INTRODUCTION:

Benzoctamine (Tacitin*) [(9, 10-dihydro-9, 10-ethanoanthracen-9-yl)-N-methylmethanamine] R, Figure 1, that has been synthesized and developed into a clinically useful drug for the treatment of anxiety by the Ciba-Geigy research group. The key step in the synthesis of benzoctamine was [4+2] cycloaddition of ethylene with 9-anthracenecarboxaldehyde ¹.

The homologues of homobenzoctamine, homomaprotiline and bishomobenzoctamine were synthesis by using [3+4] and [4+2] cycloaddition ^2-5.

MATERIAL AND METHODS:

General

All the common solvents and chemicals were of analytical grade or purified by distillation. The synthesized of compounds was ascertained by thin layer chromatography (TLC). The purity and Melting points were determined on a Mel-Temp (Melting temperature) II apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer 883 spectrophotometer and peaks are expressed as ν (cm^-1). ¹HNMR and ¹³CNMR spectra were recorded on a JEOL ECP 400 (400 MHz) instrument in CDCl₃ and chemical shifts are expressed as δ ppm, and coupling constants J are given in Hertz.

9-vinylanthracene (R2):

Anthrone (4.86 g, 25 mmol) is slowly added to a solution of vinylmagnesium bromide prepared from magnesium (1.2 g, 50 mmol) and bromoethene (5.30 g, 50 mmol) in tetrahydrofuran (100 ml).The mixture was stirred for 8 h at room temperature and then hydrolyzed by addition of saturated ammonium chloride solution (125 ml), the organic layer was separated, and the aqueous layer was extracted with ether (125 ml). The combined organic layer was washed with water, dried over MgSO₄ anhydrous and the solvent was evaporated. To the crude product was added 25 ml benzene, 5 g P₄O₁₀ and stirred for 6 h at room temperature. The P₄O₁₀ was filtered off and the benzene was removed under vacuum. The crude product was purified by flash column chromatography (hexane-dichloromethane 1:1) give pure 9-vinylanthracene (R2) yield 4.1 g, 84 %, as yellow crystals, m.p: 68^oC. IR (KBr): ν max/cm^-1: 3064, 2935, 2852, 1620, 1445, 729 cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 5.38 (1H, dd, J 1.48, 10.24 Hz, H2’), 5.84 (1H, dd, J 1.48, 17.00 Hz, H2’), 6.75 (1H, q, J 11.72 Hz, H1’), 7.20-8.39 (9H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 115.30, 126.75-138.06.

12-bromo-9-vinyl-9,10-dihydro-9,10-ethanoanthracen-12-carbaldehyde (R3):

9-vinylanthracene (4.19 g, 19.58 mmol) and α-bromoacroline (5.30 g, 39.24 mmol) in benzene (21ml) was heated under reflux 24 h and allowed to cool to room temperature. The reaction mixture was concentrated and the crude product was purified by flash column chromatography on silica gel (ethyl acetate-petroleum ether 1:35) give pure (R3) yield 4.89 g.74 %, as white crystals, m.p:159^oC. IR (KBr): ν max/cm^-1: 3069, 2953, 2849, 1719, 1458, 750 cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 2.27 (1H, dd, J 2.20, 11.72 Hz, H11), 3.05 (1H, dd, J 2.96, 11.72 Hz, H11), 4.36 (1H, t, J 2.92 Hz, H10), 5.61 (1H,d, J 18.36 Hz, H2’), 6.22 (1H,d, J 11.76 Hz, H2’), 6.71 (1H, q, J 11.72 Hz, H1’), 7.24-7.53 (8H, m, aromatic-H). ¹³C-NMR (CDCl₃/400MHz, δ): 41.43, 43.82, 56.73, 72.57, 123.38-143.37, 190.55.

13-hydroxy-9-vinyl-9,10-dihydro-9,10-propanoanthracen-12-one (R4):

To a solution of [4+2] adduct (4.50 g, 13.27 mmol) in THF (47 ml) was added 1M aqueous NaOH (49 ml). The mixture was stirred at room temperature for 4 h, extracted with ether twice, washed with water, dried with Na₂SO₄ and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (ethyl acetate- petroleum ether 1:5) give (R4) yield 2.57 g. 70%, as white crystals, m.p.189^oC. IR (KBr): ν max/cm^-1: 3552, 3449, 3080, 2901, 1692, 1640, 1472, 1451 cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 2.82 (1H, dd, J 2.92, 13.20 Hz, H11), 3.11 (1H, dd, J 5.12, 10.28 Hz, H11), 3.61 (1H, d, J 3.64 Hz, OH), 4.10 (1H, t, J 2.92 Hz, H10), 4.38 (1H, d, J 3.68 Hz, H13), 5.69 (1H, d, J 17.60 Hz, H2’), 5.89 (1H, d, J 11.72 Hz, H2’), 6.31 (1H, q, J 11.72 Hz, H1’), 7.22-7.67 (9H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 43.39, 49.78, 54.69, 81.46, 120.19, 125.53-142.75, 208.56.

9,10-dihydro-9-vinyl-9,10-propanoanthracen-12-one (R5):

To a solution of SmI₂ (6.43 g, 15.90 mmol) in THF (6 ml) was added solution of compound 6 (2.20 g, 7.96 mmol) in THF (19 ml). The mixture was stirred at room temperature for 4 h, hexane was added. The mixture was filtered concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate 5:1) give (R5) yield 1.8 g, 87 %, as yellow crystals m.p.143^oC. IR (KBr): ν max/cm^-1: 3069, 2926, 1692, 1640, 1474, 1451, 1400, 1224, 1180, 1121, 1003, 955, 928, 779, 667, 631, 557, 482. ¹H-NMR (CDCl₃/400 MHz, δ): 2.84 (2H,d, J 4.40 Hz, H11), 2.88 (2H, s, H13), 4.31 (1H, t, J 4.40 Hz, H10), 5.52 (1H, d, J 17.60 Hz, H2’), 5.77 (1H, d, J 11.00 Hz, H2’), 6.39 (1H, q, J 11.00 Hz, H1’), 7.20-7.41 (9H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 43.36, 50.58, 53.11, 116.55, 125.33-142.67, 208.33.

9-vinyl-9,10-dihydro-9,10-propanoanthracen (R6):

A mixture of ketone () (1.50 g, 5.76 mmol), KOH (1.29 g, 22.98 mmol), hydrazine hydrate (4.1 g, 82.01 mmol) and triethyleneglycol (7 ml) was stirred at 150 ºC for 5 h. Then the water was removed by a Dean-Stark separator, and the reaction mixture was heated for a further 5 h to 200–210 ºC. After cooling to room temperature, the reaction mixture was treated with dil. HCl (until pH = 2 was reached). The aqueous layer was extracted with toluene, and the combined organic phases were washed with brine, dried with MgSO₄ and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate 5:1) give (R6) yield 1.12 g. 79 % as light yellow oil. IR (KBr): ν max/cm^-1: 3019, 2932, 1640, 1473, 1455, 1290, 1224, 1164 751cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 1.24-1.38 (2H, m, H12), 1.65-1.69 (2H, m, H11), 1.74 (2H, t, J 6.60 Hz, H13), 4.10 (1H, t, J 4.40 Hz, H10), 5.52 (1H, d, J 17.00 Hz, H2’), 5.71 (1H, d, J 11.00 Hz, H2’), 6.28 (1H, q, J 11.00 Hz, H1’), 7.18-7.58 (9H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 23.11, 29.78, 31.40, 43.37, 49.30, 50.58, 115.55, 124.72-144.13.

9-(2-hydroxyethyl)-9,10-dihydro-9,10-propanoanthracen (R7):

Added dropwise borane (BH₃) in THF (1.70 ml, 1.70 mmol, 1.00 M solution in THF) to hydrocarbon (1 g, 4.06 mmol) in THF (10 ml) at 0^oC then after that stirring the mixture for 10-12 h at room temperature, then after that added water (2 ml), 3M NaOH (2m) and H₂O₂ (2 ml) and stirring continued for 8 h. The mixture was diluted with water and extracted with ether after that dried the combined organic layers over Na₂SO₄ anhydrous and the solvent was evaporated. The crude product was purified by flash column chromatography by using silica gel, (diethyl ether – Petrolum ether) (1:1) give (R7) yield 0.61 g 57 % as liquid oil. IR (KBr): ν max/cm^-1: 3600, 3084, 2930, 1451, 1150, 1140 cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 1.12-1.35 (2H, m, H12), 1.57 (2H, t, J 6.60 Hz, H13), 1.75-2.18 (4H, m, H1’, H11), , 3.64 (2H, t, J 6.60 Hz, H2’), 3.99 (1H, t, J 4.40 Hz, H10), 7.15-7.43 (9H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 26.57, 39.26, 41.85, 45.59, 46.63, 50.91, 58.32, 123.66-143.17.

9-(2-chloroethyl)-9,10-dihydro-9,10-propanoanthracen (R8):

A mixture of the alcohol (0.40 g, 1.51 mmol) and triphenylphosphane (0.53 g, 2.03 mmol) in CCl₄ (14 ml) was heated was reflux for 10-12 h. The mixture was filtered and the residue was washed with Petrolum ether. After removal of the solvent, the crude product was purified by flash column chromatography by using silica gel, (diethyl ether – Petrolum ether) (1:10) give (R8) yield 0.37 g 87 % as liquid oil. IR (KBr): ν max/cm^-1: 3002, 2925, 1471, 1450, 912 cm^-1. ¹H-NMR (CDCl₃/400 MHz, δ): 1.15-1.38 (2H, m, H12), 1.64-1.92 (4H, m, H11, H13), 2.05-2.18 (2H, m, H1’), 3.65 (2H, t, J 5.60 Hz, CH₂Cl), 4.15 (1H, t, J 2.92 Hz, H10), 7.15-7.34 (9H, m, aromatic-H). ¹³C-NMR CDCl₃/400 MHz, δ): 26.55, 39.12, 41.23, 41.87, 45.81, 46.94, 50.78, 123.63-143.21.

9,10-dihydro-9-(2-methylaminoethyl)-9,10-propanoanthracene (R9):

Added solution of methylamine in ethanol (8 ml) to chloride (0.30 g, 1.06 mmol) and the reaction mixture was heated under a pressure of 200 atm by using Autoclave to 100^oC for 18-20 h. Then after cooling to room temperature after removal of the solvent, the solid residue was dissolved in methanol (5 ml) and hydrogenated at atmospheric pressure by using solid catalyst composed such as Raney nickel (0.1 g). After filtration and the solvent was evaporated, the mixture was diluted with ice cold half-concentrated HCl. The aqueous layer was washed with CHCl₃ (2*), then the aqueous layer was treated with solid KOH to reach PH = 12, saturated with NaCl and extracted with CHCl₃ (2*). The combined organic phases were washed with brine and K₂CO₃ anhydrous, after then solvent was evaporated gave the amine (R9) yield 0.19 g 64 %. IR (KBr): ν max/cm^-1: 3449, 3338, 2962, 2926, 2852, 1668, 1475, 1450, 1378, 1260 cm^-1. ¹H-NMR (MeOH/400 MHz, δ):1.15 (2H, t, J 4.40 Hz, H13), 1.18–1.52 (6H, m, H1’, H11, H12), 2.39 (3H, s, CH₃), 2.50–2.52 (2H, m, H2’), 2.53 (1H, s, NH), 3.95 (1H, t, J 4.40 Hz, H10), 7.16–7.43 (8H, m, aromatic-H). ¹³C-NMR (CDCl₃/400 MHz, δ): 26.81, 29.68, 36.69, 39.11, 42.50, 43.37, 46.95, 49.18, 123.75-143.53.

RESULTS AND DISCUSSION:

In this present study, we using a different method to the synthesis of corresponding of [9,10-Dihydro-9-(2-methylaminoethyl)-9,10-propanoanthracene] R9, was synthesized in eight steps starting from anthrone (as shown in Scheme.1).

The first step in the preparation of [(9,10-Dihydro-9,10-propanoanthracen-9-yl)-Nmethylethanamine] takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of anthrone (R1) with vinyl magnesium bromide prepared from magnesium and bromoethene in tetrahydrofuran followed by dehydration using P₄O₁₀to give 9-vinyl anthracene (R2)^6-8. This compound is characterized by using spectral analysis, the IR spectrum of compound (R2) the shows absorption band in the range of 3064-2853 cm^-1 for (C-H stretching aroma) and shows a peak in the range of 1620-1445 cm^-1 for (C=C stretching), and the absorption band observed at 729 cm^-1 for (C-H bonding). The ¹H NMR spectrum exhibit a characteristic doublet of doublet at δ 5.38 ppm for (one proton, H2’) and exhibit doublet of doublet at δ 5.84 ppm for (one proton, H2’), and shows quartet at δ 6.75 ppm for (one proton, H1’), and shows multiple in the range of 7.21-8.40 for (9 proton aromatic). The ¹³C-NMR shows one peak at δ 115.33 ppm for (carbon C1’), and peaks in the range of δ 134.38-138.06 ppm for (carbons C2’ and C aromatic).

The Diels-Alder reaction between 9-vinyl anthracene (R2) and α-bromoacrolein to gave the cycloadduct (R3)^9-14. IR spectra shows a strong peak at 1719 and cm^-1 for (C=O) and shows absorption band in the range of 3069-2849 cm^-1 for (C-H stretching aroma).The ¹ H-NMR exhibit a characteristic doublet of doublet at δ 2.27 ppm for (one proton, H11) and doublet of doublet at δ 3.05 ppm for (one proton, H11) and exhibit a characteristic triplet at δ 4.36 ppm for (one proton , H10) shows a characteristic singlet at δ 9.29 ppm for (CHO). The ¹³C-NMR shows one peak in δ 190.55 ppm for carbon (C=O).

Treatment of cycloadduct (R3) with 1M aq NaOH resulted in transformation into the ring expanded α-hydroxy ketone (R4). The broad peak in IR in the range 3552-3449 cm^-1 for (O-H stretching) and shows a peak in the range of 3080-2901 cm^-1 for (C-H stretching aroma) and shows strong peak at 1692 cm^-1 for (C=O). The ¹H NMR spectrum of (R4) shows a characteristic doublet at δ 3.57 ppm for (one proton, OH). The ¹³C-NMR exhibit one peak at δ 208.56 ppm for carbon (C=O).

Deoxygenation of (R4) by samarium iodide led to the desired key intermediate ketone (R5)¹⁵.This compound is confirmed by IR which shows one strong peak at 1719 cm^-1 for (C=O) and disappearance broad peak in the range 3552, 3449 cm^-1 for (O-H stretching).

Wolff-Kishner reduction of the ketone (R5) gave the tetracyclic hydrocarbon (R6)¹⁶.The IR spectrum of (R6) disappearance a strong peak at 1719 cm^-1 for (C=O). The ¹H-NMR shows multiple in the range of δ 1.24-1.38 ppm for (two proton H 12) and disappearance the singlet peak at δ 1.25 ppm for (two proton H13) and exhibit a characteristic triplet at δ 1.74 ppm for (two proton H13). The ¹³C-NMR disappearance of singlet peak at δ 208.56 ppm for (C=O) indicative of transference carbonyl to methylene.

Hydroboration-oxidation of the tetracyclic hydrocarbon (R6) with BH₃.THF gave alcohol (R7) ³. The IR shows broad peak in 3600 cm^-1 for (O-H stretching).

Conversion alcohol (R7) into the chloride by using triphenylphosphane in CCl₄ gave (R8). The IR spectrum shows peak in the range 3002, 2925cm^-1for (C-H stretching aroma) and showed a peak in the range of 1471-1450 for (C=C stretching), and disappearance broad peak at 3600 cm^-1 for (O-H stretching).

The final steps involve convert the chloride (R8) by solution of methylamine in methanol afforded the [(9,10-Dihydro-9,10-propanoanthracen-9-yl)-Nmethylethanamine] (2)¹⁷. The IR spectrum shows one peak in the range of 3449-3338 cm^-1 for (N-H secondary amine), and exhibit absorption band in the range of 2962-2852 cm^-1 for (C-H stretching aroma), and shows a peak in the range of 1668-1450 cm^-1 for (C=C stretching). In the ¹HNMR exhibit a characteristic triplet at δ 1.15 ppm for (two proton , H13) and shows two peak singlet at δ 2.39 ppm and δ 2.53 ppm due to the active (3H, CH₃, N-H protons).

CONCLUSIONS:

The above described sequence represents a successful eight-step synthesis of the last compound. The key step was cycloaddition of α-bromoacrolein with 9-vinylanthracene.

ACKNOWLEDGEMENTS:

Project was supported by King Saud University, Deanship of Scientific Research and College of Science Research Center.

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Received on 19.09.2012 Modified on 09.10.2012

Asian J. Research Chem. 5(12): Dec., 2012; Page 1460-1463