Synthesis of Phenazines

CgHeNj. Brown-yellow crystals m.p. 103-104 C, b.p. 256 258°C. Its solutions reduce Ag ions and it is used as a photographic developer. It is also used as a dye-precursor, for the synthesis of phenazine derivatives and for characterizing inter alia) a-diketones. 

W 0 H L - A U E Phenazine synthesis Synthesis of phenazine N-oxide from anilines and nitrobenzene... 

The best-studied system producing antibiotics in the rhizosphere are fluorescent pseudomonads, producing up to seven different compounds, as summarized in Fig. 9 2-hydroxyphenazine-l-carboxylate, phenazine-l-carboxylate, 2-hydroxy-phenazine, pyrrolnitrin, pyocyanine, 2.4-diacetylphloroglucinol. and pyoluteorin (48). Nine genes have been identified in the synthesis of phenazine-1-carboxylic... 

Figure 10 Predicted roles of gene products involved in the synthesis of phenazine-1-carboxylic acid by P. jluorescens 2-79. (From Ref. 48.)...

Another novel synthesis of phenazines was introduced by Vagg and co-workers <00JHC151>. The key step was the reaction of dicarboxylic acid 230 with various 1,2-diamines to give 231, 232, and 233. Each was a potential polydentate ligand capable of interacting with DNA via their extended phenanthroline or phenazine components. 

Table 2 Synthesis of phenazine ethers 10,44a-g by etherification of 2-hydroxyphenazine (9) with ROMs(-Br) and their redox potentials vs. SHE as determined by cyclic voltammetry in phosphate buffer at pH 7 using HMDE...

Phenazines and their derivatives are known to be biologically significant molecules, especially in the field of photodynamic therapy. A recent example of the preparation of red shifted azine dyes potentially for photodynamic therapy was reported by Gloster and coworkers <99JHC25>. The synthesis of phenazine 171 from 170 was thought to take place through the following mechanism. 

The synthesis of phenazine derivatives and phenazine oxide based on the condensation of aromatic nitro compounds with aromatic amines in an alkaline medium (sodium hydroxide), reported for the first time by Wohl [12] in 1901, was of similar character ... 

The crucial step in the synthesis of phenazine is the construction of the central heterocyclic ring. Because of the deactivation of the benzenoid rings towards electrophilic substitution reactions, derivatives are mainly prepared from appropriately substituted synthons. 

Synthesis of phenazines. Holliman et at.1 used nitrobenzene as both solvent and oxidizing agent for the cyclization of 2-ami nodi phenylamines to phenazines. The reaction rate is dependent upon substituents present and their positions. 

Ch. 1 General Methods for the Synthesis of Phenazine, Its Homologs, and Derivatives Not Containing Condensed Nuclei Ch. 2 Phenazine and Its Homologs Ch. 3 Hydrogenated Derivatives of Phenazine... 

This two-step process is analogous to, but much more efficient than, the classic Wohl-Aue synthesis of phenazines [233]. The versatility of this approach has been demonstrated by the synthesis of 1-methoxyphenazine that can be obtained from two different pairs nitroarene-aniline , namely, nitrobenzene-wta-anisidine or weta-nitroanisole-aniline (Scheme 98) [84]. 

Karami, B. and Khodabakhshi, S. 2011. A facile synthesis of phenazine and quinoxaline derivatives using magnesium sulfate heptahydrate as a catalyst. J. Serb. Chem. Soc. 76(9) 1191-1198. 

Scheme 7. Synthesis of Phenazine-5,10-dioxide via the Beirut Reaction...

Another early approach to the synthesis of phenazines was the condensation of substituted catechols (o-hydroxyphenol) and benzene-1,2-diamine neat or in the presence of Pb02, first reported in 1886. The synthesis of the natural antibiotic pyocyanin from 3-methoxycatechol and benzene-1,2-diamine using this Pb02-catalyzed procedure was reported by Surrey. The mechanism is believed to proceed via a dione intermediate upon hydrogen abstraction (Scheme 8). ... 

Observed limitations include partial decarboxylation during ring closure in the synthesis of phenazine-1,9-dicarboxylic acid as well as poor yield and very low reactivity of ketal-protected ketone diphenylamine in the cyclization step of saphenic acid synthesis. The deprotected ketone was cyclized and reduced in one step, affording the desired saphenic acid in satisfactory yields. 

In 2013, a palladium-catalyzed double M-aiylation of l,2-diamino(hetero)-arenes with l,2-dihalo(hetero)arenes for the synthesis of phenazines and pyridoquinoxalines was developed by Laha and co-workers. A variety of functional groups, which included base-sensitive groups, were tolerated under the optimized conditions to afford phenazines or p3aidoquinoxalines in good to excellent yields (Scheme 3.4). 

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