Facile Synthesis of Methyl 2-amino-3-(2-methyl-3-quinolyl)propanoate$Mark Hadden and Paul J. Stevenson*School of Chemistry, The Queen's University of Belfast, Belfast, UK BT9 5AGMethyl 4-acetyl-5-(2-nitrophenyl)pyrrolidine-2-carboxylate 5, readily available in one step by a 1,3-dipolarcycloaddition, undergoes reduction, cyclisation and fragmentation to the corresponding quinoline when treated withhydrogen and palladium.Quinolines are common in nature and form the core unitof a number of bioactive substances.1 3-Quinolylalanine 1is a useful unusual amino acid and has been used in thesynthesis of bioactive peptides,2 and 4-quinolylalanine 2is an intermediate in the synthesis of the antiulcer drug(S)-(£¾)rebamipide 33 (Scheme 1).Methods for preparingquinolines have been reviewed4 with a popular methodbeing the Friedlander quinoline synthesis. We now report amild facile approach to the synthesis of 2-methylquinolinyl-alanine methyl ester based on a three component coupling,namely o-nitrobenzaldehyde, glycine methyl ester andmethyl vinyl ketone.In model studies directed towards the synthesis ofthe substituted pyrroloquinoline skeleton 7, present inmartinelline,5 the 1,3-dipolar cycloaddition of imine 4,derived from glycine methyl ester and o-nitrobenzaldehyde,with methyl vinyl ketone was investigated (Scheme 2).Using the modied literature conditions,6 silver acetate and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile thereaction was complete within 1 h at room temperature andgave the all-cis trisubstituted pyrrolidine 5 in 34% isolatedyield. As expected the reaction was completely regio- andstereo-selective giving only the racemic diastereoisomer 5.The low yield of 5 is largely due to the instability ofthe imine 4 in the presence of base (DBU).Reduction ofpyrrolidine 5 with hydrogen and palladium gave none of theexpected pyrroloquinoline 7 but instead gave predominantlythe quinoline derivative 8.Presumably the intermediateb-amino imine 6 is unstable, even under the reducing reac-tion conditions, and simply aromatises by loss of amine,giving amino acid ester 8. When the hydrochloride salt ofthe amine 5 was employed a much cleaner reaction resultsand quinoline 8 was isolated in 72% yield after a basicwork-up.In conclusion we have demonstrated that 1,3-dipolarcycloaddition is an eective method for coupling thecomponents glycine methyl ester, o-nitrobenzaldehyde andmethyl vinyl ketone for a quinoline synthesis.Since goodasymmetric induction is achieved when chiral a,b-unsaturated ketones are employed in 1,3-dipolar cyclo-addition reactions,7 this methodology should be amenableto chiral quinoline amino acids.ExperimentalIR spectra were recorded on a Perkin-Elmer Model 983G instru-ment coupled to a Perkin-Elmer 3700 Data Station as potassiumbromide (KBr) disks or lms (liquids), 1H NMR spectra at 300 and500 MHz using General Electric QE 300, Bruker DPX 300 andDRX 500 spectrometers.Chemical shifts are given in ppm (d) down-eld from tetramethylsilane as internal standard. Mass spectra wererecorded using a Double Focusing Triple Sector VG Auto Spec andaccurate molecular masses were determined by the peak matchingmethod using peruorokerosene as standard reference and wereaccurate to within 20.006 mass unit. In both cases chemicalionisation was employed giving rise to M 1 peaks. AnalyticalTLC was carried out on Merck Kielselgel 60254 plates and the spotsvisualised using a Hanovia Chromatolite UV lamp.Flash chroma-tography was eected using Merck Kielselgel 60 (230¡Ó400 mesh).Methyl 4-Acetyl-5-(2-nitrophenyl )pyrrolidine-2-carboxylate 5.Asolution of glycine methyl ester hydrochloride (1.82 g, 14.5 mmol),ethyldiisopropylamine (1.88 g, 14.5 mmol) and o-nitrobenzaldehyde(2.00 g, 13.2 mmol) in methylene chloride (10 ml) was stirred for20 min. The solvent was then removed at room temperature anddry acetonitrile (40 ml) added to the residue. This slurry was addedto a mixture of silver acetate (4.41 g, 26.4 mmol), DBU (4.02 g,26.4 mmol) and methyl vinyl ketone (4.02 g, 26.4 mmol) in dryacetonitrile (60 ml) at 0 8C with magnetic stirring.After 20 minsaturated ammonium chloride solution (50 ml) was added followedJ. Chem. Research (S),1998, 796¡Ó797$Scheme 1Scheme 2 (i) Methyl vinyl ketone, DBU, silver acetate in MeCN;(ii) hydrogen, Pd/C$This is a Short Paper as dened 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.796 J. CHEM. RESEARCH (S), 1998by diethyl ether (30 ml) and methylene chloride (80 ml) and stirredfor 10 min. The insoluble material was ltered o, and the organiclayer separated and dried over magnesium sulfate. Concentrationgave a brown oil which was puried by ash chromatographyto give compound 5 (1.31 g, 34%) as a clear oil, Rf 0.55 (ether)[C14H16N2O5 requires 293.1137 (M 1). Found 293.1137]; ~max(KBr, lm) 3339, 2954, 1741, 1710, 1525 cm£¾1.H (CDCl3,500 MHz). Coupling constants (J) are given in Hz. 1.67 (3 H, s,CH3CO), 2.36 (1 H, dt, J 13.1, 8.3, NCHCHH), 2.45 (1 H, ddd,J 13.1, 7.7, 5.1, NCHCHH), 3.82 (3 H, s, OCH3), 3.82 (1 H, td,J 8.0, 5.3, CH3COCH), 3.94 (1 H, t, J 7.7, NCHCO2Me), 4.91(1 H, d, J 8.0, ArCHN), 7.41 (1 H, td, J 7.4, 1.4, ArH-4), 7.61(1 H, td, J 7.7, 1.2, ArH-5), 7.87 (1 H, dd, J 7.9, 1.3, ArH-6),7.91 (1 H, dd, J 8.1, 1.3, ArH-3).C (CDCl3, 75.438 MHz) 31.4,33.0, 52.7, 54.9, 59.6, 60.9, 124.7, 128.9, 130.1, 133.8, 135.2, 149.3,173.9, 209.0. m/z 293 (M 1, 12), 244(15), 231(62), 214(28),171(33), 143(85), 83(100), 49(100%).Methyl 2-Amino-3-(2-methyl-3-quinolyl )propanoate 8.Ether (10 ml)was saturated with hydrogen chloride. This was then added to asolution of compound 5 (90 mg, 0.31 mmol) in methanol (5 ml) andthe resulting solution stirred for 10 min.The solvents were removedunder reduced pressure and methanol (10 ml) added followed by10% palladium on charcoal (5 mg). The resulting mixture wasplaced under 1 atm of hydrogen for 15 h. The solution was lteredthrough Celite and saturated sodium bicarbonate (5 ml) added tothe ltrate. This was extracted with methylene chloride (310 ml),dried over magnesium sulfate and concentrated. Flash chromatog-raphy gave compound 8 (54 mg, 72%) as a pale yellow oil, Rf0.32 (ethyl acetate¡Ómethanol 19:1) [C14H16N2O2 requires 245.1290(M 1).Found 245.1290]; ~max (KBr, lm) 3367, 2951, 1737 cm£¾1.H (CDCl3, 300 MHz) 1.87 (2 H, br, NH2), 2.74 (1 H, s, CH3),2.95 (1 H, dd, J 14.2, 8.5, ArCHH), 3.31 (1 H, dd, J 14.2,5.2, ArCHH), 3.71 (3 H, s, CH3O), 3.76 (1 H, dd, J 8.5, 5.2,CH2CHCO2Me), 7.56 (1 H, s, Ar H-4), 7.57 (1 H, m, ArH-6), 7.72(1 H, t, J 8.5, ArH-7), 7.78 (1 H, d, J 8.0, ArH-5), 8.72 (1 H, d,J 8.7, Hz ArH-8).C (CDCl3, 125.758 MHz) 15.0, 39.0, 52.3,54.6, 119.7, 126.2, 127.6, 127.8, 129.9, 130.7, 139.2, 140.3, 146.2,175.0. m/z 245 (M 1, 10), 243(19), 183(25), 167(18), 158(64),156(100), 114(27), 88(25%).We thank the Department of Education N. Ireland(D.E.N.I.) for a studentship.Received, 29th June 1998; Accepted, 24th August 1998Paper E/8/04962IReferences1 J. P. Michael, Nat. Prod. Rep., 1997, 14, 11.2 C. K. Acosta, M. L. Bahr, J. E. Burdett, J. W. Cessac, R. A.Martinez, P. N. 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