Pyrazine alkylated, formation

Although the heteroaryl Heck reactions of chloropyrazines with pyrrole itself were low-yielding for both mono- and bis-arylation products, better yields were obtained for N-phenylsulfonylpyrrole. Bulkier alkyl substituents on the pyrazine ring promoted the formation of C(3)-substituted pyrroles. The C(3)-substituted pyrrole 64 was the major product (62%) for the coupling of 1 and Al-phenylsulfonylpyrrole, while C(2)-substituted pyrrole 63- was a minor product (15%). 

The direct alkylation of aminopyrazines is usually unsatisfactory as a synthetic method because it mainly takes place at the most basic ring nitrogen. However, 3,6-diamino-2,5-dicyanopyrazines are successfully alkylated by treatment with alkyl iodide or bromide in protic solvent in the presence of alkali such as NaOH in dimethylacetamide (DMA) to form bis(dialkylamino)pyrazines <1998DP(39)49>. Reaction of 2,6-diamino-3,5-diarylpyrazine with methylglyoxal in aqueous HCl-ethanol led to -alkylation but no formation of the expected bicyclic imidazolo[l,2- z]pyrazine <2001S768>. 

Lipid-Protein-Carbohydrate Interactions. Evidence for such complex interaction was recently reported by Huang et al (36) who observed that the addition of corn lipids to zein and corn carbohydrates enhanced the formation of alkylpyrazines, indicating that lipid-derived free radicals may accelerate the rate of Maillard reactions. Two of the alkylpyrazines, identified in such mixtures after heating for 30 minutes at 180°C, have 5-carbon alkyl substitution at the pyrazine ring and could only be explained by interaction of lipid or lipid decomposition products. These authors suggested that condensation of amino ketones, formed by protein-carbohydrate interaction, may yield 3,6-dihydropyrazine which would in turn react with pentanal, a lipid oxidation product, to form 2,5-dimethyl-3-pentylpyrazine. 

Heterocyclic compounds are primarily formed through non-enzymatic browning reactions. Recent studies of deep-fat fried food flavors led to the identification of pyrazines, pyridines, thiazole, oxazoles and cyclic polysulfides which had long-chain alkyl substitutions on the heterocyclic ring. The involvement of lipid or lipid decomposition products in the formation of these compounds could account for the long-chain alkyl substitutions. Model systems were used to study the participation of lipids in the formation of pyrazines, pyridines, thiophenes and cyclic polysulfides. 

Interest in the influence of lipids on pyrazine formation has recently been generated by the identification of long-chain alkyl-substituted heterocyclic compounds in foods and in model systems. Pyrazines in this category include 2-heptylpyrazine isolated from french fried potato flavor (7), and 2-methyl-3(or 6)-pentylpyrazine and 2,5-dimethyl-3-pentylpyrazine, isolated from extruded zein/corn amylopectin/corn oil systems (8, 9). Only the involvement of lipids or lipid-decomposition products in the formation of these compounds could account for the long-chain alkyl substitution on the pyrazine ring. 

In some recent research on flavor formation during deep-fat frying at Rutgers University, a number of heterocyclic compounds with long-chain alkyl substituents were found the volatiles of fried chicken (15) and fried potato (16). These included pyridines, thiazoles, oxazoles, trithiolanes and a pyrazine. Only the involvement of lipids or lipid degradation products in the formation of... 

The conversion of one (unsubstituted-alkyl) pyrazine into another such pyrazine by extranuclear alkylation has been covered in Section 3.2.1.4. The similar formation of (substituted-alkyl)pyrazines is illustrated here. 

Insertion of imsymmetrical heterocumulenes such as 0=C=X (X = S, NR), into an N-Si bond can produce two different constitutional isomers [8]. In the case of compound 1 and X = NR, R = alkyl or aryl, there is rapid insertion into both N-Si functions and the resulting situation is extremely complex with respect to the configurational (0,N-silylation) and conformational isomerism [5, 8, 10]. In contrast, 0=C=S inserts rapidly into only one N-Si bond of 1, there is no evidence for any second insertion even after several days. The formation of small amounts of pyrazine as oxidation product even under strictly anaerobic conditions suggests some electron transfer reactivity. Spectroscopic [10] and especially the structural evidence given below show that of the two conceivable constitutional isomers [11] of the insertion reaction only the 0-Si bonded species 2 with intact thiocarbonyl function is formed. 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

A variety of methods exists for the synthesis of optically active amino acids, including asymmetric synthesis [85-93] and classic and enzymatic resolutions [94-97], However, most of these methods are not applicable to the preparation of a,a-disubstituted amino acids due to poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated, including alkylation of 2-aminobutyric acid using a camphor-based chiral auxiliary and chiral phase-transfer catalyst. A process based on Schollkopf s asymmetric synthesis was developed (Scheme 12) [98]. Formation of piperazinone 24 through dimerization of methyl (5 )-(+)-2-aminobutyrate (25) was followed by enolization and methylation to give (35.6S)-2,5-dimethoxy-3,6-diethyl-3.6-dihydropyrazine (26) (Scheme 12). This dihydropyrazine intermediate is unstable in air and can be oxidized by oxygen to pyrazine 27, which has been isolated as a major impurity. 

Halogens attached to pyrazine react readily with 2>aminopyridine with the formation of a doubly fused imidazole ring. 2-Aminopyridines carrying alkyl or alkoxy groups react at ambient temperature while two halogen atoms or a nitro group inhibit the cyclization. 

This method is well suited to the formation of symmetrical pyrazines, " but if both diketone and diamine are unsymmetrical, two isomeric pyrazines are formed. The dihydro-pyrazines can be dehydrogenated and they will also react with aldehydes and ketones, with introduction of another alkyl group at the same time as achieving the aromatic oxidation level. ... 

Transition metal-catalyzed cross-coupling reactions of halogenopyrazines is an efficient synthetic method for alkyl-, alkenyl-, and alkynylpyrazines (Section 6.03.5.4.2). Palladium and nickel complexes are particularly effective as catalysts in this reaction. The Wittig reaction of halogenomethyl-pyrazines likewise leads to the formation of alkenylpyrazines (Section 6.03.8.1). Dehalogenation of halogeno pyrazines is a very practical synthetic method for alkyl- or aryl-substituted pyrazines. For example, phenylpyrazine has been prepared by catalytic hydrogenolysis of the 2-chloro-3-phenyl compound in the presence of triethylamine. This product is also obtained by decarboxylation of... 

Manley et al. (1974) suggested that cyclopentapyrazines may result from the condensation of 2-hydroxy-3-methylcyclopent-2-en-l-one (D.68) with glyoxal or pyruvaldehyde and amino acids, and a mechanism of formation has also been suggested from a study on popcorn flavor by Walradt et al. (1970). Vitzthum and Werkhoff (1975) reported 17 new alkylated five-and six-membered bicyclic pyrazines in roasted coffee the mass spectra of these new constituents and particularly the fragmentation pathways of 2-methyl-(O.50) and of 6,7-dihydro-5-methyl-5//-cyclopentapyrazine (0.51) are discussed in detail. 

A more original pathway for formation of dihydrocyclopentapyrazines has been proposed by Flament (1981). The reaction of 2,3-dihydropyrazines with aldehydes and ketones allowed the preparation of numerous and original trisubstituted pyrazines. When a, (3-unsaturated carbonyl compounds were used, the formation of bicyclic pyrazines was observed. Transitory 2,3-dihydropyrazines which certainly result from the trimolecular condensation of an a-dicarbonyl fragment with a diol in the presence of ammonia can condense with a, 3-unsaturated compounds, giving 6,7-dihydro-5//-cyclopentapyrazine (0.49) and various alkylated homologs. 

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