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Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 259--261, January, 2005

259

Heterocycles with a bridgehead nitrogen atom.
16.* Assembly of a peri fused system from an angular tricycle by recyclization of an oxazole ring into pyrrole one
E. V. Babaev, A. A. Tsisevich, D. V. Al´bov, V. B. Rybakov, and L. A. Aslanov Department of Chemistry, M. V. Lomonosov Moscow State University, 1 Leninskie Gory, 119992 Moscow, Russian Federation. Fax: +7 (095) 932 8846. E mail: babaev@org.chem.msu.su
An unusual example of the recyclization of the tricyclic 6,7,8,9 tetrahydrooxazo lo[3,2 a]quinolinium system into the 8,9 dihydro 7H pyrrolo[3,2,1 ij]quinoline system was discovered. The reaction is a topological modification of the known conversion of oxazo lo[3,2 a]pyridinium salts into indolizines. The structural feature of this transformation is a change of the annelation type in the tricycle from the angular one to peri fusion of three rings. Key words: recyclization, oxazole, pyrrole, indolizine, annelation, peri fused rings, X ray diffraction analysis.

Earlier,2,3 we discovered a new family of recyclization reactions of the oxazole ring into the pyrrole one, through which fused oxazolo[3,2 a]pyridinium salts 1 were con verted to 5 substituted indolizines 2 virtually inaccessible in any other ways (Scheme 1).
Scheme 1

additional ring A instead of the methyl group (as in salts 1 and 3) (Scheme 2). In this case, the ring A originally fused only with the pyridine ring of salt 4 would become additionally fused with a newly formed pyrrole ring to give system 5. Therefore, the overall structural recon struction of tricycles 45 would be an example of an extremely rare mode of transformation of an angular struc ture (three rings with two fused sides) into a peri fused system (three rings are all fused in pairs).
Scheme 2

Most likely, the conversion proceeds4 through the for mation of pyridinium intermediate 3, in which cyclo condensation of a new pyrrole ring involves the methyl group of the salt 3. An interesting topological modification of this trans formation could be conversion of tricyclic systems 4 con taining a methylene fragment (as in cation 4) as part of an
* For Part 15, see Ref. 1.

We experimentally performed this unusual topo logical transformation with 6,7,8,9 tetrahydrooxazo lo[3,2 a]quinolinium salt 6 as a tricyclic system of the type 4 (Scheme 3). Tricycle 6 was synthesized in three steps starting from available tetrahydroquinolone 7. To construct the oxazole

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 253--255, January, 2005. 1066 5285/05/5401 0259 © 2005 Springer Science+Business Media, Inc.


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Scheme 3 C(11) C(10) C(8) C(13) C(7) C(6) C(5) N(20) C(21) C(25) C(24) C(23) Fig. 1. Structure 10a (from X ray diffraction data). The selected bond lengths in the tricycle are: Bond C(1)--C(2) C(1)--C(9) C(1)--C(12) C(2)--C(3) C(2)--C(14) C(3)--N(4) N(4)--C(9) N(4)--C(5) C(1)--C(6) d/å 1.455 1.357 1.526 1.386 1.455 1.360 1.410 1.378 1.352 (3) (3) (3) (3) (3) (2) (3) (3) (3) Bond C(5)--N(20) C(6)--C(7) C(7)--C(8) C(7)--C(13) C(8)--C(9) C(1)--C(10) C(10)--C(11) C(11)--C(12) d/ å 1.408 1.449 1.345 1.510 1.406 1.519 1.521 1.532 (3) (3) (3) (3) (3) (3) (3) (3) C(22) N(4) C(9) C(12) C(1) C(2) C(14) C(3) C(19) C(15) C(16) C(17) Cl(1)

C(18)

8--11: Ar = p Cl--Ph (a), p NO2--Ph (b) 10: X = CH2 (a), O (b)

ring of system 6, selective N phenacylation in the pyridone fragment of compound 7 was required. Using Bradsher´s known methodology,5 which employs a protective methyl group to prevent O phenacylation, we obtained 2 methoxy derivative 8. Reactions of the latter with halogen ketones yielded, via simultaneous N phenacylation and O de methylation, the desired intermediate products 9a,b. Their cyclodehydration into tricycles 6a,b was carried out by successive treatment with sulfuric and perchloric acids. The 1H NMR spectra of perchlorates 6 contain no signals for two methylene protons; instead, a low field aromatic singlet for the oxazole ring appears at 9.4--9.6. Earlier, compounds 6a, 8, and 9a were synthesized and character ized by X ray diffraction data.6 In reactions with secondary amines or sodium methoxide, the obtained representatives of the angular tricyclic system 6 smoothly underwent recyclization to give amino or methoxy derivatives of 8,9 dihydro 7H pyrrolo[3,2,1 ij]quinolines 10 and 11 with the peri fused

rings. The 1H NMR spectra of heterocycles 10 and 11 contain no signals for one of the methylene units (as distinct from salts 6), while the low field singlet for the oxazole ring is replaced by a singlet for the pyrrole ring at 7.2--7.4. The structure of the tricycle obtained was un ambiguously proved by X ray diffraction analysis for com pound 10a (Fig. 1); the structure will be extensively dis cussed elsewhere*. The discovered transformation opens up a new strat egy of the synthesis of the pyrrolo[3,2,1 ij]quinoline sys tem. Compounds of this class first obtained in the 1980s7,8 attracted attention as agonists of dopamine receptors.9 Note that amino or alkoxy derivatives of this system have been unknown hitherto. Our subsequent studies will be devoted to the effects of the substituent nature in the pyridine ring and the size of the saturated fragment in system 6 on the recyclization in question. Experimental
1H NMR spectra were recorded on a Bruker AC 400 instru ment. The syntheses and X ray diffraction analysis of compounds

* The material is being prepared for publication.


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6a and 9a were described earlier.6 Compound 7 was prepared according to a known procedure.10 2 Methoxy 4 methyl 5,6,7,8 tetrahydroquinoline (8). A mix ture of 4 methyl 5,6,7,8 tetrahydroquinolin 2 one ( 7) (57 mmol), CH3I (72 mmol), and freshly prepared and well dried Ag2CO3 (28.5 mmol) in 90 mL of benzene was refluxed for 50 to 60 h in a light protected flask. The precipitate was filtered off, the solvent was removed from the mother liquor, and the residue was distilled in vacuo while collecting a fraction with b.p. 147 °C (20 Torr). The yield of compound 8 was 3.8 g (38%), m.p. 40--41 °C (cf. Ref. 6: m.p. 35--40 °C). 4 Methyl 1 (4 nitrophenacyl) 5,6,7,8 tetrahydroquinolin 2 one (9b). A solution of compound 8 (25 mmol) and 4 nitro phenacyl bromide (20 mmol) in 40 mL of MeCN was refluxed for 40 h. The precipitate was filtered off and recrystallized from acetonitrile. The yield of compound 9b was 3.56 g (55%), m.p. 194--196 °C. Found (%): N, 5.50. C18H18N2O4. Calculated (%): N, 5.56. 1H NMR (DMSO d6), : 8.33 (m, 4 H, ArH); 6.14 (s, 1 H, H(3)); 5.52 (s, 2 H, NCH2); 2.47 (m, 4 H, CH2); 2.12 (s, 3 H, CH3); 1.74 (m, 4 H, CH2). 5 Methyl 2 (4 nitrophenyl) 6,7,8,9 tetrahydrooxazo lo[3,2 a]quinolinium perchlorate (6b). Compound 9b (5 mmol) was carefully dissolved in 30 mL of conc. H 2SO4 and left at room temperature for 16 h. The mixture was carefully poured into 300 mL of water and allowed to cool. Then 70% HClO4 (15 mL) was added dropwise. The precipitate was filtered off, washed with water to a neutral reaction, and dried. The yield of compound 6b was 1.93 g (95%), m.p. 283--285 °C. Found (%): N, 6.75. C18H17N2O3·ClO4. Calculated (%): N, 6.85. 1H NMR (DMSO d6), : 9.62 (s, 1 H, H(1)); 8.50, 8.28 (both m, 2 H each, ArH); 8.23 (s, 1 H, H(4)); 3.13, 2.82 (both m, 2 H each, CH2); 2.60 (s, 3 H, CH3); 1.90, 1.99 (both m, 2 H each, CH2). Recyclization of salts 6 in the presence of secondary amines (general procedure). A secondary amine (1 mL, ~20 fold excess) was added to a solution of perchlorate 6 (0.5 mmol) in 10 mL of acetonitrile. The mixture was refluxed to give a crimson solu tion, which rapidly turned greenish yellow. The resulting solu tion was poured into water. The precipitate was filtered off, dried, and recrystallized from acetonitrile. 1 (4 Chlorophenyl) 6 methyl 4 piperidino 8,9 dihydro 7H pyrrolo[3,2,1 ij]quinoline (10a) was obtained from perchlorate 6a and piperidine. The reaction duration was 2 min. The yield of compound 10a was 98%, m.p. 138--139 °C (yellow prismatic crystals). X ray diffraction data are shown in Fig. 1. Found (%): N, 7.61. C23H25ClN 2. Calculated (%): N, 7.68. 1H NMR (DMSO d6), : 7.51, 7.33 (both m, 2 H each, ArH); 7.18 (s, 1 H, H(3)); 5.76 (s, 1 H, H(6)); 3.00 (m, 4 H, CH2); 2.95, 2.74 (both m, 2 H each, CH2); 2.15 (s, 3 H, CH3); 2.00 (m, 2 H, CH2); 1.80, 1.67 (both m, 4 H each, CH2). 6 Methyl 4 morpholino 1 (4 nitrophenyl) 8,9 dihydro 7H pyrrolo[3,2,1 ij]quinoline (10b) was obtained from perchlorate 6b and morpholine. The reaction duration was 4 h. The yield of

compound 10b was 40%, m.p. 218--220 ° C. Found (%): N, 11.05. C22H23N3O3. Calculated (%): N, 11.13. 1H NMR (CDCl3), : 8.25, 7.73 (both m, 2 H each, ArH); 7.40 (s, 1 H, H(3)); 5.88 (s, 1 H, H(6)); 3.95, 3.10 (both m, 4 H each, CH2); 3.03, 2.80 (both m, 2 H each, CH2); 2.19 (s, 3 H, CH3); 2.06 (m, 2 H, CH2). 4 Methoxy 6 methyl 1 (4 nitrophenyl) 8,9 dihydro 7H pyrrolo[3,2,1 ij]quinoline (11b). Perchlorate 6b (0.5 mmol) was added to a solution of MeONa in methanol (prepared from Na metal (7.4 mmol) and anhydrous MeOH (10 mL)). The reaction mixture was left for 16 h. The precipitate that formed was fil tered off and recrystallized from acetonitrile. The yield of com pound 11b was 0.10 g (62%), m.p. 183--185 °C. Found (%): N, 8.50. C19H 18N 2O 3. Calculated (%): N, 8.69. 1H NMR (CDCl3), : 8.23, 7.72 (both m, 2 H each, ArH); 7.48 (s, 1 H, H(3)); 5.56 (s, 1 H, H(6)); 4.02 (s, 3 H, OCH3); 3.02, 2.77 ( both m, 2 H each, CH2); 2.19 (s, 3 H, CH3); 2.05 (m, 2 H, CH2).

This work was financially supported by the Russian Foundation for Basic Research (Project No. 04 03 32823 a). References
1. E. V. Babaev and G. A. Tikhomirov, Khim. Geterotsikl. Soedin., 2005, 135 [Chem. Heterocycl. Compd., 2005, No. 1 (Engl. Transl.)]. 2. E. V. Babaev and A. V. Efimov, Khim. Geterotsikl. Soedin., 1997, 7, 998 [Chem. Heterocycl. Compd., 1997, 33, 875 (Engl. Transl.)]. 3. E. V. Babaev, A. V. Efimov, D. A. Maiboroda, and K. Jug, Eur. J. Org. Chem., 1998, 1, 193. 4. E. V. Babaev, J. Heterocycl. Chem., 2000, 37, 519. 5. C. K. Bradsher and M. F. Zinn, J. Heterocycl. Chem., 1967, 4, 66. 6. D. V. Al´bov, V. B. Rybakov, E. V. Babaev, and L. A. Aslanov, Kristallografiya, 2004, 49, 476 [Crystallogr. Repts, 2004, 49, 430 (Engl. Transl.)]. 7. M. Cardellini, G. M. Cingolani, F. Claudi, G. Cristalli, U. Gulini, and S. Martelli, J. Org. Chem., 1982, 47, 688. 8. M. Noguchi, N. Tanigawa, and S. Kajigaeshi, J. Heterocycl. Chem., 1985, 22, 1049. 9. F. Claudi, G. Cristalli, S. Martelli, V. Perlini, M. Massi, and F. Venturi, J. Med. Chem., 1986, 29, 1061. 10. T. Kato, M. Sato, M. Noda, and T. Itoh, Chem. Pharm. Bull., 1980, 28, 2244.

Received October 18, 2004; in revised form December 10, 2004