Synthesis of 1-substituted 4-[4-(1 H -indol-3-yl)butyl]piperazines

A convenient synthetic route for preparation of various 4-[4-(1 H -indol-3-yl)butyl]piperazines bearing heterocyclic and aliphatic substituents in position 1 has been developed. During this work some synthetic possibilities of common precursor, 4-[4-(1 H -indol-3-yl)butyl]piperazine, were studied and evaluated

Further alkylation or arylation of 4-(1H-indol-3-yl)butyl]piperazine (2) with various alkyl halides was carried out in acetonitrile in the presence of base (DIPEA or potassium carbonate) and gave desired products 13a-i in high yields (Scheme 3).In contrast, arylation with various pyridine or pyrimidine halides was inconsistent, target products have not formed or formed in very low yields even when copper or palladium catalysis was applied.Due to the structural similarity of compounds 13-15 with Panobinostat (LBH-589) we expected their possible anti-cancer activity.Thus the antiproliferative activity of these compounds was tested in vitro. 17All compounds were inactive against tested human solid tumor cancer cell lines (HeLa (cervix), Ishikawa (endometrial), SW1573 (non-small cell lung), T-47D (breast), and WiDr (colon).

Experimental Section
General.Melting points were determined in open capillaries and are uncorrected.NMR spectra were recorded on Varian Unity Inova (300 MHz for 1 H NMR and 75 MHz for 13 C NMR) using residual solvent peaks as internal standards.The purity of compounds was monitored by TLC using silica gel 60 F254 aluminum plates (Merck).Column chromatography was carried out using silica gel 60 (0.04 -0.063 mm) (Roth).

General procedure for the synthesis of compounds 8a and 8b. Ethyl 4-[4-(1H-indol-3yl)butanoyl]-1-piperazinecarboxylate (8a).
To the stirred solution of 4-(1H-indol-3-yl)butanoic acid (1 g, 4.9 mmol) and trimethylamine (0.5 g, 4.9 mmol) in 10 mL of THF, ethyl chlorocarbonate (0.54 g, 4.9 mmol) solution in 10 mL of THF was added dropwise at 0-3 ºC.After the formation of white precipitate the reaction mixture was stirred at 0-3 ºC for 1 h.Then the precipitate (triethylamine hydrochloride) was filtered off and washed with 10 mL of THF.Filtrate was used in the next step without isolation of the intermediate product.Filtrate was added dropwise to a solution of ethyl piperazine-1-carboxylate (1.2 g, 7.35 mmol) in 10 mL of THF at 0-3 ºC and the resulting mixture was stirred at room temperature overnight.The precipitate was filtered off, washed with 5 mL of THF and the mother liquid was concentrated under the reduced pressure.The solid residue was dissolved in 5 mL of dichloromethane and washed twice with 5 mL of saturated sodium carbonate aqueous solution, and with 5 mL of water.Organic phase were dried with anhydrous Na2SO4 and solvent was evaporated under reduced pressure.Product was purified by recrystallization from toluene/hexane mixture yielding 1.1 g (65%) of pure product 8a. 1

3-[4-Oxo-4-(1-piperazinyl)butyl]-1H-indole (3).
To a solution of compound 8b (1.1 g, 3 mmol) in 15 mL of methanol, 1 mL of conc.HCl was added and the solution was stirred under reflux temperature for 1.5 h.Reaction mixture was cooled down and after the addition of 5 mL of water neutralized with saturated sodium carbonate solution.The product was extracted with DCM (2 × 5 mL).Organic phases were combined, washed with water (2 × 5 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure.Product was purified by column chromatography eluting with methanol/ammonium hydroxide mixture.Yield 0.4 g (50%) of pure product 3. 1

Method B. Reduction of 3-(4-oxo-4-piperazin-1-ylbutyl)-1H-indole (3) with AlCl3.
To the ice cold suspension of LiAlH4 (0.9 g, 24.3 mmol) in dry THF (50 mL) the suspension of AlCl3 (1.1 g, 8.1 mmol) in dry ether (50 mL) was added keeping the reaction mixture temperature below 3°C.To the resulting solution the solution of compound 3 (2.2 g, 8.1 mmol) in dry THF (50 mL) was added dropwise keeping the reaction mixture temperature below 3 °C.Reaction mixture was stirred for 30 min, quenched with 2 mL of water and 4 mL of 25% solution of NaOH in water, and stirred for additional 2 h.Formed precipitate was filtered off, washed with THF and filtrate was concentrated under reduced pressure.Product was purified in the same way as described above.Yield 1.4 g (67%) of title compound.

4-(1H-Indol-3-yl)butan-1-ol (10).
LiAlH4 (18 g, 0.473 mol) was added in small portions to 750 mL of dry THF, then the solution of methyl 4-(1H-indol-3-yl)butanoate (9) (86 g, 0.394 mol) in 750 mL of THF was added to the reaction mixture dropwise (reaction is exotermic) and the resulting mixture was stirred at reflux temperature for 10 min.After cooling the reaction mixture to 15 ºC, an excess of lithium aluminum hydride was carefully quenched with acetone (approximately 300 mL, until gel is destroyed and small grey particles are formed) and 10% KOH ice cold solution in water (approximately 250 mL, until precipitate becomes white).The precipitated white solid was filtered off, washed with THF, the mother liquid was concentrated under reduced pressure.The resulted residue was dried by coevaporation twice with DCM and twice with toluene yielding 74 g (99%) of compound 10.Product was used in the next step without additional purification. 1