Conjugated azoalkenes. Part 13. Facile and high-yield synthesis of new 1-amino-3-cyano-2,3-dihydropyrrol-2-ols and 1-amino-3-cyano-1H-pyrrol-2(3H)-ones

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Conjugated Azoalkenes. Part 13.' Facile and High-yield Synthesis of New 1-Amino-3-cyano-2,3-di hydropyrrol-2-01s and I -Amino-3-cyano-1 H-pyrrol- 2(3H)-ones Orazio A. Attanasi,s Lucia De Crescentini,a Alexander McKillop,b Stefania Santeusanioa and Franco Serra-Zanetti8 a lstituto di Chimica Organica della Facolta di Scienze, Universita di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy School of Chemical Sciences, University of East Englia, Norwich NR4 7TJ, UK Cyano derivatives containing active methine hydrogen readily underwent 1,4-conjugate addition to conjugated azoalkenes, to give initially hydrazones which cyclised to 1-amino-3-cyano-2,3-dihydropyrrol-2-01s and 1 -amino-3-cyano-l H-pyrrole-2(3H) -ones. Both processes took place in high yield and under mild reaction conditions. Recently we reported that reaction of conjugated azoalkenes with 0-cyano ketones gives 1-aminopyrrole-3-carbonitrilesor 1,3a,6,6a-tetrahydropyrrolo2,3-bpyrroles depending on the molar ratios of the reagents.' In both cases reaction proceeds by initial 1,4-conjugate addition of the P-cyano ketones to the azo-ene system, and heterocyclisation at this stage gives the 1-aminopyrrole-3-carbonitriles. Alternatively, further addition of the intermediate 1,Cadduct to an excess of the azoalkene leads to a bis-adduct, double ring closure of which gives the 1,3a,6,6a-tetrahydropyrrolo2,3-bpyrroles.We have also shown that the related condensations of P-cyano esters with the azoalkenes resulted in two successive 1P-conjugate additions followed by double ring closure to the cyano groups to give, via a postulated iminopyrroline intermediate, pyrrolo2,3-b- pyrroles as the exclusive products.2 Finally, some years ago we described the preparation of 2,3-dihydropyrrol-2-01~ by reaction of conjugated azoalkenes with P-dicarbonyl com-pound~.~~These various reactions, which generally proceed in excellent yield and under very mild reaction conditions, are simple and flexible methods for the preparation of a wide range of highly substituted mono-and bi-cyclic five-membered heterocyclic compounds.In continuation of our work in this area we now describe the reactions of conjugated azoalkenes with cyano derivatives containing active methine hydrogen.Results and Discussion The conjugated azoalkenes la4 undergo smooth reaction with a-acetylphenylacetonitrile 2a in the presence of a catalytic amount of sodium methoxide to give, in high yield and oia the 1,4-addition adducts 3, the l-amino-2-hydroxy-2,3-dihydropyr-role-3-carbonitriles 4a-h (Scheme 1). When tetrahydrofuran Un i R1-$ki Me R1, Me II + Ph-CH-C-Me -""+g=, N-NH-~2H -R2 ICN Ph I Me la-h 2a 3-Ir/ J 4a-h Scheme I Reagents and conditions: i, THF-MeONa, room temp.; ii, room temp. or heat (THF) was used as solvent with azoalkenes la-h, at room temperature, the red colour of the conjugated azoalkene was not discharged until after CQ. 10 min. TLC examination of the mixture at this stage revealed that both the hyrazone inter- mediates 3 and the dihydropyrroles 4a-h were present in the mixtures in varying amounts.Attempts to isolate the pure intermediates 3 in the cases of the reactions with the azoalkenes la-h under the same conditions were unsuccessful, and only the dihydropyrroles 4a-d could be directly isolated, even after only a few minutes. In the cases of the azoalkenes le-h, the reactions in THF at room temperature did not proceed to completion. They were carried through to completion by heating the mixture under reflux for a further 8-17 h, and the dihydropyrroles 4e-h were obtained in high yield. In the case of azoalkenes le-g, reaction with 2a in methanol at 0-5 "C resulted in the separation of colourless powders from solution. These could be isolated and characterised as the hydrazono derivatives 3a-c.Even at 0-5 "C, however, monitoring of the mixtures by TLC revealed that both the intermediates 3a-c and the cyclised products 4e-g were present in solution. Attempts to isolate the pure intermediates 3 under the same conditions were unsuccessful in the other cases. Yields and reaction times for preparation of the intermediates 3a-c and the l-amino-2-hydroxy-2,3-dihydropyrrole-3-carbonitriles4a-h are given in Table 1. We have also studied the base-catalysed reactions of the conjugated azoalkenes la-h with ethyl phenylcyanoacetate 2b in THF (Scheme 2). Use of sodium methoxide as base at room temperature results in rapid, high yield formation of the hydrazone intermediates 5a4, but attempted cyclisation of these with preformed methoxide as base led to the formation of n ';c Me Et la-h 2b Sa-h 0 6a-f Scheme 2 Reagents and conditions: i, THF-MeONa, room temp.; ii, THF-MeOH, NaH, room temp 3100 J.CHEM. SOC. PERKIN TRANS. 1 1992 Table 1 Yields and reaction times for the synthesis of intermediates 3a-c and pyrroles 4a-h from conjugated azoalkenes la-h and a-acetylphenylacetonitrile 2a t/h Product Yield" () 1 2 R' RZ 3 4 344 aa C0,Me C02Me b 0.2 a a 91 ba C0,Et C0,Me b 0.2 a b 93 ca C02Me C0,Bu' b 0.2 a c 98 da C02Et C0,Bu' b 0.2 a d 94 ea C0,Me CONH, 2.0 O.2/08.Oe a e 80 fa C0,Et CONH, 1.0' 0.2/10.0 b f 81 ga C0,Me CONHPh 0.5' 0.2/ 17.0 c g 83 ha C02Et CONHPh b 0.2j12.0' a h 88 (I Yield of pure isolated product.The reaction directly provided pyrroles 4a-d and 4h, without the possibility to isolate the intermediates 3. Reaction time for the formation of the intermediates 3a-c. Reaction time for the formation of the intermediates 3a-in methanol at 0-5 "C. Reaction time for the direct conversion at room temperature of the starting materials la4 and 2a into pyrroles 4a-d. The first reaction time indicates the time at room temperature for the disappearance of conjugated azoalkenes leh, and the second reaction time refers to the additional time under reflux for the complete formation of pyrroles 4e-h. Table 2 Yield data for the synthesis of hydrazones 5a-h and pyrroles 6a-f from conjugated azoalkenes la-h and ethyl phenylcyanoacetate 2b" Product Yield () 1 2 R' R2 5 6 5 6 a b C0,Me C0,Me a a 90 68 b b C0,Et C0,Me b b 95 68 c b C0,Me C02Bu' c c 97 70 d b C0,Et C0,Bu' d d 97 78 e b C0,Me CONH, e e 95 87 f b C0,Et CONH, f f 97 86 gh b b C0,Me CO2Et CONHPh CONHPh g c h c 78 99 C C a All reaction times were 0.1 h.Yield of pure isolated product. The conversion of hydrazones 5g and 5h into pertinent pyrroles 6 produced intricate reaction mixtures. complex mixtures of products. By contrast, the one-pot conversion of a mixture of la-h and 2b to the previously unknown 1-amino-3-cyano- lH-pyrrol-2(3H)-ones 6a-f could be effected easily by brief treatment first with sodium methoxide to give the hydrazone intermediates 5a-h, followed by addition of sodium hydride to induce cyclisation to 6a-f.Each reaction only required a few minutes to go to completion, and yields of the dihydropyrroles 6a-f were good to excellent. Yields and reaction times for the synthesis of the hydrazone intermediates 5a-h and the 1-amino-3-cyano- lH-pyrrol-2(3H)-ones are listed in Table 2. The overall reactivity patterns outlined in Scheme 1 are in good agreement with our previous findings that reactions of conjugated azoalkenes with P-dicarbonyl compounds gave 2,3- dihydropyrrol-2-01~, structure confirmation of which has been provided by an X-ray diffraction In the case of the sodium hydride induced cyclisation of the hydrazone inter- mediates 5a-f to the dihydropyrroles 6a-f, however, cyclisation rather unexpectedly involves the ester group rather than the cyano group. As far as we are aware, with the exception of one particular case where electronic and mesomeric effects seem to play a determining role, this represents the first general case where heterocyclisation involves the ester group and leads to pyrr01-2-ones.~,~*~ Experimental Alkoxycarbonylazoalkenes la4 and aminocarbonylazo-alkenes' leh were prepared as previously reported. a-Acetylphenylacetonitrile 2a and ethyl phenylcyanoacetate 2b were commercial materials (Aldrich) and were used without further purification.M.p.s were determined in capillary tubes with a Buchi apparatus, and are uncorrected. Frequently, the range of m.p.is large because the products are mixtures of isomeric forms, and the products often decompose at the m.p. Yields are of isolated products. IR spectra were obtained for Nujol mull or in solution (CCl,) with a Perkin-Elmer 298 spectrophotometer. All 'H NMR spectra at 200 MHz were recorded with a Bruker AC-200 spectrometer in C2H6-DMS0 solution. Chemical shifts (6) are reported downfield from Me, as internal standard. The abbreviations used are as follows: s, singlet; d, doublet, t, triplet; q, quartet; my multiplet; br, broad; D,O-exch., D20 exchange. Macherey-Nagel precoated silica gel SIL G-25 uv254 plates (0.25 mm) were employed for analytical thin layer chromatography (TLC), and Baker silica gel (0.0634.200 mm) for column chromatography.All compounds prepared gave satisfactory elemental analyses (C 0.4; H _+ 0.4; N f0.3). Typical Procedure for the Synthesis of 1-Amino-2-hydroxy-2,3-dihydropyrrole-3-carbonitriles4a-h.-To a stirred solution of the azoalkene la-h (1 mmol) in THF (3 cm3) was added dropwise a solution of a-acetylphenylacetonitrile 2a (1 mmol) and sodium methoxide (0.1 mmol) in THF (3 cm')). The mixture was magnetically stirred at room temperature until the orange- red colour of the azoalkene disappeared and checked by TLC. In the case of azoalkenes la4 the reaction directly afforded the products 4 in ca. 10 min, while in the case of the azoalkenes la-h a TLC check revealed as major components two spots corresponding to the intermediate 3 and product 4 in different ratio.In this last case the reaction was completed by heating under reflux for an additional 8-17 h, until the intermediate 3 was completely converted into relevant product 4. In all cases, THF was evaporated under reduced pressure and the crude pyrroles 4a-h were purified by chromatography on a silica gel column (cyclohexaneeethyl acetate). Further purification was effected by crystallization from dichloromethane-pentane (or light petroleum 30-60 "C).For the isolation of the 1,4-adduct intermediate 3a-c the reaction was carried out at 0-5 "C (ice-bath) using methanol as solvent. The white solid which formed was collected by filtration. Typical Procedure for the Synthesis of 1-Arnino-3-cyano- 1 H-pyrrole-2(3H)-ones 6a-f.-To a stirred solution of the azoalkene la-h (1 mmol) in THF (3 cm3) was added dropwise a solution of ethyl phenylcyanoacetate 2b (1 mmol) and sodium methoxide J.CHEM. SOC. PERKIN TRANS. 1 1992 (0.1mmol) in THF (3 cm3). The mixture was magnetically stirred at room temperature (-5 min) until the reaction was complete (TLC: two spots as major components). The products were purified by chromatography on a silica gel column (cyclohexane-ethyl acetate) and identified as mixtures of isomers of the 1,4-adduct intermediates 5a-h. To a stirred solution of the adduct 5a-h (1 mmol) in THF-CH,OH (l:l, 6cm3) was added a catalytic amount of NaH. The conversion occurred rapidly (ca. 5 min) and was monitored by TLC.Alternatively, the two above-described reactions may be carried out in one-flask. The first mixture was allowed to stand in THF at room temperature with sodium methoxide under magnetic stirring until conjugated azoalkenes disappeared (monitoring by TLC). Then freshly prepared sodium methoxide, from sodium hydride and methanol, was added to the reaction mixture. Finally, the reaction mixture was concentrated to a small volume under reduced pressure, and the residue was dissolved in ethyl acetate and the solution extracted with aqueous sulfuric acid (1). The organic phase was separated, washed with water, dried (magnesium sulfate), and concen- trated under reduced pressure to give the pyrroles 6a-f. The products 6 were purified by chromatography on a silica gel column (cyclohexane-ethyl acetate).Further purification was effected by crystallization from THF-pentane or dichloro-methane-light petroleum, b.p. 30-60 "C. Intermediates 3.-Methyl 4-cyano-2-(methoxycarbonylhydra-zono)-5-oxo-4-phenyfhexane-3-carboxylate3a. M.p. 179-1 83 "C; v,,,/cm-' 3460,3340, 3280, 3220, 2240, 1740, 1720, 1695and 1585;6, 1.62(3 H, S, COMe), 2.32 (3 H, S, Me), 3.71(3 H, S, CO,Me), 4.73(1 H, s, CH), 6.30 (2 H, br s, NH,, D,O-exch.), 7.40-7.54(5 H, m, Ph) and 9.26(1 H, s, NH, D,O-exch.) (Found: C, 58.3;H, 5.6;N, 17.2.C,,H,,N,O, requires C, 58.2;H, 5.5; N, 17.0). Ethyl 4-cyano-2-(methoxycarbonyfhydrazono)-5-oxo-4-phen-yfhexane-3-carboxylate 3b. M.p. 157-160"C; v,,,/cm-' 3460, 3340,3290, 3220, 2240, 1740, 1720, 1700 and 1580;6, 1.19 (3H, t, J 7,C02CH2Me),1.63(3H, s, COMe), 2.32 (3 H, s, Me), 4.13-4.23 (2 H, q, J7,C02CH,Me), 4.72(1 H, s, CH), 6.30 (2 H, br s, NH,, D,O-exch.), 7.40-7.54(5 H, m,Ph) and 9.29(1 H, s, NH, D,O-exch.) (Found: C, 59.5;H, 5.6; N, 16.4.C1 7H20N404 requires C, 59.3;H, 5.8; N, 16.3).Methyl 2-(tert-butoxycarbonylhydrazono)-4-cyano-5-oxo-4-phenylhexane-3-carboxylate 3c. M.p. 164-168 "C; vmax/cm-l 3365, 3200, 3095, 2240, 1745, 1730, 1680 and 1590;6, 1.73 (3 H, s, COMe), 2.35 (3 H,s, Me), 3.72 (3 H,s, C02Me),4.91 (1 H, s, CH), 7.00-7.57(10H, m, 2 x Ph), 8.39(1 H, s, NH, D,O-exch.) and 9.84(1 H, s, NH, D,O-exch.) (Found: C, 64.8; H, 5.6;N, 14.0.C2,H2,N404 requires C, 65.0;H, 5.5; N, 13.8). Pyrroles 4.-Methyf 4-cyano-5-hydroxy-1-(methoxycarbonyf-amino)-5-methyf-4-phenyf-4,5-dihydropyrrofe-3-carboxyfate4a. M.p.77-82"C; v,,,/cm-' 3290, 2240, 1735, 1690and 1530;6, 0.80and 1.52(3H,2s,Me),2.22and2.24(3H,2s,Me),3.43and 3.48(3 H, 2s, CO,Me), 3.60and 3.66(3 H, 2s,CO,Me), 6.40 and 7.30(1 H, 2 s, OH, D,O-exch.), 7.33and 7.36(5 H, 2s, Ph) and 9.50and 9.60(1 H, 2s, NH, D,O-exch.) (Found C, 59.3;H, 5.6;N, 12.3.C17H19N305requires C, 59.1;H, 5.5; N, 12.2). Ethyl 4-cyano-5-hydroxy- 1-(methoxycarbonylamino)-5-meth-yf-4-phenyf-4,5-dihydropyrrofe-3-carboxyfate4b.M.p. 58-65 "C; vmax/cm-'3440, 3380, 3280, 2270, 1740,1690and 1535;aH 0.83and 1.52 (3 H, 2 s, Me), 0.86and 0.97(3 H, 2 t, J 7, C02CH2Me),2.22and 2.24 (3 H,2 s, Me), 3.61 and 3.66 (3 H, 2 s, CO,Me), 3.88-3.98 (2 H, m, C02CH2Me), 6.40and 7.30 (1 H, 2s, OH, D,O-exch.), 7.33and 7.36(5 H, 2s, Ph) and 9.50 and 9.60(1 H, 2s, NH, D,O-exch.) (Found: C, 59.9;H, 5.7;N, 12.0.C,8H,,N@, requires C, 60.2;H, 5.9;N, 11.7). Methyl l-(tert-butoxycarbonyfamino)-4-cyano-5-hydroxy-5-3101 methyf-4-phenyf-4,5-dihydropyrrofe-3-carboxyfate4c. M.p. 77-88 "C; v,,,/cm-' 3390, 3230, 2240, 1700, 1680 and 1625; 6, 0.83and 1.52 (3 H, 2s, Me), 1.40 and 1.43(9H, 2s, Bu'), 2.21and 2.24(3 H,2s,Me),3.42and 3.47(3H,2s,C02Me),6.30 and 7.21(1 H, 2s, OH, D,O-exch.), 7.30and 7.34(5 H, 2s, Ph) and 8.70and 9.50(1 H, 2s, NH, D,O-exch.) (Found: C, 61.8; H, 6.7;N, 10.6.C20H25N305 requires C, 62.0;H, 6.5;N, 10.8). Ethyl l-(tert-butoxycarbonyfamino)-4-cyano-5-hydroxy-5-methyl-4-phenyf-4,5-dihydropyrrofe-3-carboxyfate4d. M.p.56-62"C; v,,,/cm-' 3435, 3385, 3280,2280, 1740, 1720, 1690and 1540;6, 0.83and 1.52 (3 H, 2s, Me), 0.89and 1.00(3H, 2t, J 7,CO2CH,Me), 1.39and 1.43(9H, 2s, Bu'), 2.21and 2.23 (3 H, 2s, Me), 3.67-3.94 (2 H, m, C02CH2Me), 6.30and 7.20(1 H, 2s, OH, D,O-exch.), 7.32and 7.34(5 H, 2s, Ph) and 8.70and 9.40(1 H, 2s, NH, D,O-exch.) (Found: C, 63.1;H, 6.8;N, 10.3. C21H27N30, requires C, 62.8;H, 6.8;N, 10.5). Methyl 4-cyano-5-hydroxy-5-methyl-4-phenyl-l-ureido-4,5-dihydropyrrofe-3-carboxyfate 4e. M.p. 147-1 54 "C; vmax/cm-' 3500,3400, 3360, 3260,3220,2240,1700, 1680,1630and 1580; dH 0.80 and 1.53 (3 H, 2s, Me), 2.23and 2.26 (3 H, 2 s, Me), 3.44and 3.48 (3 H, 2s, C02Me), 6.00(2H, br s, NH2, D20- exch.), 6.18and 7.22(1 H, 2s, OH, D,O-exch.), 7.30and 7.37 (5 H, 2s, Ph) and 8.00and 8.54(1 H, 2br s, NH, D,O-exch.) (Found: C, 58.2;H, 5.7;N, 16.8.C,6H18N,0, requires C, 58.2; H, 5.5; N, 17.0). Ethyl 4-cyano-5-hydroxy-5-methyl-4-phenyl-1-ureido-4.5-di-hydropyrrofe-3-carboxylate 4f.M.p. 147-1 53 "C; v,,,/cm-' 3480, 3350, 3300, 3210, 2250, 1695, 1680,1625 and 1580;6, 0.81and 1.53 (3 H, 2 s, Me), 0.88 and 1-00(3 H, 2 t, J 7, C02CH2Me),2.23and 2.26 (3 H, 2s, Me), 3.88-3.99 (2 H, m, CO2CH,Me), 6.01(2H, br s, NH,, D,O-exch.), 6.38and 7.32 (1 H, s, OH, D,O-exch.), 7.33and 7.37(5 H, 2s, Ph) and 8.10 and 8.58 (1 H, 2br s, NH, D,O-exch.) (Found: C, 59.4;H, 5.7; N, 16.5.C17H,oN,0, requires C, 59.3;H, 5.8; N, 16.3). Methyl 4-cyano-5-hydroxy-5-methyl-4-phenyl-1-(N'-phenyl-ureido)-4,5-dihydropyrrole-3-carboxy fa te 4g.M.p. 129-135 O C; v,,,/cm-' 3310, 2240, 1675, 1620, 1590 and 1530; 6, 0.83 and 1.55 (3 H, 2s, Me), 2.29 (3 H, s, Me), 3.47and 3.60 (3 H, 2s, CO,Me), 6.27and 7.31(1 H, 2s, OH, D20-exch.), 6.70-7.35 (10H, m, 2 x Ph), 8.18(1 H, s, NH, D,O-exch.) and 8.95 (1 H, s, NH, D,O-exch.) (Found: C, 65.2;H, 5.6; N, 13.6. C,,H,,N,O, requires C, 65.0;H, 5.5; N, 13.8). Ethyl 4-cyano-5-hydroxy-5-methyl-4-phenyl-l-(N'-phenyl-ureido)-4,5-dihydropyrrole-3-carboxyfate4h. M.p. 125-132"C; vmax/cm-'3340,3280,3240,2240,1685,1665,1630and 1595;6, 0.86and 1.55 (3 H, 2s, Me), 0.93 (3 H, t, J 7,CO,CH,Me), 2.29 (3H, s, Me), 3.88-3.95 (2 H, m, CO,CH,Me), 6.30and 7.31(1 H, 2s, OH, D,O-exch.), 6.75-7.45(10H, m, 2 x Ph), 8.19(1 H, s, NH, D20-exch.) and 9.00(1 H, s, NH, D,O-exch.) (Found C, 65.8; H, 5.6;N, 13.2.C,,H,,N,O, requires C, 65.7;H, 5.7;N, 13.3).Intermediates 5.-Ethyf 2-cyano-3-(methoxycarbonyf)-4-(methoxycarbonylhydrazono)-2-phenylpentanoate5a. M.p. 136 139"C; vmax/cm-l 3280,3180,2250,1755, 1740,1710 and 1490; 6, 1.12 (3 H, t, J 7,C02CH2Me),1.50and 1.85 (3 H, 2s, Me), 3.38and 3.58 (3 H, 2 s, CO,Me), 3.66and 3.69 (3 H, 2 s, CO,Me), 4.05-4.25 (2 H, m, CO2CH,Me), 4.50and 4.57(1 H, 2s, CH), 7.41-7.55(5 H, m, Ph) and 9.80and 10.25(1 H, 2s, NH, D,O-exch.) (Found: C, 57.7;H, 5.9;N, 11.0.C18H21N306 requires C, 57.6;H, 5.6;N, 11.2). Ethyl 2-cyano-3-(ethoxycarbonyf)-4-(methoxycarbonylhydra-zono)-2-phenyZpentanoate 5b.M.p. 122-127"C; vmax/crn-l 3330,3200,2240, 1755, 1740, 1720 and 1520;8, 0.84(3H, t, J 7,CO,CH,Me), 1.11-1.24 (3 H, m, CO,CH,Me), 1.54and 1.87 (3 H,s, Me), 3.60and 3.69(3 H,2 s,C02Me),3.87 (2 H,q,J7, CO,CH,Me), 4.13-4.21 (2 H, m, CO2CH,Me), 4.49and 4.56 3 102 (1H, 2 s, CH), 7.40-7.54(5H, m, Ph) and 9.89and 10.20 (1 H, 2 s, NH, D,O-exch.) (Found: C, 58.3; H, 5.7;N, 10.9. Cl9H,,N3O, requires C, 58.6;H, 5.9;N, 10.8). Ethyl4-(tert-butoxycarbonylhydrazono)-2-cyano-3-(methoxy-carbonyl)-2-phenylpentanoate5. M.p. 140-144"C; v,,,/cm-' 3215,3150,3115,2250, 1755, 1740, 1735, 1690 and 1490;6, 1.08-1.14 (3 H, m, C02CH2Me), 1.39and 1.45 (9 H, 2 s, Bu'), 1.50and 1.85 (3H, 2 s, Me), 3.39and 3.70 (3 H, 2 s, CO,Me), 4.10-4.23 (2 H, m, C0,CH2Me), 4.47and 4.57 (1 H, 2 s, CH), 7.42-7.54 (5 H, m, Ph) and 9.53and 9.83 (1H, 2 s, NH, D,O- exch.) (Found: C, 60.6;H, 6.3;N, 10.2.C21H2,N,0, requires C, 60.4;H, 6.5;N, 10.0).Ethyl 4-( tert-butoxycarbonylhydrazono)-2-cyano-3-(ethoxy-carbonyl)-2-phenylpentanoate5d. M.p. 121-125 "C; v,,,/cm-' 3220, 3150, 3110, 2250, 1745, 1735, 1690 and 1490;6, 0.8 1 (3H, t, J 7,CO2CH,Me), 1.07-1.15 (3 H, m,C02CH2Me),1.39 and 1.45 (9 H, 2 s, Bu'), 1.51 and 1.83 (3H, 2 s, Me), 3.84 (2 H, q, J 7,COzCH2Me),3.98-4.15 (2 H, m,CO,CH,Me), 4.42and 4.52(1H, 2 s, CH), 7.41-7.58(5 H, m, Ph) and 9.45and 9.71 (1H, 2 s, NH, D,O-exch.) (Found: C, 61.5;H, 6.7;N, 9.9. C,,H,,N,O, requires C, 61.2;H, 6.8;N, 9.7). Ethyl4-(carbamoylhydrazono)-2-cyano-3-(methoxycarbonyl)-2-phenylpentanoate 5e.M.p. 138-142"C; v,,,/cm-' 3460, 3280, 3220, 3160, 2250, 1745, 1740, 1700, 1595 and 1490;6, 1.07-1.19 (3 H, m,CO,CH,Me), 1.60and 1.92(3H, 2 s, Me), 3.44 and 3.72 (3 11, 2 s, CO,Me), 4.06-4.20 (2 H, m, CO,CH,Me), 4.59and 4.72 (1 H, 2 s, CH), 6.01and 6.70 (2 H, 2 s, NH2, D,O-exch.), 7.35-7.60 (5 H, m, Ph) and 9.28and 6.93 (1H, 2 s, NH, D,O-exch.) (Found: C, 56.7;H, 5.6;N, 15.5. C,,H,,N,O, requires C, 56.6;H, 5.9;N, 15.4). Ethyl 4-(carbamoylhydrazono)-2-cyano-3-(ethoxycarbonyl)-2-phenylpentanoate5f.M.p. 150-154"C; v,,,/cm-l 3460, 3280, 3230, 3160, 2240, 1755, 1740, 1705, 1595 and 1490;6, 0.85 (3H, t, J7,CO,CH,Me), 1.08-1.22 (3 H, m, CO,CH,Me), 1.61 and 1.91 (3H, 2 s, Me), 3.90 (2 H, q, J 7,CO,CH,Me), 4.10-4.21(2H, m, CO,CH,Me), 4.55and 4.75 (1 H, 2s, CH), 6.00and 6.80(2H, 2 s, NH,, D,O-exch.), 7.45-7.60 (5 H, m, Ph) and 9.35 and 9.81 (1 H, 2 s, NH, D,O-exch.) (Found: C, 57.7;H, 5.9;N, 15.0.C18H,,N,05 requires C, 57.9;H, 7.1;N, 14.8).Ethyl 2-cyano-3-(methoxycarbonyl)-2-phenyl-4-(N'-phenyl-carbamoy1hydrazono)pentanoate5g. M.p. 163-165"C; v,,,/cm-' 3360,3200,3090,3060,2250,1740, 1735, 1690, 1680, 1595 and 1490;6, 0.99and 1.15 (3H, 2 t, J 7,CO,CH,Me), 1.75and 2.04(3H, 2 s, Me), 3.49and 3.76 (3 H, 2 s, Me), 4.08-4.22 (2 H, m, CO,CH,Me), 4.77and 4.93 (1 H, 2 s, CH), 7.03-7.67 (10 H, m, 2 x Ph), 8.42and 8.47 (1 H, 2 s, NH, D,O-exch.) and 9.90 and 10.24 (1 H, 2 s, NH, D,O-exch.) (Found: C, 63.3;H, 5.5;N, 12.8.C23H24N405requires C, 63.5;H, 5.4;N, 13.1).Ethyl 2-cyano-3-(ethoxycarbonyl)-2-phenyl-4-(N'-phenylcar-bamoy1hydrazono)pentanoate 5h. M.p. 157-160"C; v,,,/cm-l 3360, 3190,3090,3060,2240, 1740, 1730, 1690, 1680, 1595 and 1475;6, 0.86-1.22 (6 H, m,2 x C02CH2Me),1.74and 2.02 (3H, 2 s, Me), 3.90-4.22 (4 H, m, 2 x CO,CH,Me), 4.70and 4.89(1H, 2 s, CH), 7.28-7.70 (10 H, m,2 x Ph), 8.40and 8.47 (1H, 2 s, NH, D,O-exch.) and 9.85 and 10.25 (1 H, 2 s, NH, D,O-exch.) (Found: C, 63.8;H, 5.9;N,12.8.C24H26N405 requires C, 64.0H, 5.8;N, 12.4). Pyrroles 6.-Methyl 4-cyano- 1-(methoxycarbonylamino)-2-methyl-5-oxo-4-phenyl-1,4-dihydropyrrole-3-carboxylate 6a. M.p. 7 1-78 "C v,,,/cm-' 3280,2250,1775,1750,1710and 1645; 6, 2.49 (3 H, S, Me), 3.67 (3 H, s, CO,Me), 3.75 (3 H, s, CO,Me), 7.39-7.49 (5 H, m, Ph) and 10.52 (1 H, s, NH, D,O- exch.) (Found: C, 58.2;H, 4.9;N,12.6.Cl6HI5N3O5requires C, 58.4; H, 4.6;N, 12.8).Ethyl 4-cyano-1-(methoxycarbonylamino)-2-methyl-5-oxo-4-phenyl-1,4-dihydropyrrole-3-carboxylate6b. M.p. 69-75"C; J. CHEM. SOC. PERKIN TRANS. 1 1992 v,,,/cm-' 3280, 2240, 1770, 1750, 1705 and 1640 6, 1.06 (3H, t, J 7,C02CH2Me), 2.44 (3 H, s, Me), 3.72(3 H, s, CO,Me), 4.06 (2 H, q, J7,C0,CH2Me), 7.31-7.45 (5 H, m, Ph) and 10.50 (1 H, s, NH, D,O-exch.) (Found: C, 59.8;H, 4.9;N, 12.6.CI7Hl7N3O5requires C, 59.5;H, 5.0;N, 12.2). Methyl 1-(tert-butoxycarbonylamino)-4-cyano-2-methyl-5-oxo-4-phenyl-1,4-dihydropyrrole-3-carboxylate6c. M.p. 95-100"C; v,,,/cm-' 3290, 2240, 1775, 1740, 1710 and 1640;6, 1.43(9H, s, Bu'), 2.47 (3 H, s, Me), 3.61(3H, s, CO,Me), 7.34-7.49(5H, m, Ph) and 10.20 (1 H, s, NH, D,O-exch.) (Found: C, 61.3;H, 6.0;N, 11.5.C19H,,N,0, requires C, 61.4;H, 5.7;N, 11.3). Ethyl 1-(tert-butoxycarbonylamino)-4-cyano-2-methyl-5-oxo-4-phenyl-1,4-dihydropyrrole-3-carboxylate6d.-M.p. 69-75"C; v,,,/cm-' 3280, 2240, 1770, 1735, 1710 and 1640;dH 1.14 (3 H, t, J 7,CO,CH,Me), 1.45 (9 H, s, Bu'), 2.48 (3 H, s, Me), 4.12(2H, q, J7,CO,CH,Me), 7.42-7.54 (5 H, m, Ph) and 10.25 (1 H, s, NH, D,O-exch.) (Found: C, 62.5;H, 6.3;N, 11.1.C20H23N305requires C, 62.3;H, 6.0;N, 11.0). Methyl 4-cyan0-2-methyl-5-0~0-4-phenyl-1-ureido-1,4-dihy-dropyrrole-3-carboxylate6e.M.p. 120-122 "C; vmax/cm-l 3440, 3240,3190,2240,1770, 1715, 1690, 1675, 1660, 1590 and 1535; 6, 2.40 (3 H, S, Me), 3.58 (3H, S, CO,Me), 6.55(2H, S, NH,, D,O-exch.), 7.30-7.46 (5 H, m,Ph), and 8.86(1H, s, NH, D,O- exch.) (Found: C, 57.4;H, 4.7;N, 17.6.C15H14N,04 requires C, 57.3;H, 4.5;N, 17.8).Ethyl4-cyan0-2-methyl-5-0~0-4-phenyl-1-ureido-1,4-dihydro-pyrrole-3-carboxylate 6f.M.p. 94-100"C; v,,,/cm-' 3440, 3250, 3190,2240, 1770, 1710, 1695,1680,1655,1600and 1535; 6, 1.05 (3 H, t, J 7,C02CH,Me), 2.38 (3H, S, Me), 4.04 (2 H, q, J 7,CO,CH,Me), 6.58(2H, s, NH,, D,O-exch.), 7.31-7.40 (5H, m, Ph) and 8.92 (1H, s, NH, D,O-exch.) (Found: C, 58.6;H, 5.2;N, 17.1.Cl6Hl6N4O4 requires C, 58.5;H, 4.9;N, 17.1). Acknowledgements This research was supported by financial assistance from Consiglio Nazionale delle Ricerche (Roma), Minister0 dell'- Universita e della Ricerca Scientifica e Tecnologica (Roma), and Regione Marche (Ancona). Tests on the anticancer and anti-AIDS activity of these compounds were performed under the auspices of the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, USA. References 1 Part 12; 0.A. Attanasi, L. De Crescentini, S. Santeusanio, F. Serra-Zanetti, A. McKillop and 2. Liao, J. Chem. SOC.,Perkin Trans. I, 1992,1009. 2 0. A. Attanasi, S. Santeusanio, F. Serra-Zanetti, E. Foresti and A. McKillop, J. Chem. SOC.,Perkin Trans. I, 1990,1669. 3 (a) 0.A. Attanasi, S. Santeusanio and F. Serra-Zanetti, Gazz. Chim. Itaf., 1989, 119, 631; (6) 0.A. Attanasi, M. Grossi, F. Serra-Zanetti and E. Foresti, Tetrahedron, 1987,43,4249. 4 0. A. Attanasi, P. Filippone, A. Mei, A. Bongini and E. Foresti, Tetrahedron, 1990,46,5685. 5 0.A. Attanasi and L. Caglioti, Org. Prep. Prpced. Int., 1986, 18, 299 and references cited therein. 6 0. A. Attanasi, P. Filippone, A. Mei and S. Santeusanio, Synthesis, 1984,873. 7 0.A. Attanasi, P. Filippone, A. Mei and S. Santeusanio, Synthesis, 1984,671. Paper 2/03484K Received1stJuly 1992 Accepted 28thAugust 1992