Studies on pyrrolidinones. synthesis of <i>N</i>‐(2‐nitrobenzyl)pyroglutamic acid

Rigo, Benoı̂t; Dolaine, RÉGis; Ghammarti, Samira El; Couturier, Daniel

doi:10.1002/jhet.5570330411

Journal of Heterocyclic Chem

1996

DOI: 10.1002/jhet.5570330411

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Studies on pyrrolidinones. synthesis of N‐(2‐nitrobenzyl)pyroglutamic acid

Benoı̂t Rigo

RÉGis Dolaine

Samira El Ghammarti

et al.

Abstract: While methyl N‐(4‐nitrobenzyl)pyroglutamate can be obtained from methyl N‐trimethylsilylpyroglutamate, the best way to obtain methyl N‐(2‐nitrobenzyl)pyroglutamate is to react 4‐nitro benzyl bromide with the iminoether derived from methyl pyroglutamate.

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Cited by 11 publications

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“…Within the framework of a program aimed at the synthesis of condensed hexahydroindolizine diones 1 [1] we needed a convenient supply of pyroglutamic acids 2a-d in high yield (Figure 1). The reaction of benzyl chlorides or bromides with activated forms of pyroglutamic esters such as an N-sodium salt [2], an N-silyl derivative [3] or an iminoether [4] was described in the literature. It is also possible to synthesize an open form of the lactam ring which is subsequently cyclized.…”

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Studies on Pyrrolidones. An Improved Synthesis of N‐Arylmethyl Pyroglutamic Acids

Bourry¹,

Akué‐Gédu²,

Rigo³

et al. 2004

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Low solubility of the aromatic aldehyde in a water/ethanol medium can prevent the sodium borohydride reductive alkylation of the sodium salt of glutamic acid. In that case, the reductive alkylation can be realized in methanol by using a triethylammonium salt. The uses of 2 molar equivalent of triethylammonium salt of glutamic acid for one molar equivalent of aldehyde strongly raise the yields. Cyclization of the N-substituted glutamic acids obtained gives then N-arylmethyl pyroglutamic acids in good yields.J. Heterocyclic Chem., 40, 989 (2003).Within the framework of a program aimed at the synthesis of condensed hexahydroindolizine diones 1 [1] we needed a convenient supply of pyroglutamic acids 2a-d in high yield (Figure 1). The reaction of benzyl chlorides or bromides with activated forms of pyroglutamic esters such as an N-sodium salt [2], an N-silyl derivative [3] or an iminoether [4] was described in the literature. It is also possible to synthesize an open form of the lactam ring which is subsequently cyclized. In that way the reaction of dimethyl bromoglutarate with a benzyl amine [5] or of diisopropyl glutamate with a benzyl halide [6] yields good results, but there is a high risk of dialkylation of the amine. A more interesting method is the reductive alkylation of dimethyl [7a] or diisopropyl [7b] glutamate that is versatile and gives good yields.All these reactions can be used for our purpose but are at least two or three steps away from glutamic acid. They also suffer from the handling of large amounts of sodium hydride, or of the need to synthesize intermediates such as iminoethers, silyl derivatives or diisopropyl esters. Another method, the reductive amination of the dialkaline salt of glutamic acid in methanol [8a] or in water [8b], has been reported in the past. Decroix described a considerable improvement of this synthesis [9a]: equimolar amounts of the disodium salt of glutamic acid and of an aromatic aldehyde were dissolved in an 85/15 water/ethanol mixture then cooled. A sodium borohydride reduction [9b] of this solution was performed; more aldehyde (0.2 eq.) in ethanol was then added. After a second reduction step, also performed under cooling, ethanol was removed by evaporation. Excess aldehyde and the benzylic alcohol by-product were removed by a diethyl ether extraction. Acidification of the aqueous phase then led to a precipitate of N-arylmethyl glutamic acid which readily cyclizes in refluxing ethanol. By using this method we obtained, as described [9], a 90 % yield of acid 2e (Ar = Ph) (Scheme 1).It is possible to obtain acids 2a-d by using the procedures previously described and some of these results have already been published [1c,2a] (Scheme 2). When we tried Decroix's method, poor results were obtained with aldehydes 3a-d, probably because of the low solubility of theses aldehydes in the 85/15 water/ethanol solvent. These aldehydes can be dissolved by using a larger ethanol content (water/ethanol: 35/65) but this leads to a biphasic medium with only a small improvement in the yiel...

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confidence: 99%

Studies on Pyrrolidones. An Improved Synthesis of N‐Arylmethyl Pyroglutamic Acids

Bourry¹,

Akué‐Gédu²,

Rigo³

et al. 2004

ChemInform

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ChemInform Abstract: Studies on Pyrrolidinones. Synthesis of N‐(2‐Nitrobenzyl)pyroglutamic Acid (VII).

Rigo¹,

Dolaine²,

Ghammarti³

et al. 1997

ChemInform

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Studies on pyrrolidinones. Synthesis of 1‐[(N‐acetylarylamino)methyl]pyroglutamic acid derivatives

Ghammarti¹,

Rigo²,

Mejdi³

et al. 1998

Journal of Heterocyclic Chem

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Studies on pyrrolidinones. synthesis of N‐(2‐nitrobenzyl)pyroglutamic acid

Abstract: While methyl N‐(4‐nitrobenzyl)pyroglutamate can be obtained from methyl N‐trimethylsilylpyroglutamate, the best way to obtain methyl N‐(2‐nitrobenzyl)pyroglutamate is to react 4‐nitro benzyl bromide with the iminoether derived from methyl pyroglutamate.

Cited by 11 publications

References 19 publications

Studies on Pyrrolidones. An Improved Synthesis of N‐Arylmethyl Pyroglutamic Acids

Studies on Pyrrolidones. An Improved Synthesis of N‐Arylmethyl Pyroglutamic Acids

ChemInform Abstract: Studies on Pyrrolidinones. Synthesis of N‐(2‐Nitrobenzyl)pyroglutamic Acid (VII).

Studies on pyrrolidinones. Synthesis of 1‐[(N‐acetylarylamino)methyl]pyroglutamic acid derivatives

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