the basis of the parallelism existing between the reactivity of different... 

It is now established that the orientation of the reductive halogenation is controlled by nitrogen positions 3 and 7 are occupied first, then 1 and 9. Thus Schmalz and Burger obtained 3-chloro-lO-methyl-phenothiazine (45) from lO-methylphenothiazine-5-oxide (44) and hydrochloric acid, and 3,7-dichloro-lO-methyl-phenothiazine (47)... 

The mechanism of the reductive halogenation is still controversial. Two types of mechanism have been invoked.The first involves the formation of phenazathionium halides, followed by the nucleophilic attack of the halide ion. The second consists of an oxidation of the acid by the sulfoxide oxygen the halogen thus formed electrophilically attacks the reduced phenothiazine. 

We believe that, in the reductive halogenation, the halogens almost certainly enter the phenothiazine ring via both of the mechanisms discussed above. 

In earlier literature there are reports of the formation of perhalides on treatment of phenothiazine with bromine and iodine these are now considered to be charge-transfer complexes. The phenothiazine component normally acts as a donor and the electronegative halogens as acceptors, but here total transfer of electrons occurs and the phenothiazine is oxidized. Phenothiazine and 3,7-dimethylpheno-thiazine behave similarly in the presence of strong organic acceptors, like dicyanobenzoquinone and dichlorodicyanobenzoquinone. ... 

Although the reaction of chlorine and bromine with phenothiazine has been long investigated, reproducible methods leading to well-defined halogenated derivatives were described only within the last 15 years. Even for products like 1,3,7,9-tetrachlorophenothiazine which were characterized in the earlier literature, the definitive demonstration of the positions occupied by the chlorine atoms was performed only recently, and the methods of preparation have been substantially improved. 

Chlorinated, brominated, and iodinated derivatives have been prepared by halogenation of phenothiazine. Direct fluorination is unknown. All fluorinated phenothiazines (see, for example. Roe and Little ) have been made by ring closure. Thiocyanation of phenothiazine has also been reported. 

The preparative value of metalation reactions consists primarily in the possibility of obtaining 1- and 4-substituted phenothiazines, which are difficult to prepare by other methods. Also lithiation at position 3 by halogen-metal exchange using triphenylsilyllithium presents interesting possibilities. 

The consequences of methylation and hydroxylation of phenothiazine for the ESR spectra of its cation-radicals were noted early by Billon et Bodea and Silberg have described a series of halogenated pheno-thiazinyls and the effect of progressive halogenation on their g-values. 

The reaction of phenothiazine with halogens is a complex subject certainly radicals are involved. Alcais and Rau showed that the first step of interaction between phenothiazines without an V-substituent and bromine, in a variety of solvents, is irreversible electron transfer to give the... 

---