An intramolecular C–N cross-coupling of β-enaminones: a simple and efficient way to precursors of some alkaloids of Galipea officinalis

2-Aroylmethylidene-1,2,3,4-tetrahydroquinolines with the appropriate substituents can be suitable precursors for the synthesis of alkaloids from Galipea officinalis (cuspareine, galipeine, galipinine, angustureine). However, only two, rather low-yielding procedures for their synthesis are described in the literature. We have developed a simple and efficient protocol for an intramolecular, palladium or copper-catalysed amination of both chloro- and bromo-substituted 3-amino-1,5-diphenylpent-2-en-1-ones leading to the above-mentioned tetrahydroquinoline moiety. The methodology is superior to the methods published to date.

S3 localized on a difference Fourier map, however to ensure uniformity of treatment of crystal, all hydrogen atoms were recalculated into idealized positions (riding model) and assigned temperature factors H iso (H) = 1.2 U eq (pivot atom) or of 1.5U eq (methyl). H atoms in methylene, vinylidene moieties and hydrogen atoms in aromatic rings were placed with C-H distances of 0.96 Å and 0.93 Å, and 0.86 Å for N-H bond.
The crude solid was separated by suction, dried and recrystallized from petroleum ether/chloroform mixture giving 7.8 g of white solid (33% yield) with mp 96-100 °C (ref. [8] reports 99-100 °C). Proton NMR spectrum is in accordance with ref. [8] Method B: A three-necked flask fitted with a dropping funnel, reflux condenser and thermometer was charged with 85% formic acid (8 mL, 180 mmol). After cooling the solution to 5 °C, triethylamine (2.7 mL, 27 mmol) was added dropwise maintaining the temperature below 10 °C. Subsequently, 2-bromobenzaldehyde (7a, 5 g, 27 mmol) and Meldrum´s acid (3.9 g, 27 mmol) were added to the solution and the mixture was refluxed for 4 h. Afterwards the mixture was cooled to an ambient temperature and poured onto ice-cold water (30 mL). The resulting suspension was acidified by 5.5M HCl until pH ≈ 1 and stored in a refrigerator overnight. The precipitated crystals were filtered with suction, washed with water (3  20 mL), dried in desiccator and dissolved in chloroform (100 mL). Undissolved impurities were filtered off. The filtrate was concentrated to the volume of about 10 mL and petroleum ether (15 mL General procedure for the synthesis of -diketones 4a-h A three-necked flask (100 mL) fitted with a dropping funnel and reflux condenser was charged with 1.1-2 equivalents of the base (see details at individual compounds). The apparatus was evacuated and backfilled with argon three-times. Subsequently, the base was suspended in anhydrous THF (20 mL). In the case of using a toluene solution of t-AmOK as the base the empty apparatus was 3 evacuated and backfilled with argon and the solution of the base was thereafter added via syringe. After homogenization of the mixture by intensive stirring (in the cases of using solid t-BuONa or t-BuOK, resp.), the solution of the ketone 6 (8.5 mmol) in S12 anhydrous THF (8 mL) was added dropwise during 10 min. The mixture was then stirred for 30 min. at room temperature.
Afterwards, the solution of the ester 5 (8.5 mmol) in anhydrous THF (8 mL) was added dropwise during 15 min. The reaction mixture was then stirred over 1-2 nights (see details at individual compounds) at room temperature under argon atmosphere.
Subsequently, saturated aqueous NH 4 Cl (15-40 mL, depending on the amount of the base) was added into the reaction mixture, the organic layer was separated and the aqueous layer was extracted with EtOAc (3  35 mL). The organic layers were combined, washed with saturated aqueous NaHCO 3 (2  35 mL) and brine (1  35 mL) and dried over anhydrous sodium sulfate. The volatile components were evaporated under reduced pressure. The residue was subjected to purification either through Cu 2+ complex (the procedure published in [13] was adopted, for details vide infra) or chromatography or recrystallization (see details at individual compounds).

Purification of crude -diketones through copper-diketonate complex
To a solution of crude β-diketone (9 mmol) in EtOH (3.6 mL), the solution of CuCl 2 ·2H 2 O (0.77 g, 4.5 mmol) in EtOH (7.7 mL) was added. A solution of NaOH (0.36 g, 9 mmol) in water (2 mL) was added dropwise. After 30 min. of stirring the pH of the solution was 6-7 and the green-gray precipitate of Cu 2+ complex was formed, filtered off, washed three-times with EtOH and dried on the air. The dried complex was dissolved in diluted (1:9) H 2 SO 4 (7 mL) and DCM (5 mL) and stirred for 1.5 h at 60 °C. The mixture was cooled down and extracted with DCM (3  20 mL). The combined organic layers were dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.

S13
The following compounds were prepared using the above-mentioned procedure:
Purification: the product was precipitated from the residue by EtOH in an ultrasonic bath and isolated by suction. Another part of the product can be obtained by evaporation of ethanol and subjecting the residue to a column chromatography (silica gel DCM).   The pure products were isolated by a column chromatography, precipitation from the crude mixture or recrystallization (see details at individual compounds).
The following compounds were prepared according to the above-mentioned protocols:        Method C: An oven-dried vial equipped with magnetic stir bar and fitted with a Teflon septum was charged with CuI, ligand, base and substrate 3a (for details see Table 1, Entries 6-9). The vessel was 3 evacuated and backfilled with argon. Subsequently dry toluene (5 mL) was added via syringe and the mixture was heated at 100 °C for 18-20 h. The mixture was cooled and transferred into a separatory funnel. Conc. aqueous ammonia (1 mL) was then added together with EtOAc (5 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (3  5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo.
The following compounds were prepared using the above-mentioned procedures: