General electrochemical Minisci alkylation of N-heteroarenes with alkyl halides

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of N-heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors. Primary, secondary and tertiary alkyl radicals have been shown to be efficiently generated and coupled with a large variety of N-heteroarenes. The method presents a very high functional group tolerance, including various heterocyclic-based natural products, which highlights the robustness of the methodology. This applicability has been further proved in the synthesis of various interesting biologically valuable building blocks. In addition, we have proposed a mechanism based on different proofs and pieces of electrochemical evidence.


General methods and starting materials
Starting materials 1a-h, 1k-1y, 2a-p as well as solvents for the reactions, were acquired from commercial sources (tetrahydrofuran was inhibitor free, water was tab water). Starting materials 1i, 1j and 10 were synthesized following a procedure described in the literature. 1 For thin layer chromatography (TLC), silica gel plates with fluorescence indicator 254 nm were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of potassium permanganate in water followed by heating. Flash column chromatography was performed using Geduran® Silica Gel 60 (0.040-0.063 nm). Cyclohexane, ethyl acetate, dichloromethane and methanol for flash chromatography were acquired from commercial sources and were used without previous purification. NMR spectra were acquired on a Bruker Avance 300 MHz spectrometer, running at 300 and 75 MHz for 1 H and 13 C, respectively. 19 F-NMR spectra were acquired on a Bruker Avance 500 MHz spectrometer, running at 471 MHz. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3, 7.26 ppm for 1 H-NMR and 77.2 ppm for 13 C-NMR). 13 C-NMR was acquired on a broad band decoupled mode. The following abbreviations are used to describe peak patterns when appropriate: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), bs (broad singlet), tt (triplet of triplets), td (triplet of doublets). Electrospray ionization has been used for measuring the exact mass (indicated for each case): MS (ESI) (Electrospray ionization mass spectroscopy) was acquired with an Agilent Technologies 6120 Quadrupole LC/MS. In this technique, MassWorks software ver. 4.0.0.0 (Cerno Bioscience) was used for the formula identification. MassWorks is a MS calibration software which calibrates for isotope profile as well as for mass accuracy, allowing highly accurate comparisons between calibrated and theoretical spectra. 2 S4 2. Optimization tables Table 1. Alkylation of 4-methylquinoline.

General procedure A: Alkylation of heteroaryl compounds
Diphenyl phosphate (25.0 mg, 1 equiv.), ammonium hexafluorophosphate (81.5 mg, 5 equiv.) and a magnetic stirrer were added to a 5 mL ElectraSyn vial. Reagents were dissolved in THF (2 mL) and to the stirred solution were added 1 (0.1 mmol) and 2 (5 equiv.), followed by water (1 mL). The vial was closed, reticulated vitreous carbon was used as working electrode and nickel foam as counter electrode, ElectraSyn 2.0 was set at constant current (10 mA) during 120 min.
The crude mixture was then diluted with ethyl acetate, extracted with saturated aqueous solution of NaHCO3 (2 x 5 mL), washed with brine (3 x 30 mL), dried over anhydrous MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography using silica gel and the eluent indicated in each case.

2-Cyclohexyl-4-methylquinoline (3a)
Following the general procedure A; 4-methylquinoline 1a (13.2 μL, 0.  Spectra data are consistent with those reported in the literature. 3 The reaction was scaled up to 1.0 mmol. Procedure A was followed using a 10 mL ElectraSyn vial as 6 mL of THF and 3 mL of water were used as solvents. The reaction was carried out at 10 mA for 16 hours. After workup and purification as described above, 3a (167 mg, 75% yield) was obtained as a slightly yellow oil.

General procedure B: Alkylation, allylation and benzylation of acridine
Acridine 1 (17.9 mg, 1 equiv.), ammonium hexafluorophosphate (82 mg, 5 equiv.) and a magnetic stirrer were added to a 5 mL ElectraSyn vial. Reagents were dissolved in 2 mL of THF (or Me-THF) and to the stirred solution were added trifluoroacetic acid (7.3 μL, 1 equiv.) and 2 (5 equiv.), followed by water (1 mL). The vial was closed, reticulated vitreous carbon was used as working electrode and zinc as counterelectrode, ElectraSyn 2.0 was set at constant current (10 mA) during 42 min. The crude mixture was then diluted with diethyl ether, extracted with saturated aqueous solution of NaHCO3 (2 x 5 mL), wahsed with brine (3 x 30 mL), dried over anhydrous MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash column chromatography using the eluent indicated in each case.

Cyclic Voltammetry
CVs were performed under argon atmosphere at room temperature, using 0.25 M tetrabutylammonium hexafluorophosphate (TBAPF6) solution in acetonitrile (CH3CN) as electrolyte. Measurements were carried out by using an Ivium CompaqStat potentiostat interfaced with a computer. A standard three-electrode electrochemical cell was used.
Potentials were referred to an Ag/AgCl, TBAPF6 0.4 M reference electrode in ethylene glycol, and measured potentials were calibrated using an internal Fc/Fc+ standard. The working electrode used to perform the experiments was a glassy carbon electrode. The counterelectrode consisted of a Pt electrode immersed in a conductive solution.