Of phenoxazines

Aromatic denitrocyclizations have been used for many years in some well-known synthetic reactions. Probably the best known example is the Turpin synthesis of phenoxazines and similar synthesis of phenothiazines. The classical setup used usually base-catalyzed reactions in polar protic solvents, very often alcohols. In many cases using polar aprotic solvents was found advantageous. Besides the mentioned influence of the H-bonding, better ionization and lower solvation of the nucleophile are also important. Sf Ar reactions proceed through strongly polarized complexes, which are well soluble and highly polarized in polar aprotic solvents. 

The best-known example of the denitrocyclization reactions is probably the Turpin synthesis of phenoxazines 179 (1891JCS714, 1899CB2601,... 

Direct bromination of phenoxazine (103 X = O) gave rise to a mixture of 3-bromo- and 3,7-dibromo-phenoxazine. Reaction with thionyl chloride gave the 1,3,7,9-tetrachloro derivative (60JGU1872). 

Phenoxazines — The two main types of phenoxazines are the ommochromes and the microbial phenoxazines. The biosynthesis of ommochromes occurs via the kynurenine pathway. The tryptophan amino acid is converted to formylkynurenine and then to kynurenine and 3-hydroxykynurenine. Not all the steps of ommochrome synthesis are completely elucidated yet. Ommatins are dimers and ommins are oligomers of 3-hydroxykynurenine. - The papiliochromes are derived from tyrosine as well as from the tryptophan pathway. The key intermediate in the formation of papiliochromes is N-beta-alanyldopamine (NBAD). Papiliochromes are synthesized in special wing scale cells, before melanins. " "... 

The blue dye (47), formed from the autoxidation of 4-/V,TV-di methyl-amino-2-hydroxyaniline, is the oxygen analogue of methylene blue. The autoxidation of 1,2,4-trihydroxybenzene, carried out in the presence of ammonia, gives the hydroxyphenoxazinone dye (48) via a 2,4-dihydroxyani-line intermediate (Scheme 17). Many types of phenoxazines, phenazines, and phenoxazinium salts can be obtained by autoxidation of polyhydroxyben-zenes and their amino derivatives. Some autoxidative dyes may give poly-... 

Based on the well-known reaction of phenoxazine with phosgene,15 leuco Basic Blue 3 was treated with phosgene to form the stable 10-chlorocarbonyl-3,7-diethylaminophenoxazine (39) which can be isolated and further reacted with alcohol or amine.16... 

Thimmaiah, K.N., Horton, J.K., Qian, X.D., Beck, W.T., Houghton, J.A. and Houghton, J. (1990) Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Communications, 2, 249-259. 

Kinetics of the acid hydrolysis of A-alkenyl derivatives of phenoxazine, phenoth-iazine, and carbazole in aqueous dioxane suggest an ASe2 mechanism, based on the activation parameters and isotope effects. ... 

The metalation of phenoxazine has also been investigated, but in contrast to phenothiazine, direct lithiation at C-l can only be achieved in very low yield (58JA2195 68JMC807). Fortunately, however, the carboxylate protection method is just as efficient as that with phenothiazine, and the... 

Due to their synthetic accessibility, phenoxazines of the type 8 are the best-known 1,4-oxazines whose 4-nitrogen has been reacted with electrophiles. The nucleophilicity of this nitrogen can be compared to that of diphenylamine, and numerous examples of alkylation and acylation have been reviewed already in early literature <1962HC(17)377>. This section therefore includes only examples of N-arylation of phenoxazines (Equation 3) that were not included in CHEC(1984) <1984CHEC(3)995>. 

A mixture consisting of phenoxazine (54 mmol), sodium t-butoxide (77 mmol), tris(dibenzylidene acetone)dipalladium(0) (1.1 mmol), and tri(/-butyl)-phosphine (1.1 mmol) were dissolved in 250 ml of xylene and then heated to 80°C for 12 hours. Thereafter, the reaction mixture was cooled to ambient temperature, quenched with 200 ml of distilled water, and extracted with xylene/water, 1 1. 

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). 

Table 4 Changes in polyamine levels during cell death induced by 3 hours of phenoxazine derivatives (WM7, WM8)...

Table 2 Cytotoxic activity of phenoxazines (WM1-24) against human tumor and normal cells ...

Even before the first synthesis of phenoxazine—reported in 1887 by Bernthsen1—two dyestuffs with the phenoxazine ring system, Meldola s blue and gallocyanine, were commercially available. After its discovery, however, the chemistry of the phenoxazines lay dormant for nearly half a century. Only during the last 10 years has this class of compound aroused renewed interest, as evidenced by the discovery of naturally occurring and biologically active phenoxazines. 

The usual synthesis of phenoxazines makes use of suitable ortho-disubstituted benzenes, starting from which the oxazine skeleton is completed by ring closure. As intermediates, during the different ring... 

The classical method for preparing phenoxazines, based upon Bernthsen s first synthesis of phenoxazine, consisted in the pyrolytic condensation of o-aminophenols with catechols. Kehrmann and Neil7 pointed out, as early as 1914, that phenoxazine can be obtained with... 

By investigating the influence of the acid strength of various proton donor catalysts on the kinetics of the reaction, Antoni8 showed that the reaction rate increases with decreasing pK . This explained why several authors7,9 10 had obtained better yields with o-aminophenol hydrochloride (pK 4.5) than with catechol (pK 9.9) however the yield of phenoxazine did not exceed 30%. 

The condensation of o-nitrochlorobenzenes with o-methoxyphenol enables the preparation of phenoxazines substituted in position 2,28,29 which is an important position in connection with biological properties (see Section V,B). 

The ultraviolet spectra of phenoxazine and of several 2-substituted phenoxazines, recorded in Table I, exhibit two bands at 224-247 m/i (log e 4.30-4.73) and 318-328 mfi (log e 3.84-4.01), while the acetyl-substituted phenoxazines present a third absorption band at about 270 m(i (aromatic ketone band). It can be seen from this table that A-alkylation has only a slight influence upon the position and intensity of these bands, and merely produces small bathochromic shifts. 

The infrared spectra of phenoxazine and of a few substituted phenoxazines have been reported,29, 37-42 but without a general discussion. 

The spectrum of phenoxazine reveals the characteristic absorptions of orsubstituted benzene rings and those of a secondary amino group. All phenoxazines so far investigated show the NH stretching... 

The radical ion of phenoxazine has a uniformly spaced four-line spectra with the line intensities in the ratio 1 2 2 1. The measured coupling constant was 9.83 gauss, the line width 8.19 gauss, and the g value 2.0049. This hyperfine structure can be interpreted as a basic three-line splitting by the nitrogen-14 nucleus (nuclear spin 1) and a doublet splitting with nearly identical spacing due to the attached acidic proton (nuclear spin ). 

A number of ESR spectra of semiquinone radicals, formed as intermediate reduction products of phenoxazine dyestuffs, have been investigated by Heineken and Bruin in acid and in alkaline solution.49,50... 

Phenoxazines are known to be readily oxidized. According to Musso88 the first stage in the oxidation of phenoxazine with ferric... 

Friedel-Crafts substitution of phenoxazine or V-acetylphenoxazine with acetyl chloride in the presence of aluminum chloride was found to give a C-monoacetylphenoxazine.11,58 This acetylphenoxazine, which was first formulated as 3-acetylphenoxazine,11 was shown later by Vanderhaeghe37 to be 2-acetylphenoxazine (27) this conclusion was supported also by the examination of the infrared and ultraviolet... 

Similarly, 2-chloroacetylphenoxazine, 2-propionylphenoxazine, and 2-butyrylphenoxazine have been obtained by Friedel-Crafts condensation of phenoxazine with the proper acyl halides.58-60... 

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