Pte ane pri © ‘ACTS CCHEMICA SEANDINAVICA Addition of Secondary Amines to Maleamic Esters and Maleimides Jan Bergman* and Thomas Brimert Department of Organic Chemistry, Royal Institute of Technology, $-100 44 Stockholm, Sweden and Department of Organic Chemistry, CNT, NOVUM Research Park, S-141 57 Huddinge, Sweden Bergman, J. and Brimert,T., 1999, Addition of Secondary Amines to Maleamic Esters and Maleimides.” “Acta Chem. Scand, 53 4836, 0 Acta Chemica Scandinavica 1999. Contrary to some literature claims, secondary amines such as piperidine or their acetates do not promote the cyclization of maleanilc esters with activated orth alky! groups to form 2-quinolones, but instead they add to the maleic double bond, to produce 3-aminosuocinimides or S-aminosuecinamic esters, depending on the conditions used. This and similar reactions were studied and also an alternative synthesis of -nito-3-(2-0xo-2-piperidin-L-ylethyl)-34-dihydro- ‘quinolin-2(1 one was achieved utilizing the Sehmidt reaction as the key slp, We have recently developed a method! to construct 4 and 6nnitroindoles via the anions of imidate derivatives of 3 or S-nitro-2-alkylanilines as indicated in Scheme | ‘The presence of a nitro group in an activating position was found to be necessary for the reaction to take place at room temperature. Base-induced eyclizations of non- activated imidates such as 1 and 2 to 3, and 4 (Fig. 1), respectively, do? occur around 180 200°C, i.e. only 100°C lower than a normal Madelung cyclization’ a reaction which presumably involves the formation of @ dianion® from the substrate (an N-acyl-2-alkylaniline) and the base (alkoxide or amide). In connection with these studies we became interested in a reported, seemingly related, cyclization® of the maleanilic ester Sb to the quinolone 7 in the presence of ve = CY Scheme 1. Synthesis of indoles from imidates. j, HCIOEts, reflux; i, KOEt, (COzEt)2, OME, BT. NO: Fig. 1. Imidates 1 and 2 eye "To whom correspondence should be addressed 48 © Acta Chemice Scandinavica 531999) 49-56 piperidinium acetate at 100°C. Furthermore if Sb could be converted into an imidate, the mode of cyclization might be changed providing a route towards 2-vinyl- indoles, such as 8. Repetition of the reported sequence gave the precursor Sb in a good yield; however, the purported cyclization to a quinolone did not occur, as evidenced by the presence of an intact methyl group in the product. However, incorporation of a molecule of piperidine had clearly occurred. Results Treatment of Sb with piperidinium acetate at 90-100°C, readily gave a product which featured a signal at .2 ppm (this peak is a doublet for reasons discussed below) in the 4HINMR spectrum, that integrated to 3 H and thus originates from a methyl group as was also confirmed by a DEPT experiment. Furthermore, signals from the piperidine ring appeared at 2.9, 1.6 and 1.5 ppm. These data, together with the fact that the IR and “HNMR. spectra lacked NH signals, strongly suggest that the zs oy a x 3 4 to the corresponding indoles 3 and 4 when treated with base at 180-200°C.ADDITION OF AMINES TO MALEAMIC ESTERS AND MALEINIDES. O LT LT LG LG? ed a: 1: ReMe o: 7 ‘ Fig. 2. Quinolone 7 was claimed in the literature to be the product of the reaction between ester Sb and piperiinium acetate. product is N-(2-methyl-S-nitropheny!)-3-(piperidin-1- yl)pyrrolidine-2,S-dione (9). Less basic amines react in the same manner, e.g indoline and 5b gave 11. The same is also true for more basic amines such as pyrrolidine, which under the same conditions reacts with Sb to form the succinimide 9e. Changing the position of the nitro group from the S- to the 3- position did not affect the general outcome of the reaction. Thus the methyl ester 6b gave N- (2-methyl-3-nitrophenyl)-3-(piperidin-I-y1)pyrrolidine-2,5- dione (10) when treated with piperidinium acetate at 90-100°C, When performed at room temperature, the reaction yielded the amide 13a and the E-methyl ester 12 in a 1:2 ratio, but then a solvent (we chose DMF) was needed since the reactants are solids. Once again, other amines react in the same fashion. Thus morpholine and pyrrolid- ine gave 13b and 13c, respectively. The work-up and chromatographic purification of the crude reaction mixtures from these reactions, containing Ore ow Ly oo VU (Cty = CH.CH,OCH, CH, Xie N02 12, 13 and occasionally some of the imide 9, proved to be rather tedious. It was then found that ifthe free amine was employed with methanol instead of DMF as the solvent, the work-up was simplified considerably and in most cases high yields of 13 spontaneously crystallised from the reaction mixture and could easily be obtained in a pure state by simple filtration. No traces of the E- ester 12 were found, and only in the case of pyrrolidine as the base were 17a and 9¢ formed as well. If ethanol was used as the solvent, transesterification occurred and the ethyl esters 134-f were also formed in good yields An experiment with piperidinium acetate was also performed at 0°C resulting, after 30min, in a 20% conversion of the Z-ester Sb into the E-ester 12 with the other 80% unaffected. The esters were distinguished by their NMR coupling constants, 13.3 Hz for the Z-isomer and 15.5 Hz for the E-isomer. The structures of 92-e were proved by independent syntheses from the maleimide 14 (see Scheme 2) N-Phenyl maleimide likewise added piperidine yielding Fig. 3. Succinimides formed when maleamic esters were heated with secondary ammonium acetates Lom oH op TRA ome B oO ; QO 1a X= (CHa, R= Me 13h: X= -CHCHLOCH: Cy, R= Me Ne Xe-iChi)e, Re EL X-CHEHOCH,CHy, R=Et IBEX SICH De R=EL Fig. 4. Products from the reaction of maleamic ester 5b with secondary amines at room temperature. SX rE R = oy LER OY or ag oh, A ok OY F 1 90: X =4CHH Sb: X = “CH: CH,OCH,CH SACD ‘Scheme 2, Independent synthesis of 9a-e: i, Maleic anhydride, heat; i, piperidinium, morphalinium or pyrrolidinium acetate ‘and OMF. 49BERGMAN AND BRIMERT e ° Wa: R=Me MR et Fig. §. Products from the reactions between maleimides and secondary amines, the N-phenylsuccinimide 18. Similar additions are known in the literature, e.g. Hill e al.” have added indoline to N-phenylmaleimide using acetic acid as the solvent and isolated _3(indolin-I-yl)-N-phenylpyrrolidine-2,5-dione (16). Repetition of this reaction gave a product with similar 'H NMR data to Hill’s adduet, but with a dissimilar melting point and IR spectrum, than those reported, As evidenced by mass spectrometry, which featured a retro addition to indoline and N-phenyl- maleimide, however, the structure is without doubt 3- (indotin-1-yl)-N-phenylpyrrolidine-2,5-dione. Further- more the SC NMR spectrum exhibited three CH, signals (8 48.1, 31.1 and 27.6) and one CH signal (8 54.9) as well as two carbonyl signals (6 174.9 and 173.9) that coincided (vibrating at 1711em~') in the infrared spectrum, If, in the reaction between maleimide 14 and an ‘appropriate amine (see Scheme 2) the solvent is changed to methanol or ethanol, 13a-f are formed as the mai products. The reactions of pyrrolidine were the only ceases where formation of the other regioisomers (17a and 17b) could be observed The quinolone 7 was eventually prepared by an altern- ative route as outlined in Scheme 3. Thus (6-nitto- oxoindan-2-yl)acetic acid® was treated? with oxalyl chlor- ide to give the acid chloride, which was directly converted into the piperidide 18 in a good yield. This piperidide was then subjected to a Schmidt reaction" which afforded the desired product 7, No traces of the other possible produet 7-nitro-3-(1- ‘oxo-2-piperidin-1-ylethyl)-3,4-dihydroisoquinolin-1(2H)- fone could be detected, which is consistent with the observation" that alkyl aryl ketones prefer to undergo an aryl migration in the Schmidt reaction. This behavior is even more pronounced with substrates bearing a nitro ‘group meta or para to the ketone carbonyl, as Tomita etal. have shown." oop ‘The quinolone 7 was readily characterized, using IR and NMR spectroscopy, and the data were, as expected, quite different from those of the compound previously claimed to have the structure 7. Furthermore it was demonstrated that 7 was not even formed in trace amounts when Sb was treated with piperidinium acetate, at 100°C. Discussion Contrary to assertions in a recent paper,"? addition of amines to N-substituted maleimides are known and uused”° in organic syntheses of various 3-amino- succinimides. Thus Sharpless and Flavin" for instance readily obtained an adduct from maleimide and piperid- ine. However, to our knowledge there is no report involving addition of amines to maleanilic esters with concurrent cyclisation to 3-aminosuccinimides. From the results we conclude that the reaction pro- ceeds through an attack of the amine on the maleanilie ester, cither on the E-isomer or on the Z-isomer. Then, if the temperature is elevated, the resulting suecinamic ester can eyclize to form an imide. If, on the other hand, a Tower temperature is used, the amine will not add, although at 0°C it still promotes the isomerisation of the double bond. It should be noted that an attempted isomerisation with thiourea (24 h, RT in DME) afforded only starting materials and no traces of the E-isomer. Interestingly the 'H NMR spectra of the 3-amino-N- (2-methylpheny! )pyrrolidine-2,5-90%. N-(2-Methyl-3-nitrophenyl)maleamic acid (6a). A solu- tion of maleic anhydride (20g, 20mmol) in ether 2 (20 ml) was added to solution of 2-methyl-3-nitro- aniline (3.0 g, 20 mmol) in ether (70 ml), This mixture was left to stand for 60h and then filtered and washed with cold ether, giving 4.53 g (91%) of long white needles. Mop. 154°C, IR (KBr): 3253, 1714, 1632, 1978, 1531, 1360, 850, 734 em~!. "HNMR (DMSO-d,): 812.9 (1H, s) 10.13 (1H, 8), 7.73. (1 H, d), 7.68 (1 Hd), 7.43 (1H 10, 6.60 (1H. de J=12.1 Hz), 6.28 (1 Hed. J=12.1 Ha), 2.28 (31H, s). SC NMR (DMSO-d,): 8 166.5 (s), 164.0 (5), 1508 (5), 137.4 (5), 132.9 (4), 129.9 (d), 129.1), 126.7 (8), 126.5 (4), 121.0 (@), 13.6 (q). N-(2-Methyl-Scnitrophenyl)maleamie acid methyl ester (Sb).* N-(2-Methyl-S-nitrophenyl)maleamic acid (Sa, 2.508, 10 mmol), methanol (25 ml) and sulfuric acid (d=1.84, 0.04 ml, 0.8 mmol) were heated to boiling and then left at RT for 48h. Long white needles were then collected, yielding 1.96 g (74%). M.p.119-120°C. IR (KBr): 1716, 1519, 1553, 1345 em~!. 1H NMR (CDC\): 8 10.65 (1 H, s), 8.88 (1H, s), 7.85 (1H, d), 7.28 (1H, 4d), 644 (1H, dy J=13.28H2), 6.24 (1H, d, 13.27Hz), 381 GH, 9, 240 GH, 9. °C NMR (CDCI): 6 166.9 (5), 162.0 (8), 146.4 (3), 139.2 (4), 136.6 (6), 136.5 (s), 130.7 (@), 125.7 (@), 119.5 (@), 1174), 52.8 (q), 18.5 (q). N-(2-Methyl-3.nitrophenyl)maleamic acid methyl ester (6b). N-(2-Methyl-3-nitrophenyl)maleamic acid (6a, 4.50 g, 18 mmol), methanol (150 ml) and sulfuric acid (d=1.84, 3 drops from a Pasteur pipette) were heated to boiting and then left to stand for 60 h. The solution was then concentrated and the product crystallized from the remaining solution as long pale yellow needles, which were collected by filtration and washed with coo! meth- anol. This gave 307g (65% yield) of pure 6b Mp. 120-121 °C. IR (KBr): 2940, 1725, 1689, 1530, 1366, 1282em~". "HNMR (CDCI): 6 11.03 (1H, 5), 8.43 (1H, d), 7.95 (1H, d), 7.66 (1H, 0), 682 (1H, d, J=1331 Hz), 6.62 (1H, d, J=13.33 Hz), 418 3 H, 3), 2.78 (3H, 8). "C NMR (CDCI): 6 167.4 (5), 162.6 (3), 151.6 (8), 140.1 (4), 137.8 (8), 128.3 (@), 127.0 (€), 126.0 (€), 126.05), 121.3 (4), $33 (@), 142 (a.