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Heteroannelation of 3,4-dihydroisoquinoline with (3H,5H)-3-acylthiophene-2,4-diones: on...
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Heteroannelation of 3,4-dihydroisoquinoline with (3H,5H)-3-acylthiophene-2,4-diones: one-stage synthesis of new heterocyclic steroid analogues, 8-aza-16-thiagonanes
作者:
Marina V. Budnikova,
期刊:
Mendeleev Communications
(RSC Available online 1999)
卷期:
Volume 9,
issue 5
页码: 208-209
ISSN:0959-9436
年代: 1999
出版商: RSC
数据来源: RSC
摘要:
Mendeleev Communications Electronic Version, Issue 5, 1999 (pp. 171–212) Heteroannelation of 3,4-dihydroisoquinoline with (3H,5H)-3-acylthiophene-2,4-diones: one-stage synthesis of new heterocyclic steroid analogues, 8-aza-16-thiagonanes Marina V. Budnikova,* Dmitry B. Rubinov, Lev G. Lis and Alexander L. Mikhal’chuk Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus.Fax: + 7 017 263 7274; e-mail: rubinov@ns.iboch.ac.by New 8-aza-16-thiasteroid analogues, benzo[a]thieno[f]quinolizines, have been synthesised by the [2 + 4]heteroannelation of 3,4-dihydroisoquinoline with 3-acylthiotetronic acids. Condensed carbocycles and heterocycles are usually prepared by the following two ways: (1) a convergent synthesis which consists in the consecutive addition of rings to a principal carbocyclic or heterocyclic substrate and (2) a block synthesis when previously synthesised molecular units are combined at the final stage.1 The block strategy is more effective, and a large number of condensed nitrogen-containing heterocycles have been prepared in this manner, namely, benzo[a]- and dibenzo- [a,f]quinolizines,2(a) benzo[a]furo[f]quinolizines,2(b) benzo[a]- pyrrolo[f]quinolizines,2(c) benzo[a]pyrimidino[4,5-f]quinolizines2(d) and many others.3 All of the above compounds have been synthesised according to a single classical strategy involving the annelation ([2 + 4]cyclocondensation) reaction of cyclic Schiff’s bases, usually 3,4-dihydroisoquinolines, with b-dicarbonyl or b,b'-tricarbonyl compounds and their enol derivatives.2,3(b)–(d) To prepare new heterocycles, we tried to extend this approach by using 3,4-dihydroisoquinoline 1 and 3-acylthiotetronic acids such as (3H,5H)-3-acetylthiophene-2,4-dione 2a and (3H,5H)- 3-propionylthiophene-2,4-dione 2b in the annelation.4 We found that [2 + 4]cyclocondensation takes place when a mixture of compounds 1 and 2a or 2b is boiled in glacial acetic acid.† The reaction products are new heterocycles, benzo[a]thieno[f ]- quinolizines 3a,b.‡ Note that contrary to cyclocondensations with the participation of 2-acetylcyclohexane-1,3-diones2(a),5 and dihydrodehydracetic acid,3(a) which proceed in rather mild conditions, the reaction of 1 with 3-acylthiotetronic acids 2a,b, similarly to condensations with 2-acetylcyclopentane-1,3-dione6 and 3-acetyltetronic2(b) and 3-acetyltetramic2(c) acids, requires prolonged heating (8–15 h).We believe that this feature of b,b'-tricarbonyl compounds with five-membered rings is due to steric hindrances of the attack on a ring carbonyl by nitrogen atoms of Schiff’s bases. Prepared ABCD-tetracyclic 8-aza-16-thiagona-12,17-diones (benzo[a]thieno[4,3-f]quinolizines) 3a,b,5 as well as all their analogues which can be synthesised by this method, offer promise as biologically active substances and models for studying the structure–activity relationship in immune regulators such as † A mixture of 1.86 g (14.2 mmol) of 3,4-dihydroisoquinoline 1 and 2.24 g (14.2 mmol) of 3-acylthiotetronic acids 2a,b4 in 50 ml of glacial acetic acid was refluxed for 9 h and then allowed to cool to room temperature overnight.The precipitated orange crystals were separated, washed with acetic acid–diethyl ether (1:1), dried and recrystallised from a mixture of acetic and trifluoroacetic acids. Thus, 3.00 g (78.5%) of 8-aza-16-thiagona-1,3,5(10),13-tetraen-12,17-dione 3a (mp 320 °C, decomp.) and 3.01 g (75.6%) of 11-methyl-8-aza-16-thiagona-1,3,5(10),13- tetraen-12,17-dione 3b (mp 288–297 °C, decomp.) were obtained.condensed dibenzo[a,f]- and benzo[a]hetareno[f]quinolizine derivatives.7 Referenses 1 A. A. Akhrem and Yu. A. Titov, Total Steroid Synthesis, Plenum Press, New York, 1970. 2 (a) M. von Strandtmann, M. P. Cohen and J. Shavel, Jr., J. Org. Chem., 1966, 31, 797; (b) A. A. Akhrem, F. A.Lakhvich, L. G. Lis and V. N. Pshenichny, Zh. Org. Khim., 1979, 15, 1396 [J. Org. Chem. USSR (Engl. Transl.), 1979, 15, 1247]; (c) A. A. Akhrem, F. A. Lakhvich, V. N. Pshenichny, O. F. Lakhvich and B. B. Kuz’mitsky, Dokl. Akad. Nauk SSSR, 1978, 240, 595 (in Russian); (d) A. L. Mikhal’chuk, O. V. Gulyakevich, K. L. Krasnov, V. I. Slesarev and A. A. Akhrem, Zh. Org. Khim., 1993, 29, 1236 (Russ.J. Org. Chem., 1993, 29, 1026). 3 (a) A. A. Akhrem, A. M. Moiseenkov and V. A. Krivoruchko, Izv. Akad. Nauk SSSR, Ser. Khim., 1973, 1302 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1973, 22, 1258); (b) A. L. Mikhal’chuk, O. V. Gulyakevich, V. P. Peresada, A. M. Likhosherstov and A. A. Akhrem, Zh. Obshch. Khim., 1993, 63, 701 (Russ. J. Gen. Chem., 1993, 63, 494); (c) O. V.Gulyakevich and A. L. Mikhal’chuk, Dokl. Ross. Akad. Nauk, 1995, 345, 776 [Dokl. Chem. (Engl. Transl.), 1995, 345, 322]; (d) O. V. Gulyakevich and A. L. Mikhal’chuk, Dokl. Ross. Akad. Nauk, 1996, 350, 781 [Dokl. Chem. (Engl. Transl.), 1996, 350, 263]. 4 D. M. O’Mant, J. Chem. Soc. (C), 1968, 1501. 5 (a) A. L. Mikhal’chuk, O. V. Gulyakevich, A. A. Zenyuk, A. V. Korchik, L. G. Lis, V. A.Khripach, L. I. Ukhova and A. A. Akhrem, Dokl. Akad. Nauk SSSR, 1991, 317, 1397 [Dokl. Chem. (Engl. Transl.), 1991, 317, 106]; (b) O. V. Gulyakevich, A. L. Mikhal’chuk, A. I. Verenich, D. B. Rubinov, A. A. Zenyuk and A. A. Akhrem, Enaminy v organicheskom sinteze (Enamines in Organic Synthesis), Ur. Otd. RAN, Ekaterinburg, 1996, p.111 (in Russian); (c) A. L. Mikhal’chuk, O.V. Gulyakevich and A. A. Akhrem, Khim. Geterotsikl. Soedin., 1993, 86 [Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 74]. ‡ For 3a: 1H NMR (200 MHz, CDCl3, TMS) d: 3.15 [t, 1H, C(11)HB, J 18.0 Hz], 3.22 [ttt, 1H, C(6)Ha, J 11.0, 13.0, 3.0 Hz], 3.29 [mmm, 1H, C(6)He, J 13.0, 3.0, 3.0 Hz], 3.45 [dd, 1H, C(11)HA, J 18.0, 5.0 Hz], 3.88 [ttt, 1H, C(7)Ha, J 13.0, 11.0, 3.0 Hz], 4.34 [mmm, 1H, C(7)He, J 13.0, 3.0, 3.0 Hz], 4.58 [d, 1H, C(15)HB, J 18.5 Hz], 4.68 [d, 1H, C(15)HA, J 18.5 Hz], 5.46 [dd, 1H, C(9)HX, J 18.0, 5.0 Hz], 7.20–7.48 [m, 4H, C(1)H, C(2)H, C(3)H, C(4)H]. 13C NMR (90 MHz, CF3CO2D, TMS) d: 30.056, 35.227, 40.850, 49.006, 60.724 (C-9), 109.985 (C-12), 127.263, 130.190, 130.866×2, 132.296, 134.287, 177.985 (C-14), 190.453, 200.015. IR (KBr, n/cm–1): 3100–2830, 1685 (sh.), 1672, 1608, 1580, 1565–1540, 1473–1445, 1396, 1347, 1320, 1285, 1230, 876, 830, 769.UV [EtOH, lmax/nm (e)]: 202.4 (36070), 230.0 (11595), 265.0 (13630), 302.4 (12245); lmin/nm (e): 219.1 (10235), 245.9 (6450), 280.0 (8985). Found (%): C, 66.24; H, 4.79; N, 5.07; S, 12.12. Calc. for C15H13NO2S (%): C, 66.40; H, 4.83; N, 5.16; S, 11.82. MS, m/z: 271.34. For 3b: 1H NMR (200 MHz, CDCl3, TMS) d: 0.78 [d, 3H, C(11)Me, J 7.0 Hz], 2.74 [m, 1H, C(11)He, J 4.0, 7.0 Hz], 2.99 [tt, 1H, C(6)He, J 4.0, 4.0, 12.0 Hz], 3.12 [ddd, 1H, C(6)Ha, J 4.0, 12.0, 12.0 Hz], 3.50 [ddd, 1H, C(7)Ha, J 4.0, 12.0, 12.0 Hz], 4.04 [d, 1H, C(15)HB, J 18.0 Hz], 4.16 [tt, 1H, C(7)He, J 4.0, 4.0, 12.0 Hz], 4.24 [d, 1H, C(15)HA, J 18.0 Hz], 5.10 [d, 1H, C(9)Ha, J 4.0 Hz], 7.15 [dd, 1H, C(1)H, J 2.0, 8.0 Hz], 7.21–7.42 [m, 3H, C(2)H, C(3)H, C(4)H].IR (KBr, n/cm–1): 3100–2830, 1698 (sh.), 1630, 1596, 1573, 1560 (sh.), 1500, 1477, 1460 (sh.), 1405, 1380, 1360–1330, 1307, 1292, 1240, 897, 811, 797, 770, 755. UV [EtOH, lmax/nm (e)]: 264.6 (15860), 303.9 (12950); lmin/nm (e): 238.1 (6290), 281.2 (7280). Found (%): C, 67.27; H, 5.14; N, 4.87; S, 11.50.Calc. for C16H15NO2S (%): C, 67.34; H, 5.30; N, 4.91; S, 11.24. MS, m/z: 285.36. N S R O O O 1 2a,b N S O O R H A B C D 3a,b AcOH D a R = H b R = Me 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Mendeleev Communications Electronic Version, Issue 5, 1999 (pp. 171–212) 6 A. A. Akhrem, A. M. Moiseenkov, V. A. Krivoruchko, F. A. Lakhvich and A. I. Poselenov, Izv. Akad. Nauk SSSR, Ser. Khim., 1972, 2078 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1972, 21, 2014). 7 (a) N. A. Konoplya, O. V. Gulyakevich, A. L. Mikhal’chuk and B. B. Kuz’mitsky, Vesti Akad. Nauk Belarusi, Ser. Khim. Nauk, 1994, 91 (in Byelorussian); (b) A. A. Akhrem, B. B. Kuz’mitsky, F. A. Lakhvich, V. A. Khripach and Yu. L. Zhuravkov, Khymiya i biologiya immunoregulyatorov (Chemistry and Biology of Immunoregulators), Zinatne, Riga, 1985, p. 265 (in Russian). Received: 30th December 1998; Com. 98/1419
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