Pyrazines from 1,2-dicarbonyl compound

Coffee flavors form during roasting from dicarbonyl compounds which derive from carbohydrates. The thermal degradation of hexoses is thought to be the preciu ors of fin ones like HDMF. The presence of alkylpyrazines affords the characteristic roast notes. These pyrazines are formed through Strecker degradation and the condensation of the resulting Strecker products (60). 

One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyI compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The N-protected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. 

Whereas it was reported in CHEC-II(1996) <1996CHEC-II(7)229> that examples of this system were rare, the increase in synthetic activity since then has been significant. Such compounds can be obtained using either a thiophene or a pyrazine precursor. Virtually all of the molecules prepared from thiophene precursors follow the pathway shown in Equation (185). The appropriate diaminothiophenes 491, usually obtained by reduction of the corresponding nitro groups, are condensed with the desired 1,2-dicarbonyl compound under generally mild conditions to yield 492. 

Several mechanisms have been reported for pyrazine formation by Maillard reactions (21,52,53). The carbon skeletons of pyrazines come from a-dicarbonyl (Strecker) compounds which can react with ammonia to produce ot-amino ketones as described by Flament, et al. (54) which condense by dehydration and oxidize to pyrazines (Figure 6), or the dicarbonyl compounds can initiate Strecker degradation of amino acids to form ot-amino ketones which are hydrolyzed to carbonyl amines, condensed and are oxidized to substituted... 

The imidazole part of the IQ-compounds suggests creatinine as a common precursor. The remaining parts of the IQ-compounds could arise from Maillard reaction products, e.g., 2-methylpyri-dine or 2,5-dimethylpyrazine. These two compounds could be formed through Strecker degradation. In Maillard reactions, this is induced by a-dicarbonyl compounds derived from carbohydrates, which are thereby converted to pyrroles, pyridines, pyrazines, etc. (8). 

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... 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Starting from diaminomaleonitrile (377), condensations with 1,2-dicarbonyl compounds lead to pyrazine-2,3-dicarbonitriles (378) which allow a nucleophilic displacement of one cyano group by... 

Azole approach. The reaction of 4,5-diaminoisoxazoles (46) with 1,2-dicarbonyl compounds represents a convenient route to pyrazines (73JHC181, 68T4907) the reaction is analogous to the formation of quinoxalines from o-phenylenediamine. 

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). 

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... 

PYRAZINES FROM a, p-DIAMINO OR a,P-DIIMINO COMPOUNDS AND REAGENTS OTHER THAN a, p-DICARBONYL... 

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). 

The preparation of cyanopyrazines by primary synthesis has been described in Section II.IH (286-288) and Section 11.2 (353-360). Further data have been recorded on the condensation of diaminomaleonitrile with glyoxal (1434, 1435), with a variety of 1,2-dicarbonyl compounds (1435, 1436), and Bredereck and Schmotzer (1044) have described the preparation from the tetramer of hydrocyanic acid with /J,p -dibromobenzil and p,p -diphenoxybenzil of 2,3-bis(p-bromo-phenyl)-5,6-dicyanopyrazine and 2,3-dicyano-5,6-bis(p-phenoxyphenyl)pyrazine, and with phosgene in dioxane of 2,3-dicyano-5,6-dihydropyrazine. Other preparations are described in Section II.3 (158, 383-387), with further data given in references 1050, 1154 and 1180, Section 11.5 (454) and Section 11.7 (484-486, 488-490). 

A related synthesis of fused pyrazines employs 3,4-dlamlnothlophenes (ingeniously prepared from pyridine as depicted below) as latent enediamines condensation with 1,2-dicarbonyl compounds gives thieno(3,4-b)pyrazines which would appear to potential intermediates to novel pyrazines by reductive desulfurization. 

The synthesis of the pteridine ring system has been approached by two obvious routes one is the fusion of the pyrazine ring onto a pre-formed 4,5-diamino-pyrimidine, and the second, the elaboration of the pyrimidine ring on a pre-formed pyrazine. The first of these, the Isay synthesis, suffers from the disadvantage that condensation of the heterocyclic 1,2-diamine with an unsymmetrical 1,2-dicarbonyl compound... 

The major route to these compounds involves condensation of 2,3-diaminopyridines with a-dicarbonyl compounds. Other methods of forming the pyrazine ring have occasionally been employed. These are particularly useful when the products from the standard condensation are of uncertain orientation. Such approaches have made use of the condensation of 2-amino-3-nitrosopyridines with compounds containing active... 

Pyrido[3,4-b]pyrazines substituted in the pyridine ring are available from the reactions of suitably substituted 3,4-diaminopyridines and the appropriate dicarbonyl compounds. No problems are encountered with diamines substituted with halogen or hydroxy groups. Similarly the pyridones 7 provide the oxo compounds 8 and 9. In contrast, 3,4-diamino-5-nitropyridine did not react with glyoxal, and only a low yield of 2,3-dimethyl-8-nitropyrido[3,4-b]pyrazine could be obtained using diacetyl. ... 

The retrosynthesis (see Fig. 6.22) of the pyrazine system is based on principles proven valid for the other azines. Bond fission at the imine function (retrosynthetic step a) leads to 1,2-dicarbonyl compounds 14 and 1,2-diaminoethenes 15 as starting materials for the direct pyrazine synthesis by cyclocondensation. The dihydropyrazines 16 and 18 (from the retroanalysis operation b and c) are alternative starting materials which are accessible from the 1,2-diaminoethanes 17 and 14 or from the ar-amino ketones 19. 

As with pyrazines (Section 6.2.7.1), phenazines, the dibenzo derivatives of pyrazine, can also be prepared from the reaction of diamines and dicarbonyl compounds. Chattopadhyaya and co-workers utilized this method to build phenazine systems in the synthesis of [Ru(phen)2dppz] 228, which were used for structure elucidation of nucleic acids without radioactive probes <01JACS3551>. The phenazine component of [Ru(phen)2dppz] was prepared by condensation of 226 and 3,4-diaminobenzoic acid. Diketone complex 226 was prepared by two consecutive ligand displacements from RuQs. 

---