Phenazine, reduction

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

Methyl coenzyme M reductase plays a key role in the production of methane in archaea. It catalyzes the reduction of methyl-coenzyme M with coenzyme B to produce methane and the heterodisulfide (Figure 3.35). The enzyme is an a2P2Y2 hexamer, embedded between two molecules of the nickel-porphinoid F jg and the reaction sequence has been delineated (Ermler et al. 1997). The heterodisulfide is reduced to the sulfides HS-CoB and HS-CoM by a reductase that has been characterized in Methanosarcina thermoph-ila, and involves low-potential hemes, [Fe4S4] clusters, and a membrane-bound metha-nophenazine that contains an isoprenoid chain linked by an ether bond to phenazine (Murakami et al. 2001). 

As in the case of thiazine and oxazine leuco dyes described earlier, the reductive acylation of the phenazine dye 52 results in the acylation of the exocyclic amino group.18 The phenazine leuco obtained 53 retains the exocyclic amide group on oxidation resulting in the acylated phenazine dye 54, the color of which is different from the one intended. 

The reduction of tetrazolium salts by NADH is greatly accelerated by electron transfer agents (ETAs) such as phenazine methosulfate (PMS 233) or its derivatives.451-454 Other classes of ETAs such as quinones.455,456 ferricinium,457 phenothiazine,458 the viologens,459 acridiniums,460 and phe-nazinium or quinoxalinium salts461 as well as the enzyme diaphorase462 have been used. 

In the field of the reductive (bio)transformation of priority pollutants, the reported redox mediator molecules include cytochromes, pyridines, cobalamins, porphyrins, phenazines, flavines, and quinines [12-15]. However, Quinones have been studied as the most appropriate RM for the reductive (bio)transformation of azo dyes [12]. 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

Recently a colorimetric method for estimation of erythrocytic G-6-PDH was described (El). This procedure is based upon the interaction of phenazine methosulfate as electron carrier between NADPH2 formed in the reaction and dichloroindophenol, the rate of the reduction of the latter compound being followed at 620 mp. 

Nitrogen heteroaromatics are expected to be useful probases. The cathodic reduction of phenazine, (31), resembles closely that of (29a) [70,71], and the kinetic basicity of (31) is comparable to that of (29a) [54]. However, application of (31) as a PB in electrosynthesis has not been reported, and there is only a single report concerning the use of the radical anion of acridine, (32), as an EGB [72]. 

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. 

Quite recently, the structure of pelagiomicins B (60) and C (61) was confirmed by a synthesis starting from griseoluteic acid (62) [60]. In the first synthesis of 62, Holliman et al. employed the reductive cyclization of o-nitrodi-phenylamines using NaBH4 to yield phenazines [84]. To this end, 3-amino-4-methoxybenzyl alcohol (99) was treated with methyl 2-bromo-3-nitrobenzoate (100) to yield the o-nitrodiphenylamine 101, which by reductive cyclization... 

Kamikawa et al. chose the first option to generate the benthocyanin skeleton [91]. To begin with, 100 and aniline 126 are transformed into o-nitrodi-phenylamine 127 by intermolecular N-arylation. Reduction of the nitro group and selective bromination produces 128, and this time an intramolecular Buch-wald-Hartwig reaction is used to derive a mixture of the desired phenazine 129 and the elimination product 130. The fundamental problem with this approach relates to the selective introduction of the halogen substituent that is required for the intramolecular N-arylation. 

Preferential reduction of a nitro group in the presence of a carbonyl group in 4-nitroacetophenone ISD, intramolecular rearrangements of o-nitro-benzanilides 32) intramolecular cyclizations of o-nitro-ferf-anilines to benzimidazol-1-oxides 153,154) cyclizations of acylated 2-nitrodiphenylamines to phenazine-l-oxides i ), intramolecular additions of nitro groups to double bonds 156) remarkably ef-... 

The preparation and structure of [Ru(phen)2(l,5,6,10-tetraazaphenanthrene)]Cl2 have been reported NMR spectroscopic data provide insight into the hydrophilic properties of the complex. The bpy-containing complexes [Ru(bpy)2(92)] + and [ Ru(bpy)2 2(M 92)] ((92) = dipyrido(2,3-a 2, 3"-/z)phenazine) were described earlier in the chapter.The analogous [Ru(phen)2(92)] and [ Ru(phen)2 2(M 92)]" have also been prepared and characterized, as has [ (phen)2Ru(/i-92) 3Ru] +. The electronic spectra exhibit intense MLCT bands in the visible region the electrochemical properties of the complexes have been investigated and for [ (phen)2Ru(/i-92) 3Ru], two sets of reduction waves centered on ligand (92) are separated by those assigned to phen reductions. ... 

The activity of complex II (succinate dehydrogenase) is measured as the succinate-dependent reduction of decylubiquinone, which is in turn recorded spectro-photometrically through the reduction of dichlorophenol indophenol at 600 nm (e 19,100-M -cm Fig. 3.8.5). In order to ensure a linear rate for the activity, the medium is added with rotenone, ATP, and a high concentration of succinate. As noticed previously for complex I, decylubiquinone is not a perfect acceptor for electrons from the membrane-inserted complex II [70]. Malonate, a competitive inhibitor of the enzyme, is used to inhibit it. Rather than decylubiquinone, phenazine methosulfate can be utilized, which diverts the electrons from the complex before they are conveyed through subunits C and D, therefore allowing measurement of the activity of subunits A and B. 

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). 

Attempted reduction of 2,3-diphenylquinoxaline by lithium results in cyclodehydrogenation to dibenzo[a,c]phenazine (77).93 2-Benzoyl-3-phenylquinoxaline is reduced by sodium amalgam to the red 2-benzoyl-3,4-dihydro-3-phenylquinoxaline (78a - - -78b).94... 

Phenazines can be obtained from o-nitrodiphenylamines by reduction or from o-aminodiphenyla-mines by oxidative techniques. The preferred method is that of phenazine 9,10-dioxides from benzofuran, thus benzofuroxans, itself with hydroquinone, gives the 2-hydroxy derivative (Scheme... 

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