Vinyltriphenylphosphonium Salt Mediated Serendipitous Synthesis of a Functionalized Pyrroloisoindole Derivative. New Synthesis of Trimethyl 5-Arylpyrrole- 2,3,4-tricarboxylates{ IssaYavari* and Mohammad Reza Islami Chemistry Department,TarbiatModarres University, P.O. Box14155-4838,Tehran, Iran N-Hydroxyphthalimide undergoes a complex reaction with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine yielding a multiply functionalized pyrroloisoindole derivative which is then converted to trimethyl 5-arylpyrrole-2,3,4-tricarboxylate derivatives.We have recently described1 the synthesis of functionalized 2H-chromene derivatives 1 from the reaction of triphenyl- phosphine, 2-hydroxybenzaldehyde and dialkyl acetylene- dicarboxylates using an intramolecular Wittig reaction.2±6 With the purpose to prepare isoindoloisoxazoles, e.g. 2, N-hydroxyphthalimide was treated with dimethyl acetylene- dicarboxylate (DMAD) and triphenylphosphine. However, the isoindoloisoxazole derivative 2 was not observed but tri- methyl 9-oxo-9H-pyrrolo[1,2-a]isoindole-2,3,4-tricarboxylate (3) was isolated in fairly high yield.Compound 3 was con- verted to the densely functionalized pyrrole derivatives 4±6. O CO2R CO2R 1 N O O MeO2C CO2Me 2 N O MeO2C CO2Me 3 N MeO2C CO2Me 4 R = CH2OH 5 R = CO2Me 6 R = CO2Et H R CO2Me CO2Me The structures of compounds 3±6 were deduced from their elemental analyses and their IR, 1H NMR and 13C NMR spectra.The mass spectra of these compounds dis- played molecular ion peaks at m/z 343, 347, 375 and 389, respectively. The base peak in the mass spectra of com- pounds 3 and 4 corresponds to M+ ¡ OCH3. Any initial fragmentation involved the loss of ester moieties. The 1H and 13C NMR data for compounds 3±6 are shown in Table 1. The 1H NMR spectrum of 3 exhibited three single sharp lines readily recognizable as arising from methoxy (d 3.91, 3.92 and 3.94) protons along with a fairly complex multiplet in the aromatic region.The noise- decoupled 13C NMR spectrum of 3 showed 17 distinct resonances in agreement with the pyrroloisoindole structure. Partial assignments of these resonances are given in Table 1. Several examples are known in which a heterocyclic alkene is formed from a phosphorane connected to a carbonyl group by a chain containing a heteroatom.1±6 Thus the isoindoloisoxazole derivative 2 (see Scheme 1) may be considered as the primary product of an intramolecular Wittig reaction.Such an addition±cyclization product apparently results from the initial addition of triphenylpho- sphine to the acetylenic ester and concomitant protonation of the 1:1 adduct, followed by attack of the anion of N-hydroxyphthalimide on the vinyltriphenylphosphonium cation to form the phosphorane, which is converted into 2. We have not established a mechanism for the for- mation of trimethyl 9-oxo-9H-pyrrolo[1,2-a]isoindole-2,3,4- tricarboxylate (3), but a reasonable possibility is indicated in Scheme 1.The ®nal step of this mechanism involves the loss of a MeO2C-CO group as a negatively charged entity. Although this step may seem uncommon, migration of alkoxycarbonyl groups as negatively charged species are not unknown.7 Compound 3 can be reduced to trimethyl 5-(2-hydroxy- methylphenyl)pyrrole-2,3,4-tricarboxylate (4) using sodium borohydride in dimethylformamide±methanol (1:1). The 1H J. Chem. Research (S), 1998, 166±167$ N O O OH MeO2C C C CO2Me + Ph3P DMAD CH2Cl2 r.t. N O O O N O O O – CHCO2Me C PPh3 CO2Me Ph3P C MeO2C CHCO2Me N O O MeO2C CO2Me N O O MeO2C CO2Me –Ph3PO H 2 DMAD N O MeO2C MeO2C OH CO2Me CO2Me N O C CO2Me MeO2C O CO2Me CO2Me 3 – + Scheme 1 $This is a Short Paper as de®ned in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). *To receive any correspondence. 166 J. CHEM. RESEARCH (S), 1998NMR spectrum of 4 displayed four single sharp resonances for methoxy (d 3.68, 3.82 and 3.94) and methylene (d 4.50) protons, along with a multiplet in the aromatic region as well as two fairly broad peaks at d 3.0 and 10.8 for the OH and NH groups, respectively. The latter signals rapidly dis- appeared on addition of D2O. The noise-decoupled 13C NMR spectrum of 4 is similar to that of 3, except for the presence of a new resonance at d 63.40 for the CH2-O group, and the absence of one of the carbonyl resonances (see Table 1).The nitrogen atom of the ¢çve-membered lactam incor- porated in structure 3 is a pyrrole nitrogen and the pyrrole ring has three electron-withdrawing ester groups. Thus, the peptide linkage is expected to be fairly labile to nucleophilic attack and opening. Although compound 3 is stable in hot ethanol and can be recrystallized from this solvent, it under- goes a smooth reaction with strong nucleophiles, such as alkoxide ions.8 When compound 3 was treated with sodium methoxide in methanol at room temperature it was con- verted to the tetracarboxylate 5 in 96% yield. The same reaction, using sodium ethoxide in ethanol, provided tri- methyl 5-(2-ethoxycarbonylphenyl)pyrrole-2,3,4-tricarboxy- late (6) in 90% yield.The 1H and 13C NMR spectra of compounds 5 and 6 are given in Table 1. The 13C chemical shifts of 5 and 6 are similar to those of 4, except for the presence of a new alkoxycarbonyl moiety, and the absence of the hydroxymethyl resonance (see Table 1).Experimental Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. Elemental analyses for C, H and N were performed using a Heracus CHN-O-Rapid analyser. IR spectra were measured on a Shimadzu IR-460 spectrometer. UV spectra were measured for solutions in ethanol (95%) on a Shimadzu UV-2100 spectrometer. 1H and 13C NMR spectra were measured with a JEOL EX-90A spectrometer at 90 and 22.6 MHz, respectively.Mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of 70 eV. N-Hydroxyphthalimide and dimethyl acetylenedicarboxylate were obtained from Fluka (Buchs, Switzerland) and were used without further puri¢çcation. Preparation of Trimethyl 9-oxo-9H-pyrrolo[1,2-a]isoindole-2,3,4- tricarboxylate (3).�¢To a magnetically stirred solution of triphenyl- phosphine (0.26 g, 1 mmol) and N-hydroxyphthalimide (0.16 g, 1 mmol) in dichloromethane (15 ml), a mixture of dimethyl acetyl- enedicarboxylate (0.24 ml, 2 mmol) in dichloromethane (2 ml) at ¢§10 8C was added dropwise over 10 min.The reaction mixture was then allowed to warm up to room temperature and then stirred for 24 h. The solvent was removed under reduced pressure and ethanol (20 ml) was added. The product was obtained by ¢çltration and washed with ethanol (10 ml). Recrystallization from ethanol gave yellow crystals of trimethyl 9-oxo-9H-pyrrolo[1,2-a]isoindole- 2,3,4-tricarboxylate 3, 0.32 g, mp 178¡¾180 8C, yield 95%, max (KBr) cm¢§1: 1794 (C1O, lactam), 1742, 1716 and 1714 (C1O, ester).m/z 343 (M+, 55%), 312 (M+ ¢§ OCH3, 100), 195 (M+ ¢§ 2CO2CH3 ¢§ OCH2, 65), 194 (M+ ¢§ 2CO2CH3 ¢§ OCH3, 5) (Found: C, 59.1; H, 4.0; N, 4.0. C17H15HO7 requires C, 59.48; H, 3.82; N, 4.08%). Preparation of Trimethyl 5-(2-Hydroxymethylphenyl)pyrrole-2,3,4- tricarboxylate (4).�¢To a magnetically stirred solution of 3 (0.34 g, 1 mmol) in N,N-dimethylformamide¡¾methanol (1:1, 6 ml), a mixture of sodium borohydride (0.04 g, 1 mmol) in cold methanol (5 ml) was added dropwise.The reaction mixture were stirred for 10 min and then HCl (2 ml, 2.5 M) and water (20 ml) was added and the resulting mixture extracted with chloroform (310 ml). The organic phase was dried over Na2SO4. Removal of the solvent under reduced pressure gave an oily residue which was puri¢çed by silica gel (Merck silica gel 60, 230¡¾400 mesh) column chromatography using diethyl ether¡¾ethyl acetate¡¾heptane (1.5:1:1.5) as eluent.The solvent was removed under reduced pressure and trimethyl 5-(2-hydroxymethylphenyl)pyrro,3,4-tricarboxylate 4 was ob- tained as light yellow oil, 0.17 g, yield 50%, max (KBr) cm¢§1 3440 (OH), 3255 (NH), 1735, 1718 and 1713 (3C1O). m/z 347 (M+, 40%), 316 (M+ ¢§ OCH3, 100), 284 (M+ ¢§ 2OCH3 ¢§ H, 90), 298 (M+ ¢§OH3 ¢§H2O, 25). (Found: C, 58.6; H, 5.2; N, 3.5, C17H17NO7 requires C, 58.79; H, 4.93; N, 4.03%).Preparation of Trimethyl 5-(2-Methoxycarbonylphenyl)pyrrole- 2,3,4-tricarboxylate (5). General Procedure.�¢To a magnetically stirred solution of 3 (0.34 g, 1 mmol) in methanol (5 ml), a mixture of sodium methoxide (0.11 g, 2 mmol) in methanol (5 ml) was added dropwise. The reaction mixture was stirred for 30 min at room tem- perature and then water (5 ml) was added. After neutralization with HCl (0.1 M), the mixture was extracted with chloroform (310 ml).The combined chloroform solution was dried over Na2SO4. The product (light yellow oil, 0.36 g, yield 0.96%) was obtained by removal of the solvent under reduced pressure. max (KBr)/cm¢§1 3250 (NH), 1723, 1715, 1696 and 1698 (C1O, ester); m/z 375 (M+, 74%), 343 (M+ ¢§ MeOH, 70), 312 (343 ¢§ OCH3, 100), 284 (343 ¢§ CO2Me, 22) (Found: C, 57.3; H, 4.5; N, 3.7. C18H17NO8 requires C, 57.61; M, 4.57; N, 3.73%). Selected Data for 6.�¢Light yellow oil (0.35 g, yield 90%).max (KBr)/cm¢§1 3240 (NH), 1715, 1710 1696 and 1690 (C1O, ester); m/z 389 (M+, 60%), 343 (M+ ¢§ EtOH, 45), 312 (343 ¢§ OCH3, 100), 222 (312 ¢§ OMe ¢§ CO2Me, 42). (Found: C, 56.7; H, 4.9; N, 3.7. C19H19NO8 requires C, 56.62; H, 4.92; N, 3.60%). Received, 31st January 1997; Accepted, 28th October 1997 Paper E/7/00719A References 1 I. Yavari and A. Ramazani, J. Chem. Res. (S), 1996, 382. 2 P. Ferrer, C. Avendno and M. Sollhuber, Liebigs Ann.Chem., 1995, 1895. 3 K. B. Becker, Tetrahedron, 1980, 36, 1717. 4 E. Zbiral, Synthesis, 1974, 775. 5 E. E. Schweizer, J. G. Liehr and D. J. Monaco, J. Org. Chem., 1968, 33, 2416. 6 I. Yavari, A. Ramazani and A. Yahya-Zadeh, Synth. Commun., 1996, 26, 4495. 7 J. A. Damavandy and R. A. Y. Jones, J. Chem. Soc., Perkin Trans. 1, 1981, 712; J. N. Marx, J. C. Argyle and L. R. Norman, J. Am. Chem. Soc., 1974, 96, 2121; R. M. Acheson and R. F. Flowerday, J. Chem. Soc., Perkin Trans. 1, 1974, 2339. 8 We are grateful to a referee of this paper for suggesting reaction of 3 with nucleophiles. Table 1 Proton and13CNMR data for compounds 3^6 Compound 1H/13C d (ppm) (CDCl3^Me4Si) 3 1H 3.91, 3.92 and 3.94 (9 H, 3 s, 3, OCH3), 7.2^8.2 (4 H, m, Ar) 13C 52.28, 52.61 and 52.81 (9 H, 3 s, 3 OCH3), 111.21, 121.27, 130.52, 130.75, 132.79 and 142.16 (6 C), 124.85, 126.44, 130.43 and 135.64 (4 CH), 158.16, 160.65, 161.95 and 163.98 (4 C1O) 4 1H 3.0 (1 H, br s, OH), 3.68, 3.82 and 3.94 (9 H, 3 s, 3 OCH3), 4.50 (2 H, s, CH2), 7.3^7.6 (4 H, m, Ar), 10.8 (1 H, br s, NH) 13C 51.63, 52.28 and 52.77 (3 OCH3), 63.4 (CH2), 112.96, 119.73, 124.32, 129.83, 129.90 and 138.90 (6 C), 127.62, 129.74, 131.57 and 138.70 (4 CH), 160.20, 163.62 and 166.26 (3 C1O) 5 1H 3.58,3.66,3.69and3.95(12H,4 s,4OCH3), 7.3^8.1 (4 H, m, Ar), 10.3 (1 H, br s, NH) 13C 50.90, 51.79, 51.81 and 52.20 (4 OCH3), 112.47, 123.91, 128.88, 129.73, 130.83 and 131.40 (6 C), 118.74, 130.91, 131.08 and 139.18 (4 CH), 160.27, 162.64, 165.61 and 166.38 (4 C1O) 6 1H 1.11 (3 H, t, J = 7.2Hz, CH3), 3.58, 3.68 and 3.94 (9 H, 3 s, 3 OCH3), 4.12 (2 H, q, J 7.2Hz, OCH2), 7.3^8.1 (4 H, m, Ar), 10.3 (1 H, br s, NH) 13C 13.72 (CH3), 51.35, 52.29 and 52.69 (3 OCH3), 61.20 (OCH3), 112.96, 124.36, 129.29, 130.27, 131.20 and 131.62 (6 C), 118.99, 131.41, 131.60 and 139.84 (4 CH), 160.68,163.05,166.10and 166.55(4C1O) J. CHEM. RESEARCH (S), 1998