Enantiospecific Three‐Component Alkylation of Furan and Indole

Abstract Furan‐ and indole‐derived boronate complexes react with alkyl iodides under radical (photoredox) or polar (SN2) conditions to generate three‐component alkylation products with high efficiency and complete stereospecificity. The methodology allows the incorporation of versatile functional groups such as nitriles, ketones, esters, sulfones, and amides, providing rapid access to complex chiral heteroaromatic molecules in enantioenriched form. Interestingly, while indolyl boronate complexes react directly with alkyl halides in a polar pathway, furyl boronates require photoredox catalysis. Careful mechanistic analysis revealed that the boronate complex not only serves as a substrate in the reaction but also acts as a reductive quencher for the excited state of the photocatalyst.

Oxidation Procedure A Iodine (265 mg, 1.00 mmol, 5.00 equiv.) and potassium acetate (195 mg, 2.00 mmol, 10.0 equiv.) were added to the reaction mixture under vigorous stirring conditions. The reaction mixture was stirred at r.t. until full conversion was achieved (as judged from TLC analysis), typically 10 -60 minutes. The reaction mixture was then diluted with EtOAc (150 mL) and washed with a 20% solution of sodium thiosulfate (50 ml), twice with water (100 mL + 4 mL brine to induce phase separation), and finally with brine (100 mL). The resulting organic phase i In case of volatile alkyl iodides (ethyl iodoacetate, iodoacetonitrile, perfluoroalkyl iodides), N2 sparging was performed on the photocatalyst solution prior to the addition of the alkyl halide under a nitrogen atmosphere.

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was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by FCC.
Oxidation Procedure Bonly for aryl ketones The reaction mixture was diluted with EtOAc (150 mL) and washed with water (100 mL + 4 mL brine to induce phase separation) and brine (100 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. The reaction crude product was transferred to a 50 mL flask, diluted with DMF (2.6 mL) and cooled down to -20 °C. To this solution, 550 μL of a sodium hypochlorite solution (>8% available chlorine) was added dropwise and the resulting solution was stirred until full conversion was achieved (as judged from TLC analysis), typically 10 -30 minutes. The reaction mixture was removed from the cold bath, and 40 mL of a saturated sodium thiosulfate solution (at r.t.) was quickly poured into the reaction mixture.
The mixture was then diluted with a 20% solution of sodium thiosulfate (50 ml) and extracted twice with EtOAc (2 x 80 mL). The organic phases were combined and washed twice with water (100 mL + 4 mL brine to induce phase separation), and finally with brine (100 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by FCC. 1.5 equiv.) in DMF (2.0 mL) was added quickly by syringe, and the mixture was stirred vigorously for 16 h. Oxidation procedures A (see previous section, reaction time was normally 60 minutes) or C were then carried out.

General Procedure for Indole Three Component Couplings
Oxidation Procedure C The reaction mixture was cooled down to 0 °C. 300 μL of an aq. 2M NaOH solution and 200 μL of an aq. solution of H2O2 (30% W/V) were simultaneously added dropwise to the reaction mixture under vigorous stirring and left at the same temperature for 1 hour. The reaction mixture was then diluted with EtOAc (150 mL) and washed with a 20% solution of sodium thiosulfate (50 ml), twice with water (100 mL + 4 mL brine to induce phase separation), and finally with brine (100 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by FCC.
The crude product was purified by FCC (n-hexane/EtOAc = 100/0 to 96/4) to afford the title compound 13j as a colourless oil in 71% yield (30 mg). The enantiomeric ratio was determined

Rf
Variable temperature NMR analysis was used to give insights into the origin of this phenomenon. As depicted in Figure S1 the two sets of signals were found to coalesce at 120 °C in DMSO-d6, suggesting that at 25 °C 14h is present in solution as two conformers (most likely originating from restricted rotation around C2-C1') that interconvert at a slower rate than the NMR timescale. In figure S1, the relevant section of the spectrum performed at 120 °C clearly shows a single set of signals for the three methyl groups within the menthyl moiety in 14h, indicating a d.r. >95:5.

Fluorescence Quenching Experiments
The emission spectra were recorded using a Varian Cary Eclipse fluorimeter, equipped with a Xenon pulse lamp, pulsed frequency 80 Hz, pulse width at half peak height ~ 2 µs, peak power equivalent to 75 kW. 2 mL of a 6.68·10 -4 M solution of Ru(bpy)3·6H2O in dry DMF (spectrophotometric grade) were placed in a Hellma ® fluorescence cuvette, 10x10 mm light S20 path Supersil ® quartz, equipped with PTFE lid. The solution was degassed through nitrogen sparging for three minutes, and analysed immediately. The excitation wavelength was fixed at 465 nm (incident light slit regulated to 10 mm), while the emission light was acquired from 515 nm to 700 nm (emission light slit regulated to 10 mm). For quenching data the emission wavelength was fixed to 615 nm. Different solutions, with different concentration of quencher were prepared and analysed following the procedure detailed above. The concentration of Ru photocatalyst was maintained constant, varying only the quencher concentration.   The excited state lifetime for Ru(bpy)3·6H2O in DMF at r.t. is τ0 = 912·10 -9 s. [8] From this data it is possible to calculate the bimolecular quenching constant (kq) using eq. (1). [9] eq. (1) kq = Ksv/τ0

Stern-Volmer Plot
The excited Ru(bpy)3·6H2O is quenched by boronate complex 2a with a bimolecular quenching constant kq = 1.98·10 9 M -1 ·s -1 , which is close to the diffusion limit, generally considered to be approximatively k0 ≈ 1·10 10 for small organic molecules in solution. [9] In conclusion, the Ru excited state is readily quenched by the boronate complex 2a while no interactions were observed with iodoacetonitrile 6a. These data strongly support the mechanism reported in Scheme 4.

Electrochemical Experiments
Cyclic voltammetry analyses were performed using a Basi Epsilon EC potentiostat.
Electrochemical grade tetrabutylammonium hexafluorophosphate (242 mg, 0.625 mmol) was added to a 6.25 mL, 4 mM solution of analyte (2a or 6a) in dry DMF and the solution was vigorously bubbled with argon for 5 minutes under stirring prior to the measurement. The stirring was then stopped, and the solution was allowed to reach quietness, after which the measure was carried out under an argon atmosphere. The anodic/cathodic peak potentials were measured using a glassy carbon working electrode, a platinum wire counter electrode, and a 3 M NaCl Ag/AgCl reference electrode at 200 mV/s scan rate using ferrocene as internal standard. The measurements are reported in graphs vs SCE, considering the conversion SCE = +420 mV Fc/Fc + . [10] Ep were obtained from the graphs as the potential corresponding to the maximum current observed. To better evaluate compounds' redox potential, Ep/2 were used [10] and measured as the potential corresponding to the half value of the maximum current intensity observed.

Quantum Yield Measurements
The quantum yield was measured for the reaction of furan with cyclohexylboronic acid pinacol ester (1a) and iodoacetonitrile (6a). The reaction was performed in a quartz cuvette (path length: l = 1.0 cm) positioned 5 cm away from a single 0.1 W blue LED (λmax = 450 nm).

Determination of the Photon Flux:
The photon flux of the LED setup was determined using standard ferrioxalate actinometry. [11] A 0.15 M ferrioxalate solution was prepared by dissolving 2.21 g of potassium ferrioxalate trihydrate in 30 mL of 0.05 M aq. H2SO4. A buffered phenanthroline solution was prepared by dissolving 50 mg of 1,10-phenanthroline 11.25 g of NaOAc•3H2O in 50 mL of 0.5 M aq.
H2SO4. Both solutions were stored in amber bottles in the dark.
Whilst working under red light, 1.0 mL of the 0.15 M ferrioxalate solution was added to a quartz cuvette (l = 1.0 cm). The cuvette was placed 5 cm from a single blue LED and irradiated for specific time internals of between 10 and 60 s. After irradiation, 0.50 mL of the 1,10phenanthroline solution was added to the cuvette. The mixture was left to stand for approximately 30 minutes before the absorbance at λ = 510 nm was measured by UV/Vis spectroscopy using a Perkin Elmer Lambda 25 UV/Vis Spectrophotometer. The absorbance of a non-irradiated sample was also measured.
The number of moles of Fe 2+ formed was calculated using: Where V is the total volume of the solution after the addition of 1,10-phenanthroline (0.0015 L), ΔA is the difference in absorbance at λ = 510 nm between the irradiated and non-irradiated ferrioxalate solutions, l is the optical path length of the irradiation cell (1.0 cm), and ε is the molar absorptivity of the Fe(phen)3 2+ complex at λ = 510 nm (11,100 L mol -1 cm -1 ).

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The moles of Fe 2+ were plotted as a function of time: The photon flux was then calculated using: Where Φ is the quantum yield of the ferrioxalate actinometer (1.0 at λ = 450 nm), [11a] (5 mL) before concentration in vacuo. The yield was determined by 1 H NMR using dibromomethane as an internal standard to be 24%. The reaction was repeated a second time, giving a yield of 23%. Average yield = 23.5%.
The quantum yield (Φ) was then calculated using:

Φ = mol product photon flux • t • f
Where t is the time (1200 s) and f is the fraction of light absorbed by the Ru(bpy)3Cl2 catalyst at λ = 450 nm (for a 6.7 x 10 -4 M solution in DMF, this was determined by UV/Vis spectroscopy to be 0.998).

Control Experiments for Indole Three Component Couplings
Procedure for the reaction carried out in the presence of 1,1-diphenylethylene