By primary synthesis

The preparations of hydroxypyrazines by primary syntheses have been described in Chapter II, and are summarized briefly, together with further data, as follows Section II.IG, from the reaction of a, 3-dicarbonyl compounds with ammonia [282 (cf. 281, 280), 283, 285] with additional information (1042, 1043) Section II.IM, from 1,2-dicarbonyl compounds with a-amino acids (311) Section II.IN, from a-amino acids through piperazine-2,5-diones (93,95,101,282,312,313)with additional data (843) Section 11.10, from aldehyde cyanohydrins ( ) [317-319 (cf. 282)1 and Section II.IP, from o-nitromandelonitrile and ethereal hydrogen cyanide (325). The preparations from a,iJ-dicarbonyl compounds with a,/ -diamino compounds are described in Section 11.2 (60, 80, 358, 359, 361-365b, 365d, 366-375) additional data have also been reported (824, 825, 827,845,846,971, 1044, 1045) and some reaction products have been isolated as the dihydro-pyrazines (340,341,357). 

Bredereck and Schmotzer (1044), from diaminomaleonitrile (DAMN hydrogen cyanide tetramer) and oxalyl chloride, prepared 2,3-dicyano-5,6-dihydroxy-pyrazine but Stetten and Fox (1049) could not prepare 23-diamino-5-hydroxy-pyrazine from glycine amide and oxamide. Section 11.3 lists preparations from a, -diamino or a, -diimino compounds and reagents other than a,0-dicarbonyl compounds (384) with additional data (1050) and oxidation of 23-dichloro-quinoxaline with hot aqueous potassium permanganate gave 23-dicarboxy-5,6-dihydroxypyrazine (1051). 

Section II.S includes the cleavage of pteridines and related ring systems to yield hydroxypyrazines (375, 420, 429, 433-434, 440, 441,445,448,449). Additional data are given in references 372,907,1052 and 1053. 2-Amino-6-(p-fluorophenyl)-4-hydroxypteridine with 4A sodium hydroxide at 170 gave 3-carboxy-5-(p-fluorophenyl)-2-hydroxypyrazine, and a similar preparation of the isomeric 6-(p-fluorophenyl)pyrazine was also described (347). 

Section II.7 describes some ring closures of the C-C-N-C-C, N-C-C-N-C-C, and N-C-C-N-C-C-N systems to give hydroxypyrazines (248, 365a, 477, 479, 480-483) more information can be found in reference 1054. Newbold and Spring (89) described the reaction of 2-bromo-A -(r-methyl-2 -oxopropyl)propionamide with ethanolic ammonia to give 2-hydroxy-3,5,6-trimethylpyrazine and Masaki et al. (551) have described the reaction of A -leucyl-6 -benzyIhydroxylamine (2) with phenacyl bromide in methanol saturated with ammonia to give 3-hydroxy-2-isobutyl-5-phenylpyrazine and 2,5-diphenylpyrazine. 

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Metathetical reactions of pyrimidines have been studied widely over the last hundred years. Indeed, probably 90% of all known pyrimidines have been made from a relatively few pyrimidine substrates available by primary synthesis. 

The least troublesome routes to 3,4-dihydro- and 1,2,3,4-tetrahydro-quinazoline are probably the reduction of quinazoline by sodium borohydride, in water for the former or in methanol for the latter. Both must be isolated as salts. The dihydroquinazoline may be formed also by reduction with LAH in ether (65JHC157). In contrast, 5,6,7,8-tetrahy-droquinazoline is best made by primary synthesis from 2-formylcyclohexanone and for-mamide (57CB942) or from cyclohexanone and trisformamidomethane (60CB1402). 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

R = H) is made similarly from its ester (789 R = Et), itself prepared by several obvious steps (see (i) below) from the pyrimidine (788) which can be made by primary synthesis (66AP362). 4-Aminopyrimidine-5-carbonitrile (790 R = CN), which may be made by primary synthesis, undergoes hydrolysis in alkali to the amino acid (790 R = C02H) it may be made similarly from the amide (790 R = CONH2) (53JCS331). 

A second practical route to AT-unsubstituted amides is by the controlled hydrolysis of nitriles, which can often be made (in the 5-position) by primary synthesis or (elsewhere) by displacement of an ammonio grouping. Thus 4,6-dimethylpyrimidine-2-carbonitrile (798 R = CN) in warm aqueous ammonia gives the amide (798 R = CONH2) in good yield... 

The O-alkyl derivatives of those A-oxides, which exist partly or entirely as (V-hydroxy tautomers, may be made by primary synthesis (as above) or by alkylation. Thus, 5,5-diethyl-1-hydroxybarbituric acid (936 R = H) with methyl iodide/sodium ethoxide gives the 1-methoxy derivative (936 R = Me) or with benzenesulfonyl chloride/ethoxide it gives the alkylated derivative (936 R = PhS02) (78AJC2517). 

The simplest pyrimidine antibiotic is bacimethrin, 5-hydroxymethyl-2-methoxypyrimidin-4-amine (985), which was isolated in 1961 from Bacillus megatherium and is active against several yeasts and bacteria in vitro as well as against staphylococcal infections in vivo it has some anticarcinoma activity in mice (69MI21301). It may be synthesized by LAH reduction of ethyl 4-amino-2-methoxypyrimidine-5-carboxylate (984) which may be made by primary synthesis in poor yield, or better, from the sulfone (983) (B-68MI21304). 

Most halogenoalkyl- and halogenoarylquinoxalines have been made by primary synthesis (see Chapter 1) or by direct halogenation of alkyl- or arylquinoxalunes (see Section 2.2.4). However, other minor procedures may be used, as illustrated in the following classified examples. 

Nearly all such quinoxalinones have been made either by primary synthesis (see Chapter 1) or by N-alkylation of tautomeric quinoxalinones (see Section 4.1.2.2). However, several recently used minor routes are illustrated by the following examples. 

Most alkylthioquinoxalines (nuclear and extranuclear) have been made by primary synthesis (see Chapter 1), by alkanethiolysis of halogenoquinoxalines (see Sections 3.2.3 and 3.4.4), or by alkylation of quinoxalinethiones (see Section 5.1.2) the formation of a diquinoxalinyl sulfide during thiolysis of a halogenoqui-noxaline has been noted in Section 3.2.3. 

Preparation. A few such derivatives have been made by primary synthesis (see Sections 1.6.7 and 1.8) or by arenesulfinolysis of halogenoquinoxalines (see Sections 3.2.7 and 3.4.4) but most have been prepared by the oxidation of alkyl-or arylthioquinoxalines (see Section 5.2.2). In addition, recently used minor routes are represented in the following examples. 

Many nitroquinoxalines have been prepared by primary synthesis (see Chapter 1), from halogeno quinoxalines (see Section 3.2.7), or by passenger introduction (e.g., on deoxidative alkylation of an M-oxide see Section 4.6.2.2). However, one major route and one minor preparative route remain, and they are illustrated in the following subsections. 

By primary synthesis (nuclear, extranuclear, primary, secondary, or tertiary) Chapter 1. 

The major preparative routes to hydrazinoquinoxalines, by primary synthesis (Chapter 1) and by hydrazinolysis of halogenoquinoxalines (Sections 3.2.1 and 3.4.1) have been covered already minor routes by hydrazinolysis of alkoxy-, alkylthio-, alkylsulhnyl-, or alkylsulfonylquinoxalines do not appear to have been used recently. 

Several routes to such derivatives have been covered already by primary synthesis (Chapter 1), from quinoxalinecarboxylic acids (Section 7.1.2), from quinoxalinecarboxylic esters (Section 7.2.2), and from quinoxalinecarbonyl halides (Section 7.3). Other preparative routes are illustrated in the following classified examples. 

These major routes to quinoxalmecarbonitriles have been covered already by primary synthesis (Chapter 1), by cyanalysis of halogenoquinoxalines (Section 3.2.5), by deoxidative cyanation of quinoxaline N-oxides (Section 4.6.2.2), by cyanolysis of nitroquinoxalines (Section 6.1.2.2), from primary quinoxalina-mines by a Sandmeyer-type reaction (Section 6.3.2.3), from quaternary ammonio-quinoxalines with cyanide ion (Section 6.3.2.4), and by dehydration of quinoxalinecarboxamides (Section 7.4.2). Those remaining preparative routes that have been used recently are illustrated in the following examples. 

The main preparative routes to quinoxaline ketones have been discussed earlier by primary synthesis (Chapter 1), by extranuclear acylation of alkylquinoxalines (Section 2.2.4), by oxidation of appropriate alkylquinoxalines (also Section 2.2.4), by displacement of a halogeno substituent (Section 3.2.7), by oxidation of... 

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