567 Acta Chim. Slov. 1999, 46(4), pp. 567-586 REACTIONS OF 5-SUBSTITUTED (S)-l-ACYL-3-[(E>(DIMETHYLAMINO)- METHYLIDENE]PYRROLIDINE-2-ONES AND (S)-3-E)-(DIMETHYL- AMINO)METHYLIDENE]TETRAHYDROFURAN-2-ONES WITH AMINES. PREPARATION OF INTERMEDIATES IN THE ‘RING SWITCHING’ SYNTHESIS OF HETEROARYLALANINE- AND HETEROARYLLACTIC ACID DERIVATIVES AND THEIR ANALOGS Marko Škof, Jurij Svete*, Branko Stanovnik* Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia Simona Golič-Grdadolnik National Institute of Chemistry, Ljubljana, Slovenia (Received 26.10.1999) Abstract. - 5-Substituted (S)-1-acyl-3-[(E)-(dimethylamino)methylidene]pyrrolidin-2-ones 1-3 and (S)-3-[(E )-(dimethylamino)methylidene]-5-(methoxycarbonyl)tetrahydrofuran-2-one 4, chiral cyclic analogs of 2-substituted alkyl 3-(dimethylamino)propenoates, were treated with alkyl, aryl, and heteroarylamines 6-25 under mild conditions to give 5-substituted («S)-3-[(substituted amino)methylidene]pyrrolidin-2-ones 26-47 and (S)-3-[(E)-(substituted amino)methylidene]-tetrahydrofuran-2-ones 48-52 as intermediates in a ‘ring switcing’ synthesis of 3-heteroarylalanine- and 3-heteroaryllactic acid derivatives and their analogs. Introduction. - In the last few decades, several synthetic method for the preparation of 3-heteroarylalanines have been developed due to their occurrence in nature, biological activity, and synthetic aplicability [1]. Among various synthetic approaches, transformations of commercially available a-amino acids, such as serine, Dedicated to Prof. Dr. Drago Leskovšek on the occasion of his 80th birthday 568 aspartic acid, and glutamic acid, found a wide applicability in the preparation of 3-heteroarylalanines [2]. Recently, Young and coworkers reported the synthesis of 3-pyrazolyl-, 3-isoxazolyl-, and 3-pyrimidinyl-alanines from (S)-3-formylpyroglutamic acid derivatives, using a ‘ring switching’ strategy [3]. On the other hand, our previous study on the chemisty of polyfunctional alkyl 2-substituted 3-(dimethylamino)propenoates showed, that this type of compounds can serve as versatile, simple, and efficient synthetic tool for the preparation of a variety of heterocyclic systems, a,b-dehydro-a-amino acid derivatives and peptides, as well as N-protecting reagents in the peptide synthesis [4, 5]. In this connection, we introduced 5-substituted (S)-1-acyl-3-[(E)-(dimethyl-amino)methylidene]-pyrrolidin-2-ones 5–7 and (S)-3-[(E)-(dimethylamino)-methylidene]tetrahydrofuran-2-ones 8 and 9 which can be prepared in 2–3 steps from commercially available precursors 1–4 (Figure 1). Compounds 5–9 are actually optically active cyclic analogs of alkyl 2-substituted 3-(dimethylamino)propenoates and were used as precursors for the preparation of optically active 3-heteroarylalanine-, 3-heteroarylalaninol-, and 3-heteroaryllactic acid derivatives and for a stereoselective preparation of heterocyclic systems with a-amino acid structural element [6–11]. In continuation of our work in this field, we now report the preparation of 5-substituted (S)-3-[(substituted amino)methylidene]pyrrolidin-2-ones 30–51 and (S)-3-[(E)-(substituted amino)methylidene]tetrahydrofuran-2-ones 52– 56 as intermediates in a ‘ring switching’ synthesis of 3-heteroarylalanine-, 3-heteroarylalaninol-, and 3-heteroaryllactic acid derivatives [8–11]. Figure 1 HOOC \ HO H HOOC HO ^O O MeOOC COOBu-t Me2N 5 MeOOC» O ' ' COPh J^ Q COPh /NyO Ph W^-NW \> \s / / Me2N Me2N 6 7 MeOOC Me2N 8 Ph O Me2N 9 O O O O N O O O O 569 Table 1. List of Compounds 10-56. ^ o R-NHo 10-29 Me2N 5-9 , „ HN R 30-56 Compounds 10-56 Amines 10-29 Products 30-56 (Boc = COOBu-t, Bz = PhCO) R X = N-Boc X = N-COPh X = N-COPh X = 0 Y = COOMe Y = COOMe Y = CH20Bz Y = COOMe CH2COOMe (10) 30 43 benzyl (11) 31 - phenyl (12) 32 - 3-bromophenyl (13) 33 - 3-methylphenyl (14) 34 - 4-methylphenyl (15) - - 3-nitrophenyl (16) 35 - 1-naphthyl (17) 36 - pyridinyl-2 (18) 37 - 5-chloropyridinyl-2 (19) - 44 4-methylpyridinyl-2 (20) 38, (42, X = NH) 45 6-chloropyridazinyl-3 (21) - - 4,6-dimethylpyrimidinyl-2 (22) - 46 pyrazinyl-2 (23) - 47 isoxazolyl-3 (24) 39 - 5-methylisoxazolyl-3 (25) - 48 thiazolyl-2 (26) 40 - lH-l,2,4-triazolyl-3 (27) - - ethane-1,2-diyl (28) 41 - piperazin-l,4-diyl (29) - 49 50 51 52 53 54 55 56 Results and discussion. - Starting compounds 5-9 were prepared by treatment of the corresponding 5-substituted (S-y-butyrolactams and (S-y-butyrolactones, prepared 570 from compounds 1–4, with bis(dimethylamino)-tert-butoxymethane (Bredereck's reagent) according to the procedures described previously [6, 7, 11]. Compounds 5–9 were then treated with the following alkyl-, aryl-, and heteroarylamines: glycine methyl ester hydrochloride (10), benzylamine hydrochloride (11), aniline (12), 3-bromoaniline (13), 3-methylaniline (14), 4-methylaniline (15), 3-nitroaniline (16), 1-naphthylamine (17), 2-aminopyridine (18), 2-amino-5-chloropyridine (19), 2-amino-4-methylpyridine (20), 3-amino-6-chloropyridazine (21), 2-amino-4,6-dimethylpyrimidine (22), aminopyrazine (23), 3-aminoisoxazole (24), 3-amino-5-methylisoxazole (25), 2-aminothiazole (26), 3-amino-1H-1,2,4-triazole (27), 1,2-diaminoethane (28), and piperazine (29) to give the corresponding 5-substituted (S)-3-[(substituted amino)-methylidene]pyrrolidin-2-ones 30–51 and (S)-3-[(substituted amino)methylidene]-pyrrolidin-2-ones 52–56 (Table 1). Scheme 1 MeOOC, COOBu-f i O Me2N 5 R-NH2 10-14, 16-18, 20, 24, 26 EtOH/HCI or AcOH, 20°C MeOOC COOBu-f 5 \__f2 30-40 4 3^. HN R1 MeOOC, MeOOC, COOBu-f Me2N 5 COOBu-f i V V0 Me2N H2N 28 NH2, AcOH, 20°, 2h ^N NH2 ! J Me 20 AcOH, reflux MeOOC COOBu-f f-BuOOO. M N \ MOOCM MeOOC -NH ^^^ ''COOMe HN- 41 *»/ "vjjC HN >—N 42 Me 5 571 Reactions of (S)-tert-butoxycarbonyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (5) with amines 10–14, 16–18, 20, 24, 26 and 28 were carried out in ethanol or acetic acid at room temperature in order to avoid the removal of acid-labile tert-butoxycarbonyl group to give substitution products 30–40. However, with 1,2-diaminoethane (41) 2 equivalents of starting compound 5 were employed to afford bis-substitution product 41. Treatment of 5 with 2-amino-4-methylpyridine (20) in refluxing acetic acid furnished (S)-3-[(4-methyl-2-pyridinylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (42), unsubstituted at the position 1 in the pyrrolidine ring. (Scheme 1). Scheme 2 MeOOC X COPh N O / Me2N 6 R-NH2 10, 19, 20, 22, 23, 25 EtOH/HCI or AcOH, 20°-reflux MeOOC COPh N O HN 43-48 MeOOC O Ph \ COPh i ,N O O / Me2N 6 COPh i N O / Me2N 7 HN NH 29 AcOH, 20° O PhOC O R-NH2 19, 22, AcOH, reflux Ph' COOMe MeOOČ 49 COPh N O O COPh 5\ /2 4 3 \\ / HN 50, 51 MeOOC» ^ r^ R-NH2 15, 20-22, 27, AcOH, reflux / Me2N 8 MeOOC .0 O HN 52-56 R N N R R 572 On the other hand, (S)-1-benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (6), (S)-1-benzoyl-5-benzoyloxymethyl-3-[(E)-(dimethyamino)methylidene]pyrrolidin-2-one (7), and (S)-3-[(E)-(dimethylamino)-methylidene]-5-(methoxycarbonyl)tetrahydrofuran-2-one (8), which are more stable under acidic conditions, were treated with amines 10, 15, 19–23, 25, 27, and 29 at 20– 120°C to give mono-substitution products 43–56. Again, treatment of piperazine (29) with 2 equivalents of (S)-1-benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (6) afforded a bis-substitution product 56 (Scheme 2). Structures of products 30–56 were determined by NMR and elemental analyses. The (E)-orientation around the exocyclic C=C duoble in compound 44, determined by NMR (NOESY) experiments, is in accordance with the orientation in acyclic 3-(substituted amino)propenoates since the 3-amino group is always trans-oriented with respect to the ester group [4–6] (Scheme 3). Scheme 3. NMR (NOESY) determination of orientation around C=C double bond in compound 44 (R = 5-chloropyrimidinyl-2). COPh i j- NI 1 \ / ^ dH3'–H4 (nm) dNH–H4 (nm) /T )—" 44 / 'v u.{ 3' \ \ ^ / Calculated Found Calculated Found 0.39 (E) 0.33 0.28 (Z) 0.27 (E) 0.27 0.46 (Z) Preparation and isolation of compounds 30–56 suggests, that the ‘ring switching’ transformation of 3-[(dimethylamino)methylidene]pyrrolidin-2-ones and 3-[(dimethylamino)methylidene]tetrahydrofuran-2-ones into 3-heteroaryl substituted a-amino- and a-hydroxy acids and a-amino alcohols proceeds predominantly via initial substitution of the dimethylamino group, followed by substitution at the ring carbonyl group (path B). This observation is also in accordance with the results of Young and coworkers and with our previous results in acyclic 3-(dimethylamino)propenoate series [3–5] (Figure 2). 573 Figure 2. Proposed mechanism for ‘ring switching’ transformation of 5–9 with dinucleophiles. / B Nu Me 2 N^ H path A path B HX O R^\ / /\ Nu Me2N J H HX O. ^Nu -Nu Experimental General. All starting materials were commercially available (in most cases from Fluka) and purified following the standard techniques. The following compounds were prepared according to the procedures described in the literature: (S)-1-tert-butoxycarbonyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one 5 [7], (S)-1-benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one 6 [6], (S)-1-benzoyl-5-benzoyloxymethyl-3-[(E)-(dimethylamino)-methylidene]pyrrolidin-2-one 7 [11], and (S)-3-[(E)-(dimethylamino)methylidene]-tetrahydrofuran-2-one 8 [7]. Column chromatography: silica gel, Fluka, Kieselgel 60. TLC: Merck, Alufolien Kieselgel 60 F 254, 0.2mm. M.p.: Kofler micro hot stage. Optical rotations: Perkin-Elmer 241 MC polarimeter. 1H-NMR and 13C-NMR: Bruker Avance DPX 300 spectrometer. Elemental analyses: Perkin-Elmer CHN Analyser 2400. Preparation of (S)-1-tert-butoxycarbonyl-3-[(E)-(substituted amino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-ones 30–40. General procedure. A mixture of (S)-1-tert-butoxycarbonyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one 5 (298 mg,1 mmol), substituted amine 10–14, 16–18, 20, 24, or 26 (1 mmol), ethanol or acetic acid (100%, 5 ml), and hydrochloric acid (36%, 0.1 ml, 1 mmol) [12] was stirred at room temperature for several hours. Volatile components were evaporated in vacuo, the residue was triturated with an appropriate solvent, and the R H 574 precipitate was collected by filtration to give compounds 30–40. In this manner, the following compounds were prepared: (S)-1-tert-Butoxycarbonyl-3-[(methoxycarbonylmethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (30). This compound was prepared from glycine methyl ester hydrochloride (10) and 5 in ethanol, stirring for 2 h, trituration with water. Yield: 77% (0.265 g). M.p. 144–146°C (EtOH/H2O). [a]D23 –10.4° (c = 0.72, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 1.38 (9H, s, CMe3); 2.34 (1H, br d, J = 15.7 Hz, 4– Ha); 2.82 (1H, dd, J = 11.3, 15.1 Hz, 4–Hb); 3.66 (3H, s, OMe); 3.69 (3H, s, OMe); 4.03 (2H, d, J = 5.8 Hz, CH2NH); 4.59 (1H, dd, J = 3.3, 10.7 Hz, 5–H); 6.90–6.97 (1H, m, NH); 7.07 (1H, br d, J = 13.1 Hz, 3’–H). Anal. calc. for C15H22N2O7 (342.34): C, 52.63; H, 6.48; N, 8.18; found: C, 52.62; H, 6.56; N, 8.14. (S)-1-tert-Butoxycarbonyl-3-[(benzylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (31). This compound was prepared from benzylamine hydrochloride (11) and 5 in ethanol, stirring for 2 h, trituration with water. Yield: 71% (0.256 g). M.p. 154–156°C (EtOH/H2O). [a]D23 +1.6° (c = 1.12, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 1.37 (9H, s, CMe3); 2.34 (1H, dd, J = 2.1, 16.1 Hz, 4–Ha); 2.83 (1H, dd, J = 11.3, 16.1 Hz, 4–Hb); 3.67 (3H, s, OMe); 4.36 (2H, d, J = 5.3 Hz, CH2NH); 4.57 (1H, dd, J = 3.6, 10.8 Hz, 5–H); 7.15–7.35 (7H, m, Ph, 3’–H, and NH). Anal. calc. for C19H24N2O5 (360.40): C, 63.32; H, 6.71; N, 7.77; found: C, 63.22; H, 6.96; N, 7.74. (S)-1-tert-Butoxycarbonyl-3-[(anilino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (32). This compound was prepared from aniline (12) and 5 in ethanol, stirring for 2 h, trituration with ethanol. Yield: 86% (0.298 g). M.p. 186–188°C (EtOH/H2O). [a]D23 –9.9° (c = 0.85, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 1.44 (9H, s, CMe3); 2.63 (1H, ddd, J = 1.9, 2.9, 16.6 Hz, 4–Ha); 3.07 (1H, ddd, J = 2.2, 10.8, 16.9 Hz, 4–Hb); 3.74 (3H, s, OMe); 4.72 (1H, dd, J = 3.3, 10.7 Hz, 5–H); 6.95–7.01 (1H, m, 1H–Ph); 7.15 (2H, d, J = 7.8 Hz, 2H–Ph); 7.29–7.35 (2H, m, 2H–Ph); 7.64 (1H, 575 d, J = 13.1 Hz, 3’–H); 9.01 (1H, d, J = 13.1 Hz, NH). Anal. calc. for C18H22N2O5 (346.38): C, 62.42; H, 6.40; N, 8.09; found: C, 62.05; H, 6.43; N, 7.94. (S)-1-tert-Butoxycarbonyl-3-[(3-bromoanilino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (33). This compound was prepared from 3-bromoaniline (13) and 5 in ethanol, stirring for 2 h, trituration with water. Yield: 88% (0.374 g). M.p. 170– 172°C (EtOH/H2O). [a]D23 +3.1° (c = 1.01, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.60 (1H, deg dt, J = 2.5, 16.6 Hz, 4–Ha); 3.03 (1H, ddd, J = 2.1, 10.7, 16.6 Hz, 4–Hb); 3.71 (3H, s, OMe); 4.70 (1H, dd, J = 3.2, 10.7 Hz, 5–H); 7.09– 7.29 (3H, m, 3H–Ar); 7.33 (1H, s, 1H–Ar); 7.61 (1H, d, J = 12.8 Hz, 3’–H); 9.04 (1H, d, J = 12.8 Hz, NH). Anal. calc. for C18H21BrN2O5 (425.27): C, 50.84; H, 4.98; N, 6.59; found: C, 51.09; H, 5.09; N, 6.55. (S)-1-tert-Butoxycarbonyl-3-[(3-methylanilino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (34). This compound was prepared from 3-methylaniline (14) and 5 in acetic acid, stirring for 2 h at 20°, trituration with acetic acid. Yield: 66% (0.238 g). M.p. 195–197°C (EtOH/H2O). [a]D23 +2.8° (c = 1.01, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.28 (3H, s, Ar–Me); 2.58 (1H, deg dt, J = 2.8, 16.7 Hz, 4–Ha); 3.02 (1H, ddd, J = 2.2, 10.7, 16.7 Hz, 4–Hb); 3.71 (3H, s, OMe); 4.68 (1H, dd, J = 3.3, 10.7 Hz, 5–H); 6.77 (1H, d, J = 7.4 Hz, 1H–Ar); 6.91 (1H, d, J = 7.4 Hz, 1H–Ar); 6.96 (1H, s, 1H–Ar); 7.16 (1H, deg t, J = 7.4 Hz, 1H–Ar); 7.61 (1H, d, J = 13.1 Hz, 3'–H); 8.92 (1H, d, J = 13.1 Hz, NH). Anal. calc. for C19H24N2O5 (360.40): C, 63.32; H, 6.71; N, 7.77; found: C, 63.06; H, 6.97; N, 7.73. (S)-1-tert-Butoxycarbonyl-3-[(3-nitroanilino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (35). This compound was prepared from 3-nitroaniline (16) and 5 in ethanol, stirring for 2 h, trituration with ethanol. Yield: 95% (0.372 g). M.p. 194–196°C (EtOH). [a]D23 –7.6° (c = 1.04, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 1.42 (9H, s, CMe3); 2.69 (1H, m, 4–Ha); 3.06 (1H, m, 4–Hb); 3.72 (3H, s, OMe); 4.72 (1H, dd, J = 3.3, 10.6 Hz, 5–H); 7.55–7.73 (4H, m, 4H–Ar); 7.94 (1H, br s, 3’–H); 9.32 (1H, d, J = 576 11.7 Hz, NH). Anal. calc. for C18H21N3O7 (391.38): C, 55.24; H, 5.41; N, 10.74; found: C, 55.59; H, 5.47; N, 10.91. (S)-1-tert-Butoxycarbonyl-3-[(1-naphthylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (36). This compound was prepared from 1-naphthylamine (17) and 5 in acetic acid, stirring for 6 h, trituration with water. Yield: 93% (0.368 g). M.p. 95–98°C (H2O). [a]D23 +27.3° (c = 0.86, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 1.42 (9H, s, CMe3); 2.78 (1H, ddd, J = 2.1, 3.0, 16.9 Hz, 4–Ha); 3.15 (1H, ddd, J = 2.2, 10.7, 16.8 Hz, 4–Hb); 3.73 (3H, s, OMe); 4.72 (1H, dd, J = 3.4, 10.7 Hz, 5–H); 7.23 (1H, d, J = 13.1 Hz, 1H–Ar); 7.37–7.69 (5H, m, 4H–Ar and 3'–H); 7.90– 7.97 (1H, m, 1H–Ar); 8.23–8.28 (1H, m, 1H–Ar); 9.03 (1H, d, J = 12.4 Hz, NH). Anal. calc. for C22H24N2O5 (396.44): C, 66.65; H, 6.10; N, 7.07; found: C, 66.44; H, 6.22; N, 7.06. (S)-1-tert-Butoxycarbonyl-3-[(2-pyridinylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (37). This compound was prepared from 2-aminopyridine (18) and 5 in acetic acid, stirring for 2 h, trituration with water. Yield: 91% (0.316 g). M.p. 185–188°C (EtOH/H2O). [a]D23 –5.7° (c = 0.72, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.63 (1H, ddd, J = 2.3, 3.4, 16.6 Hz, 4–Ha); 3.05 (1H, ddd, J = 2.4, 10.9, 16.6 Hz, 4–Hb); 3.71 (3H, s, OMe); 4.71 (1H, dd, J = 3.2, 10.7 Hz, 5–H); 6.91–6.95 (2H, m, 2H–pyridine); 7.64–7.94 (1H, m, 1H–pyridine); 8.21–8.25 (2H, m, 1H-pyridine and 3'–H); 9.56 (1H, d, J = 12.5 Hz, NH). Anal. calc. for C17H21N3O5 (347.37): C, 55.78; H, 6.09; N, 12.10; found: C, 58.68; H, 6.28; N, 12.03. (S)-1-tert-Butoxycarbonyl-3-[(4-methyl-2-pyridinylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (38). This compound was prepared from 2-amino-4-methylpyridine (20) and 5 in acetic acid, stirring for 1 h, trituration with water. Yield: 90% (0.326 g). M.p. 172–174°C (EtOH/H2O). [a]D23 +108.9° (c = 0.90, DMF). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.26 (3H, s, Het–Me); 2.61 (1H, ddd, J = 2.2, 3.1, 16.8 Hz, 4–Ha); 3.04 (1H, ddd, J = 2.4, 10.7, 16.7 Hz, 4–Hb); 3.71 577 (3H, s, OMe); 4.70 (1H, dd. J = 3.3, 10.7 Hz, 5–H); 6.75 (1H, s, 1H–pyridine); 6.78 (1H, d, J = 5.3 Hz, 1H–pyridine); 8.09 (1H, d, J = 5.1 Hz, 1H–pyridine); 8.21 (1H, br d, J = 12.3 Hz, 3'–H); 9.47 (1H, d, J = 12.3 Hz, NH). Anal. calc. for C18H23N3O5 (361.39): C, 59.82; H, 6.41; N, 11.63; found: C, 60.10; H, 6.80; N, 11.71. (S)-1-tert-Butoxycarbonyl-3-[(3-isoxazolylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (39). This compound was prepared from 3-aminoisoxazole (24) and 5 in acetic acid, stirring for 2 h, trituration with water. Yield: 88% (0.296 g). M.p. 187–189°C (EtOH/H2O). [a]D23 +22.2° (c = 0.68, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.59 (1H, deg dt, J = 2.6, 16.9 Hz, 4–Ha); 3.02 (1H, ddd, J = 2.5, 10.6, 16.9 Hz, 4–Hb); 3.71 (3H, s, OMe); 4.69 (1H, dd. J = 3.2, 10.6 Hz, 5–H); 6.45 (1H, d, J = 1.7 Hz, 1H-isoxazole); 7.50 (1H, d, J = 11.5 Hz, 3'–H); 8.70 (1H, d, J = 1.7 Hz, 1H–isoxazole); 9.65 (1H, d, J = 11.8 Hz, NH). Anal. calc. for C15H19N3O6 (337.33): C, 53.41; H, 5.68; N, 12.46; found: C, 53.53; H, 5.95; N, 12.35. (S)-1-tert-Butoxycarbonyl-3-[(2-thiazolylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (40). This compound was prepared from 2-aminothiazole (26) and 5 in acetic acid, stirring for 2 h, trituration with water. Yield: 72% (0.256 g). M.p. 173–175°C (EtOH/H2O). [a]D23 +76.3° (c = 0.56, DMF). 1H-NMR (300 MHz, (D6)DMSO): 1.41 (9H, s, CMe3); 2.59 (1H, ddd, J = 2.3, 3.0, 17.0 Hz, 4–Ha); 3.03 (1H, ddd, J = 2.6, 10.6, 17.0 Hz, 4–Hb); 3.71 (3H, s, OMe); 4.70 (1H, dd. J = 3.2, 10.6 Hz, 5–H); 7.08 (1H, d, J = 3.5 Hz, 1H-thiazole); 7.31 (1H, d, J = 3.5 Hz, 1H-thiazole); 7.79 (1H, br s, 3'–H); 10.52 (1H, br s, NH). Anal. calc. for C15H19N3O5S (353.39): C, 50.98; H, 5.42; N, 11.89; found: C, 50.88; H, 5.69; N, 11.77. (S,S)-N,N'-bis-[(1-tert-Butoxycarbonyl-5-methoxycarbonyl-2-oxopyrrolidin-3-ylidene)methyl]-1,2-diaminoethane (41). A mixture of (S)-1-tert-butoxycarbonyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one 5 (596 mg, 2 mmol), 1,2-diaminoethane 28 (60 mg, 1 mmol), and acetic acid (100%, 5 ml) was stirred at room temperature for 2 hours. Volatile components were evaporated in vacuo, water (10 ml) and ethanol (1 ml) were added to the residue, and the precipitate was 578 collected by filtration to give 41. Yield: 68% (0.386 g). M.p. 172–175°C (EtOH/H2O). [a]D23 +38.1° (c = 0.73, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 1.37 (18H, s, 2 x CMe3); 2.29 (2H, br d, J = 15.0 Hz, 2 x 4’–Ha); 2.77 (2H, br deg t, J = 13.2 Hz, 2 x 4’– Hb); 3.31 (4H, s, 1–CH2 and 2–CH2); 3.68 (6H, s, 2 x OMe); 4.53 (2H, dd. J = 3.8, 10.8 Hz, 2 x 5’–H); 6.73 (2H, br d, J = 13.2 Hz, 2 x 3’’–H); 7.05 (2H, d, J = 13.6 Hz, 2 x NH). Anal. calc. for C26H38N4O10 (566.60): C, 55.11; H, 6.76; N, 9.89; found: C, 54.80; H, 6.67; N, 9.91. (S)-3-[(4-methyl-2-pyridinylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (42). A mixture of (S)-1-tert-butoxycarbonyl-3-[(E)-(dimethylamino)-methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one 5 (298 mg, 1 mmol), 2-amino-4-methylpyridine 20 (108 mg, 1 mmol), and acetic acid (100%, 5 ml) was stirred at reflux temperature for 2 hours. Volatile components were evaporated in vacuo, the residue was triturated with a mixture of water and methanol (1 : 1, 5 ml), and the precipitate was collected by filtration to give 42. Yield: 61% (0.158 g). M.p. 202–205°C (MeOH/H2O). [a]D23 +111.1° (c = 0.65, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.24 (3H, s, Het– Me); 2.76 (1H, ddd, J = 2.4, 3.3, 16.9 Hz, 4–Ha); 3.07 (1H, ddd, J = 2.5, 9.8, 16.8 Hz, 4–Hb); 3.69 (3H, s, OMe); 4.29 (1H, dd. J = 3.6, 10.0 Hz, 5–H); 6.67–6.69 (2H, m, 2H– pyridine); 7.77 (1H, s, 1–H); 7.93 (1H, deg dt, J = 2.2, 12.0 Hz, 3'–H); 8.02 (1H, d, J = 5.7 Hz, 1H–pyridine); 9.01 (1H, d, J = 12.0 Hz, 3’–NH). Anal. calc. for C13H15N3O3 (261.28): C, 59.76; H, 5.79; N, 16.08; found: C, 59.52; H, 5.78; N, 15.92. Preparation of (S)-1-benzoyl-3-[(substituted amino)methylidene-]-5-(methoxycarbonyl)pyrrolidin-2-ones 43–48. General Procedure. A mixture of (S)-1-benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one 6 (302 mg,1 mmol), substituted amine 10, 19, 20, 22, 23,or 25 (1 mmol), and ethanol or acetic acid (100%, 5 ml) was stirred at 20–120°C for several hours. Volatile components were evaporated in vacuo, the residue was triturated with an appropriate solvent, and the precipitate was collected by filtration to give compounds 43–48. In this manner, the following compounds were prepared: 579 (S)-1-Benzoyl-3-[(methoxycarbonylmethylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (43). This compound was prepared from glycine methyl ester hydrochloride (10) and 6 in ethanol, stirring at 20°C for 2 h, trituration with methanol. Yield: 90% (0.310 g). M.p. 157–160°C (MeOH). [a]D23 +4.1° (c = 1.0, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.45–2.52 (1H, m, 4–Ha); 2.97 (1H, br dd, J = 11.5, 14.9 Hz, 4–Hb); 3.66 (3H, s, OMe); 3.70 (3H, s, OMe); 4.06 (2H, d, J = 5.7 Hz, CH2NH); 4.83 (1H, dd, J = 3.8, 11.6 Hz, 5–H); 7.13 (1H, br d, J = 13.6 Hz, 3’–H); 7.22–7.31 (1H, m, NH); 7.36–7.43 (2H, m 2H–Ph); 7.47–7.52 (3H, m, 3H–Ph). Anal. calc. for C17H18N2O6 (346.33): C, 58.96; H, 5.24; N, 8.09; found: C, 58.73; H, 5.24; N, 7.81. (S)-1-Benzoyl-3-[(E)-(5-chloro-2-pyridinylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (44). This compound was prepared from 2-amino-5-chloropyridine (19) and 6 in acetic acid, reflux for 2 h, trituration with methanol. Yield: 87% (0.336 g). M.p. 231–233°C (MeOH). [a]D23 +38.63° (c = 1.17, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.76 (1H, ddd, J = 2.3, 3.0, 16.6 Hz, 4–Ha); 3.19 (1H, ddd, J = 2.3, 10.2, 16.6 Hz, 4–Hb); 3.73 (3H, s, OMe); 4.94 (1H, dd, J = 3.4, 10.2 Hz, 5–H); 7.01 (1H, d, J = 9.0 Hz, 1H–pyridine); 7.41–7.46 (2H, m, 2H–Ph); 7.53–7.57 (3H, m, 3H– Ph); 7.78 (1H, dd, J = 2.6, 8.7 Hz, 1H–pyridine); 8.17 (1H, br d, J = 11.7 Hz, 3'–H); 8.27 (1H, d, J = 2.3 Hz, 1H-pyridine); 9.91 (1H, d, J = 11.7 Hz, NH). Anal. calc. for C19H16ClN3O4 (385.80): C, 59.15; H, 4.18; N, 10.89; found: C, 59.04; H, 4.06; N, 10.63. (S)-1-Benzoyl-3-[(4-methyl-2-pyridinylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (45). This compound was prepared from 2-amino-4-methylpyridine (20) and 6 in acetic acid, reflux for 2 h, trituration with methanol/water. Yield: 94% (0.342 g). M.p. 202–204°C (MeOH/H2O). [a]D23 +59.2° (c = 0.51, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.27 (3H, s, Het–Me); 2.72–2.77 (1H, m, 4–Ha); 3.18 (1H, dd, J = 10.9, 15.3 Hz, 4–Hb); 3.72 (3H, s, OMe); 4.93 (1H, dd. J = 2.7, 10.0 Hz, 5–H); 6.79 580 (2H, br s, 2H–pyridine); 7.41–7.55 (5H, m, Ph); 8.08 (1H, d, J = 5.0 Hz, 1H–pyridine); 8.26 (1H, br d, J = 12.0 Hz, 3'–H); 9.68 (1H, d, J = 12.4 Hz, NH). Anal. calc. for C20H19N3O4 (365.38): C, 65.74; H, 5.24; N, 11.50; found: C, 65.45; H, 5.49; N, 11.22. (S)-1-Benzoyl-3-[(4,6-dimethyl-2-pyrimidinylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (46). This compound was prepared from 2-amino-4,6-dimethylpyrimidine (22) and 6 in acetic acid, reflux for 2 h, trituration with methanol. Yield: 80% (0.296 g). M.p. 217–219°C (MeOH). [a]D23 +26.0° (c = 1.02, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 2.33 (6H, s, 2Het–Me); 2.80 (1H, ddd, J = 2.1, 3.2, 17.0 Hz, 4–Ha); 3.17 (1H, ddd, J = 2.3, 10.2, 17.0 Hz, 4–Hb); 3.72 (3H, s, OMe); 4.90 (1H, dd, J = 3.4, 10.2 Hz, 5–H); 6.82 (1H, s, 1H–pyrimidine); 7.41–7.46 (2H, m, 2H–Ph); 7.53–7.57 (3H, m, 3H–Ph); 8.21 (1H, br d, J = 12.1 Hz, 3'–H); 10.27 (1H, d, J = 12.1 Hz, NH). Anal. calc. for C20H20N4O4 (380.40): C, 63.15; H, 5.30; N, 14.73; found: C, 63.07; H, 5.27; N, 15.06. (S)-1-Benzoyl-3-[(2-pyrazinylamino)methylidene]-5-(methoxycarbonyl)-pyrrolidin-2-one (47). This compound was prepared from 2-aminopyrazine (23) and 6 in acetic acid, reflux for 2 h, trituration with methanol. Yield: 79% (0.268 g). M.p. 175– 177°C (MeOH). [a]D23 +45.2° (c = 0.95, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.81 (1H, ddd, J = 2.1, 3.2, 16.5 Hz, 4–Ha); 3.23 (1H, ddd, J = 2.6, 10.2, 16.6 Hz, 4– Hb); 3.73 (3H, s, OMe); 4.96 (1H, dd. J = 3.0, 10.2 Hz, 5–H); 7.41–7.46 (2H, m, 2H– Ph); 7.54–7.58 (3H, m, 3H–Ph); 8.12–8.14 (1H, m, 3'–H); 8.16 (1H, d, J = 2.6 Hz, 1H-pyrazine); 8.25 (1H, dd, J = 1.5, 2.6 Hz, 1H-pyrazine); 8.35 (1H, d, J = 1.5 Hz, 1H– pyrazine); 10.07 (1H, br d, J = 6.8 Hz, NH). Anal. calc. for C18H16N4O4 (352.34): C, 61.36; H, 4.58; N, 15.90; found: C, 61.34; H, 4.58; N, 15.77. (S)-1-Benzoyl-3-[(5-methyl-3-isoxazolylamino)methylidene]-5-(methoxy-carbonyl)pyrrolidin-2-one (48). This compound was prepared from 3-amino-5-methylisoxazole (25) and 6 in acetic acid, reflux for 2 h, trituration with methanol. Yield: 83% (0.294 g). M.p. 209–210°C (MeOH). [a]D23 +22.9° (c = 0.99, CHCl3). 1H- 581 NMR (300 MHz, (D6)DMSO): 2.33 (3H, s, Het–Me); 2.72 (1H, ddd, J = 2.1, 3.3, 16.5 Hz, 4–Ha); 3.13 (1H, ddd, J = 2.3, 10.2, 16.6 Hz, 4–Hb); 3.74 (3H, s, OMe); 4.91 (1H, dd. J = 3.3, 10.2 Hz, 5–H); 6.13 (1H, s, 1H-isoxazole); 7.40–7.57 (6H, m, 5H–Ph and 3’–H); 9.74 (1H, br s, NH). Anal. calc. for C18H17N3O5 (355.34): C, 60.84; H, 4.82; N, 11.83; found: C, 60.50; H, 4.78; N, 11.63. (S,S)-N,N'-bis-[(1-Benzoyl-5-methoxycarbonyl-2-oxopyrrolidin-3-ylidene)-methyl]piperazine monohydrate (49). A mixture of (S)-1-benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one 6 (604 mg, 2 mmol), piperazine 29 (86 mg, 1 mmol), and acetic acid (100%, 5 ml) was stirred at reflux temperature for 1.5 hour. Volatile components were evaporated in vacuo and the residue was purified by column chromatography using a mixture of chloroform and methanol (5:1) as eluant. Fractions containing the product were combined, volatile components were evaporated in vacuo, methanol (3 ml) was added to the residue, and the precipitate was collected by filtration to give 49. Yield: 71% (0.438 g). M.p. 291– 293°C (MeOH). [a]D23 +3.8° (c = 0.84, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.82 (2H, dd, J = 2.8, 15.0 Hz, 2 x 4’–Ha); 3.33 (2H, m, 2 x 4’–Hb); 3.35 (8H, s, 4 x CH2–piperazine); 3.70 (6H, s, 2 x OMe); 4.79 (2H, dd. J = 4.0, 10.9 Hz, 2 x 5’–H); 7.07 (2H, br s, 2 x 3’’–H); 7.36–7.41 (4H, m, 4H–Ph); 7.46–7.53 (6H, m, 6H–Ph). Anal. calc. for C32H32N4O8 x H2O (618.64): C, 62.13; H, 5.54; N, 9.06; found: C, 61.93; H, 5.55; N, 9.09. Preparation of (S)-1-Benzoyl-5-benzoyloxymethyl-3-[(substituted amino)-methylidene]pyrrolidin-2-ones 50, 51. General procedure. A mixture of (S)-1-benzoyl-5-benzoyloxymethyl-3-[(E)-(dimethylamino)methylidene]pyrrolidin-2-one 7 (378 mg,1 mmol), substituted amine 19 or 22 (1 mmol), and acetic acid (100%, 5 ml) was refluxed for several hours. Volatile components were evaporated in vacuo, the residue was triturated with an appropriate solvent, and the precipitate was collected by filtration to give compounds 50 and 51, respectively. In this manner, the following compounds were prepared: 582 (S)-1-Benzoyl-5-benzoyloxymethyl-3-[(5-chloro-2-pyridinylamino)methylidene]-pyrrolidin-2-one (50). This compound was prepared from 2-amino-5-chloropyridine (19) and 7, reflux for 3 h, trituration with methanol. Yield: 85% (0.391 g). M.p. 144– 148°C (MeOH). [a]D23 +203.6° (c = 0.62, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.71 (1H, ddd, J = 1.3, 2.8, 15.1 Hz, 4–Ha); 3.13 (1H, ddd, J = 1.9, 9.0, 15.4 Hz, 4–Hb); 4.50 (1H, dd, J = 2.8, 11.1 Hz, 5'–Ha); 4.77 (1H, dd, J = 3.6, 11.1 Hz, 5'–Hb); 4.80–4.85 (1H, m, 5–H); 7.24 (1H, d, J = 9.0 Hz, 1H–pyridine); 7.34–7.58 (8H, m, 8H–Ph); 7.73 (1H, dd, J = 2.6, 9.0 Hz, 1H–pyridine); 7.85–7.88 (2H, m, 2H–Ph); 7.91 (1H, br d, J = 11.7 Hz, 3'–H); 8.21 (1H, d, J = 2.4 Hz, 1H–pyridine); 9.94 (1H, d, J = 12.1 Hz, NH). Anal. calc. for C25H20ClN3O4 (461.90): C, 65.01; H, 4.36; N, 9.10; found: C, 64.80; H, 4.76; N, 9.02. (S)-1-Benzoyl-5-benzoyloxymethyl-3-[(4,6-dimethyl-2-pyrimidinylamino)-methylidene]pyrrolidin-2-one (51). This compound was prepared from 2-amino-4,6-dimethylpyrimidine (22) and 7, reflux for 2 h, trituration with methanol. Yield: 74% (0.336 g). M.p. 123–126°C (MeOH). [a]D23 +12.8° (c = 0.72, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.33 (6H, s, 2Het–Me); 2.91 (1H, deg dt, J = 2.7, 16.6 Hz, 4–Ha); 3.02 (1H, ddd, J = 2.6, 9.0, 16.9 Hz, 4–Hb); 4.49 (1H, dd, J = 3.8, 11.3 Hz, 5’–Ha); 4.70 (1H, dd, J = 3.8, 11.3 Hz, 5’–Hb); 4.80–4.88 (1H, m, 5–H); 6.80 (1H, s, 1H– pyrimidine); 7.35–7.52 (7H, m, 7H–Ph); 7.58–7.63 (1H, m, 1H–Ph); 7.85–7.88 (2H, m, 2H–Ph); 8.18 (1H, br d, J = 12.1 Hz, 3'–H); 10.21 (1H, d, J = 12.1 Hz, NH). Anal. calc. for C26H24N4O4 (456.49): C, 68.41; H, 5.30; N, 12.27; found: C, 68.63; H, 5.28; N, 12.51. Preparation of (S)-3-[(substituted amino)methylidene]-5-(methoxycarbonyl)-tetrahydrofuran-2-ones 52–56. General procedure. A mixture of (S)-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)tetrahydrofuran-2-one 8 (199 mg, 1 mmol), substituted amine 15, 20–22 or 27 (1 mmol), and ethanol or acetic acid (100%, 5 ml) was stirred at 20–120°C for several hours. Volatile components were evaporated in vacuo, the residue was triturated with an appropriate solvent, and the precipitate was 583 collected by filtration to give compounds 52–56. In this manner, the following compounds were prepared: (S)-3-[(4-Methylanilino)methylidene]-5-(methoxycarbonyl)tetrahydrofuran-2-one (52). This compound was prepared from 4-methylaniline hydrochloride (15) and 8 in ethanol, stirring at 20°C for 1 h, trituration with ethanol/water. Yield: 99% (0.258 g). M.p. 177–178°C (EtOH/H2O). [a]D23 +75.5° (c = 0.99, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 2.24 (3H, s, Ar–Me); 2.90 (1H, ddd, J = 2.0, 4.7, 16.2 Hz, 4–Ha); 3.21 (1H, ddd, J = 2.1, 10.1, 16.2 Hz, 4–Hb); 3.73 (3H, s, OMe); 5.11 (1H, dd, J = 4.7, 10.1 Hz, 5–H); 7.05–7.12 (4H, m, 4H–Ar); 7.66 (1H, dt, J = 1.9, 13.2 Hz, 3’–H); 9.97 (1H, d, J = 13.1 Hz, NH). Anal. calc. for C14H15NO4 (261.27): C, 64.36; H, 5.79; N, 5.36; found: C, 64.16; H, 5.95; N, 5.34. (S)-3-[(4-Methyl-2-pyridinylamino)methylidene]-5-(methoxycarbonyl)tetrahydro-furan-2-one (53). This compound was prepared from 2-amino-4-methylpyridine (20) and 8 in acetic acid, reflux for 30 minutes, trituration with water. Yield: 70% (0.183 g). M.p. 151°C (EtOH/H2O). [a]D23 +0.8° (c = 1.01, CHCl3). 1H-NMR (300 MHz, (D6)DMSO): 2.28 (3H, s, Het–Me); 2.93 (1H, ddd, J = 2.2, 4.7, 16.4 Hz, 4–Ha); 3.24 (1H, ddd, J = 2.2, 10.0, 16.4 Hz, 4–Hb); 3.74 (3H, s, OMe); 5.14 (1H, dd. J = 4.7, 10.0 Hz, 5–H); 6.79 (1H, s, 1H–pyridine); 6.81 (1H, d, J = 5.3 Hz, 1H-pyridine); 8.10 (1H, d, J = 5.1 Hz, 1H–pyridine); 8.29 (1H, dt, J = 2.3, 12.4 Hz, 3'–H); 9.67 (1H, d, J = 12.4 Hz, NH). Anal. calc. for C13H14N2O4 (262.26): C, 59.54; H, 5.38; N, 10.68; found: C, 59.28; H, 5.40; N, 10.67. (S)-3-[(6-Chloro-3-pyridazinylamino)methylidene]-5-(methoxycarbonyl)tetra-hydrofuran-2-one (54). This compound was prepared from 3-amino-6-chloropyridazine (21) and 8 in acetic acid, reflux for 2 h, trituration with ethyl acetate. Yield: 96% (0.271 g). M.p. 221–223°C (ethyl acetate). [a]D23 +3.1° (c = 0.42, DMF). 1H-NMR (300 MHz, (D6)DMSO): 3.00 (1H, ddd, J = 2.2, 4.5, 16.4 Hz, 4–Ha); 3.30 (1H, ddd, J = 2.6, 10.2, 16.5 Hz, 4–Hb); 3.74 (3H, s, OMe); 5.19 (1H, dd. J = 4.5, 9.8 Hz, 5–H); 7.37 (1H, d, J 584 = 9.0 Hz, 1H-pyridazine); 7.73 (1H, d, J = 9.0 Hz, 1H-pyridazine); 8.22 (1H, d, J = 12.0 Hz, 3'–H); 10.04 (1H, d, J = 12.0 Hz, NH). Anal. calc. for C11H10ClN3O4 (283.67): C, 46.57; H, 3.55; N, 14.81; found: C, 46.58; H, 3.53; N, 14.67. (S)-3-[(4,6-Dimethyl-2-pyrimidinylamino)methylidene]-5-(methoxycarbonyl)-tetrahydrofuran-2-one (55). This compound was prepared from 2-amino-4,6-dimethylpyrimidine (22) and 8 in acetic acid, reflux for 2 h, trituration with ethyl acetate. Yield: 92% (0.254 g). M.p. 138-140°C (ethyl acetate). [a]D23 +1.1° (c = 0.76, CH2Cl2). 1H-NMR (300 MHz, (D6)DMSO): 2.35 (6H, s, 2Het-Me); 2.94 (1H, ddd, J = 2.3, 4.5, 17.0 Hz, 4-Ha); 3.25 (1H, ddd, J = 2.6, 10.0, 16.0 Hz, 4-Hb); 3.72 (3H, s, OMe); 5.13 (1H, dd. J = 4.7, 10.0 Hz, 5-H); 6.84 (1H, s, 1H-pyrimidine); 8.22 (1H, br d, J = 12.4 Hz, 3'–H); 10.26 (1H, d, J = 12.1 Hz, NH). Anal. calc. for C13H15N3O4 (277.28): C, 56.31; H, 5.45; N, 15.15; found: C, 55.94; H, 5.28; N, 14.97. (S)-3-[(l,2,4-Triazol-3-ylamino)methylidene]-5-(methoxycarbonyl)-tetrahydro-furan-2-one (56). This compound was prepared from 3-amino-1,2,4-triazole (27) and 8 in acetic acid, reflux for 2 h, trituration with ethyl acetate. Yield: 97% (0.231 g). M.p. 222–224°C (ethyl acetate). [a]D23 -1.0° (c = 0.89, DMF). 1H-NMR (300 MHz, (D6)DMSO): 2.87 (1H, ddd, J = 2.1, 4.7, 16.7 Hz, 4-Ha); 3.19 (1H, ddd, J = 2.3, 10.2, 16.6 Hz, 4-Hb); 3.72 (3H, s, OMe); 5.10 (1H, dd. 7= 4.5, 9.8 Hz, 5-H); 7.83 (1H, br d, J = 12.4 Hz, 3'–H); 8.34 (1H, s, 1H-triazole); 10.08 (1H, d, 7= 11.3 Hz, NH); 11.96 (1H, br s, NH-triazole). Anal. calc. for C9H10N4O4 (238.20): C, 45.38; H, 4.23; N, 23.52; found: C, 45.37; H, 3.96; N, 23.19. Acknowledgement. The financial support from the Ministry of Science and Technology, Slovenia, is gratefully acknowledged. References and notes. [1] For a review see: P. Kolar, A. Petrič, M. Tišler, J. Heterocyclic Chem. 1997, 34, 1067-1098. 585 [2] For an illustration see: J. J. Nestor, Jr., B. L. Horner, T. L. Ho, G. H. Jones, G. I. McRae, J. Med. Chem. 1984, 27, 320-325; H. L. Sham; H. Stein, J. Cohen, J. Chem. Soc, Chem. Commun. 1987, 1792-1793; J. J. Hansen, B. Nielsen, P. Krogsgaard-Larsen, L. Brehm, E. O. Nielsen, D. R. Curtius, J. Med. Chem. 1989, 32, 2254-2260; W. C. Patt, R. W. Skeean, B. A. Steinbaugh, Synth. Commun. 1990, 20, 3097-3102; K. Burger, M. Gold, H. Neuhauser, M. Rudolph, E. Höß, Synthesis 1992, 1145-1150; B. Ebert, S. Lenz, L. Brehm, P. Bregnedal, J. J. Hansen, K. Fredriksen, K. P. Bogeso, P. Krogsgaard-Larsen, J. Med. Chem. 1994, 37, 878-884; J. Svete, B. Stanovnik, M. Tišler, J. Heterocyclic Chem., 1994, 31, 1259-1266; U. Bratušek, I. Kejžar, J. Svete, B. Stanovnik, Acta Chim. Slov. 1996, 43, 105-117; M. Škof, J. Svete, and B. Stanovnik, J. Heterocyclic Chem., 1997, 34, 853-856. [3] A. N. Bowler, P. M. Doyle, D. W. Young, J. Chem. Soc, Chem. Commun. 1991, 314-316; A. Dinsmore, P. M. Doyle, D. W. Young, Tetrahedron Lett. 1995, 36, 7503-7506; A. N. Bowler, A. Dinsmore, P. M. Doyle, D. W. Young, J. Chem. Soc, Perkin Trans. 1 1997, 1297-1306. [4] For short reviews see: B. Stanovnik, Molecules 1996, 1, 123-127; B. Stanovnik, ‘Methyl 2-Benzoylamino-3-dimethylaminopropenoate in the Synthesis of Heterocyclic Systems’ in ‘Progress in Heterocyclic Chemistry,’ Vol 5, ed. by H. Suschitzky and E. F. V. Scriven, Pergamon Press, Oxford, 1993, pp 34-53. [5] For recent publications see: J. Svete, M. Aljaž-Rožič, B. Stanovnik, J. Heterocyclic Chem. 1997, 34, 177-193; L. Selič, S. Golič-Grdadolnik, B. Stanovnik, Helv. Chim. Acta 1997, 80, 2418-2425; J. Smodiš, B. Stanovnik, Tetrahedron 1998, 54, 9799-9810; L. Selič, B. Stanovnik, Helv. Chim. Acta 1998, 81, 1634-1639; L. Selič, S. Strah, R. Toplak, B. Stanovnik, Heterocycles 1998, 47, 1017-1022; L. Pizzioli, B. Ornik, J. Svete, B. Stanovnik, Helv. Chim. Acta 1998, 81, 231-235; U. Bratušek, A. Hvala, B. Stanovnik, J. Heterocyclic Chem. 1998, 35, 1281-1284; G. Soršak, S. Golič-Grdadolnik, B. Stanovnik, J. Heterocyclic Chem. 1998, 35, 1275-1279; L. Selič, B. Stanovnik, J. Heterocyclic Chem. 1998, 35, 1527-1529; L. Selič, B. Stanovnik, Synthesis 1999, 479-482; R. Toplak, J. Svete, B. Stanovnik, S. Golič-Grdadolnik, J. 586 Heterocyclic Chem. 1999, 35, 225-235; R. Toplak, J. Svete, S. Golič- Grdadolnik, B. Stanovnik, Coll. Czech. Chem. Commun. 1999, 64, 177-189. [6] M. Škof, J. Svete, B. Stanovnik, L. Golič, S. Golič-Grdadolnik, L. Selič, Helv. Chim. Acta 1998, 81, 2332-2340. [7] M. Škof, J. Svete, M. Kmetic, B. Stanovnik, S. Golič-Grdadolnik, Eur. J. Org. Chem. 1999, 1581-1584. [8] M. Škof, J. Svete, B. Stanovnik, Heterocycles 1999, 51, 1051-1058. [9] M. Škof, J. Svete, B. Stanovnik, Heterocycles 2000, 52 (No. 2), in print. [10] M. Škof, J. Svete, B. Stanovnik, J. Heterocyclic Chem. in print. [11] M. Škof, J. Svete, B. Stanovnik, submitted for publication. [12] Reactions with methyl glycinate hydrochloride (10) or benzylamine hydrochloride (11) in ethanol were carried out without the addition of hydrochloric acid. Povzetek. - 5-Substituirani (S)-l-acil-3-[(E)-(dimetilamino)metiliden]pirolidin-2-oni 5-7 in 3-[(E)-(dimetilamino)metiliden]-5-(metoksikarbonil)tetrahidrofuran-2-on 8, kiralni ciklični analogi 2-substituiranih alkil 3-(dimetilamino)propenoatov, reagirajo z različnimi alkil-, aril-, and heteroarilamini 10-29 pod blagimi pogoji, pri čemer nastanejo 5-substituirani ( S)-3-[(substituirani amino)metiliden]pirolidin-2-oni 30-51 in (S)-3-[(substituirani amino)metiliden]tetrahidrofiiran-2-oni 52-56 kot intermediati v 'ring switching' sintezi derivatov 3-heteroarilalanina, 3-heteroarilmlečne kisline in njihovih analogov.