2-Pyrrolidinones and 3-Pyrrolin-2-ones: A Study on the Chemical Reactivity of These Structural Moieties

2.1. Reactions of Enolates Derived from 2-pyrrolidinone and N-tert-butoxycarbonyl-2-pyrrolidinone with Iodine and Diphenyl Disulfide. For execution of the reactions described in Scheme 1, we used as starting material the commercial reagent 2-pyrrolidinone(1), and for protection of the lactamic nitrogen of 1, we planned to use the electron withdrawing group tert-butoxycarbonyl (Boc). This choice was due to the facility to be removed and also because this group increases the acidity of the hydrogens alpha to the carbamate group [2]. This enhancement of reactivity of the alpha hydrogens, in basic conditions, would be useful in posterior reactions. Thus, the treatment of 1 with a suspension of NaH in THF followed by reaction with (Boc)2O [3] generated a compound characterized by 1H NMR as the pyrrolidinone 2. The substance 2 was partially converted to a product identified by 1H NMR as the thiophenoxylactam 3, as result of alpha deprotonation of the carbamate of 2 with LDA solution [4], followed by nucleophilic substitution of the generated lithium enolate with diphenyl disulfide [5]. At the 1H NMR spectrum of 3, signals were detected relative to two isomers in the proportion (10 : 1) measured by integrals relative to methyls of the groups tert-butoxycarbonyl at δ 1.52 (major isomer) and δ 1.43 (minor isomer). The isomers 4a-b, characterized by 1H NMR (Table 2), were obtained by addition reaction of iodine to silyl enol ether [6] derived from 2-pyrrolidinone(1) (Scheme 1). The moderate yield of this reaction (25%), in relation to high yields described for iodination of silyl enol ethers derived from -caprolactams [7] and δ-valerolactams [6], was attributed to the high tension of the γ-lactamic ring of 1 turning it more reactive and, therefore, susceptible to the formation of byproducts.


Introduction
In connection with our studies on the syntheses of potentially bioactive 2-pyrrolidinones and 3-pyrrolin-2-ones [1], we describe in this paper the results of the performed study on the chemical reactivity of these structural moieties in reactions of addition, nucleophilic substitution, elimination, and reduction as well as the protection of the lactamic nitrogen.

Reactions of Enolates Derived from 2-pyrrolidinone and N-tert-butoxycarbonyl-2-pyrrolidinone with Iodine and
Diphenyl Disulfide.For execution of the reactions described in Scheme 1, we used as starting material the commercial reagent 2-pyrrolidinone (1), and for protection of the lactamic nitrogen of 1, we planned to use the electron withdrawing group tert-butoxycarbonyl (Boc).This choice was due to the facility to be removed and also because this group increases the acidity of the hydrogens alpha to the carbamate group [2].This enhancement of reactivity of the alpha hydrogens, in basic conditions, would be useful in posterior reactions.Thus, the treatment of 1 with a suspension of NaH in THF followed by reaction with (Boc) 2 O [3] generated a compound characterized by 1 H NMR as the pyrrolidinone 2. The substance 2 was partially converted to a product identified by 1 H NMR as the thiophenoxylactam 3, as result of alpha deprotonation of the carbamate of 2 with LDA solution [4], followed by nucleophilic substitution of the generated lithium enolate with diphenyl disulfide [5].At the 1 H NMR spectrum of 3, signals were detected relative to two isomers in the proportion (10 : 1) measured by integrals relative to methyls of the groups tert-butoxycarbonyl at δ 1.52 (major isomer) and δ 1.43 (minor isomer).
The isomers 4a-b, characterized by 1 H NMR (Table 2), were obtained by addition reaction of iodine to silyl enol ether [6] derived from 2-pyrrolidinone(1) (Scheme 1).The moderate yield of this reaction (25%), in relation to high yields described for iodination of silyl enol ethers derived from -caprolactams [7] and δ-valerolactams [6], was attributed to the high tension of the γ-lactamic ring of 1 turning it more reactive and, therefore, susceptible to the formation of byproducts.

Elimination Reactions of Hydrogen Iodide on 3-iodine-2pyrrolidinone.
The study of elimination of hydrogen iodide on 3-iodine-2-pyrrolidinone was based on a method of dehydrohalogenation reported in the literature [8].The results from that study, performed with the pyrrolidinones 4a-b, are described in Scheme 2 and Table 1.
After the respective times of reaction described in Table 1, crude products were isolated, filtered over column chromatography of silica gel, and then analysed by 1 H NMR. The signals of hydrogens relative to elimination product 5 were not observed at the spectrum of experiment 1.However, Scheme 2: Reagents: Experiment 1: 4 (1.0 equiv), LiCl (5.0 equiv); Experiment 2-3: 4 (1.0 equiv), Et 3 N (5.0 equiv).
we verified a larger proportion of the thermodynamic isomer 4b in relation to the kinetic isomer 4a previously obtained at low temperature in the experiment described in Scheme 1.
In experiments 2 and 3 where there was substitution of LiCl for a stronger base (Et 3 N), we observed, in their 1 H NMR spectra, signals relative to olefinic hydrogens C3-H and C4-H of the substance 5 at δ 6.1 and 7.1 ppm, respectively.At the spectrum of product from experiment 3, where the reaction was accomplished with heating, we verified the absence of signal relative to hydrogen C3-H of the isomer 4a indicating total isomerization of 4a to 4b.

Reactions of Reduction of the Carbamate and Aldol
Addition on N-tert-butoxycarbonyl-2-pyrrolidinone.We used as starting material in these reactions the pyrrolidinone 2, previously obtained in the conditions described in Scheme 1, and the reaction conditions for execution of this study were based on procedures reported in the literature (Scheme 3).Thus, NaBH 4 in methanol was used for reduction of the carbamate at lactamic ring of the pyrrolidinone 2 [9].The product from this reaction was characterized by 1 H NMR as the hemiaminal 6.The mixture of isomers 7, characterized by 1 H NMR, was obtained by aldol addition of enolate derived from the pyrrolidinone 2 to benzaldehyde [10].

Evaluation of the Reactivity of N-benzyl-3-pyrrolin-2one in Reactions of Reduction and Additions of Carbanion and Benzylamine.
For execution of the reactions described in Scheme 4, we used as substrate N-benzyl-3-pyrrolin-2-one (8), which was previously obtained [1].Thus, the treatment of 8 with TMSCl followed by reaction with the Grignard reagent PhMgBr and CuBr•SMe 2 [11][12][13] generated a product identified by 1 H NMR, IR, and LRMS as the hemiaminal 9.The compound 10, identified by 1 H NMR, was obtained by hydrogenation of 8 with hydrogen and the Pearlman catalyst Pd(OH) 2 /C [14].The reaction of 8 with S-α-methylbenzylamine generated a complex mixture of substances.After a detailed analysis of 1 H NMR, 13 C NMR, 1 Hx 1 H-Cosy, HETCOR, IR and GC/MS spectra, we propose the structure of the probable isomers 11-13 as products of that reaction, resulting from the speculative mechanism depicted in Scheme 5.The proposition of the substances 11-13 as the probable products from that reaction was reinforced at the GC/MS spectra by the peaks at m/z 281 (T R 2.1, 7.4 and 8.4 min), attributed to the protonated [M + H] + ions of that mixture of isomers.The reactions described in Scheme 4 clearly show the low reactivity of lactam 8 in conjugate addition reactions of carbanion (condition a) and amine (condition c).In condition a the addition of TMSCl, to the reaction medium, generally used to activate the C-4 position to the nucleophilic attack of carbanion, was not able to do this; the substrate 8 was reduced in situ yielding compound 9.In condition c lactam 8 was totally inert to the conjugate addition reaction of amine, furnishing probable products of opening of the lactamic ring.There was evidence of condition b, the better reactivity of double bond C3-C4 in relation to benzyl group attached to lactamic nitrogen in hydrogenation reaction, using a specific catalyst for hydrogenolysis of benzyl group (the Pearlman catalyst).

Reinvestigation of the Byproduct Obtained in the Protection Reaction of the Lactamic Nitrogen on 3-pyrrolin-2-one.
In previous publication [1] we described the protection of the lactamic nitrogen on 3-pyrrolin-2-one(5) with (Boc) 2 O in a multigram scale (4.7 g of 5) and 40% yield.In this paper we describe the results of this reaction performed in milligram scale (0.65 g of 5) (Scheme 6).We obtained  compound 18 as the major product, previously described [1], after purification over column chromatography of silica gel.An apolar fraction was also isolated and identified by 1 H NMR and 13 C NMR as the byproduct 19 (10 : 1) and 61% of general yield.The increase of yield observed in this reaction, accomplished in milligram scale, was attributed to the better homogeneity of the reagents that usually occurs in these conditions.We propose that compound 19 was obtained as result of in situ acylation of the enol form derived from lactam 18 with (Boc) 2 O.That kind of equilibrium between 3pyrrolin-2-ones and their enol forms, in basic medium, was previously described [15].[1], the conjugate addition reaction of nitromethane to α,β-unsaturated system of N-tert-butoxycarbonyl-3-pyrrolin-2-one(18) proceeded in smooth conditions.We planned to use compound 18 as substrate for accomplishment of that conjugate addition reaction with other nucleophiles, based on previous experiments reported in the literature.Thus, the addition of amines [15] and malonate anion [16] to α,β-unsaturated system of 18 was evaluated.The results from these addition reactions are displayed in Table 3 with the respective products analysed by NMR.The mixture of compounds obtained in experiment 1 suggests that addition of benzylamine was initially performed on the carbamate at the lactamic ring of 18 to yield a product of opening of the γ-lactam, amide 21.This compound underwent subsequent in situ reaction of conjugate addition with benzylamine to furnish amide 22.In experiment 2 the reaction was accomplished without H 2 O, and a mixture of isomers 24 was obtained.The product from experiment 3 was identified by 1 H NMR and 13 C NMR as a mixture of isomers 26.4-phenyl-2-pyrrolidinone(27), previously obtained [17], was performed in the conditions described in Scheme 7. In conditions a we used as deprotonating agent the base NaH, and the generated amide ion was acylated with (Boc) 2 O [3].

Protection of the Lactamic Nitrogen on 4-phenyl-2pyrrolidinone. The protection of the lactamic nitrogen on
In conditions b we used the base KH with catalytic amount of the crown ether 18-crown-6 [18] and with benzyl bromide as alkylating agent.Products 28 and 29 were identified by 1 H NMR, 13 C NMR, IR, and LRMS.

Conclusions
In summary, the chemical reactivity of 2-pyrrolidinones and 3-pyrrolin-2-ones was evaluated in different reaction conditions.The reactions presented in this paper led to the preparation of functionalized γ-lactams, and, therefore, they can be useful for future studies with these classes of substances.

Experimental
Infrared spectra were recorded on a Perkin Elmer-1600 model 1605 spectrophotometer (KBr).NMR spectra were recorded on a Varian Gemini-200 ( 1 H: 200 MHz and 13 C: 50.3 MHz) spectrometer, using CDCl 3 as the solvent and TMS as internal standard.Coupling constants (J) are reported in Hertz (Hz), and multiplicities are indicated as singlet (s), broad singlet (bs), doublet (d), broad doublet (bd), double doublet (dd), triplet (t), and multiplet (m).Low-resolution mass spectra (LRMS) were obtained by electron impact (70 eV) on a Varian GC-MS Saturn 2000 spectrometer.Thin-layer chromatography was performed on aluminium sheets coated with 60 F 254 silica and visualization by UV light and/or for contact of the plates with 7% ethanolic solution of phosphomolybdic acid and posterior heating.The purifications by column chromatography were performed on silica gel (230-400 mesh).The solvents and reagents were dried and purified by usual procedures [19].

N-benzyl-2-hydroxy-pyrrolidine(9)
4.10.1.Preparation of the Grignard Reagent.A mixture of magnesium (0.027 g, 1.111 mmol), bromobenzene (0.11 mL, 1.044 mmol), and THF (5.0 mL) was heated at reflux, under magnetic stirring and argon atmosphere for 3 h.It was then allowed to cool at room temperature, and the recently prepared solution of the Grignard reagent was used in the following reaction.

Reaction of PhMgBr-CuBr
•SMe 2 with N-benzyl-3pirrolin-2-one (8), TMSCl/THF.The recently prepared solution of the Grignard reagent (5.0 mL) was added to a stirred suspension of CuBr•SMe 2 (0.031 g, 0.151 mmol) in THF (0.5 mL) at room temperature and stirred for 10 minutes under argon atmosphere.The stirred mixture was put in a bath at −78 • C, and then a solution of lactam 8 (0.116 g, 0.669 mmol) and TMSCl (0.17 mL, 1.339 mmol) in THF (2.0 mL) was added.The mixture was left at −78 • C for 3 h and then allowed to reach the room temperature.The mixture was transferred to a separatory funnel, and EtOAc (40 mL) was added and then washed with saturated solution of NH 4 Cl (1 × 20 mL).The organic layer was separated, and the aqueous phase was extracted with EtOAc (1 × 40 mL).
The organic extracts were dried with Na 2 SO 4 , filtered, and concentrated in vacuum.The crude product was purified over column chromatography of silica gel eluted with EtOAc.A brownish crystalline residue was obtained characterized as compound 9 (0.078 g, 66%).R f 0.24 (EtOAc).IR (KBr) ν max /cm  (10).A mixture of lactam 8 (0.100 g, 0.577 mmol), 20% Pd(OH) 2 /C (0.041 g, 0.0577 mmol), and MeOH (6.0 mL), inside a round-bottom flask, was submitted to hydrogen atmosphere (balloon) under magnetic stirring and room temperature for 12 h.The mixture was filtered, concentrated in vacuum, and then purified over column chromatography of silica gel eluted with EtOAc.

Table 1 :
Evaluation of the elimination reactions performed with lactam 4.

Table 2 :
1H NMR data of the isomers 4a and 4b.

Table 3 :
Reactions of lactam 18 with some nucleophiles.
separated, and the aqueous phases were extracted with EtOAc (2 × 50 mL).The organic extracts were dried with Na 2 SO 4 , filtered, and concentrated in vacuum.The crude product was purified over column chromatography of silica gel eluted with 20% EtOAc/hexane.Pyrrolidinone 3 (0.070 g, 16%) was obtained as a colourless oil, and substrate 2 (0.247 g, 47%) was recovered without reacting.
room temperature for 1 h.Aqueous solution of 10% HCl (v/v) was added until pH 1, and the mixture was transferred to a separatory funnel, diluted with EtOAc (50 mL), and then washed with H 2 O (1 × 50 mL).The organic layer was separated, and the aqueous phase was extracted with EtOAc (1 × 50 mL).The organic extracts were dried with Na 2 SO 4 , filtered, and concentrated in vacuum.