198 J. CHEM. SOC. PERKIN TRANS. I 1989 A Dehydrogenation Route to Azomethine Ylides and Isoindoles Ronald Grigg * and Frances Heaney Department of Chemistry, Queen*sUniversity, Belfast 8T95AG, Northern Jreland Dehydrogenation of methyl 1,2,3,4-tetrahydroisoquinolin-2-yl-and P-carbolin-9-yl-acetates with palladium black in dimethylformamide generates anti-azomethine ylides stereospecifically. The analogous reaction with methyl isoindolin-2-ylacetate gives the corresponding isoindole. Both types of product can be trapped by N-methylmaleimide. The mechanism of the dehydrogenation processes is discussed. There has been a great resurgence of interest recently in new methods of generating azomethine ylides. Methods have been developed involving oxazolines,' desilylation of N-(silyl-methyl)imines2 and related precursor^,^ 1,2-prototropy in activated imines4 and related metal ion catalysed proce~ses,~ decarboxylation of imines of a-amino acids,6 tertiary amine oxide^,^ and deprotonation of intermediate iminium species.8 We now report a further and radically different method, dehydrogenation, for the generation of these reactive in-termediates.A solution of compound (1) (1 mol) and N-methyl-maleimide (NMM) (2 mol) when heated in dimethylformamide (DMF) at 110 "C for 18 h in the presence of palladium black afforded a 1 :1 mixture of cycloadducts (2) and (3) in 65 H amp;02Me (1) HR 04,h Me (4) a; R=C02Me, R1=H (3) b; R=H. R'=COzMe combined yield. Excess of NMM was used to regenerate the active palladium catalyst by acting as a recipient for the hydrogen removed from (1) in the dehydrogenation process.The stereochemistry of (2) and (3), which was established by n.0.e. experiments, indicates the arzti-dipole (4a) is involved in the cycloaddition process. No adducts arising from the syn- dipole (4b) were detected. Our wide experience with NMM as a dipolarophile indicates that its high reactivity ensures trapping of the dipole mixture produced under kinetic control,6 i.e.before any equilibration (4a) c(4b). Thus, the dehydrogenation results in stereospecific formation of (4a). An analogous result was obtained with (5) which, under the same conditions, afforded a 1:1 mixture of (6) and (7), both of which are derived from the anti-dipole (8).No adducts arising from the corresponding syn-dipole were detected. Both (4a) and (8) can also be intercepted by dimethyl fumarate to give analogous adducts in 5@-60 yield. In the case of (5) the reaction was noticeably slower and had proceeded to ca. 67 conversion after 40 h. Thus, (1) reacts with dimethyl fumarate and palladium black to afford a 1:1mixture of (9) and (10) (50 combined yield) together with ca. 10 of a third, as yet unidentified, product. An attempt to generate a dipole from (11) (NMM, DMF, 110"C, 18 h) using palladium black led to the formation of (12) in ca. 60 yield. This result indicates that the initial dehydrogenation involves the benzylic methylene group, i.e. proceeds via (13), and that deprotonation leading to the isoindole (14) is preferred over deprotonation leading to dipole (15).Moreover, the acyclic tertiary amino acid ester (16) does not give a dipole under the same conditions. Palladium catalysts have long been known to dealkylate tertiary amines uia an intermediate iminium species followed by hydrolysis Scheme 1 (a).9 The failure of the acyclic substrate (14) to dehydrogenate under the same conditions? as (l), (5), and (11), and of the cycloadducts to further dehydrogenate, leads us to conclude that stereochemical factors are important in the dehydrogen- ation process. Hence we suggest co-ordination of palladium to the nitrogen atom facilitates insertion into the sr-CH bond provided the dihedral angle between the X-CHand N-Pd bonds is near, or equal to, zero Scheme l(b).The iminium species Nole uddd in prmf. When compound (14) is treated with palladium black and NMM under more vigorous conditions (xylene, 140deg;C), stereospecific anti-dipole formation occurs and a ca. 2: 3 mixture of e~o-and endo-cycloadducts is obtained in CLZ.40 yield. J. CHEM. SOC. PERKIN TRANS. I 1989 199 H (51 0"QO Me Me (6) (7) H rt--fiC02Me Me02Cut--f-- COzMe 1 1 MeOzC H A " (8 (9) (10) C02Me I PhCH2 N CHzCOzMe cxNJC02"' I MeH R R R 1 -Pd bsol;,+-/-HZO_ bsol;NH R / bsol; /N-cH bsol; R /bsol;R A PdH Scheme 1. + 0 3 then undergoes deprotonation furnishing either the dipoles (4a) and (8) or the isoindole (14). A related dehydrogenation of hydroxylamines to nitrones has been reported.lo Stereospecific formation of the anti-dipole suggests the intervention of an oxazoline intermediate (Scheme -2).Oxazolines are known to ring open to azomethine ylides. ' Our previously reported generation of azomethine ylides from primary and secondary amines and bifunctional carbonyl compounds' also furnishes anti-dipole stereospecifically. H$'OMe H -A;/A MeOzC H Me0 Scheme 2. Experimental Preparation of Cycloadducts (2) and (3).-A mixture of methyl 1,2,3,4-tetrahydroisoquinoline-2-ylacetate(2.05 g, 10 mmol), N-methylmaleimide (2.2 g, 20 mmol), and palladium black (200 mg, 2 mmol) in DMF (70 ml) was stirred and heated at 110 "Cfor 18 h. The reaction mixture was cooled, diluted with CHCI, (50 ml), and filtered.The solvent was removed under reduced pressure to leave a dark brown viscous oil whose 'H n.m.r. spectrum showed it to comprise a 1: 1 mixture of (2) and (3), together with a small amount of unchanged starting material. Purification by column chromatography on silica eluting with ether-light petroleum (b.p. 40-60 "C) (2: 1, v/v) afforded (2) (1 g) and (3)(1 g) (65 combined yield) Found (mixed isomers): C, 64.75; H, 5.85;N,8.7.C,,H,,N,O, requires C, 64.95; H, 5.75; N,8.90; m/z (mixed isomers) 314 (M', 25) and 255 (100). (2). Colourless hexagonal plates from ether-light petroleum (b.p. 40-60 "C), m.p. 142-144 "C; G(CDC1,) 7.4, 7.2, and 7.1 (3 x m,4H, ArH),4.51 (d, 1 H, J7.3 Hz, 5-H),4.23 (s, 1 H, 2-H), 3.76 (s, 3 H, OMe), 3.72 (t, 1H, J7.5 Hz, 4-H), 3.62 (d, 1 H, 3-H), 3.15-2.68 (m, 4 H, 2 x CH,), and 2.85 (s, 3 H, NMe).(3). Fine colourless needles from ether-light petroleum (b.p. 4amp;-60"C), m.p. 145-146 "C; F(CDCl,), 7.4, 7.2, and 7.1 (3 x m, 4 H, ArH), 4.84 (br s, 1 H, 5-H), 4.06 (d, 1 H,J7.6 Hz, 2- H), 3.83 (s, 3 H, OMe), 3.57 (t, 1H, 3-H), 3.49 (dd, 1 H, J2.4 and 8.0 Hz, 4-H), 3.32 and 3.18 (2 x m, 2 x 1 H, NCH,), 3.05 (s, 3 H, NMe), and 3.02 and 2.60 (2 x m, 2 x 1 H, ArCH,). Acknowledgements We thank the Department of Education for Northern Ireland, May and Baker Limited, and Queen's University for support. References 1 E. Vedejs and J. Grissom, J. Am. Chem. Soc., 1988,110,3238;J. Org. Chem., 1988, 53, 1876. 2 E. Vedejs and G. R. Martinez, J. Am. Chem.Soc., 1979,101,6452; E. Vedejs and F.G. West, Chem. Rev., 1986,86,941;A. Mosonomi, Y. Sakata, and H. Sakurai, Chem. Lett., 1984,1117; K. Achiwa and M. Sekiya, Heterocycles, 1983, 120, 167; W. K. Anderson and T. T. J. CHEM. SOC. PERKIN TRANS. I 1989 Dabrah, Synth. Commun., 1986, 16, 559; A. Padwa, P. Eisenbarth, M. K. Venkatramanan, and G. S. K. Wong, J. Org. Chem., 1987,52, 2427. 3 E. Vedejs and F. G. West, J. Org. Chem., 1983,48,4773;A. Padwa, G. Haffmans and M. Thomas, J. Org. Chem., 1984,49,3314;0.Tsuge, S. Kanemasa, A. Hatada, and K. Matsuda, Bull. Chem. Soc. Jpn., 1986, 59, 2537. 4 R. Grigg, J. Komp, and N. Thompson, Tetrahedron Lett., 1978,2827; R. Grigg, H. Q. N. Gunaratne, V. Sridharan, and S. Thianpatanagul, ibid., 1983, 24, 4363; R.Grigg, Chem. Soc. Rev., 1987, 16, 89. 5 R. Grigg, H. Q. N. Gunaratne, and V. Sridharan, Tetrahedron, 1987, 43, 5887; D. A. Barr, R. Grigg, H. A. N. Gunaratne, J. Kemp, P. McMeekin, and V. Sridharan, ibid., 1988, 44, 557; 0. Tsuge, S. Kanemasa, and M. Yoshioka, J. Org. Chem., 1988,53, 1384. 6 H. Ardill, R. Grigg, V. Sridharan, and S. Surendrakumar, Tetruhedron, 1988,44,4953and references therein. 7 J. Chastenet and G.Roussi, J. Org. Chem., 1988,53,3808. 8 H. Ardill, R. Grigg, V. Sridharan, S. Surendrakumar, S. ThianpatanaguI, and S. Kanajun. J. Chem. Soc., Chem. Commun., 1986,602. 9 S.-T. Murahashi, T. Hirano, and T. Yano, J. Am. Chem. Soc., 1978, 100, 348; S.-I. Murahashi and T. Watanabe, ibid., 1979,101,7429. 10 S.-I. Murahashi, H. Mitsui, T. Watanabe, and S.-I. Zenki, Tetrahedron Lett., 1983,24, 1049. Received 24th August 1988; Puper 8/03434F
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