An efficient synthesis of 3-ethoxypyrrolidine-2,5-diones and cis -2,3,3a,6a-tetrahydrofuro[2,3-c ]pyrrole-4,6(5 H )-diones from β -cyanocarboxylic acids

A simple and convenient procedure for the synthesis of a new series of 3-ethoxypyrrolidine-2,5-diones and cis -2,3,3a,6a-tetrahydrofuro[2,3-c ]pyrrole-4,6(5 H )-diones derivatives is described. All compounds were obtained from the direct cyclization of two β -cyanocarboxylic acids with primary amines and amino alcohols in short reaction time and good yields


Introduction
Pyrrolidin-2,5-diones, commonly referred to as succinimides, are cyclic imides structurally characterized by the presence of the fragment -(CO)NR(CO)-as belonging to the five-membered ring. 1 These imides show great bioactive and pharmacological potential acting as enzyme inhibitors, 2 analgesics, 3 antimicrobial agents, 4 anxiolytics, 5 cytotoxic, 6 but mainly as anticonvulsants. 7The anticonvulsant action of these compounds can be exemplified by ethosuximide (Figure 1), one of the first drugs used to treat epilepsy.Often this pharmacological activity is justified by the presence of the -CO(NR)CO-fragment in their structures, 8 which is present in molecules of other drugs with anticonvulsant activity recognized as, for example, phenobarbital and phenytoin (Figure 1).Several methods for the synthesis of succinimides are described in the literature.A method commonly used to obtain these compounds involves cyclization reactions of succinic anhydrides, succinic or succinamic acids with nitrogen nucleophiles such as amines, hydrazines and hydrazides. 2,9In general, these reactions are carried out in aqueous solution and high temperatures.Usually, succinic acids are obtained by the hydrolysis of the cyano group of dinitriles, 10 whereas, procedure for the synthesis of succinimides, without carrying out first the hydrolysis of the CN group, is underexplored. 11Recently it has been reported that succinimides can also be synthesized by addition reactions of amines to olefinic bond of maleimides, 12 by ring expansion of β-lactams, 13 by carbonylation reactions of alkynes 14 and α,β-unsaturated amides 15 or biotransformation of maleimides promoted by fungi. 16However, these methods, except one which is carried out by the reaction of amines with maleimides, involve catalysts of difficult access and reaction mechanisms still poorly understood.
We postulated that the readily available β-cyanocarboxylic acids could be convenient building blocks for the synthesis of new series of N-substituted 3-ethoxypyrrolidine-2,5-diones and cis-2,3,3a,6a-tetrahydrofuro [2,3-c]pyrrole-4,6(5H)-diones analogous to the ethosuximide drug.We had two paths to carry out the reaction to afford the desired succinimides; by performing first the hydrolysis of the β-cyano group to a carboxylic acid 10 followed by the condensation with primary amines, as usually reported, 9 or to carry out the direct condensation of β-cyanocarboxylic acids with primary amines, which is the path we are proposing in this study (Scheme 1).The second choice, lead to the desired N-substituted succinimides in one-pot reaction and with very good yields.Scheme 1. Synthetic strategy for the synthesis of succinimides.

Table 2. Structures and yields of compounds 11-13
Entry a Yields of isolated compounds.
Compounds 6j and 6k were obtained as mixtures of diastereoisomers due to the presence of two stereogenic centers in their chemical structures.Although, compound 4 has two stereogenic centers, it was obtained as a racemic mixture of isomers, which was evidenced by the presence of only a pair of signal in both 1 H and 13 C NMR spectroscopy. 17In order to verify if intermediate 4 was obtained as the cis-or trans-isomer, a condensation reaction of this compound with primary amines 5a-k was carried out and the corresponding cis-2,3,3a,6a-tetrahydrofuro [2,3-c]pyrrole-4,6(5H)-diones 7a-k where obtained (Scheme 3).However, the compounds 7j and 7k also showed mixtures of diastereoisomers due to the presence of an additional stereogenic center from the amino alcohols 5j and 5k.Scheme 3. Cis-isomers of compounds 7a-k.
According to Ibnusaud and Thomas 20 the reaction of 5-oxotetrahydrofuran-3,4-dicarboxylic esters with primary amines can only lead to the corresponding succinimides if the two carboxyl groups are in cis-position; otherwise, succinamic esters are obtained.Thus, we confirmed that the compound 4 was obtained only as the cis-isomer since the corresponding cis-2,3,3a,6atetrahydrofuro[2,3-c]pyrrole-4,6(5H)-diones 7a-k were the only obtained products.
We propose that the mechanism of formation of 3-ethoxypyrrolidine-2,5-diones and their related compounds, as shown in Scheme 4, starts with the reaction of the carboxylic acid 3 with the amines 5a-k leading to the carboxylic acid salt I, which under elevated temperature undergoes pyrolysis giving the amide II.The nitrogen of the amide group of structure II attacks the carbon of the nitrile group forming the cyclic structure III, which under proton transfer, results the pyrrolidinone IV.Compound IV undergoes hydrolysis of the imino group to lead the intermediate V that is in equilibrium with the structure VI, which by elimination of ammonia, furnishes the 3-ethoxypyrrolidine-2,5-diones 6a-k.This mechanism is also suggested to obtain the corresponding cis-2,3,3a,6a-tetrahydrofuro [2,3-c]

Experimental Section
General.3-Ethoxypyrrolidine-2,5-diones 6a-k, cis-2,3,3a,6a-tetrahydrofuro [2,3-c]pyrrole-4,6(5H)-diones 7a-k, and bis-3-ethoxypyrrolidine-2,5-diones 11-13 were identified by 1 H and 13 C NMR techniques, mass spectrometry (GC-MS), and High Resolution Mass Spectrometry analysis.The correct assignment of the 1 H NMR spectra of the products 6a-k, 7a-k, and 11-13 was carried out using 2D COSY experiment.The High Resolution Mass Spectra (HRMS) were registered on a LC-MS-TOF Bruker Daltonics Micro Ic from the Department of Chemistry of University of São Paulo (USP), São Paulo, SP, Brazil.The mass spectra were registered on an HP 5973 MSD connected to an HP 6890 GC.The GC was equipped with a split-splitless injector, auto-sampler, cross-linked HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier gas.The 1 H and 13 C NMR spectra were acquired on a Bruker DPX200 or DPX400 spectrometer in CDCl3 with TMS as the internal reference.

General experimental procedure for the synthesis of N-alkyl(aryl)-3-ethoxypyrrolidine-2,5diones 6a-k and N-alkyl(aryl)-cis-2,3,3a,6a-tetrahydrofuro[2,3-c]pyrrole-4,6(5H)-diones 7ak.
To a solution of 3-cyano-3-ethoxypropionic acid 3 or 2-cyanotetrahydrofuran-3-carboxylic acid 4 (5.0 mmol) in water (10 mL), amines 5a-k (5.0 mmol) was added.The reaction mixture was stirred at 140 °C until all the water was distilled off.After the distillation of the water, the temperature of the oil bath was raised to 180 °C and the reaction was maintained at this temperature for 1.5 h.The reaction was cooled to room temperature and chloroform (30 mL) was added to the reaction flask in order to solubilize the remaining oil in the flask.The solution was dried (Na2SO4), filtered and evaporated.Compounds 6 and 7 were obtained as brown or yellow oils in good yields and were purified by column chromatography on silica gel as the stationary phase and 50% chloroform/ethyl acetate solution as the mobile phase.
Selected spectral data of the products (6 and 7)

Supplementary Material Available
Experimental procedures, characterization data (for all the products), copies of 1 H and 13 C NMR spectra associated with this paper can be found in the online version.