Pyrazinic Acid Amide

Perhydropyrido[l,2-fl]pyrazin-l-one N-oxide 167 was formed from 1-hydroxypipecolic acid amide 261 by reverse Cope elimination by heating in CHCI3. Similar reaction of 1-hydroxypipecolinate 262 resulted an 1 5 30 equilibrium mixture of 262, 263, and 264 (07TL1683). 

Cyclization of pipecolic acid amide 267 on the action of HATU and Hiining s base afforded a 1 1 diastereomeric mixture of perhydropyrido [l,2-a]pyrazine-l,4-dione 268 (06JOC8934). 

Condensation of 1,2-diaminopropane and 2,3-dioxobutane similarly gives 5,6-dihydro-2,3,5-trimethylpyrazine which is oxidized to the corresponding pyrazine in 58% yield by treatment with potassium hydroxide pellets.111 Hydroxypyrazines are very conveniently prepared from a,j8-dicarbonyl compounds and a-amino acid amides [Eq. (1)],30,112 and pyrazinecarboxylic acids have been prepared by condensation of an a,)5-diketone with an a,/ -diaminocarboxylic acid, followed by oxidation (Scheme 2). Thus, condensation of benzil and... 

SYNS ALDINAiMID 2-CARBAMYL PYRAZINE D-50 F.PRA7.TN MK 56 NCI-C01785 PYRAZINAMIDE PYRAZINEAMIDE PYRAZINE CARBOXYLAMIDE PYRAZINOIC ACID AMIDE TEBRAZID... 

DichIoro-2-(trichloromethyl)imidazo[4,5-i ]pyrazine (238) was converted into the 2-carboxylic acid ethyl ester (239) by treatment with silver nitrate in ethanol (80JHC381). The ester was converted into the acid, amide and nitrile (240). 

Pyrazines Carboxylic acid amides from carboxylic acid bromides O... 

Some synthetic approaches to pyrazines relied on metal-assisted reactions. A synthesis of 6-substituted 5H-pyrrolol2,3-bJpyrazines via Pd-catalyzed heteroannulation from W-(3-chloropyrazin-2-yl)methanesulfonamide and alkynes was developed <04TL8087>, and 3- and 5-substituted 2(l//)-pyrazinones were prepared by Suzuki and Heck reactions using 3,5-dichloro-2(l//)-pyrazinones <04TL1885>. An improved synthesis of 6-substituted-5//-pyrrolo 2,3-iiJ-pyrazines via microwave-assisted Pd-catalyzed heteroannulation was developed <04TL8631>, and the reaction of a-diazo-P-keto esters with Boc amino acid amides in the presence of a Rh catalyst gave, after air oxidation, pyrazin-6-ones 111, which were then converted into tetrasubstituted pyrazines 112 <04OL4627>. 

Hebeisen P, Panousis CG, Roever S, Wright M (2009) 3-Trifluoromethyl-pyrazine-2 carboxylic acid amide derivatives as hdl-cholesterol raising agents. US2009/247550... 

Carboxylic acid, 161, also serves as starting material for a substituted pyrazine that has proven to be an important diuretic agent. As the first step in the synthesis the acid is converted to the corresponding amide (165). Treatment with a single equivalent of hypobromous acid effects Hoffmann rearrangement of only one of the amide groups. Ethanolysis of the intermediate carbamate leads directly to the amino ester (166). Exposure of the... 

Dihydropyrazolo[l,5-a]pyrazine-4,7-diones 205 were synthesized by Nikulnikov et al. using tcrt-butyl isocyanide 209 as a convertible isocyanide [62]. The Ugi reaction of tert-butyl isocyanide and pyrazole-3-carboxylic acids 208 with various aldehydes 206 and amines 207 yields tert-butyl amides 210, which undergo cycli-zation into glacial acetic acid under microwave irradiation (Scheme 37). 

Construction of pyrazine rings from a-amino nitriles has been sometimes completed through multistep reactions. For example, 2-aminopyrazine 1-oxide 163 is synthesized via amide intermediate 162 formed by reaction of methyl a-aminocyanoacetate with a-oximino carboxylic acid (Scheme 45) <1994H(38)1581>. 

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