Xz.dbd6;Yndash;ZH systems as potential 1,3-dipoles. Part 9. Aza-allyl anion precursors from the reaction of (1,3-dioxoindan-2-ylidene)malononitrile with alpha;-amino acids and their methyl esters

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 541 X-Y-ZH Systems as Potential 1,3-Dipoles. Part 9.”Aza-ally1 Anion Precursors from the Reaction of (1.3-Dioxoindan-2-ylidene)malononitrile with a-Amino Acids and their Methyl Esters Ronald Grigg * and Theeravat Mongkolaussavaratana Department of Chemistry, Queen’s University, Belfast 5 T9 5AG, Northern Ireland ~~ Glycine, valine, and a-amino acid esters react with (1,3-dioxoindan-2-ylidene)malononitrile (1) by a Michael addition-elimination mechanism with replacement of one cyano group by the a-amino acid or a-amino acid ester entity. These adducts undergo a triethylamine-catalysed stereospecific cycloaddition to N-methylmaleimide at room temperature with loss of the remaining cyano group in 70% yield. The cycloaddition is believed to be a [3+ 21 anionic cycloaddition involving a hydrogen-bonded aza-ally1 anion.Junek and co-workers have shown that (1,3-dioxoindan-2- y1idene)malononitrile (1) reacts with alkylamines, arylamines, and hydrazines by a Michael addition-elimination mechanism with loss of one cyano group to give the corresponding mono- WNNR’R~ 0 (2)ajR1= R2=alkyl bjR1= H, R’ = aryl cjR’= H,RZ =NMeZ amino derivatives (2a-~).~1,2-Diaminoaryl compounds similarly effect elimination of both cyano groups with formation of compounds (3) and (4).3 Simple MO calculations showed 0 NcPCN 1’ (31 (4) that the Michael addition-limination sequence was preferred over attack at the carbonyl groups leading to imine f~rmation.~ The reactions of the malononitrile (1) with a-amino acids or their esters have not been reported and we thought that the expected products (5) of such reactions might function as precursors of azomethine ylides.Thus, we have shown in extensive studies5 that imines of a-amino acids’ and their esters undergo thermal equilibration with the corresponding azomethine ylides by a formal 1,2-H shift [(6) (7)]. Azomethine ylide (7) formation is stereospecific and kinetically controlled.6 For the malononitrile (5), azomethine ylide formation might occur in a number of ways including a 1,5-H shift (5, arrows) generating compound (8)followed by prototropy [(S) (9)].The potential for 1,5-H shifts has proved a valuable concept in identifying other substrates as potential 1,3-dipoles in both oximes ’and iminium species,8 although precise mechanistic details of these processes remain to be elucidated.Glycine reacted rapidly (10 min) with the malononitrile (1) in aqueous ethanol at 50°C to give compound (5a; R = H) in 0 Ar AN --CH /R‘COzR’ (5)a;R’ =H b:R’ =Et c;R’ =Me (71 0 0 (8) H’ (9) 42% yield. Most other a-amino acids (alanine, phenylalanine, tryptophan, leucine, and isoleucine) reacted with compound (1) in aqueous acetonitrile at 50 “C to give (1,3-dihydroxy-2H- inden-2-y1idene)malononitrile ( but none of the corres-ponding Michael addition-limination product (5a) was detected except for valine which gave a low (14%) yield of compound (5a; R = Pr’) in addition to compound (10).The formation of the reduction product (10) suggests that the amino acids are being oxidised to the corresponding imino acids (11). However, no attempt was made to investigate the fate of the a-amino acids in these latter cases. In contrast to the a-amino acids, the corresponding esters react with the malononitrile (1) in acetonitrile at room temperature to give the expected adducts (5b; R = H) and (5c, R = Me, Pr’, Ph, CH,CO,Me) in 53-68% yield as yellow crystalline solids. The amino acid adduct (5a; R = H) reacts with N-methyl- maleimide in aqueous dimethylformamide at 100 “C over 30 min to give the cycloadduct (12a; R = H) in 71% yield. The a-amino acid ester derivatives (5b; R = H) and (5c; R = Me 542 J. CHEM. SOC. PERKIN TRANS.I 1988 (101 (1 1) (121a; R~=H b;R'=Et c;R1=Me or Ph) react with N-methylmaleimide in acetonitrile at room temperature over 1 h in the presence of 1 mol equiv. of triethyl-amine to give the corresponding cycloadducts (12b; R = H) and (12c; R = Me, Ph) in 70% yield whilst compound (9; R = Pr' or CH,CO,Me) failed to react even in boiling aceto- nitrile. In the absence of triethylamine, the cycloaddition is slow and incomplete after 16 h at room temperature. The amino- methylpyridine (13) reacts with the malononitrile (1) to give 0 Me Li+ (18) compound (14). Alternatively the reaction of compounds (13), (l), and N-methylmaleimide in acetonitrile at room temperature in the presence of 1 mol equiv. of triethylamine gives the corresponding cycloadduct (15) directly.We have previously identified a range of groups Z, including the 2-pyridyl entity, that activate a-methine protons in imines (16) sufficiently to promote ylide formation (17).lo The stereochemistry of the cycloadducts (12a-c) and (15) was established by n.0.e. difference spectroscopy. A typical set of values is provided by (12a; R = H,) in which irradiation of H, effects enhancement of the signals of both HA (16.5%) and H, (12.5%). The precise nature of the 4~-component in the cycloadditions leading to compounds (12a-c) and (15) is not clearly defined although the efficacy of triethylamine in promoting the cyclo- addition suggests the reaction probably involves a [3 +21 anionic cycloaddition rather than the azomethine ylide (9). Anionic cycloadditions involving aza-ally1 anions were first reported by Kauffmann et al.," although there is a distinct possibility that these reactions involve the lithiated anion (18) (19) 0 (20) Scheme.J. CHEM. SOC. PERKIN TRANS. I 1988 and are examples of metallo-1,3-dipoles. 12*13 Another problem is that the remaining cyano group in the malononitrile (5) could be lost subsequent to (19 arrows), or prior to (Scheme), cycloaddition. Other possible reactive intermediates include compound (20)(Scheme), the anion (21), and the triethyl- ammonium hydrogen-bonded species (22).We have recently described anionic 4x-sulphinyl aminomethamide species related to compound (20).14It is clear from the stereochemistry of the cycloadducts that the reactive 4x-species must have a configur- ation analogous to compound (21) or (22).Bifurcated and trifurcated hydrogen bonding of the type suggested in com- pounds (21)and (22)are well known ' and we have previously 0 R3N + ( 21 1 (221 suggested that hydrogen bonding is an important feature in the stereospecific, kinetically controlled, formation of azomethine ylides from imines of a-amino acid esters6 On balance, we favour anionic cycloaddition via compound (21)or (22)with loss of cyanide subsequent to cycloaddition for these processes. Experimental General spectroscopic details were as previously noted.16 (1,3- Dioxoindan-2-y1idene)malononitrile(1) was prepared accord- ing to the literature procedure.' Reaction qf ( 1,3-Dioxoindan-2-ylidene)malononitrile(1) with x-Amino Acids-Glycine.Glycine (36 mg, 4.8 mmol) in water (10 ml) was added to a solution of (1,3-dioxoindan-2-ylidene)-malononitrile (1 g, 4.8 mmol) in ethanol (40 ml) at 50 "C. The mixture was stirred at 50 "C for 10 min and then allowed to cool to room temperature when the product (5a; R = H) crystallised as yellow plates (540 mg, 4473, m.p. 187-189 "C (Found: C, 59.15; H, 3.25; N, 10.9. Cl,H,N204~0.5H,0 requires C, 58.85; H, 3.4; N, 10.55%);m/z (%) 256 (M', 13), 212 (loo), 185 (44), and 44 (46); vmax,3 230, 2 210, 1 715, 1 695, and 1 650 cm-'; GCCDCl, + (CD,),SO] 7.77 (4 H, s,ArH) and 4.37 (2 H, s, CH,). Valine.Valine (560 mg, 4.8 mmol) in water (20 ml) was added to a solution of (1,3-dioxoindan-2-ylidene)malononitrile(1 g, 4.8 mmol) in acetonitrile (40 ml).The mixture was stirred at 50°C for 20 min during which time the by-product (1,3- dihydroxy-2H-indene-2-ylidene)malononitrde(300 mg, 30%), m.p. 250 OC precipitated and was filtered off. Concentration of the filtrate afforded the product (5a; R = Pr') as yellow needles (200 mg, 14%), m.p. 165-166°C (Found: C, 64.2; H, 4.8; N, 9.65. C,6HI4N2O4 requires C, 64.4; H, 4.75; N, 9.4%); m/z (%) 298 (M', 27), 283 (34), 254 (45), 211 (75), and 44 (100); vmaX. 3 200, 2 210, 1725, 1690, and 1640 cm-'; 6[CDCl, + (CD,),SO] 10.16 (1 H, s, NH), 7.85 (4 H, m, ArH), 4.42 (1 H, br s, CHN), 2.50 (1 H, m, CH), and 1.07 (6 H, t, 2 x Me).Reaction of'(1,3-Dioxoindan-2-ylidene)malononitrile(1) with a-Amino Acid Esters.-Ethyl glycinate. Glycine ethyl ester hydrochloride (670 mg, 4.8 mmol) and (1,3-dioxoindan-2-y1idene)malononitrile (1 g, 4.8 mmol) were suspended in 20% (v/v) aqueous acetonitrile (25 ml). Triethylamine (0.7 ml, 5 mmol) was added and the mixture stirred at room temperature for 20 min. The solvent was then evaporated and the residue crystallised from methylene dichloride-ethanol to afford the product (5bR = H) as yellow needles (720 mg, 5373, m.p. 135- 136 "C (Found: C, 63.45; H, 4.4; N, 10.05. Cl,Hl,N,04 requires C, 63.35; H, 4.25; N, 9.85%); mjz (%) 284 (M', 52),211(loo), and 184 (44); v,,,. 3 240,2 240,l 725,l 700, and 1 650 cm-'; 6 9.87 (1 H, s, NH), 7.77 (4 H, m, ArH), 4.43 (2 H, d, CH,), 4.31 (2 H, 9, CH,O), and 1.33 (3 H, t, MeCH,).Methyl alaninate. Reacted in a similar manner to that described above using alanine methyl ester hydrochloride. The product (9;= Me) (67%) crystallised from methylene R dichloride-methanol as yellow needles, m.p. 166-1 67 "C (Found: C, 63.2; H, 4.1; N, 9.85. C1,H,,N20, requires C, 63.35; H, 4.25; N, 9.85%); m/z (%) 284 (M', 23), 225 (loo), and 198 (67); vmaX.3 260,2 240, 1 740, 1 705, and 1 660 cm-'; 6 9.95 (1 H, d, NH), 7.77 (4 H, m, ArH), 4.67 (1 H, m, CHMe), 3.86 (3 H, s, MeO), and 1.70 (3 H, d, CHMe). Methyl ualinate. Reacted in a similar manner to that described above using valine methyl ester hydrochloride. The product (9;= Pr') (65%) crystallised from aqueous methanol R as yellow needles, m.p.98-99 "C (Found: C, 65.2; H, 4.95; N, 9.05. C17H16N204 requires C, 65.35; H, 5.15; N, 8.95%); m/z (%) 312 (M', 21), 253 (loo), and 226 (20); vmaX.3 240, 2 200, 1 730, 1 700, and 1 655 cm-I; 6 10.1 1 (1 H, d, NH), 7.77 (4 H, m, ArH), 4.51 (1 H, dd, CHN), 3.86 (3 H, s, MeO), 2.45 (1 H, m, CH), and 1.10 (6 H, m, 2 x Me). Methyl phenylglycinate. Reacted in a manner analogous to that described above. The product (542; R = Ph) (65%) crystallised from methylene dicbloride-methanol as yellow needles, m.p. 16b-161 "C (Found: C, 69.55; H, 4.05; N, 8.1. C,oH14N,04 requires C, 69.35; H, 4.05; N, 8.1%); m/z (%) 346 (M', 4), 287 (loo), and 260 (26); v,,,. 3 190,2 240, 1 730, 1 705, and 1 660 cm-'; 6 10.56 (1 H, d, NH), 7.75 (4 H, m, ArH), 7.44 (5 H, m, ArH), 5.60 (1 H, d, CHN), and 3.86 (3 H, s, MeO).Dimethyl aspartate. Reacted in a similar manner to that described above. The product (5c; R = CH,CO,Me) (68%) crystallised from methylene dichloride-methanol as yellow needles, m.p. 157-158 "C (Found: C, 59.65; H, 4.1; N, 8.3. C17H14N206 requires C, 59.65; H, 4.1; N, 8.2;%); m/z (%) 342 (M', 38), 283 (41), and 251 (100); v,,,. 3 180,2 230, 1 735, 1 705, and 1 655 cm-'; 6 10.32 (1 H, d, NH), 7.76 (4 H, m, ArH), 4.90 (1 H, m, CHN), 3.80 and 3.85 (2 x 3 H, 2 x s, 2 x MeO), and 3.29 and 3.07 (2 H, 2 x dd, CH,CH). 2-Aminomethylpyridine. (1,3-Dioxoindan-2-ylidene)malono-nitrile (500 mg, 2.4 mmol) and 2-aminomethylpyridine (0.25 ml, 2.4 mmol) were dissolved in acetonitrile (20 ml) and the resulting mixture was stirred at room temperature for 1 h during which time the product (14) (420 mg, 61%) crystallised as yellow plates, m.p.177-179°C (Found: C, 70.6; H, 3.9; N, 14.35. C17HllN302 requires C, 70.6; H, 3.85; N, 14.55%); m/z (%) 298 (M+, loo), 262 (M -HCN, 41), 144 (24), and 107 (36); vmax, 2 240,l 695, and 1 655 cm-'; S[(CD,),SOJ 10.6 (1 H, s, NH), 8.6 (1 H, d, PyH), 7.85 (1 H, d, PyH), 7.78 (4 H, s, ArH), 7.45 (1 H, d, PyH), 7.36 (1 H, t, PyH), and 4.99 (2 H, s, CH,). Cycloadditions.-4-(1,3-Dioxoindan-2-ylidene)-7-methy1-6,8-dioxo-3,7-diazabicyclo[3.3.O]octane-2-carboxylicacid (12a;R = H). A mixture of the glycine derivative (5a; R = H) (256 mg, 1 mmol) and N-methylmaleimide (111 mg, 1 mmol) in 20% aqueous dimethylformamide (10 ml) was heated at 100 "C for 30 min. After addition of a little water the mixture was set aside to cool and crystallise. The product (470 mg, 71%) separated as colourless plates, m.p.250 "C (Found: C, 56.75; H, 4.0; N, 7.8. C, ,HI ,N,O,.H,O requires C, 57.0; H, 3.95; N, 7.8%); m/z (%) 296 (M' -CO,, 15); v,,,. 3 280,1720, 1 695, and 1 640 cm-'; 6CCDC1, + (CD,),SO] 10.00 (1 H br s, NH), 7.73 (4 H, m, ArH), 5.31 (1 H, d, HA), 4.76 (1 H, d, Hc),4.03 (1 H, dd, HB),and 2.79 (3 H, s, NMe). 544 J. CHEM. SOC. PERKIN TRANS. I 1988 Ethyl 4-(1,3-dioxoindan-2-ylidene)-7-methyl-6,8-dioxo-3,7-temperature for 1 h during which time the cycloadduct (1.26 g, diazabicyclo[3.3.0]octane-2-carboxylate(12b; R = H).A solu- tion of the ethyl glycinate derivative (5b R = H) (284mg, 1 mmol) and N-methylmaleimide (111 mg, 1 mmol) was dissolved in acetonitrile (20ml) and triethylamine (0.14 ml, 1 mmol) added. After the mixture had been stirred for 5 min at room temperature, the cycloadduct crystallised out and was filtered off to give the product (280 mg, 76%) as colourless plates, m.p. 250°c (Found: c, 62.1;H, 4.5; N, 7.6.C19H16N206 requires C, 61.95;H, 4.4;N, 7.6%); miz (%) 368 (M', 32),295 (62),and 238 (100);v,,,. 3 240,1 740,1 700,and 1 640 cm-'; GCCDCI, + (CD,),SO] 9.8 (1H, s, NH), 7.67(4H, m, ArH), 5.32 (1 H, d, HA), 4.87 (1 H, d, H,), 4.09 (3 H, m, HB and CH,O), 2.83 (3H, s, NMe), and 1.23 (3H, t, MeCH,). Irradiation of the signal for HA effected an enhancement in the signal for HB (12%) 70%) crystallised as yellow plates, m.p. 250 OC (Found: C, 67.75;H, 4.2;N, 11.1.CZIHlsN,O, requires C, 67.55;H, 4.05; N, 11.25%); miz (%) 373 (M', 92),262 (loo), and 228 (69);v,,,. 3 250,1 780,1 700,and 1 635 cm-'; S[(CD,),SO] 9.88 (1H, s, NH), 8.05 (1 H, d, PyH), 7.43 (1 H, m, PyH), 7.33(4H, m, ArH), 7.06(1 H, d, PyH), 6.95 (1 H, m, PyH), 5.18 (1H, d, HA), 5.05 (1 H, d, Hc), 3.80 (1 H, dd, HB), and 3.07 (3 H, s, NMe). Irradiation of the signal for HB effected enhancements in the signals for HA (17%) and H, (27.5%). Acknowledgements We thank the Home Office and Queen's University for support. and irradiation of H, also caused enhancement of HB (15.5%).Methyl 4-(1,3-dioxoindan-2-ylidene)-2,7-dimethyl-6,8-dioxo-References 3,7-diazabicyclo[3.3.O]octane-2-carboxylate(12c; R = Me).Prepared from the methyl alaninate derivative (5c; R = Me) in an analogous manner to that described above but with a reaction time of 1 h. The product (76%)crystallised as yellow plates, m.p. 250°C (Found: C, 62.15; H, 4.35;N, 7.4. C1,H,,N2O6 requires C, 61.95;H, 4.4;N, 7.6%); m/z (%) 368 (M', 14), 309 (83), and 252 (100);v,,,. 3 280,1 745,1 715,and 1 645cm-'; S[(CD,),SO] 10.2 (1 H, s, NH), 7.69(4 H, s, ArH),5.40and 3.27 (2 x 1 H, 2 x d, HA and HB), 3.25 (3 H, s, MeO), 2.80(3H, s, NMe), and 1.70 (3 H, s, Me). Irradiation of the 2-Me signal effected enhancement of the signal for H, (11%) and irradiation of HA also caused enhancement of H, (7.5%).Methyl 4-(1,3-dioxoindan-2-ylidene)-7-methyl-6,8-diox0-2-phenyl-3,7-diazabicyclo[3.3.01octane-2-carboxylate(12c; R = Ph).Prepared (75%)from the methyl phenylglycinate derivative (5c;R = Ph) in a similar manner to that described above but with a 1 h reaction time. The product crystallised as colour- less plates, m.p. 250°C (Found: C,67.2;H, 4.45;N, 6.55. C2,Hl,N,O6 requires C, 67.0;H, 4.2;N, 6.5%); m/z (yo, 130 (M', 3), 371 (loo), and 314 (69); v,,,. 3 220, 1750, 1 710,and 1 650cm-'; S[(CD,),SO] 10.84 (1 H, s, NH), 7.75 (4 H, s, ArH), 7.47(5 H, m, ArH), 5.42 (1 H, d, HA), 4.00 (1 H, d, HB) 3.57 (3H, s, MeO), and 2.92 (3H, s, NMe). Irradiation of the signal for H, caused enhancement of the signals for HA (17%) and the o-phenyl protons (11%).4-(1,3-Dioxoindan-2-ylidene)-7-methyl-6,8-dioxo-2-pyridyl-3,7-diazabicyclo[3.3.0]octane(15).2-Aminomethylpyridine (530 mg, 4.8 mmol) was added to a solution of (1,3-dioxoindan-2- y1idene)malononitrile (1 g, 4.8 mmol) and N-methylmaleimide (532mg, 4.8mmol) in acetonitrile (30ml).Triethylamine (0.7 ml, 5 mmol? was then added and the mixture stirred at room 1 Part 8, K. Amornraksa, R. Grigg, H. Q. N. Gunaratne, J. Kemp, and V. Sridharan, J. Chem. SOC.,Perkin Trans. 1, 1987, 2285. 2 H. Aigner, H. Junek, and H. Stork, Monatsh. Chem., 1970,101,1145; H. Junek, H. Aigner, and H. Fischer-Colbrie, ibid.,1972, 103, 639. 3 H. Junek, H. Fischer-Colbrie, and H. Sterk, Chem. Ber., 1977, 110, 2276. 4 H. Sterk and H.Junek, Tetrahedron, 1970, 26, 5361. 5 R. Grigg, Q. Rev. Chem. SOC.,1987, 16, 89. 6 R. Grigg, J. Kemp, and W. J. Warnock, J. Chem. SOC.,Perkin Trans. 1, 1987, 2275. 7 R. Grigg and S. Thianpatanagul, J. Chem. SOC.,Perkin Trans. 1, 1984, 653. 8 H. Ardill, R. Grigg, V. Sridharan, S. Surendrakumar, S. Thianpatanagul, and S. Kanajun, J. Chem. SOC.,Chem. Commun., 1986, 602. 9 H. Junek, H. Fischer-Colbrie, and A. Hermetter, 2.Naturforsch., Teil B, 1977, 32, 898. 10 R. Grigg, H. Q. N. Gunaratne, V. Sridharan, and S. Thianpatanagul, Tetrahedron Lett., 1983, 24, 4363. 1 I W. Bannworth, R. Eidenschink, and T. Kauffmann, Angew. Chem., Znnt. Ed. Engl., 1974,13,468;T. Kauffmann, H. Ahlers, A. Hamsen, H. Schultz, H.-J. Tillard, and A. Vahrenhorst, ibid., 1977, 16, 119. 12 R. Grigg and J. Devlin, J. Chem. SOC.,Chem. Commun., 1986, 631. 13 R. Grigg, V. Sridharan, and S. Thianpatanagul, J. Chem. SOC.,Perkin Trans. 1, 1986, 1669. 14 R. Grigg, M. Dowling, and V. Sridharan, J. Chem. SOC., Chem. Commun., 1986, 1777. 15 R. Taylor, 0.Kennard, and W. Versichel, J. Am. Chem. SOC.,1984, 106, 244. 16 R. Grigg, H. Q. N. Gunaratne, and J. Kemp, J,Chem. SOC.,Perkin Trans. 1, 1984, 41. 17 A. J. Fatiadi, Synthesis, 1978, 165. Received 20th March 1987; Paper 7/511