Chlorination of Some Alkylpyrazines<sup>1</sup>

Hirschberg, A.; Spoerri, Paul E.

doi:10.1021/jo01351a051

Cited by 26 publications

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“…General Synthetic Procedure. 2-Chloro-3-methylpyrazine containing a small amount of 2-chloro-6-methylpyrazine was prepared as described in the literature (Hirschberg and Spoerri, 1961;Lutz et al, 1964). This mixture was converted to the corresponding alkoxymethylpyrazine or thioalkoxy-methylpyrazine by reaction with the appropriate sodium alkoxide or sodium thioalkoxide.…”

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confidence: 99%

Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Parliment¹,

Epstein²

1973

J. Agric. Food Chem.

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2-Methoxy-3-isobutylpyrazine has previously been reported to be an extremely potent flavoring material with a characteristic aroma of bell peppers. Twenty-one compounds structurally related to this molecule have been synthesized in an attempt to determine structural variations of the molecule which may be made and still retain the intense bell pepper note. For this flavor effect, the alkyl chain can vary from CB to at least CS; the effect is reduced by Cg. Replacing the methoxy group by ethoxy markedly reduces the effect, and it disappears with butoxy substitution. Adding a second alkyl function on the ring reduces the bell pepper character. The effect is not limited to the 2,3 isomer, since the 2,6 isomer possesses a similar note. A most surprising result is the fact that the oxygen of the methoxy group may be replaced by sulfur with little change in character.The compound having the characteristic aroma of bell peppers was identified as 2-methoxy-3-isobutylpyrazine (structure I, R1 = isobutyl) and was shown to possess an extremely low odor threshold (Buttery et al., 1969). Subsequently this compound was also reported in peas (Murray et al., 1970), in galbanum oil (Bramwell et al., 1969), and in coffee (Friedel et al., 1971). Due to the potency and unusual character of this compound, several reports have been published which describe the synthesis and odor properties of structurally related compounds (Seifert et al., 1970(Seifert et al., , 1972. This report extends the previous work for the purpose of further defining the basic chemical structure which is responsible for the intense bell pepper note.There are a number of ways of modifying the basic 2-methoxy-3-isobutylpyrazine molecule. The effect of varying alkyl chain length of R1 in structure I is one obvious choice. Other ways of varying the molecule include: investigating other positional isomers (structures I1 and VI); preparing the dialkyl-substituted methoxy compounds (111); replacing the methoxy by higher alkoxy (IV); and replacing the oxygen by sulfur (V and VI).Gas-Liquid Chromatography. Since the synthetic procedures described below result in a mixture of the 2,3-General Foods' Technical Center, White Plains, New York 10625. and 2,6-chloroalkylpyrazine isomers (Lutz et al., 1964), final purification of the desired isomer was achieved by gas-liquid chromatography. The samples were purified on a Ys in. X 6 ft column packed with 10% DEGS on 60/80 mesh Anakrom ABS in a Perkin-Elmer Model 900 gas chromatograph. Helium carrier gas flow was 30 ml/min and detection was by flame ionization. Temperature programming was utilized and the purified compound was trapped by condensation in a Dry Ice-cooled melting point capillary tube.General Synthetic Procedure. 2-C hloro-3-methylpyrazine containing a small amount of 2-chloro-6-methylpyrazine was prepared as described in the literature (Hirschberg and Spoerri, 1961;Lutz et al., 1964). This mixture was converted to the corresponding alkoxymethylpyrazine or thioalkoxy-methylpyrazine by reaction with the appropriate ...

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confidence: 99%

Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Parliment¹,

Epstein²

1973

J. Agric. Food Chem.

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“…Since the reaction conditions at elevated temperature employed for p-xylene could not be used, we performed the chlorination of the nitrogen-containing compounds at the reflux temperature of tetrachloromethane using benzoyl peroxide as the radical initiator instead. Although comparable standard conditions have been used for methyl chlorination of 1b and 1c previously, the reported yields for the dichloride 2b were 20% [7], 23% [8] and 29% [9] while in the case of 1c the reaction afforded 70% yield of the monochloride 5c [10].…”

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confidence: 95%

Improved synthesis of bis(chloromethyl)arene monomers

Almassio¹,

Sarimbalis²,

Garay³

2005

Designed Monomers and Polymers

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We report here on the experimental conditions for radical chlorination that provide improved yields of 2,5-bis(chloromethyl) pyridine and pyrazine, as well as on theoretical calculations which were performed in order to gain some insight regarding the factors that affect reactivity in these systems. The difficulties encountered previously in the methyl functionalization of N-heteroarenes are not due to radical selectivity that produces low yield of the dichlorides or to lower reactivity of this type of compounds, but to the post-halogenation reactions that occur on the desired products. Therefore, a careful handling during and after the reaction allowed us to find conditions for product optimization of α, α -dichlorinated monomers.

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“…The title compound was prepared via a malonic ester synthesis starting with a-chloromethylpyrazine [2], and ending, after an asymmetric enzymatic hydrolysis of the racemic N-acetyl-B-2-pyrazinylalanine to the L-form of the new amino acid. The optical purity was ascertained by 'H-NMR analysis at 360 MHz of the diastereoisomeric dipeptides L-pyrazinylalanine-L-leucine and D-pyrazinylalanine-L-leucine.…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis. Starting material was a-chloromethylpyrazine obtained according to Hirschberg & Spoerri [2] by treatment of 2-methylpyrazine with one equivalent of N-chlorosuccinimide using benzoyl peroxide as catalyst. This highly unstable lacrymatory oily intermediate was not characterized but immediately condensed with the sodium salt of diethyl-a-acetamidomalonate to yield crystalline diethyl a-acetamido-a-(pyrazinylmethy1)malonate (1).…”

Section: Discussionmentioning

confidence: 99%

Synthesis of β‐pyrazinyl‐L‐alanine (Paa) and of peptide derivatives

Petermann¹,

Fauchère²

1983

Helvetica Chimica Acta

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SummaryThe title compound was prepared via a malonic ester synthesis starting with a-chloromethylpyrazine [2], and ending, after an asymmetric enzymatic hydrolysis of the racemic N-acetyl-B-2-pyrazinylalanine to the L-form of the new amino acid. The optical purity was ascertained by 'H-NMR analysis at 360 MHz of the diastereoisomeric dipeptides L-pyrazinylalanine-L-leucine and D-pyrazinylalanine-L-leucine. Hydrophobic, steric and electronic parameters for its side chain were also estimated, which can be useful for the quantitative study of structure-activity relationships of biologically active peptide derivatives. The new amino acid could be introduced in the place of phenylalanine in the enkephalin-like pentapeptide [D-alany12, le~cine~lenkephalin, thus showing good stability towards the classical methods of peptide synthesis.The folding of a biologically active peptide is controlled by the structural features of the amino acid side chains, and chemical modifications of individual side chains thus modulate its biological activity. It is therefore desirable to have selected series of residues where only one of the electronic, steric or hydrophobic properties would vary, while the others would remain approximately constant. Such series would be extremely useful for quantitative structure-activity relationships (QSAR) studies, helping to vary each structural parameter independently and to select the optimized combination of them. However, at present such series can only be put together from the known list of natural or synthetic amino acids and must therefore be completed by the synthesis of new representatives.The purpose of this work was to prepare an amino acid which would be comparable in size to phenylalanine but would display extreme electronic features. We chose P-pyrazinyl-L-alanine (3, abbreviated as Paa) because of the strong inductive electron-withdrawing effect of the pyrazinyl group. While the parent l)Abbreviations for amino acids and protected derivatives according to the IUPAC-IUB recommendations [ 121. Further abbreviations: Paa = P-pyrazinyl-L-alanine, DMF = N, W-dimethylformamide, DCHA = dicyclohexylamine, TFA = trifluoroacetic acid, TLC = thin layer chromatography, r.t. = room temperature.

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Chlorination of Some Alkylpyrazines¹

Cited by 26 publications

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Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Improved synthesis of bis(chloromethyl)arene monomers

Synthesis of β‐pyrazinyl‐L‐alanine (Paa) and of peptide derivatives

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Chlorination of Some Alkylpyrazines1

Cited by 26 publications

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Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Organoleptic properties of some alkyl-substituted alkoxy- and alkylthiopyrazines

Improved synthesis of bis(chloromethyl)arene monomers

Synthesis of β‐pyrazinyl‐L‐alanine (Paa) and of peptide derivatives

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Chlorination of Some Alkylpyrazines¹