ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 11, pp. 1605−1609. © Pleiades Publishing, Ltd., 2009.

Original Russian Text © N.G. Kozlov, E.A. Dikusar, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 11, pp. 1618 −1621.

Synthesis of m-Carborane-C-carboxylic Acid Hexahydrobenzo[a]acridine Esters N. G. Kozlov and E. A. Dikusar Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, 220072 Belarus e-mail: [email protected] Received November 26, 2008

Abstract—The possibility was demonstrated of selective preparation of m-carborane-C-carboxylic acid hexahydrobenzo[a]acridine esters both by the reaction of 1,3-diketones with azomethines obtained by condensation of m-carborane-C-carboxylic acid vanillin and vanillal esters with 1- or 2-naphthylamine and by the cascade heterocyclization of 1- or 2-naphthylamine, m-carborane-C-carboxylic acid vanillin and vanillal esters, and CHacids. DOI: 10.1134/S1070428009110049

Derivatives of carborane polyhedral claster systems are of interest for pharmacokinetic studies in the field of boron neutron capture therapy of tumors, radionuclides diagnostics and therapy [1, 2]. We formerly reported on the synthesis of esters of o- and m-carborane-C-carboxylic acid with a series of naturally occurring hydroxycontaining compounds [3, 4]. The target of this study was the preparation of new hexahydrobenzo[a]acridine esters of m-carborane-Ccarboxylic acid for their further investigation and screening as antitumor pharmaceuticals. The cascade heterocyclization (cyclocondensation) involving aromatic aldehydes, amine, and cyclic βdiketones is a convenient method of synthesis of derivatives of benzo[a]acridine, 4,7-pnenanthroline, and other fused azaheterocycles [5–7]. Yet no published information exists on the condensation with diketones of azomethines obtained from m-carborane-C-carboxylic acid vanillin and vanillal esters with 1- or 2naphthylamines. Analogs of compounds of the hexahydrobenzo[f]quinoline series obtained by this condensation and containing as the main structural fragment a partially or completely hydrogenated phenanthrene or quinoline frameworks are extensively studied due to the carcinogenic, teratogenic, and mutagenic properties of the polycyclic aromatic hydrocarbons [8, 9].

In this study the reaction was investigated between the azomethines obtained from m-carborane-C-carboxylic acid vanillin and vanillal esters I and II with 1- or 2-naphthylamines and 1,3-diketones. The feasibility of the application in this reaction as an aldehyde component of compounds I and II is due to the following reasons: the natural plant phenols (vanillin and vanillal) are convenient synthons for building up biologically active compound and for purposeful incorporating them into pharmacophoric fragments [10–13], the ester fragment of the m-carborane-C-carboxylic acid also provides a possibility of a successful synthesis of high-molecular polycyclic compounds containing diverse functional groups [14, 15]. Schiff bases III–VI were prepared by the standard procedure: boiling of equimolar amounts of m-carboraneC-carboxylic acid vanillin and vanillal esters with 1- or 2-naphthylamines in the methanol solution [16]. Azomethines III–VI were brought into the reaction with CH-acids [1,3-cyclohexanedione and 5,5-dimethyl1,3-cyclohexanedione (dimedone)] obtaining as a result the corresponding m-carborane-C-carboxylic acid 4(10,10-di-R2-8-oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)-2-R1-phenyl esters VII, IX, XI, XII and 4(9,9-di-R2-11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)-2-R1O-phenyl esters VIII, X, XII, XIV in yields from 36 to 50% calculated on the initial diketone. The derivatives of hexahydrobenzo[a]acridine VII–XIV

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KOZLOV, DIKUSAR Scheme.

NR3 O

1- or 2-naphthylamine

H C R1O

H C R1O O

O

C

C O

I, II

O

III_VI

1,3-cyclohexanedione or dimedone

H C R2

10

R2

O

C

R2 8

HN

O

4

O

11

9

O 7

R2

OR1

2

R1O

2

12

4

NH O

O

C

VII, IX, XI, XIII

VIII, X, XII, XIV C H

R1 = CH3 (I), C2H5 (II); R1 = CH3, R2 = H (VII, VIII), CH3 (XI, XII); R1 = C2H5, R2 = H (IX, X), CH3 (XIII, XIV); R3 = 1-naphthylamine (III, IV), 2-naphthylamine (V, VI).

formed at boiling the reagents for 10–15 min. Even at milder reaction conditions, for instance, at pouring into each other the warm alcoholic solutions of initial compounds, within 1 h precipitated the cyclization products. The ready formation of the cyclization products is evidently caused by the great tendency to enolization of the 1,3-diketones (see the scheme).

Cyclic 1,3-diketones in anhydrous benzene are present mainly in the keto form [17], it is therefore presumable that the reaction in benzene should be decelerated. Actually, the hexahydrobenzo[a]acridine derivatives formed only after boiling in benzene for 1.5 h. The moment of the start of reaction products formation was easy to observe: The compounds were insoluble in alcohol

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SYNTHESIS OF m-CARBORANE-C-CARBOXYLIC ACID

and benzene and precipitate from the hot solution in a crystalline state. These findings show that the cyclization process depends on the degree of the 1,3-diketone enolization. In order to increase the yield of reaction products VII– XIV and to simplify the procedure of the synthesis we carried out the three-component heterocyclization of m-carborane-C-carboxylic acid vanillin and vanillal esters II with 1- or 2-naphthylamine and 1,3-cyclohexanedione or dimedone. The reaction was performed by boiling the components in butanol. The hexahydrobenzo[a]acridine derivatives formed under these conditions within 5– 10 min. The yields of products were from 49 to 59%. As seen from the data obtained, the synthesis of m-carborane-Ccarboxylic acid benzo[a]acridine esters by the threecomponent cyclocondensation proved to be more favorable. The hexahydrobenzo[a]-acridine derivatives VII–XIV are colored crystalline substances with a definite melting point (see EXPERIMENTAL). We repeatedly discussed the probable mechanism of the three-component cyclocondensation [18]. The most probable path involves the stage of Mannich base formation that by retrohydride rearrangement transforms into aminodiketo intermediate whose heterocyclization results in compounds VII–XIV. The structure of compounds synthesized was established from the data of IR and 1H NMR spectroscopy. The IR spectra of compounds VII–XIV in contrast to initial azomethines III–VI lack the absorption band of the CH=N bond and contain several bands in the region 3070–3350 cm–1 corresponding to the NH group vibrations, and also two bands at ~1580 and 1600 cm–1 characteristic of vibrations of the conjugated ketoenamine fragment (“amide vinilog”). In the 1H NMR spectra of compounds VII–XIV the characteristic signals of protons at the atom C7(12) and of NH group appear as singlets at 5.8 and 9.8 ppm respectively. The proton signals of the CHcarborane group give rise to a broadened singlet at 4.1 ppm. In the spectra of compounds VII, VIII, XI, XII the protons of the methoxy group appear as a singlet at 3.6 ppm, aromatic protons resonances are observed in the range 6.5– 8.0 ppm. The spectra of hexahydrobenzo[a]acridines IX, X, XII, XIV are only distinguished by the presence of the signals from the ethoxy group at 1.1 t (CH3CH2O) and 3.9 q (CH3CH2O) ppm.

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EXPERIMENTAL IR spectra were recorded on a Fourier spectrophotometer Nicolet Protege-460 from pellets with KBr. NMR spectra were registered on spectrometers Bruker AC-500 (500 MHz) and Tesla BS-567 (100 MHz) from solutions in DMSO-d6 and CDCl3, internal reference TMS. Melting points were measured on a Koeffler heating block. m-Carborane-C-carboxylic acid hexahydrobenzo[a]acridine esters VII–XIV. a. A solution of 0.5 mmol of azomethine III–VI and 0.5 mmol of 1,3-diketone in 20 ml of 1-butanol was boiled till the formation of a precipitate (~10–15 min). The precipitate was filtered off, washed with hot benzene, and dried. b. A mixture of 0.35 mmol of 1- or 2-naphthylamine and 0.35 mmol of an appropriate aldehyde I or II in 20 ml of 1-butanol was boiled for 10 min, then the reaction mixture was cooled, 0.35 mmol of cyclohexane-1,3-dione or dimedone was added thereto. The mixture was boiled till the formation of a precipitate (~5 min). The precipitate was worked up as described in method a. 2-Methoxy-4-(8-oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)phenyl m-carborane-C-carboxylate (VII). Yield 50 (a), 59% (b), mp ≥ 340°C. 1H NMR spectrum, δ, ppm: 1.8 m (2H, CH ), 1.9 m (2H, 2 CH2), 2.0 m (2H, 2CH2), 2.6 m (10H, Β10H10), 3.7 t (3H, CH3O), 4.15 s (1H, CHcarborane), 5.8 s (1H, H7), 6.5–8.0 m (9Harom), 9.9 s (1H, NH). Found, %: C 61.09; H 5.46; Β 20.03; N 2.49. C27H31Β10NO4. Calculated, %: C 59.87; H 5.77; Β 19.96; N 2.59. 2-Methoxy-4-(11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)phenyl m-carborane-Ccarboxylate (VIII). Yield 45 (a), 56% (b), mp 328– 330°C. 1H NMR spectrum, δ, ppm: 1.7 m (2H, CH2), 1.9 m (2H, CH2), 2.1 m (2H, 2CH2), 2.6 m (10H, Β10H10), 3.7 t (3H, CH3O), 4.15 s (1H, CHcarborane), 5.9 s (1H, H 12), 6.5–8.0 m (9Harom), 9.8 s (1H, NH). Found, %: C 59.71; H 5.49; Β 19.86; N 2.38. C27H 31Β 10NO4. Calculated, %: C 59.87; H 5.77; Β 19.96; N 2.59. 4-(8-Oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)-2-ethoxyphenyl m-carborane-Ccarboxylate (IX). Yield 36 (a), 49% (b), mp 292–294°C. 1H NMR spectrum, δ, ppm: 1.1 t (3H, CH CH O), 1.8 m 3 2 (2H, CH2), 2.0 m (2H, CH2), 2.15 m (2H, 2CH2), 2.6 m (10H, Β10H10), 3.95 q (2H, CH3CH2O), 4.15 s (1H, CHcarborane), 5.8 s (1H, H7), 6.5–8.0 m (9Harom), 9.9 s (1H, NH). Found, %: C 60.39; H 5.40; Β 19.31; N 2.39.

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KOZLOV, DIKUSAR

C28H33Β10NO4. Calculated, %: C 60.52; H 5.99; Β 19.46; N 2.52. 4-(11-Oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)-2-ethoxyphenyl m-carborane-Ccarboxylate (X). Yield 40 (a), 54% (b), mp 328–330°C. 1H NMR spectrum, δ, ppm: 1.1 t (3H, CH CH O), 1.8 m 3 2 (2H, CH2), 2.0 m (2H, CH2), 2.15 m (2H, 2CH2), 2.6 m (10H, Β10H10), 3.95 q (2H, CH3CH2O), 4.15 s (1H, CHcarborane), 5.8 s (1H, H12), 6.5–8.0 m (9Harom), 9.9 s (1H, NH). Found, %: C 60.41; H 5.77; Β 19.62; N 2.41. C28H33Β10NO4. Calculated, %: C 60.52; H 5.99; Β 19.46; N 2.52. 4-(10,10-Dimethyl-8-oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)-2-methoxyphenyl m-carborane-C-carboxylate (XI). Yield 43 (a), 51% (b), mp 292–294OC. 1H NMR spectrum, δ, ppm: 0.9 s (3H, CH3), 1.0 s (3H, CH3), 2.0 –2.4 m (4H, 2CH2), 2.6 m (10H, Β10H10), 3.6 t (3H, CH3O), 4.15 s (1H, CHcarborane), 5.9 s (1H, H7), 6.5–8.0 m (9Harom), 9.4 s (1H, NH). Found, %: C 61.35; H 6.30; Β 19.09; N 2.27. C29H 35Β10NO 4. Calculated, %: C 61.14; H 6.19; Β 18.98; N 2.46. 4 - ( 9 , 9 - D i m e t h y l - 11 - o x o - 7 , 8 , 9 , 1 0 , 11 , 1 2 hexahydrobenzo[a]acridin-12-yl)-2-methoxyphenyl m-carborane-C-carboxylate (XII). Yield 42 (a), 56% (b), mp 318–320°C. 1H NMR spectrum, δ, ppm: 0.9 s (3H, CH3), 1.0 s (3H, CH3), 2.0–2.4 m (4H, 2CH2), 2.6 m (10H, Β10H10), 3.6 t (3H, CH3O), 4.2 C (1H, CHcarborane), 5.7 s (1H, H12), 6.60–8.0 m (9Harom), 9.9 s (1H, NH). Found, %: C 59.69; H 5.58; Β 20.08; N 2.43. C29H35Β10O4N. Calculated, %: C 59.87; H 5.77; Β 19.96; N 2.59. 4 - ( 1 0 , 1 0 - D i m e t h y l - 8 - o x o - 7 , 8 , 9 , 1 0 , 11 , 1 2 hexahydrobenzo[c]acridin-7-yl)-2-ethoxyphenyl mcarborane-C-carboxylate (XIII). Yield 39 (a), 50% (b), mp 320°C. 1H NMR spectrum, δ, ppm: 0.9 s (3H, CH3), 1.05 s (3H, CH3), 1.15 t (3H, CH3CH2O), 2.0–2.4 m (4H, 2CH2), 2.6 m (10H, Β10H10), 3.9 q (2H, CH3CH2O), 4.15 s (1H, CHcarborane), 6.0 C (1H, H 7), 6.5–8.0 m (9Harom), 9.2 C (1H, NH). Found, %: C 61.52; H 6.46; Β 19.27; N 2.41. C30H37Β10NO4. Calculated, %: C 61.37; H 6.39; Β 19.46; N 2.52. 4-(9,9-Dimethyl-11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)-2-ethoxyphenyl mcarborane-C-carboxylate (XIV). Yield 45 (a), 52% (b), mp 340–342°C. 1H NMR spectrum, δ, ppm: 0.85 s (3H, CH3), 1.0 s (3H, CH3), 1.15 t (3H, CH3CH2O), 2.0– 2.4 m (4H, 2CH2), 2.6 m (10H, Β10H10), 3.9 q (2H,

CH3CH2O), 4.2 s (1H, CHcarborane), 5.8 s (1H, H12), 6.60– 8.0 m (9H arom), 9.8 s (1H, NH). Found, %: C 60.45; H 6.46; Β 18.35; N 2.31. C30H37Β10O4N. Calculated, %: C 61.37; H 6.39; Β 18.52; N 2.40. REFERENCES 1. Soloway, A.H., Tjarks, W., Barnum, B.A., Rong, F.-G., Barth, R.F., Codogni, I.M., and Wilson, J.G., Chem. Rew., 1998, vol. 98, p. 1515. 2. Hawtorne, M.F. and Maderna, A., Chem. Rew., 1999, vol. 99, p. 3421. 3. Dikusar, E.A., Kozlov, N.G., Zvereva, T.D., Yuvchenko, A.P., and Mel’nichuk, L.A., Khim. Polim. Soedin., 2004, p. 388. 4. Dikusar, E.A., Potkin, V.I., Kozlov, N.G., Yuvchenko, A.P., Bei, M.P., and Kovganko, N.V., Zh. Org. Khim., 2008, vol. 44, p. 1321. 5. Lielbriedis, I.E., Chirkova, V.V., and Gudrinietse, E.Yu., Izv. Akad. Nauk Latv. SSR, Ser. Khim., 1969, p. 197. 6. Martinez, R., Rubio, M.F., Ramirez, G., Camacho, T., Linzaga, I.E., and Mancera, C., J. Heterocycl. Chem., 1995, vol. 32, p. 827. 7. Tonkikh, N., Duddeck, H., Petrova, M., Neilands, O., and Strakovs, A., Eur. J. Org. Chem., 1999, vol. 7, p. 1585. 8. Watts, W.J., Lawler, C.P., and Knoerzer, T., Eur. J. Pharmacol., 1993, vol. 239, p. 271. 9. Ribeiro, O., Hadfield, S.T., Clayton, A.F., Vose, C.W., and Coombs, M.M., J. Chem. Soc., Perkin Trans. I, 1983, p. 87. 10. Kozlov, N.G., Basalaeva, L.I., and Dikusar, E.A., Khim. Polim. Soedin., 2004, p. 70. 11. Skatetskii, V.V., Dikusar, E.A., and Kozlov, N.G., Abstracts of Paper, V Vserossiiskii nauchnyi seminar “Novye lekarstvennye sredstva: uspekhi i perspektivy” (5th AllRussian Sci. Meeting on New Medicines, Achievements and Prospectes), Ufa: Gilem, 2005, p. 61. 12. Dikusar, E.A., Potkin, V.I., Yuvchenko, A.P., Bei, M.P., Zvereva, T.D., and Rudakov, D.A., Abstracts of Papers, II Mezhdunarodnaya konferentsiya “Khimiya, struktura i funktsiya biomolekul” (2nd Int. Conf. on Chemistry, Structure and Function of Biomolecules), Minsk, 2006, p. 44. 13. Dikusar, E.A., Kozlov, N.G., and Potkin, V.I., Abstracts of Papers, IV Vserossiiskaya nauchnaya konferentsiya “Khimiya i tekhnologiya rastitel’nykh veshchestv” (4th All-Russian Sci. Conf. on Chemistry and Technology of Vegetal Matter), Syktyvkar, 2006, p. 65. 14. Potkin, V.I., Dikusar, E.A., Rudakov, D.A., and Yuvchenko, A.P. Abstracts of Papers, V Vserossiiskaya nauchnaya

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Biomolecules), Minsk, 2008. 16. Dikusar, E.A., Potkin, V.I., Yuvchenko, A.P., Kozlov, N.G., Zvereva, T.D., and Bei, M.P., Zh. Obshch. Khim., 2007, vol. 77, p. 1526. 17. Aren, A., Tsiklicheskie α-diketony (Cyclic α-diketons), Riga, 1961, p. 155. 18. Kozlov, N.G., Gusak, K.N., and Skatetskii, V.V., Zh. Org. Khim., 2006, vol. 42, p. 119.

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