Pyrazine dihydro-, aromatization

Partially hydrogenated pyrazine moieties in pyrido[2,3-6]pyrazines are aromatized by permanganate11,67 or iodine.7 Thus, ethyl 8-amino-3,4-dihydro-2-methylpyrido[2,3-6]pyrazine-6-carba-mate (1) with potassium permanganate in acetone yields 84% of the fully aromatic compound 2,11 another example being the oxidation of l,2,3,4-tetrahydro-2,3-dimethylpyrido[2,3-A]pyrazine (3)-67 nh2 nh2... 

An interesting photochemical approach to 4,5-disubstituted N-alkylimidazoles consists of the photolysis of 2,3-dihydro-5,6-disubstituted-pyrazines that can be easily prepared from 1,2-diketones and 1,2-diamino-alkanes. For example, the preparative-scale photolysis, in absolute EtOH with high-pressure Hg lamp (Pyrex filter), of 5,6-dimethyl- or 5,6-diphenyl-2,3-dihydropyrazines 54, yields the corresponding N-methyl-imidazoles 57 in high yields (Scheme 12.16). The reaction mechanism involves the formation of an enediimine intermediate 55, followed by cyclization and re-aromatization [41]. 

Phenylazirine (178), the photolysis product of a-azidostyrene (177), dimerizes on standing to 2,5-dihydro-3,6-diphenylpyrazine (179). The latter compound, unlike the isomeric 2,3-dihydro-5,6-diphenyl-pyrazine is readily aromatized by treatment with hydrogen peroxide in acetic acid.378 2,5-Dibenzyloxy-2,5-dihydropyrazine is prepared by... 

Azole approach. 3,4-Diamino-l,2,5-thiadiazole reacts with 1,2-dicarbonyl compounds to form pyrazines (747) (76JHC13). From the reaction of 1,2,5-thiadiazole 1,1-oxides such as (748) with o-phenylenediamine, the l,3-dihydro[l,2,5]thiadiazolo[3,4-Z>]quinoxaline 2,2-dioxide (749) is formed. To understand this reaction it is pointed out that the 1,2,5-thiadiazole 1,1-dioxide ring is to be regarded as alicyclic rather than aromatic and is strongly 7r-electron deficient. Substituents with leaving properties in the 3,4-positions are therefore readily displaced as in the reaction of (748) (75JOC2743). 

Aromatic sextets are not essential for the stability of heterocyclic rings and saturated and partially-saturated rings occur widely. These are usually named as the corresponding dihydro or tetrahydro derivatives, e.g., 37-39. The fully-saturated derivatives of pyridine and pyrazine are commonly referred to as piperidine 40 and piperazine 41. The antihypertensive calcium channel antagonist nifedipine 42 is a 1,4-dihydropyridine derivative , and sildenafil 43, which contains a piperazine ring, is a phosphodiesterase inhibitor used to treat erectile dysfunction . 

The same substrate (91) and triethyl orthoacetate, however, gave a separable mixture of 5-ethoxy-3-methoxy-5-methyl-6-phenyl-4,5-dihydro-2-pyrazine-carbonitrile (93) and 3-methoxy-5-methyl-6-phenyl-2-pyrazinecarbonitrile (94) (likewise 35 and 43%, respectively) the dihydro product (93) gave its aromatic counterpart (94) quantitatively by loss of ethanol on treatment with pyridine or triethylamine.857... 

Some very clever syntheses of pyrazines were reported. Tandem Mn02-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines was shown to give rise to quinoxalines, dihydropyrazines, pyrazines, and piperazines without the need to isolate highly reactive 1,2-dicarbonyl intermediates <03CC2286>. A new intramolecular cyclization route to highly substituted chiral 6,7-dihydro-5//-imidazo[l,5-a]pyrazin-8-ones like 157 from Meldrum s acid was developed <030L3907>, and 5-chloropyrido[3,4-6]pyrazines were prepared from 1,2-dicarbonyl compounds and 2-chloro-3,4-diaminopyridine <03H(60)925>. A synthesis of... 

This method is well suited to the formation of symmetrical pyrazines, " but if both diketone and diamine are unsymmetrical, two isomeric pyrazines are formed. The dihydro-pyrazines can be dehydrogenated and they will also react with aldehydes and ketones, with introduction of another alkyl group at the same time as achieving the aromatic oxidation level. ... 

Pyndo[2,3-()]pyrazines with a partially hydrogenated pyridine moiety have also been aromatized. 7,8-Dihydro-7-methylpyrido 2,3-6]pyrazin-6(5//)-one (7) oxidized by selenium dioxide in acetic acid affords 7-methyl pyrido[2,3-A]pyrazin-6(5//)-one (8),63 and 5,6-dihydro-5-methylpyrido-[2,3-6]pyrazine (9) is oxidized by air to give 5-methylpyrido[2,3-6]pyrazin-6(5//)-one (10).14... 

Several 5,6-dihydro-2,3-diphenylpyrido[2,3-6]pyrazines 11 have been converted into the corresponding aromatic compounds 12 through oxidation by iron(III) chloride.68... 

Attempted oxidation of the 3-oxo compound 96 with potassium permanganate resulted only in ring breakdown. Nevertheless a solution of this reagent in acetone is commonly used to oxidize compounds such as the dihydro derivative 97 to the aromatic system without further oxidation occurring. Oxidation of the tetrahydro oxo compound 98 with potassium permanganate in 2M sodium hydroxide solution at room temperature gives the 2-oxo compound 99. This compound is sensitive to oxidation, and the use of iodine has been recommended for this conversion. If alkaline potassium ferricyanide is used, the product formed is the dioxo derivative 100. The dioxo compound is also obtained from l,2-dihydro-2-oxo- or 3,4-dihydro-3-oxopyrido[2,3-b]pyrazine under the same conditions. Recently ferric chloride has been used to aromatize a series of dihydropyrido[2,3-b]pyrazines. ... 

As true reduced flavins , however, and apart from flavohydroquinone, one example of each subclass needs discussion, viz. 4a,5-dihydro-flavin( 5-blocked ) 181,182)and l,8-dihydroflavin( l/2a-blocked ) 12). Both isomers exhibit chromophores which are essentially different from flavohydroquinone, as outlined in Scheme 9. The three dihydro isomers exhibit, furthermore, totally different chemical reactivity 1,8-dihydro-flavin is aromatic with respect to electron distribution in the center (pyrazine) subnucleus, 1,5-dihydroflavin is, contrarily, antiaromatic (unless the pyrazine subnucleus is deplanarized, see below). It contains... 

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