Phenazines, formation

The limited commercial availability of substituted phenazines indicates that their synthesis presents a challenge for the synthetic chemist. To date, no efficient and generally applicable synthesis of substituted phenazines exists. Many synthetic methods are reported, most of them having severe limitations to localization and electronic character of the substituents. In general, substitutions on the phenazine core are introduced on the building blocks prior to phenazine formation. In the present section we outline the most commonly used methods, as depicted in Figure 14, and their scopes and limitations are discussed. 

Many substituted quinolines are intermediates for antimalarials. The 2,4-di-substituted quinolines are produced from aniline and 1,3-diketones by the Combes quinoline synthesis (28). The reaction of aniline with nitrobenzene in the presence of dry sodium hydroxide at 140°C leads to formation of phenazine [92-82-0] and by-products (Wohl-Aue synthesis) (29). 

Direct halogenation of quinoxaline appears to be of limited value but pyrazine may be chlorinated in the vapor phase to give monochloropyrazine at 400 °C or at lower temperatures under catalytic conditions 72AHC(14)99, and at higher temperatures tetra-chloropyrazine formation occurs in high yields. Mention has already been made of direct chlorination (see Section 2.14.2.1) of phenazine. 

Proximity effects and ortho interactions in 2,2/-disubstituted diaryl amines have been reported104. Thus, phenazine, phenazine-N-oxide and carbazole were formed by loss of small neutral fragments, such as NO, NO2 and NO3, from the molecular ions, as illustrated by the formation of carbazole from 2,2/-dinitrodiphenylamine see Scheme 34. Of particular interest is the loss of NO3, as demonstrated by high-resolution MS data and metastable ion spectra104. 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

An example of the method described is the synthesis of saphenic acid (47) that has recently been reported by Nielsen et al. [81]. Starting from properly substituted aromatic precursors 92 and 93, the naturally occurring 1,6-disub-stituted phenazine was synthesized in racemic form. Here, the first major step involves an intermolecular nucleophilic aromatic substitution that, due to the substitution pattern, has proved to be relatively unproblematic and after hydrolysis of the acetal yields the o-nitrodiphenylamine 94. Much more difficult is the ring formation leading to the final phenazine, which can best be achieved through a high excess of NaBH4, accompanied by reduction of the methyl ketone. But at 32%, the yield is still rather poor. 

Needless to say, the Buchwald-Hartwig reaction can also be usefully employed in ways other than the efficient preparation of diphenylamines. Given the respective substitution, it should be possible to bring about the phenazine skeleton by Pd-catalyzed ring formation as well. There are two ways to proceed either the substituent pattern required by the intramolecular Buchwald-Hartwig reaction is elaborated after the formation of the diphenylamine (121 124), or the starting material already contains the substituents necessary for the two JV-arylations. A reasonable starting point is the intermolecular JV-arylation of an o-haloaniline... 

Dynamic quenching of the MLCT excited state of [Ru(phen)2(dppz)] " " by H" " transfer in MeCN solution occurs for proton donors with pAa values in the range 4.7-15.7. Comparisons of the quenching have been made in the presence and absence of DNA. " The addition of Cu " " to DNA-bound [Ru(bpy)2L] " " (L is the phenazine derivative (167)) leads to luminescence quenching. This is explained in terms of complexation of Cu " " with the vacant coordination site of L in [Ru(bpy)2L] " ". Formation of the [Ru(bpy)2L] " "/Cu " " complex in the presence of DNA is proposed to place one metal center in the major groove and one in the minor groove. " ... 

Anodic oxidation of benzenesulphenanilides 56 leads to cleavage of the nitrogen-sulphur bond in the radical-cation with the formation of a nitrenium ion, which deprotonates to the nitrene. The intermediate dimerises to a phenazine [168]. 

A major group of photochemical reduction reactions are oxidation-reduction processes. As typical examples, phenazine (CXXI) and alloxan (CXXIII) are reduced by ethanol to give dihydrophenazine (CXXIl)/ 2 and alloxantin (CXXIV).42 Isatin (CXXV) in the presence of ace-naphthene (CXXVI) is reduced to isatide (CXXVII).204 The photoreaction proceeds at the expense of the alcohol, or (CXXVI) acetaldehyde and acenaphthylene (CXXVIII), are formed as by-products respectively. The formation of CXXVII may be due to the interaction of CXXV with the intermediate oxindole (CXXIX). 

In the course of probing the range of reactivity accessible to decamethyl-samarocene, substrates containing C=N double bonds as part of 6-membered heterocycles have been tested. In the reaction with pyridazine reductive carbon-carbon bond formation occurred (compare Sect. 3.2) [99], The coupled ligand bridges two Sm(III) centers via the four nitrogen positions. In the phenazine reaction one phenazine ligand is placed between the Sm(III) centers (Fig. 20 Table 16) [203]. 

A similar sequence appears to be involved in the formation of octafluoro-phenazine (40) in the oxidation of pentafluoroaniline in HOAc/H-O 2S0 ... 

The nitro group can take part in the formation of heterocyclic nitrogen-containing rings. For example, one of the well known methods for the preparation of phenazine derivatives consists in heating derivatives of 2-nitro-2 -aminodiphenyl-arnine at high temperature (Kehrmann et al. [11]) ... 

The accumulation of phenazine-1,6-dicarboxylic acid (154) by mutants of Pseudomonas phenazinium148 which normally produce hydroxy-phenazine derivatives supports a role for (154) in phenazine biosynthesis. In further studies143 with Ps. phenazinium the sequence of hydroxylative steps leading to the various phenazines has been deduced143 148 to be that illustrated in Scheme 15 the biosynthesis deduced for iodinin (156) is in agreement with earlier conclusions about its formation in cultures of another organism (Brevibacterium iodinum ).146... 

Such polycyclic aromatic hydrocarbons as anthracene or heteroaromatics as acridine, phenazine and 2,4,5-triphenyl oxazole act as Jt-donors for the Jt-acceptors AN and alkyl methacrylates [50-53]. Again, the interaction of the donor excited states with vinyl monomers leads to exciplex formation. But, the rate constants (k ) of these quenching processess are low compared to other quenching reactions (see Table 1). The assumed electron transfer character is supported by the influence of the donor reduction potential on the k value (see Table 1), and the detection of the monomer cation radicals with the anthracene-MMA system. Then, the ion radicals initiate the polymerization, the detailed mechanism of which is unsolved,... 

It should be mentioned that most natural aldolase enzymes can also be assayed using enzyme-coupled systems relaying the reaction to a redox process with NAD. The formation of NADH by active microbial colonies in expression libraries of mutant enzymes was detected colorimetrically in agar plates using phenazine methosulfate and nitroblue tetrazolium, which forms an insoluble precipitate. The assay was used by Williams et al. [14] and Woodhall et al. [15] for evolving sialic acid aldolases to accept non-natural aldehyde acceptors. 

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