Practical, metal-free remote heteroarylation of amides via unactivated C(sp3)–H bond functionalization

A simple and practical approach for the regioselective heteroarylation of amides via unactivated C(sp3)–H bond functionalization is described.


General experimental details
Commercially available reagents were used without further purification. Infrared (FT-IR) spectra were recorded on a BRUKER VERTEX 70, νmax in cm -1 . 1 H-NMR spectra were recorded on a BRUKER AVANCE III HD (400 MHz) spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl3: δ 7.26). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, br = broad, m = multiplet), coupling constants (Hz) and integration. 13 C-NMR spectra were recorded on a BRUKER AVANCE III HD (100 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 77. 16). 19 F-NMR spectra were recorded on a BRUKER AVANCE III HD (376 MHz)

General procedure for the C(sp 3 )-H heteroarylation of amides
Heteroarene 2 (0.2 mmol) and amide 1 (0.6 mmol) were loaded in a reaction vial without N2 atmosphere. Then DCE (2.0 mL) followed by PIFA (0.46 mmol) was added to the mixture. The reaction was irradiated with 2 x 50 W blue LEDs from 5 cm away and kept at 25 o C under fan cooling. After the reaction completion monitored by TLC, the mixture was neutralized by aq. KOH until pH > 8 and then extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed by brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (eluent: ethyl acetate/ petroleum ether) to give the desired products 3-5.
1y, 1z, 1ai are new compounds which were prepared according to the known procedures. [3]

General procedure for phosphoramides synthesis
To a stirred solution of amines (10 mmol) in THF (25 mL) was added triethylamine (21 mmol) at RT. Diphenylphosphinic chloride (12 mmol) or diphenyl chlorophosphate (12 mmol) in 25 mL of THF was added to the solution at 0 °C. After being stirred for 15 min at 0 °C, the reaction solution was allowed back to RT and stirred for overnight. The resulting mixture was cooled in ice bath, and diluted with CHCl3 and water. The product was extracted with CHCl3 and combined organic layer was washed by brine, 1 N HCl, sat. NaHCO3 and brine. The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/ MeOH = 95:5) to give the corresponding phosphinic amides or phosphoramidates. 8a, 8f are new compounds which were prepared according to the known procedures. [4] References: [1] T. Aubineau 13 13 13 28 (m, 1H). 13

Absorption and emission studies
Solutions of different complexes were introduced to a 1 cm path length quartz cuvette equipped with a Teflon® septum and analyzed using an Agilent Cary 5000 spectrophotometer.
For the solutions of benzenesulfonamide 1a and PIFA in DCE: 1a (0.3 mmol) and PIFA (0.23 mmol) were dissolved in DCE (2 mL). The mixtures were stirred for 5 min, then transformed to 1 cm path length quartz cuvettes, sealed with Teflon® septa and degassed with a stream of argon for 10 minutes.
For the solutions of PIFA in DCE: PIFA (0.23 mmol) were dissolved in DCE (2 mL). The mixtures were stirred for 5 min, then transformed to 1 cm path length quartz cuvettes, sealed with Teflon® septa and degassed with a stream of argon for 10 minutes.
A ferrioxalate actinometry solution was prepared by following the Hammond variation of the Hatchard and Parker procedure outlined in Handbook of Photochemistry. The actinometry solutions (1mL) were irradiated with 50 W blue LEDs (400±5 nm) for specified time intervals (0 sec, 20 sec, 40 sec, 60 sec, 80 sec and 100 sec). The UV-Vis spectra was shown in  Based on the data, we got the graph (Fig 2b) between the number of moles of products (y axis) and time (x axis). Then, photon flux was estimated to 3.78 x 10 -8 einstein S -1 by using K3[Fe(C2O4)3] as an actinometer.
Photon flux may be determined by: Photon flux = moles Fe 2+ Φ 510nm * t * F A plot of moles Fe 2+ as a function of time yields a linear equation with an intercept at zero. Division of the slope by the documented quantum yield of the actinometer (Φ = 1.14 at 405 nm) and the mean fraction of light absorbed by the ferrioxalate solution (F ~ 1 at 402 nm) provides the photon flux in einsteins s -1 .
The quantum yield is defined as: According to this relationship, the experiment procedure is as follows: For six clean tubes, according to the general procedure, the 0.1 mmol scale model reaction solution was irradiated with 50 W blue LEDs (400±5 nm) for specified time intervals (0 h, 1 h, 2 h, 3 h, 4 h and 5 h). The moles of products formed were determined by H-NMR yield with 1,3,5-trimethoxybenzene as reference standard. Based on the data, we got the graph (Fig.2c). The number of moles of products (y axis) per unit time is related to the number of photons (x axis, calculated from Photon Flux*Time). The slope gave the quantum yield (Φ) of the photoreaction, 0.048 (4.8%).