HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 5, 2011, pp. 1111-1119
Received, 8th February, 2011, Accepted, 15th March, 2011, Published online, 23rd March, 2011.
DOI: 10.3987/COM-11-12167

■ Simple Synthesis of Pratosine and Hippadine by Intramolecular Palladium-Catalyzed Cyclization and Decarboxylation

Hideaki Umemoto, Masashi Dohshita, Hiromi Hamamoto, and Yasuyoshi Miki*

Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

The palladium-catalyzed cyclization of dimethyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate in the presence of tetrakis(triphenylphosphine)palladium(0) and potassium acetate in hot 1,4-dioxane produced the 7H-pyrrolo[3,2,1-de]phenanthridine derivative, which was converted to pratosine by hydrolysis and decarboxylation. In a similar manner, hippadine was also prepared.

7H-Pyrrolo[3,2,1-de]phenanthridine alkaloids, pratosine,1 hippadine,2 and kalbretorine,3 isolated from various species of Amaryllidaceae have significant biological activities; for example, hippadine inhibits fertility in male rats4 and kalbretorine has an antitumor activity.3 Pratosine and hippadine were mainly synthesized by three methods from the 2-protected indole,5,6 indoline derivatives,7 or 7-haloindoles and related compounds.8,9 In a previous paper, we reported the synthesis of pratosine and hippadine by the palladium-catalyzed intramolecular cyclization of methyl 1-(2-bromo-4,5-dimethoxybenzyl)indole- 2-carboxylate protected 2-position of the indole moiety by an ester group.5 In this paper, we report the simple synthesis of pratosine and hippadine by the palladium-catalyzed intramolecular cyclization of dimethyl 1-(2-bromobenzyl)indole-2,3-dicarboxylates and decarboxylation.

Dimethyl 7-bromoindole-2,3-dicarboxylate (1)10 was converted to dimethyl 7-bromo-1-(3,4-dimethoxy- benzyl)indole-2,3-dicarboxylate (2) by treatment with 3,4-dimethoxybenzyl chloride in the presence of potassium carbonate. The treatment of 2 with a catalytic amount of tetrakis(triphenylphosphine)- palladium(0) ((PPh3)4Pd) in the presence of potassium acetate in hot dioxane gave a mixture of dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) and dimethyl 7H-10,11- dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4) in 35% and 3% yields, respectively (Scheme 1).

Dimethyl 9,10-dimethoxy-7H-pyrrolo[3,2,1-de]phenanthridone-4,5-dicarboxylate (7) could not be isolated by treatment of dimethyl 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6), which was prepared from dimethyl indole-2,3-dicarboxylate (5) and 2-bromo-4,5-dimethoxybenzoyl chloride, in hot dioxane in the presence of Pd(PPh3)4 and potassium acetate. The starting material was recovered. The treatment of 6 in N,N-dimethylformamide instead of dioxane at 100 °C afforded 5, which was produced by the hydrolysis of 6, in low yield (Scheme 2).

However, in a similar treatment described as 6, dimethyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-2,3- dicarboxylate (8), which was obtained from dimethyl indole-2,3-dicarboxylate (5) and 2-bromo-4,5- dimethoxybenzyl bromide,11 produced dimethyl 9,10-dimethoxy-7H-pyrrolo[3,2,1-de]phenanthridine-4,5- dicarboxylate (3) as the sole product in 76% yield (Scheme 3).

In order to investigate the negative reactivity of 6 on palladium-catalyzed intramolecular cyclization via Mizoroki-Heck reaction, 6 was subjected with phenylboronic acid in the presence of Pd(PPh3)4 and potassium acetate in hot dioxane for 7 hours. In this case, the intermolecular coupling of 6 with phenylboronic acid was occurred and dimethyl 1-(4,5-dimethoxy-2-phenylbenzoyl)indole-2,3- dicarboxylate was obtained. Therefore, this result suggests that initial formation of the intermediate (9) is proceeded in the presence of Pd(PPh3)4 and potassium acetate, but the following intramolecular cyclization would not be occurred due to the steric hindrance. (Scheme 4) Even though the exact reaction mechanism is still not clear, the difficulty of the palladium-catalyzed intramolecular cyclization on C-7 position of 1-benzoylindole derivatives reported by Itahara may support the possibility of our suggestions.12

The hydrolysis of 3 with LiOH gave the corresponding dicarboxylic acid (10), which could be converted into pratosine in 20% yield by treatment with copper chromite (CuO-Cr2O3) in hot quinoline (Scheme 5).

The reaction of dimethyl indole-2,3-dicarboxylate (5) with 2-bromo-4,5-methylenedioxybenzyl bromide13 afforded the dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)indole-2,3-dicarboxylate (11) (96%), which was treated with a catalytic amount of (PPh3)4Pd in the presence of potassium acetate in hot dioxane to produce dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12) (84%). In a manner similar to the synthesis of pratosine, the hydrolysis of 12 with LiOH gave the corresponding dicarboxylic acid (13) (85%), which could be converted into hippadine by the treatment with CuO-Cr2O3 in hot quinoline in 13% yield (Scheme 6).

ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (C) and also in part “High-Tech Research Center Project” for Private Universities and a matching fund subsidy from the Ministry of Education, Culture, Sports, Scientific and Technology-Japan (MEXT).

EXPERIMENTAL
Melting points were determined using a Yanagimoto micromelting point apparatus and are uncorrected. The 1H-NMR spectra were determined by a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as the internal standard. The IR spectra were recorded by a JASCO FT/IR-7000 spectrophotometer. The high MS were recorded using a JEOL JMS-HX100 spectrometer. Column chromatography was performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
Dimethyl 7-Bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2)
A mixture of dimethyl 7-bromoindole-2,3-dicarboxylate (1)10 (281 mg, 0.9 mmol), 4,5-dimethoxybenzyl chloride (202 mg, 1.1 mmol), and potassium carbonate (186 mg, 1.35 mmol) in acetone (3.6 mL) was refluxed for 22 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 7 : 1) to give dimethyl 7-bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2) (245 mg, 59%).
Mp. 110.5-111 °C (Et2O). IR (CHCl3) cm-1: 1710, 1735. 1H-NMR (CDCl3) δ: 3.76 (3H, s, OMe), 3.82 (3H, s, OMe), 3.87 (3H, s, OMe), 3.92 (3H, s, OMe), 5.88 (2H, s, NCH2), 6.48 (1H, dd, J = 8.5, 2 Hz, H-6'), 6.60 (1H, d, J = 2 Hz, H-2'), 6.74 (1H, d, J = 8.5 Hz, H-5'), 7.14 (1H, t, J = 8 Hz, H-5), 7.50 (1H, dd, J = 8, 1 Hz, H-6), 8.19 (1H, dd, J = 8, 1 Hz, H-4). Anal. Calcd for C21H20BrNO6: C, 54.56; H, 4.36; N, 3.03. Found: C, 54.80; H, 4.44; N, 2.99.
Intramolecular Cyclization of Dimethyl 7-Bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2): Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) and 7H-10,11-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4)
To a mixture of dimethyl 7-bromo-1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (2) (46 mg, 0.1 mmol) and potassium acetate (10 mg, 0.1 mmol) in dioxane (1.5 mL) was added Pd(PPh3)4 (6 mg, 0.05 mmol). The mixture was refluxed for 10 h under argon in the dark. Water was added to the reaction mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 3 : 1) to give dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) (13 mg, 35%) and 7H-10,11-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4) (1 mg, 3%).
Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3): Mp 123-124 °C (AcOEt). IR (CHCl3) cm-1: 1709. 1H-NMR (CDCl3) δ: 3.91 (3H, s, OMe), 3.96 (3H, s, OMe), 3.99 (3H, s, OMe), 4.02 (3H, s, OMe), 5.60 (2H, s, H-7), 6.66 (1H, s, H-8), 7.22 (1H, dd, J = 8, 7.5 Hz, H-2), 7.32 (1H, s, H-11), 7.47 (1H, dd, J = 7.5, 1 Hz, H-1), 7.78 (1H, dd, J = 8, 1 Hz, H-3). MS m/z: 381. HRMS m/z: Calcd for C21H19NO6: 381.1212. Found: 381.1239. Anal. Calcd for C21H19NO6: C, 66.14; H, 5.02; N, 3.67. Found: C, 65.92; H, 5.08; N, 3.51.
7H-10,11-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (4): IR (Nujol) cm-1: 1710. 1H-NMR (CDCl3) δ: 3.93 (6H, s, OMe), 3.96 (3H, s, OMe), 4.02 (3H, s, OMe), 5.61 (2H, s, H-7), 6.90 (1H, d, J = 8 Hz, H-8 or H-9), 6.96 (1H, d, J = 8 Hz, H-9 or H-8), 7.28 (1H, t, J = 8 Hz, H-2), 7.89 (1H, d, J = 8 Hz, H-3), 8.46 (1H, d, J = 8 Hz, H-1). MS m/z : 381. HRMS m/z: Calcd for C21H19NO6: 381.1212. Found: 381.1235.
Dimethyl 1-(2-Bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (350 mg, 1.5 mmol), 2-bromo-4,5-dimethoxybenzoyl chloride (560 mg, 2 mmol), and potassium carbonate (311 mg, 2.25 mmol) in MeCN (7.5 mL) was refluxed for 1 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (CHCl3) to give dimethyl 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6) (712 mg, quant.).
Mp 173-173.5 °C (n-hexane-AcOEt). IR (Nujol) cm-1: 1746, 1708. 1H-NMR (CDCl3) δ: 3.83 (3H, s, OMe), 3.85 (3H, s, OMe), 3.95 (3H, s, OMe), 3.98 (3H, s, OMe), 7.00 (1H, s, H-6'), 7.08 (1H, d, J = 8.5 Hz, H-7), 7.10 (1H, s, H-3'), 7.28 (1H, ddd, J = 7.7, 7.3, 1.5 Hz, H-5 or H-6), 7.37 (1H, ddd, J = 8.5, 7.7, 1 Hz, H-6 or H-5), 8.18 (1H, dd, J = 7.3, 1 Hz, H-4).
Attempt to Synthesize Dimethyl 7H-9,10-Dimethoxy-7-oxopyrrolo[3,2,1-de]phenanthridine-4,5- dicarboxylate (7) by Intramolecular Cyclization of Dimethyl 1-(2-Bromo-4,5-dimethoxybenzoyl)- indole-2,3-dicarboxylate (6)
To a mixture of dimethyl 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6) (43 mg, 0.09 mmol) and potassium acetate (9 mg, 0.09 mmol) in dioxane (1.8 mL) was added Pd(PPh3)4 (5 mg, 0.05 mmol). The mixture was refluxed for 29 h under argon in the dark. Water was added to the reaction mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 8 : 1) to give 6 (12mg, 28%).
Dimethyl 1-(2-Bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (5.0 g, 22 mmol), 2-bromo-4,5-dimethoxybenzyl bromide (6.7 g, 22 mmol) and potassium carbonate (4.5 g, 32 mmol) in MeCN (43 mL) was refluxed for 6 h. Water was added to the mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 20 : 1) to give dimethyl 1-(4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8) (7.7 g, 78%).
Mp 108-109 °C (n-hexane-AcOEt). IR (CHCl3) cm-1: 1734, 1700. 1H-NMR (CDCl3) δ: 3.52 (3H, s, OMe), 3.85 (3H, s, OMe), 3.95 (3H, s, OMe), 3.96 (3H, s, OMe), 5.44 (2H, s, NCH2), 6.25 (1H, s, H-6'), 7.04 (1H, s, H-3'), 7.25-7.34 (3H, m, arom), 8.12-8.18 (1H, m, H-4). Anal. Calcd for C21H20BrNO6: C, 54.56; H, 4.36; N, 3.03. Found: C, 54.79; H, 4.40; N, 2.79.
Intramolecular Cyclization of Dimethyl 1-(2-Bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8): Dimethyl 7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3)
To a mixture of dimethyl 1-(2-bromo-4,5-dimethoxybenzyl)indole-2,3-dicarboxylate (8) (2.9 g, 6.3 mmol) and potassium acetate (620 mg, 6.3 mmol) in dioxane (100 mL) was added Pd(PPh3)4 (364 mg, 0.32 mmol). The mixture was refluxed for 24 h under argon in the dark. Water was added to the reaction mixture and the aqueous mixture was extracted with CH2Cl2. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (CH2Cl2) to give dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]- phenanthridine-4,5-dicarboxylate (3) (1.82 g, 76%).
7H-9,10-Dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic Acid (10)
To a mixture of dimethyl 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (3) (953 mg, 2.5 mmol) in a mixture of dioxane (15 mL) and water (15 mL) was added lithium hydroxide monohydrate (420 mg, 10 mmol) and the mixture was refluxed for 2 h. The mixture was acidified with a 10% hydrochloric acid aqueous solution, and the precipitate was collected by filtration to afford 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (10) (874 mg, 99%).
Mp 222 °C (decomp.) (THF). IR (Nujol) cm-1: 3474, 3362, 1729, 1704. 1H-NMR (DMSO-d6) δ: 3.84 (3H, s, OMe), 3.90 (3H, s, OMe), 5.86 (2H, s, H-7), 7.02 (1H, s, H-8), 7.24 (1H, dd, J = 8, 7.5 Hz, H-2), 7.56 (1H, s, H-11), 7.74 (1H, dd, J = 7.5, 0.5 Hz, H-3 or H-1), 7.99 (1H, dd, J = 8, 0.5 Hz, H-1 or H-3). MS m/z: 353. HRMS m/z: Calcd for C19H15NO6: 353.0899. Found: 353.0903.
Pratosine
A mixture of 7H-9,10-dimethoxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (10) (21 mg, 0.06 mmol) and copper chromite (2 mg) in quinoline (1 mL) was refluxed for 1 h. CHCl3 was added to the mixture and the insoluble material was filtered through Celite to give a filtrate, which was washed with a 10% hydrochloric acid aqueous solution, then water and dried over Na2SO4. After filtration, the dried CHCl3 solution was concentrated under reduced pressure to afford a residue, which was purified by column chromatography (CHCl3) to give pratosine (3.3 mg, 20%).
Mp 234-235 °C (Et2O-MeOH) (lit.,1 232-233 °C); IR (Nujol) cm-1: 1670; 1H-NMR (CDCl3) δ: 4.07 (3H, s, OMe), 4.12 (3H, s, OMe), 6.90 (1H, d, J = 4 Hz, H-4), 7.48 (1H, t, J = 7.5 Hz, H-2), 7.64 (1H, s, H-8), 7.75 (1H, dd , J = 7.5, 0.5 Hz, H-3), 7.96 (1H, dd , J = 7.5, 0.5 Hz, H-1), 7.99 (1H, s, H-11), 8.05 (1H, d, J = 4 Hz, H-5). HRMS m/z (M+) Anal. Calcd for C17H13NO3: 279.0895. Found: 279.0891.
Dimethyl 7H-9,10-Methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12)
A mixture of dimethyl indole-2,3-dicarboxylate (5) (2.33 g, 10 mmol), 2-bromo-4,5-methylenedioxy- benzyl bromide (3.54 g, 12 mmol), and potassium carbonate (2.07 g, 15 mmol) in MeCN (23 mL) was refluxed for 2 h. The insoluble material was filtered through Celite to give a filtrate. The filtrate was concentrated under reduced pressure to afford dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)- indole-2,3-dicarboxylate (11) (4.26 g, 96%), which was used in next step without purification.
IR (KBr) cm-1: 1733, 1708; 1H-NMR (CDCl3) δ: 3.96 (3Hx2, s, CO2Me), 5.43 (2H, s, CH2), 5.88 (2H, s, CH2), 6.05 (1H, s, arom), 7.04 (1H, s, arom), 7.2-7.35 (2H, m, arom), 8.2-8.3 (1H, m, arom).
To a mixture of dimethyl 1-(2-bromo-4,5-methylenedioxybenzyl)indole-2,3-dicarboxylate (11) (5.13 g, 11.5 mmol) and potassium acetate (1.35 g, 13.8 mmol) in dioxane (230 mL) was added Pd(PPh3)4 (0.66 g, 0.58 mmol). The mixture was refluxed for 6 h under argon in the dark. Water was added to the reaction mixture and the aqueous mixture was extracted with CHCl3. The extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford a residue, which was recrystallized from AcOEt to give dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5- dicarboxylate (12) (3.54 g, 84%).
Mp 209-210 °C (AcOEt); IR (Nujol) cm-1: 1710, 1692; 1H-NMR (CDCl3) δ: 3.95 (3H, s, CO2Me), 4.01 (3H, s, CO2Me), 5.60 (2H, s, NCH2), 6.02 (2H, s, O-CH2-O), 6.65 (1H, s, H-8 or H-11), 7.21 (1H, t, J = 7 Hz, H-2), 7.33 (1H, s, H-11 or H-8), 7.43 (1H, br d, J = 7 Hz, H-1), 7.78 (1H, br d, J = 7 Hz, H-3). HRMS m/z (M+) Anal. Calcd for C20H15NO6: 366.0978. Found: 366.0965.
Hippadine
To a mixture of dimethyl 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylate (12) (912 mg, 2.5 mmol) in a mixture of dioxane (12.5 mL) and water (12.5 mL) was added lithium hydroxide monohydrate (525 mg, 12.5 mmol), and the mixture was refluxed for 5 h. The mixture was acidified with a 10% hydrochloric acid aqueous solution and the precipitate was collected by filtration to afford 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (13) (720 mg, 85%).
IR (KBr) cm-1: 1693; 1H-NMR (CDCl3) δ: 5.82 (2H, s, CH2), 6.08 (2H, s, CH2), 6.99 (1H, s, H-8 or H-11), 7.21 (1H, t, J = 7 Hz, H-2), 7.65 (1H, s, H-11 or H-8), 7.69 (1H, d, J = 7 Hz, H-1 or H-3), 7.95 (1H, br d, J = 7 Hz, H-3 or H-1). HRMS m/z (M+) Anal. Calcd for C18H12NO6: 338.0665. Found: 368.0675.
A mixture of 7H-9,10-methylenedioxypyrrolo[3,2,1-de]phenanthridine-4,5-dicarboxylic acid (13) (51 mg, 0.15 mmol) and copper chromite (9 mg) in quinoline (1.5 mL) was heated at 220 °C for 2.5 h. CHCl3 was added to the mixture and the insoluble material was filtered through Celite to give a filtrate, which was washed with a 10% hydrochloric acid aqueous solution, then water and dried over Na2SO4. After filtration, the dried CHCl3 solution was concentrated under reduced pressure to afford a residue, which was purified by column chromatography (n-hexane : AcOEt = 2 : 1) to give hippadine (5 mg, 13%).
Mp 215-216 °C (n-hexane-acetone) (lit.,2 209-210 °C); IR (Nujol) cm-1: 1673; 1H-NMR (CDCl3) δ: 6.17 (2H, s, CH2), 6.90 (1H, d, J = 4 Hz, H-4), 7.48 (1H, t, J = 8 Hz, H-2), 7.66 (1H, s, H-8), 7.76 (1H, dd, J = 8, 0.5 Hz, H-3), 7.92 (1H, dd, J = 8, 0.5 Hz, H-1), 7.99 (1H, s, H-11), 8.04 (1H, d, J = 4 Hz, H-5). HRMS m/z (M+) Anal. Calcd for C16H9NO3: 263.0582. Found: 263.0579.

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