Pyrrolidines. I. 1-Substituted 3-Pyrrolidinylmethyl Alcohols and Chlorides¹

Abstract

Dialkyl itaconate was condensed with various primary amines to form 1-substituted 5-oxo-3-pyrrolidinecarboxylates which were reduced to 1-substituted 3-pyrrolidinemethanols by lithium aluminum hydride. Treatment of these pyrrolidinemethanols with thionyl chloride yielded their corresponding chlorides. 1-Substituted 3-pyrrolidinylmethyl alcohols and chlorides are useful intermediates for the preparation of a number of physiologically active compounds. l-Methyl-3-pyrrolidincmethanol was also prepared from diethyl 1,3-pyrrolidinedicarboxylate either by employing lithium aluminum hydride reduction directly or by Bouveault-Blanc reduction indirectly through ethyl 3-pyrrolidinecarboxylate as an intermediate.The reaction of aniline with itaconic acid was studied by Gottlieb1 2 in 1851 and by Michael and Palmer3 in 1887. The structure of the product was established by Anschütz and Reuter4 in 1889 to be 5-oxo-l-phenyl-3-pyrrolidinecarboxylie acid. Recently Paytash and his co-workers5 used this reaction to prepare a large number of 1-substituted 5-oxo-3-pyrrolidinecarboxylic acids with various aryl, aralkyl, cycloalkyl, and heterocyclic amines in place of aniline. Itaconic acid has also been condensed with long chain alkylamines6 and methyl-amine7 to give the corresponding 1-substituted 5-oxo-3-pyrrolidinecarboxylic acids.We have found that the lower alkyl esters of itaconic acid will condense with different primary amines in equimolecular quantities to form 1substituted 5-oxo-3-pyrrolidinecarboxylates in good yields. The product obtained by condensing dimethyl itaconate with benzylamine was found to be identical with the esterification product of 1benzyl 5-oxo-3-pyrrolidinecarboxylic acid prepared according to the procedure of Paytash.5a Ethyl 1methyl -5 -oxo -3 -pyrrolidinecarboxylate has been prepared earlier by Uhle8 and by Iiardegger and Corrodi9 from -carboxysuccinic acid. The same compound was also formed by condensing diethyl itaconate with methylamine. The structure of these pyrrolidinones was further supported by the synthesis of butyl l-n-octyl-5-oxo-3-pyrrolidinecarboxylate from dibutyl itaconate and n-octyl-(1) It. F.

Synthesis of Pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates via the Hurd-Mori Reaction. Investigating the Effect of the N-Protecting Group on the Cyclization

“…Synthesis of alkyl substituted pyrrolo-thiadiazoles 4a (R = Bn) and 4b (R = Me) started from itaconic acid or its dimethylester ( Scheme 2 ). Cyclization towards the pyrrolidine system 5a/b was optimized based on a protocol by Feldkamp and coworker [ 11 ].…”

“…NaHCO 3 -solution, and repeatedly extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to give 56.92g (88% overall) of 5a [ 11 ] as colorless crystals; m.p. 71-73°C; 1 H-NMR (CDCl 3 ): 2.90-3.10 (m, 2H, H-4), 3.18-3.37 (m, 1H, H-3), 3.58 (d, J=8Hz, 2H, H-2), 3.69 (s, 3H, OCH 3 ), 4.45-4.50 (m, 2H, PhCH 2 ), 7.14-7.38 (m, 5H, arom.…”

“…Dimethyl itaconate (30g, 0.19mol) was added to aqueous methylamine solution (17.2 mL, 15.53 g, 40% solution, 0.2 mol) at 5-10°C and maintained at this temperature for another hour. Afterwards, the mixture was warmed to room temperature and stirred for 16 hours, concentrated and distilled in vacuo to give 29.0 g (95%) of 5b [ 11 ] as a colorless liquid; b.p. 160-161°C/24mbar; 1 H-NMR (CDCl 3 ): 2.60-2.75 (m, 2H, H-4), 2.86 (s, 3H, NCH 3 ), 3.16-3.38 (m, 1H, H-3), 3.40 (d, J=8Hz, 2H, H-2), 3.66 (s, 3H, OCH 3 ); 13 C-NMR (CDCl 3 ): 28.0 (q, NCH 3 ), 32.5 (t, C-4), 34.4 (d, C-3), 49.8 (t, C-2), 51.0 (q, OCH 3 ), 171.0 (s, C OOCH 3 ), 172.2 (s, C-5).…”

In silico design of bio-based commodity chemicals: application to itaconic acid based solvents

“…Another class of itaconic acid-based solvents are the N-alkyl-4-carboxypyrrolidinone esters (NACP), for which synthesis from itaconic acid was described by Wu et al as early as in 1961. 78 The experimental synthesis is a two-step procedure (esterification followed by a one-pot amine addition and cyclic amide formation), while the GRASS pathway decomposes it into three virtual transformations. It should be noted that both experimentally and virtually, the first two steps can be switched and still lead to the obtention of NACP (no.…”

Synthesis and cytotoxic effects on HeLa cervical cancer cells of (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidine

“…5 Atigadda et al 6 reported a substituted 2-pyrrolidinone that was a low nanomolar inhibitor of neuraminidase. Wu and Feldkamp 7 utilized a pyrrolidinone as a scaffold in a novel selective inhibitor of matrix metalloproteinases (MMPs).…”