Pyrrolidinone, 3-amino

Metabolism of NHEX- C in the rat results in dose dependent formation of C02> with 45% exhaled after a dose of 8 mg/kg NHEX but only 4% after 576 mg/kg (17). Similar results were obtained for NPYR and nitrosoheptamethyleneimine. At doses of 8-12 mg/kg NHEX, 33-37% of the radioactivity was excreted in the urine (17, 52). Urinary metabolites of NHEX were e-caprolactam, e-amino-caproic acid, and 6-aminocaprohydroxamic acid (52). The formation of 6-caprolactam is analogous to results with NPYR and NNN, in which 2-pyrrolidinone and norcotinine were observed as urinary metabolites. Caprolactam did not originate from hexamethylene-imine, a product of denitrosation. 

In conclusion we have presented our initial findings of exploratory research aimed at converting Glu to various products, including substituted pyrrolidinones. The chemistry highlights the dual role of acid in amino acid... 

Reaction of the 2-amino-substituted thiophene 244 with pyrrolidinone in the presence of phosphorus oxychloride led to efficient formation of the central six-membered ring of tricycle 245 in 57% yield (Equation 67)... 

The formation of oxazolidines 54 or oxazolidinones 55 is currently utilized to assign the absolute stereochemistry of diastereomers of 1,2-amino alcohols, based on H NMR analysis of the H4 and H5 protons of these heterocycles. In the case of y-amino-p-hydroxy acids, the internally cyclized pyrrolidinone 56 is also suitable for determination of the relative configurations of the y-amino and p-hydroxy groups (Scheme 23). 

Pyrrolidinones with a chiral C-5 atom have been prepared in a very simple, one-pot synthesis, by treatment of TV-alkoxycarbamoyl y-amino a,/J-unsaturated carboxylates with Mg in methanol (equation 168)602. The products are formed in 87-95% yield, with high optical purity (96-99% ee). Since this y-lactam is very important, as an intermediate and target in the synthesis of natural products, this simple reaction is a very useful addition to the synthetic chemist s arsenal. Most other preparations of this target usually lead to racemic mixtures603-606. 

Glutamic acid 1,5-Pentanediol, 2-amino-1,5-pentanediol, 4-amino-5-hydroxypentanoic acid, 4- amino-butanoic acid, 5- methyl-2-pyrrolidinone, 5 -hydroxynorvol ine, 5-(hydroxymethyl)-2-pyrrol idinone, pyroglutamic acid, 5-caprolactone Food additives, polymers, solvent Hermann, 2003 Feuchtenberger etal., 2005 Corma etal., 2007... 

Decarboxylation with concomitant dehydrogenation occurred in some cyclic amino acids. For example, (I)-proline was converted into a mixture of 1-pyrroline and its trimer. The methyl ester of (L)-proline was simply dehydrogenated to its /i-imine (69%). With two equivalents of IOB in chloroform (L)-proline was converted directly into 2-pyrrolidinone (70%). This transformation was less efficient for pipecolinic acid and ( )-pyrrolidinone-5-carboxylic acid [48]. 

Chlorination of the derivatives (500) with phosphorus oxychloride followed by reaction with ammonia, gives the 2-amino-3-bromopyridines (501). Cyclization of (501 R = 4-pyridyl) was accomplished by heating with ethyl potassium xanthate in l-methyl-2-pyrrolidinone at 160-165 °C to give the thiazolo[4,5-6]pyridine (502 R = 4-pyridyl) in near quantitative yield (Scheme 61) (94JMC248). 

Enantiomerically pure 2-azetidinones are applied to the asymmetric synthesis of nonracemic 2-piperidones. This is a novel application of 2-azetidinones <03T6445>. Because 2-azetidinones are valued as antibacterials and chiral building blocks for amino acids, peptides and 2-pyrrolidinones, they are readily accessible for application to this transformation. 

DP = dipolar aprotic solvent NMP = iV-methyl pyrrolidinone OAAT = 2-hydroxy-4,6-diamino-.s -triazine OIET = 2-hydroxy-4-(isopropylamino)-6-(ethylamino)-5-triazine OOAT = 2-hydroxy-4-hydroxy-6-amino-s-triazine PS = petroleum sulfide TBA = tetra-n-butylammonium TEA = tetraethylammonium TEOS = tetramethylorthosilicate TMA = tetramethylammonium TMU= tetramethylurea. c For reactions photoca-talyzed by POMs under anaerobic conditions, the reduced POM resulting from photooxidation of the substrate is reoxidized by reduction of protons generated in this initial substrate photooxidation step, forming H2. 

Tanaka, T., Watarumi, S., Fujieda, M., and Kouno, I. 2005. New black tea polyphenol having V-ethyl-2-pyrrolidinone moiety derived from tea amino acid theanine Isolation, characterization and partial synthesis. Food Chem. 93 81-87. 

These systems are reported as cyclopentaoxazolidines and can be obtained by conventional azeotropic dehydration of aldehydes with amino alcohols <85TL5303> for example, (S)-5-Hydroxymethyl-2-pyrrolidinone (236) was condensed with benzaldehyde to obtain the corresponding chiral 5-oxo-2-phenylperhydropyrrolo[l,2-c]oxazole (237) in excellent yield <86JOC3140>. Similar treatment of enantiomerically pure amino ketone (238) with paraformaldehyde or formalin under a variety of Mannich conditions yielded (239) <84ja5360>. These reactions are shown in Scheme 41. 

Lactams are cyclic amides and they are reduced by LiAlHq to the cyclic amine. The reduction of a typical lactam such as 2-pyrrolidinone derivative 36 presumably proceeds via initial formation of the a-amino alcohol (37), followed by elimination to an iminium salt (38), and then reduction by hydride to give the amine (39). This reaction is very useful in the synthesis of alkaloids, as seen in the reduction of 40 to 41 in 88% yield as part of Overman s synthesis of (-i-)-aloperine. O The lactam nitrogen is significantly less basic than the corresponding amine and cyclic amines are often protected as the lactam. The amine is then unmasked late in the synthetic sequence by hydride reduction. 

Two different approaches to ( —)-statine (831), an unusual amino acid component of pepstatine, both employ 793c as their starting point. In the first synthesis (Scheme 120) [183], reduction of 793c with sodium borohydride produces a mixture of two isomeric 5-hydroxy-pyrrolidinones, from which the pure cis product 824 crystallizes in 85% yield. Conversion of bisacetate 825 to thioether 826 followed by removal of the acetate and silylation of the resulting alcohol affords 827. Radical cyclization of 827 produces a 3 2 mixture of isomers 828. Desilylation and debenzylation gives 829 as a single diastereomer. The Boc-protected intermediate 830 intersects with a known synthesis of ( —)-statine (831). 

Uses of bases of this type, such as DBU and DBN have been reviewed [15] and more recently they have been used as stoichiometric bases in the synthesis of 2H-isoindoles [ 16],biaryl thioethers [17],phthalocyanines [18] and the related macrocyclic compounds [18], 2,4-dioxo-l,2,3,4-tetrahydroquinazolines [19], dihydro alanine-containing peptides [20] and [[pyrazolylmethyl)amino]-propyl azepinones and -pyrrolidinones [21]. Chiral DBU/DBN-related molecules have also been synthesized which were fovmd to be useful as catalysts in an asymmetric Michael reaction [22]. 

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