Pyrazine Esters

The following esters have been used 2-methoxycarbonyl (aq. NaOH/MeOH) (1263) 2-methoxycarbonyl-5-phenyl (85% KOH) (352) 2,5-diethoxycarbonyl-3,6-dimethyl (KOH) (18, 674) 2-chloro-3-methoxycarbonyl (K2CO3 or NaOH/ reflux) (838) 2-chloro-3-methoxycarbonyl-5,6-diphenyl (NaOMe/MeOH/reflux) (837) 5-ethoxycarbonyl-2,3-bis(5 -nitrofur-2 -yl) and its 6-methyl derivative (50% Ac0H/H2S04/reflux) (338) 2-amino-5-bromo-3-methoxycarbonyl (NaOH/reflux) (798) 2-amino-5,6-dichIoro-3-methoxycarbonyl (NaOH/reflux) (378a, 782, 809) 2-cyclohexylamino-3-methoxycarbonyl (NaOH/EtOH/reflux 1 h) (946) 2-(2, 3 -dimethylphenylamino)-3-methoxycarbonyl (NaOH/EtOH/reflux) (950) 2-amino- 

5 hloro-6-ethylamino-3-methoxycarbonyl (957) 2-amino-5-chloro-3-methoxy-carbonyl (NaOH) (150, 432a, 781, 783-785, 831) 2-(benzyloxycarbonylamino)-5-ethoxycarbonyl [Af potassium hydroxide in acetone at room temperature gave 

2- (benzyloxycarbonylamino)-5-carboxypyrazine (676, 1249) and 4 hydrochloric acid at reflux for 3 h gave 2-amino-5-carboxypyrazine (1177)] 3-amino-5-dimethyl-amino-2-methoxycarbonyl (5% NaOH/100°) (432) 2-amino-5-chloro-6-methoxy- 

2-Chloro-3-methoxycarbonyl-5,6-diphenylpyrazine refluxed with sodium methoxide gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (371) and the attempted Schmidt reaction of 2,5-dimethoxycarbonylpyrazine, in concentrated sulfuric acid with trichloroacetic acid at 60° with subsequent addition of sodium azide, gave 2,5-dicarboxypyrazine (1176). 2-Methoxy-3-methoxycarbonyl-5,6-diphenylpyrazine, when refluxed with cuprous chloride in dry dimethylformamide, gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (10%) 2-hydroxy-3-methoxycarbonyl-5,6-diphenyl-pyrazine similarly treated gave 5-hydroxy-2,3-diphenylpyrazine (30%) (837). 

Attempted Hofmann degradation of 2-carbamoyl-5-ethoxycarbonylpyrazine gave both 2,5-dicarboxypyrazine and 2-carbamoyl-5-carboxypyrazine (676). 

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Carboxypyrazines have been esterified with a variety of reagents, which are listed below with the pyrazine esters prepared in this way. Some discussion of the various reagents is given in Mager and Berends (411). 

Additional data, relevant to the preparation of pyrazine esters described in Section II. 5, are given in Reference 1161. 

A series of 2-amino-3-guanidinocarbonylpyrazines has been prepared from the corresponding 2-amino-3-alkoxycaibonylpyrazine when refluxed with guanidine or with a guanidine salt and sodium alkoxide in the alcohol. Some pyrazine esters that have been converted with guanidine to guanidinocarbonyl compounds by the above method are as follows 2-amino-3-methoxycarbonyl (787, 802) 2-amino-3-methoxycarbonyl-5-methyl(ethyl, cyclopropyl, cyclohexyl, phenyl, and... 

Cocoa contains more than 300 volatile compounds, including hydrocarbons, monocarbonyls, pyrroles, pyrazines, esters, lactones, and others. 

Dioxopiperazines are amongst the most ubiquitous of natural products (75FOR(32)57) and they are formally derived by the cyclodimerization of a-amino acids (69CCC4000) or their esters. A number of methods are available for their oxidation to the corresponding pyrazines. Treatment of 2,5-dioxopiperazines with triethyl- or trimethyl-oxonium fluorobor-ate followed by oxidation with DDQ, chloranil or iodine results in pyrazine formation, usually in high yields (Scheme 63) (72JCS(P1)2494). 

An unusual addition of acetoacetic acid to pyrido[2,3-Z>]pyrazin-2(l//)-one (400) to give (eventually) the 3-acetonyl derivative (401) was postulated (71TH21500) to occur via a cyclic transition state, and the similar addition of oxalacetic ester may occur via a related mechanism. 

Most syntheses of this type have followed the classical Gould-Jacobs pattern (Section 2.15.5.4.2) in which 2-aminopyrazines bearing a 6-substituent give esters of 8-oxopyrido[2,3-f ]pyrazine-7-carboxylic acids (424) via the usual intermediate ethoxy-methylenemalonate adducts. In some cases the isomeric pyrazino[l,2-a]pyrimidines are formed in addition (e.g. 74CPB1864). 

Pyrazine, tetrahydro-, 3, 177, 178 Pyrazine, 1,2,3,4-tetrahydro-synthesis, 3, 177 Pyrazine, 2,3,5-tri-t-butyl-synthesis, 3, 185 Pyrazine, 2,3,5-trichloro-nucleophilic substitution, 3, 176 Pyrazine, 2-vinyl-polymers, 1, 290-291 Pyrazine-3-carboxylic acid, 2-amino-methyl ester... 

H-Pyrido[2,l-i]purine-9-carboxylic acid, 7-oxo-methyl ester, 5, 566 Pyrido[2,3-6]pyrazine, amino-nucleophilic attack, 3, 253 Pyrido[2,3-h]pyrazine, 6-chloro-reactions... 

The chlorination of phosphonic and phosphinic acids and esters are of considerable importance. PCI5 can also act as a Lewis acid to give 6-coordinate P complexes, e.g. pyPClf, and pyz-PCI5, where py = C5H5N (pyridine) and pyz = cyclo-1, 4-C4H4N2 (pyrazine). ... 

A side chain carboxyl group in perhydropyrido[l,2-a]pyrazines was obtained from an ester group by acidic or alkalic hydrolysis. A side chain carboxyl group was converted into a carboxamide group by the treatment with an amine in the presence of 1-hydroxybenzotriazole (OOJAP(K)OO/ 86659). 

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... 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

Chemical libraries of /3-turn mimetics, among them highly saturated pyrazino[l,2-tf]pyrazines, were synthesized and patented as biologically useful compounds <2001W02001/000210>. Solid-phase syntheses starting from substituted a,/3-unsaturated ester templates provided differently substituted saturated heterocyclic systems, among them saturated 2,4,8-trisubstituted-pyrazino[l,2- ]pyrazine-l,6-diones <2003W02003/013740>. 

Azomethine ylides of pyrrolo[l,2- ]pyrazine <1996JOC4655> and 3,4-dihydro pyrrolo[l,2-tf]pyrazine <1997T9341> undergo 1,3-dipolar cycloadditions with a number of dipolarophiles. For example, the ylide 178 reacts with propargylic ester 179 to give the tricyclic derivative 180 (Equation 43). 

A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione <06JOC5897>. In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The A-methyl was lost and direct aromatisation occurred, presumably, due to cleavage oftheN-N bond <06SL2403>. 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

Relevant examples of enantioselective hydrogenation of aromatic N-heterocycles are given below. Scheme 16.21 shows the hydrogenation of a 2-ester substituted piperazine to the corresponding 2-substituted pyrazine with a catalyst... 

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