N R 1 N 2 4 3 4 X EWG 3 1 2 1 2 R = R¢CO, PhSO2, Me2N, Ph EWG = CO2Et, CN X = O, S N N H CO2Et N N H H CO2Et H N N CO2Et H R R N N CO2Et H 1,5-prototropy R a R b 3 a b 3¢ 6 4 7 1 2 3 4 5 6 7 8 9 10 11 12 N N H 6a 7a CO2Et H 12a b a R 3a 5 1 2 3 4 5 R 4 6b 176 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 176–177† Tandem Conjugate Carbon Addition–Intermolecular Hetero Diels–Alder Reactions using Ethyl 1H-Perimidine-2-acetate as a Ketene Aminal with Heating or Microwave Activation† Françoise Cado,a Patrick Jacquault,b Marie-Jo�elle Dozias,b Jean Pierre Bazureau*a and Jack Hamelina aSynth`ese et Electrosynth`ese Organiques 3, CNRS-UMR 6510, Bat. 10, Universit�e de Rennes 1, Campus de Beaulieu, F-35042 Rennes C�edex, France bProlabo, 54 rue Roger Salengro, F-94126 Fontenay sous Bois, France The reaction of ethyl 1H-perimidine-2-acetate 3 as a heterocyclic ketene-aminal with 2.1 equiv. of ethyl propiolate 4a or but- 3-yn-2-one 4b affords new fused perimidines in good yields by a tandem C-addition/hetero Diels–Alder reaction; the new 1-azabuta-1,3-diene intermediates are generated in situ from the initial trans C-addition products by thermal 1,5-prototropy. The hetero Diels–Alder reaction involving heterodienophiles1 and/or heterodienes2 has become a powerful tool for the construction of heterocyclic rings, particularly in natural product synthesis.3 However, the Diels–Alder reactions of 1-azabuta- 1,3-dienes of simple a,b-unsaturated imines 1 suffer from low conversion, and/or imine tautomerization precluding [4+2] cycloaddition.2a To solve these problems, various 1-azabuta- 1,3-dienes carrying substituents at the 1-position (R=acyl,3 sulfonyl,4 dimethylamino,5 phenyl6) have been developed to avoid instability arising from the imine moiety.Recently, Sakamoto et al.7 reported an interesting type of 1-azabuta-1,3-diene 2 (Scheme 1) in which the imine moiety is stabilized when introduced in a heterocyclic ring, such as 1,3-benzoxazoles and 1,3-benzothiazoles.The dienes 2 react with both electron-deficient and electron-rich dienophiles in intermolecular [4+2] cycloadditions. A recurrent theme of our ongoing studies with ethyl 1H-perimidine-2-acetate 3 (Scheme 2) is the nucleophilic reactivity of the b-position. Perimidine 3 simultaneously exhibits the distinct properties of heteroatomic systems with an excess of and a deficiency of p-electrons.8 Owing to the conjugation effect of the electron-donating amino groups and electron-withdrawing substituents, the double bond Ca�Cb is highly polarized and the electron density on Cb is increased,9 leading to greater nucleophilicity of carbon when compared to nigrogen.10 Encouraged by using perimidine 3 as an N,C bisnucleophilic synthon towards annulation from a- and b-dielectrophiles,11 we report here the first results obtained for the synthesis of new fused perimidines by a tandem conjugate C-addition–hetero Diels–Alder reaction.Moreover, as part of our programme to develop organic syntheses under microwave irradiation,12 we extended these reactions using solvent-free conditions under focused microwaves.13a Results and Discussion Treatment of 3 with 1.1 equiv. of ethyl propiolate 4a (MeOH, reflux, 3 h) mainly afforded the insoluble trans C-addition product 5a14 (Scheme 2, Table 1). Further treatment of 3 with 2.1 equiv. of 4a in refluxing ethanol for 3 h led to the fused perimidine 7a in quantitative yield (Table 1).The assigned structures of 5a and 7a were substantiated by the 1H and 13C NMR and MS analyses. Starting from 5a and 4a (5a:4a=1:1) under the same reaction conditions (EtOH, reflux, 3 h), compound 7a was also obtained in 98% crude yield: we reasoned that, by reacting the initial C-addition product 5a with 4a, the tautomer 6a might be readily trapped by an aza-Diels–Alder cycloaddition with the dienophile 4a. Interestingly, when 5a was refluxed in EtOH for 3 h, the 1H NMR spectrum of the crude reaction mixture showed the presence of compounds 3 (50%) and 7a (50%) as a result of a retro-reaction to give 3 and 4a, the latter reacting with the remaining 5a to give 7a.Finally, when an equimolecular mixture of 5a and N-phenyl- or N-methyl-maleimide as dienophile were refluxed in ethanol for 12 h, no Diels–Alder reaction took place but the labile nature of the vinylene segment of Cb in 5a was observed by identification of compounds 7a *To receive any correspondence.†This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Scheme 1 4a,5a,7a R=CO2Et 4b,5b,7b R=COMe Scheme 2 Table 1 Synthesis of perimidines 5a and 7a–b from 3 and 4a–b Product R Reaction conditions 4:3 Yield (%) 5a 7a 7b CO2Et CO2Et COMe MeOH, 65 °C, 3 h EtOH, 78 °C, 3 h EtOH, 78 °C, 5 h 1.1:1 2.1:1 2.1:1 67a 98 78b 98 50b aYield of crude 5a obtained after filtration on a Buchner funnel.bYield of crude product estimated by 1H NMR and after chromatography on silica gel.J. CHEM. RESEARCH (S), 1997 177 and 3 (7a:3=1:1): the formation of 7a can be explained via a retro-addition reaction from 5a in ethanol (Scheme 2). Mechanistically, the reaction proceeds via the initial formation of the trans compound 5a by regioselective Cb-addition of ethyl propiolate 4a to perimidine 3 which affords the 1-azabuta-1,3-diene 6a in situ, by thermal 1,5-prototropy, then 6a reacts with a second equivalent of 4a as dienophile and gives 7a by [4+2] cycloaddition.In a further demonstration of this methodology, treatment of 3 with but-3-yn-2-one 4b (EtOH, reflux, 5 h) afforded 7b together with a small amount of 5b (Scheme 2). Purification on silica gel (CH2Cl2–MeCN, 19:1 as eluent, Rf 0.36) gave pure 7b in 50% yield (Table 1). In order to shorten the synthetic route to 7a, solvent-free conditions in an oil bath or focused microwave irradiation were used.13a A Synthewave 402® microwave oven monitored by a computer which adjusts the temperature13b of the reaction mixture was used.Some typical examples are shown in Table 2. The main features of this technique are, complete addition in less than 8 minutes and ease of purification of 7a. When the same reaction mixture was heated in an oil bath previously set at the same boiling point for the same reaction time (entries 3,4 and 5,6) the results were analogous.In these cases, a specific microwave effect can be excluded as it is not expected in this polar solvent,15 but microwave heating affords a straightforward and efficient method for the preparation of 7a. Experimental General Procedure for the Preparation of Fused Perimidines 7.·A mixture of ethyl 1H-perimidine-2-acetate 3 (1 g, 3.9 mmol) and 4 (8.2 mmol) in dry ethanol (20 ml) was heated at 78 °C for 3 h under vigorous magnetic stirring.After elimination of ethanol in vacuo, the crude residue was purified by chromatography on silica gel. Solvent evaporation gave the desired compound 7 as a nearly pure oil which crystallized on standing. Diethyl 9-ethoxycarbonylmethyl-7,9-dihydropyrido[1,2-a]perimidine- 8,10-dicarboxylate 7a was prepared from ethyl propiolate 4a (0.8 g, 8.2 mmol) as a colourless powder, mp=144–146 °C (from CH2Cl2–MeCN, 19:1 as eluent, Rf 0.79), 78% yield; dH (CDCl3, 300 MHz) 1.00 (t, 3 H, J 7.1 Hz), 1.38 (t, 2Å3 H, J 7.1 Hz), 2.61 (d, 2 H, J 5.7 Hz), 3.55 (qd, 2 H, J 7.1 Hz), 4.25 (2Åq, 2Å2 H, J 7.1 Hz), 5.68 (t, 1 H, J 5.7 Hz), 6.52 (d, 1 H, H-4), 6.89 (d, 1 H, H-9), 7.21 (m, 4 H, Ar), 7.81 (s, 1 H, �CH), 12.21 (br s, 1 H, NH); dC (CDCl3, 75 MHz) 13.7 (qt, J 127, 2.7 Hz), 14.5 (qt, J 127, 2.5 Hz), 14.6 (qt, J 127, 2.5 Hz), 37.3 (td, J 132, 2.1 Hz), 50.5 (dt, J 147 Hz, CH), 60.0 (tq, J 147, 4.4 Hz), 60.2 (tq, J 147. 4.4 Hz), 60.9 (tq, J 147, 4.4 Hz), 81.8 (s, C-8), 105.5–106.1 (dd, J 161 Hz, C-1, C-6), 105.7 (s, C-10), 117.8 (s, C-6b), 119.9–121.1 (d, J 160 Hz, C-3, C-4), 127.8 (d, J 160 Hz, C-2, C-5), 131.8–134.3 (sd, C-6a, C-12a), 134.6 (s, C-3a), 135.2 (dd, J 166, 4.2 Hz, C-11), 150.2 (s, C-7a), 165., 168.3 (sm, OC), 170.1 (sm, CO) (Found: m/z, 450.1775. C25H26N2O6 requires Mr 450.1790). Ethyl 10-acetyl-9-(2-oxopropyl)-7,9-dihydropyrido[1,2-a]perimidine- 8-carboxylate 7b was prepared from but-3-yn-2-one 3b (0.56 g, 8.2 mmol) as a colourless powder, mp=182–184 °C (from CH2Cl2–MeCN, 19:1 as eluent, Rf 0.36), 50% yield; dH (CDCl3, 300 MHz) 1.39 (t, 3 H, J 7 Hz), 2.16 (s, 3 H), 2.34 (s, 3 H), 2.72 (2Åd, 2 H), 4.28–4.29 (2Åq, 2 H, J 7 Hz), 5.88 (2Åd, 1 H, J 7 Hz), 6.59 (dd, 1 H, J 7, 1.5 Hz), 7.05 (d, 1 H, J 7 Hz), 7.22 (s, 1 H, H-4), 7.22 (m, 4 H, Ar), 7.78 (s, 1 H, �CH), 12.32 (br s, 1 H, NH); dC (CDCl3, 75 MHz) 14.6 (qt, J 127, 2.5 Hz), 24.1–31.2 (2Åq, J 127 Hz), 45.5 (tm, J 130 Hz), 49.3 (dq, J 147 Hz), 60.3 (tq, J 147, 4.5 Hz), 82.2 (sd, J 2.7 Hz, C-8), 105.6 (dm, J 160 Hz, C-6), 106.4 (dd, J 160 Hz, C-1), 116.3 (sm, C-6b), 118.0 (sq, C-10), 120.3–121.4 (dm, J 160 Hz, C-3, C-4), 127.9–128.0 (d, J 160 Hz, C-2, C-5), 131.6–134.7 (sd, C-6a, C-12a), 134.7 (sm, C-3a), 136.9 (dd, J 162, 3.8 Hz, C-11), 150.2 (st, C-7a), 168.1 (sm, CO), 193.4 (sm, CO), 205.4 (sm, CO) (Found: m/z, 390.1552.C23H22N2O4 requires Mr, 390.1580). Ethyl 4-(2,3-Dihydro-1H-perimidin-2-ylidene)-4-ethoxycarbonylbut- 2-enoate 5a.·Ethyl 1H-perimidine-2-acetate 3 (1 g, 3.9 mmol) and ethyl propiolate 4a (0.42 g, 4.3 mmol) were added to dry methanol (10 ml) and the mixture refluxed at 65 °C for 3 h with vigorous magnetic stirring.The methanol was removed in vacuo and the crude reaction mixture was triturated with dry diethyl ether (20 ml). After standing (1 h), the precipitated product was filtered off, washed with diethyl ether (2Å10 ml) and dried in a dessicator over CaCl2 to afford compound 5a (0.94 g, 67%); dH ([2H6]DMSO, 300 MHz) d 1.26 (2Åt, 6 H, J 7 Hz), 4.14 (2Åq, 4 H, J 7 Hz), 6.12 (d, 1 H, �CH, J 15 Hz), 6.76 (m, 2 H, H-4, H-9), 7.15 (m, 4 H, Ar), 7.70 (d, 1 H, �CH, J 15 Hz), 11.40 (br s, 2 H, NH); dC ([2H6]DMSO, 75 MHz) 14.2 (qt, J 127, 2.5 Hz), 14.4 (qt, J 127, 2.5 Hz), 58.6 (tq, J 148, 4.8 Hz), 59.4 (tq, J 148, 4.8 Hz), 79.7 (s, Cb), 106.1 (dm, J 163 Hz, �CH), 108.0 (dd, J 166, 5.1 Hz, C-4, C-9), 115.6 (sm, C-9b), 119.1 (dm, J 160 Hz, C-5, C-8), 127.9 (d, J 159 Hz, C-6, C-7), 133.5–133.6 (s, C-3a, C-9a, C-6a), 137.5 (d, J 148 Hz, �CH), 152.4 (s, C-2), 168.5 (sd, CO), 169.5 (sd, J 9 Hz, �CH·CO) (Found: m/z, 352.1432.C20H20N2O4 requires Mr 352.1423). We are indebted to Prolabo for financial support (to F. C.) and thank Dr Jacques Perrocheau for helpful NMR discussions. Received, 10th October 1996; Accepted, 6th February 1997 Paper F/7/01052D References 1 S. M. Weinreb and R.R. Staib, Tetrahedron, 1982, 38, 3087. 2 (a) D. L. Boger and S. M. Weinreb, in Hetero Diels–Alder Methodology in Organic Synthesis, Academic Press, San Diego, 1987; (b) D. L. Boger, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 5, ch. 4.3. 3 (a) M. Teng and F. W. Fowler, J. Org. Chem., 1990, 55, 5646; (b) M. E. Jung and Y. M. Choi, J. Org. Chem., 1991, 56, 6729. 4 (a) D. L. Boger and A. M. Kasper, J. Am. Chem. Soc., 1989, 111, 1517; (b) D.L. Boger, K. C. Kassidy and S. Nakohara, J. Am. Chem. Soc., 1993, 115, 10732. 5 M. Chigr, M. Fillion and A. Rougny, Tetrahedron Lett., 1988, 29, 5913. 6 C. Trione, L. M. Toledo, S. D. Kuduk, F. W. Fowler and D. S. Grierson, J. Org. Chem., 1993, 58, 2075. 7 (a) M. Sakamoto, A. Nozoka, M. Shimamoto, H. Ozaki, Y. Suzuki, S. Yoshioka, M. Nagamo, K. Okamura, T. Date and O. Tamura, Chem. Pharm. Bull., 1994, 42, 1637; (b) J. Chem. Soc., Perkin Trans. 1, 1995, 1759; (c) M.Sakamoto, M. Nagamo, Y. Suzuki, K. Satoh and O. Tamura, Tetrahedron, 1996, 52, 733. 8 A. F. Pozharskii and V. V. Dol’nikovskaya, Russ. Chem. Rev., 1981, 50, 816. 9 S. Rajappa, Tetrahedron, 1981, 37, 1453. 10 F. Cado, P. Jacquault, J. L. Di-Martino, J. P. Bazureau and J. Hamelin, Bull. Soc. Chim. Fr., 1996, 133, 587. 11 F. Cado, J. P. Bazureau and J. Hamelin, Bull. Soc. Chim. Belg., 1996, 105, 273. 12 P. Jacquault, F. Texier-Boullet, J. P. Bazureau and J. Hamelin, International Chemical Congress of Pacific Basin Societies, Honolulu, Hawaii, 17–22 December 1995. 13 (a) R. Commarmot, R. Didenot and J. F. Gardais, Fr. Demande, 2 560 529 (Cl.B01J19/12), 06 Sep. 1985, Appl. 84/3,496, 02 Mar 1984 (Chem. Abstr., 1986, 105, 17442e) [apparatus commercialized by Prolabo (Fr) under the name Synthewave 402®]; (b) temperature measured by an IR captor: Prolabo, Fr. Pat. 62241D, 14669Fr, 23 Dec. 1991. 14 R. C. F. Jones and M. J. Smallridge, Tetrahedron Lett., 1988, 29, 5005 and references cited therein. 15 S. D. Pollington, G. Bond, R. B. Moyes, D. A. Whan, J. P. Candlin and J. R. Jennings, J. Org. Chem., 1991, 56, 1313. Table 2 Synthesis of 7a using an oil bath or under focused microwave irradiation (mw) Yield (%)a Reaction Entry t/min conditions 3 5a 7a 1d 23 e 4e 5e 6e 88 35 35 40 40 mwb oil bathc mw oil bath EtOH/mw EtOH/oil bath R2 R2 R2 R2 38 38 0000 38 38 98 98 98 98 24 24 aYield of crude product estimated by 1H NMR. bReactions were run in a focused microwave oven (Synthewave 402®). cIn a thermostatted oil bath, temperature variation �1 °C. a110 °