2.6- Dichloro-3- pyrazine

Taft reported the conversion of chloropyrazine into 2,6-dichloro-pyrazine by chlorination with sulfuryl chloride or liquid chlorine.274 This reaction is conveniently carried out in the laboratory by heating 2-chloropyrazine and sulfuryl chloride in a sealed tube at 120° for 3 hours. More recently 2,6-dichloropyrazine has been prepared in 90% yield from chloropyrazine by reaction with chlorine in dimethyl-formamide at 70°-75° 2,3-dichloropyrazine is obtained in 84% yield... 

Dithiinopyrazines have been obtained by the cyclizations of 2,3-dichloro-pyrazine with 1,2-dimercapto compounds (Scheme 24) (75USP3853901) and double 1,4-dithiine annelation has been observed in the reaction of tetra-chloropyrazine with 1,2-dimercapto-1,2-dicyanoethylene (Scheme 24) (75USP3843644 75USP3853901). 

Another exemplar of the power of multi-step library synthesis is the optimisation of a PDE2 inhibitor HTS hit (Scheme 18.36). The HTS hit itself was derived from a library that was synthesised to enrich the Pfizer screening collection. Key steps in the library synthesis involved reaction of the commercial dichloro pyrazine H with a range of alcohols, followed by reaction of the intermediate chloroalkyoxy pyrazine with hydrazine. Finally, the hydrazine pyridazine I was reacted with a number of aldehydes under oxidative conditions to form the triazolo pyrazine derivatives. This library allowed the project team to find key SAR directions for improvinbg selectivity vs. other PDEs. ... 

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

Imidazolidine, 4,5-dichloro-l,3-diacetyl-imidazo[4,5-6]pyrazine synthesis from, 5, 646 Imidazolidine, 1,3-dimethyl-conformation, 5, 355 Imidazolidine, diphenyl-dehydrogenation, 5, 427 Imidazolidine, 2-imino-1-substituted nitration, 5, 427... 

Pyrazine, 1,4-dialkyl-1,4-dihydro-isomerization, 3, 178 Pyrazine, dichloro-synthesis, 3, 187 Pyrazine, 2,3-dichloro-oxidation, 3, 169... 

Pyrazine, 2,5-dichloro-3,6-difluoro-synthesis, 3, 190-191 Pyrazine, dihydro-, 3, 177 Pyrazine, 1,2-dihydro-oxidation, 3, 178 reduction, 3, 177 Pyrazine, 1,4-dihydro-antiaromaticity, 3, 177-178 synthesis, 3, 177 Pyrazine, 2,3-dihydro-oxidation, 3, 178 Pyrazine, 2,5-dihydro-synthesis, 3, 178 Pyrazine, 3,6-dihydro-synthesis, 3, 184 Pyrazine, 2,5-dihydroxy-oxidation, 3, 175 Pyrazine, 2,3-dimethyl-1,4-dioxide... 

Treatment of bis-lactim ether 420 with BuLi, then with cw-l,4-dichloro-2-butene in the presence of Nal afforded 3,4,9,9n-tetrahydro-6//-pyrido[l,2-fl]pyrazin-4-one (421) with 96% diastereomeric excess (97TA1855). Reaction of l,2-diphenyl-6-methyl-quinoxaline with 1,4-dichlorobutane in THF in the presence of Na at —78°C afforded a 3 1 mixture of 4a,5-diphenyl-9-methyl-l,2,3,4-tetrahydro-4a//-pyrido[l,2-n]quinoxaline and 4-(4-chlorobutyl)-2,3-diphenyl-6-methyl-1,4-dihydroquinoxaline (98JHC1349). 

A mixture of 1- and 3-chloro, 1,3-dichloro, and 1,3,5-trichloro derivatives was obtained on chlorination of imidazo[l, 5-a]pyrazine (172). Bromination gave similar results (75JHC207,75JOC3373 84MI24). The 8-chloro compound is best made from the 8-oxy derivative of 172. When the 1-bromo-3-methyl derivative of 172 was treated in turn with aqueous bromine and excess dilute caustic soda, the pyrazine ring was destroyed to give 4-bromo-2-methylimidazole-5-aldehyde (75JOC3373). 

Chemoselective cyanation in the C-3 position of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one has been described by Van der Eycken et al. [27]. The procedure is similar to that reported by Alterman and Hallberg. The only difference is that CuCN was selected as transmetal-lating agent instead of Zn(CN)2. When a mixture of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one and CuCN in DMF, using Pd(PPh3)4 as a catalyst, was irradiated for 15 min at 200 °C, the desired 5-chloro-3-cyano-N-(4-methoxybenzyl)pyrazin-2(lff)-one could be isolated with a 68% yield (Scheme 69). 

The perhydropyrazino[l,2- ]pyrazine 247 was obtained in good yield when the tosyl groups of the macrocycle 246 (prepared from N-tosylated diethylenetriamine and l,3-dichloro-2-propanol) were removed (Equation 28)... 

The synthesis of the polycyclic 5-5-6-5 derivative 81 was realized by nucleophilic substitution of the 5,6-dichloro[ 1,2,5]oxadiazolo[5,4-7]pyrazine 79 with 5-aminotetrazole 80 (Scheme 17). This conversion took place at room temperature and the product 81 was isolated in moderate 36% yield. Many other heterocyclizations with N,N, N,0-, /V,.Y-bidentate nucleophiles gave the corresponding reaction in up to 93% yield <1997CHE1352>. 

Oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) converted ethyl l,2,3,4-tetrahydropyrido[2,3-A]-pyrazine-2-carboxylate 203 into the conjugated pyridopyrazine 205, while the 3-isomer 204 could not be oxidized to the corresponding aromatic heterocycle <2002T5241>. 

Reeves and Hilbrich288 have reported the catalysis by pyridines of benzyl ketone alkylation they are less efficient than aliphatic trialkylamines. Reeves and White289 have also described the reaction of alkyl bromides with sodium cyanide, where pyrazine is a better catalyst (99% yield) compared to pyridine (12% yield). Isakawa et al.289 have also carried out addition of dichloro-carbene to cyclohexene under biphasic conditions, using heterocyclic amines as catalysts (e.g., iV-butylpiperidine gives 76% yield). 

Heating with phosphoryl chloride converted 1 -hydroxy-3-phenyl-2( 1H )-pyrazinone (52) into the 2,5-dichloro derivative (53) via the 5-monochIoro species. It had been expected that chlorination would take place at C-6, but this occurred only to a minor extent. The observed chloride attack /3 to the oxygen function might be accounted for in terms of the sequence illustrated in Scheme 46 (86JHC149). Reaction mechanisms have been proposed to explain the observed a- and /3-chlorination when 2- and 3-substituted pyrazine Af-oxides are subjected to the Meisenheimer reaction. /3-Chlorination was rationalized in terms of electron withdrawal by the unoxidized nitrogen atom [84JCR(S)318] (Scheme 46). 

Ultraviolet irradiation of 4,5-dichloro-3,6-difluoropyridazine similarly gives 2,5-dichloro-3,6-difluoropyrazine. Lemal and his co-workers consider that this result also eliminates the prismane mechanism for pyridazine-pyrazine interconversion.140a Methyl-, 2,5-dimethyl-, 2,6-dimethyl-, and trimethylpyrazine are formed when cis-3,7-dihydroxy-octahydro-l,5-diazocine is passed over hot alumina [Eq. (4)].141... 

Trichloropyrazine may also be prepared by chlorination of 2,3-dichloro-pyrazine296 or, as previously mentioned, from triketopiperazine,273 296 but A-oxide rearrangement is probably the laboratory method of choice. A further application of A-oxide rearrangement for chloro-pyrazine preparation is taken from the work of Cragoe and his colleagues (Scheme 28).265... 

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