High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

The pseudo-five-component reaction between β-dicarbonyl compounds (2 molecules), diamines and α-iodoketones (2 molecules), prepared in situ from aryl ketones, was performed efficiently under mechanochemical conditions involving high-speed vibration milling with a single zirconium oxide ball. This reaction afforded symmetrical frameworks containing two pyrrole or fused pyrrole units joined by a spacer, which are of interest in the exploration of chemical space for drug discovery purposes. The method was also extended to the synthesis of one compound containing three identical pyrrole fragments via a pseudo-seven-component reaction. Access to compounds having a double bond in their spacer chain was achieved by a different approach involving the homodimerization of 1-allyl- or 1-homoallylpyrroles by application of cross-metathesis chemistry.


Experimental details and NMR spectra
4.-Preparation of compounds 12 by cross-metathesis reactions S11 5.-Copies of 1 H, 13 C and 19 F NMR spectra S13

General experimental details
All reagents (Aldrich, Fischer, Alpha Aesar) and solvents (Scharlau, Fischer) were of commercial quality and were used as received. Mechanochemical reactions were carried out in a Retsch MM200 mixer mill at a frequency of 20 Hz using a 25 mL zirconium oxide grinding jar and a single zirconium oxide ball 20 mm in diameter. Reactions were monitored by thin layer chromatography on aluminium plates coated with silica gel and fluorescent indicator (Macherey-Nagel Xtra SIL G/UV 254 ). Separations by flash chromatography were performed on silica gel (Scharlau 40-60 μm, 230-400 mesh ASTM). Melting points were determined using a Stuart Scientific apparatus, SMP3 Model, and are uncorrected. Infrared spectra were recorded with an Agilent Cary630 FTIR spectrophotometer with a diamond accessory for solid and liquid samples. NMR spectroscopic data were recorded using a Bruker Avance 250 spectrometer operating at 250 MHz for 1 H NMR and 63 MHz for 13 C NMR (CAI de Resonancia Magnética Nuclear, Universidad Complutense); chemical shifts are given in ppm and coupling constants in Hertz. High-resolution mass spectra (HRMS) were recorded on a mass spectrometer fitted with an electrospray detector (ESI) by the CAI de Espectrometría de Masas, Universidad Complutense. Elemental analyses were determined by the CAI de Microanálisis Elemental, Universidad Complutense, using a Leco 932 combustion microanalyzer.

General procedure for the synthesis of symmetrical bispyrrole derivatives 1 under solvent-free high-speed vibration milling (HSVM) conditions
The suitable ketone (1 mmol), N-iodosuccinimide (NIS, 1 mmol) and ptoluenesulphonic acid (PTSA, 10 mol %) were added to a commercially available snap closure grinding jar, along with a zirconium oxide ball. This ball mill vessel was fitted to one of the horizontal vibratory arms of the ball mill, while the other arm was occupied with an empty vessel. The ball mill was set to vibrate at a frequency of 20 s −1 for 60 min at room temperature. Then, a mixture of the corresponding diamine (0.85 mmol), the suitable -dicarbonyl compound (1.3 mmol) and cerium(IV) ammonium nitrate (CAN, 0.13 mmol) in 0.5 mL of methanol was stirred at room temperature during 30-60 min (judged by TLC), and the solvent was evaporated. The residue was transferred to the milling vessel with a Pasteur pipette or a spatula and silver nitrate (1 mmol) was added. The reaction was subjected to the vibratory movement at 20 s −1 for 60 min, affording a dark paste. Then, the reaction vessel was cleansed with ethyl acetate or dichloromethane and the suspension was filtered to remove the silver iodide precipitate. The organic layer was washed with water (2 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with a gradient from petroleum ether to 8:2 petroleum ether-ethyl acetate afforded the desired pyrrole derivatives. Compounds 1h, 1i and 1j were purified by flash chromatography eluting with a 98/2 dichloromethane/methanol mixture.
For the synthesis of compounds 1d, 1g, 1j, 1l, 1m, 1o, -iodoketones were prepared in a separate step, according to the procedure described below. These iodides were known in the literature. 1 To a solution of the suitable ketone (1 equiv) in anhydrous methanol, iodine (1 equiv) and cupper(II) oxide (1 equiv) were added. The mixture was stirred at room temperature for 5 min and, then, refluxed until no starting material was detected by TLC. The reaction was cooled, filtered and the solvent was removed. The residue was dissolved in ethyl acetate (10 mL) and washed with a 10% solution of Na 2 S 2 O 3 (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. 2 The -iodoketones thus obtained were used in the next reaction without further purification.

General procedure for the synthesis of pyrrole derivatives 11 under solventfree high-speed vibration milling (HSVM) conditions
The suitable -iodoketone (0.5 mmol), prepared following procedure described in page S3, and a mixture of amine (1 mmol), the suitable -dicarbonyl compound (0.75 mmol) and cerium(IV) ammonium nitrate (CAN, 5 mol %), previously stirred at room temperature during 30/60 min, and silver nitrate (0.5 mmol) were added to the vessel. The reaction was subjected to the vibratory movement at the same frequency for 60 min. Then, the reaction vessel was cleansed with ethyl acetate or dichloromethane and the suspension was filtered to remove the silver iodide precipitate. The organic layer was washed with water (2 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with a gradient from petroleum ether to 8:2 petroleum ether-ethyl acetate afforded the desired pyrrole derivatives 11.
Compound 11b was prepared following the general procedure for compounds 1 (page S2).