Photoinduced Remote Functionalization of Amides and Amines Using Electrophilic Nitrogen Radicals

Abstract The selective functionalization of C(sp3)−H bonds at distal positions to functional groups is a challenging task in synthetic chemistry. Reported here is a photoinduced radical cascade strategy for the divergent functionalization of amides and protected amines. The process is based on the oxidative generation of electrophilic amidyl radicals and their subsequent transposition by 1,5‐H‐atom transfer, resulting in remote fluorination, chlorination and, for the first time, thioetherification, cyanation, and alkynylation. The process is tolerant of most common functional groups and delivers useful building blocks that can be further elaborated. The utility of this strategy is demonstrated through the late‐stage functionalization of amino acids and a dipeptide.


Available Acid Chlorides
Step 1) A solution of hydroxylamine (1.0 equiv.), DMAP (0.2 equiv.) and Et 3 N (2.0 equiv.) in CH 2 Cl 2 (0.2M) was cooled to 0 °C. The acid chloride (1.0 equiv.) was added dropwise and the reaction allowed to warm to room temperature overnight. The reaction was diluted with sat. NaHCO 3 and extracted with CH 2 Cl 2 (x 3). The combined organic layers were dried (MgSO 4 ), filtered and evaporated.
Step 2) The crude methyl ester was dissolved in MeOH-H 2 O (0.1 M, 16:1) and LiOH (5.0 equiv.) was added. The reaction was stirred and monitored by TLC analysis until no starting material was observed (4-24 h). The mixture was acidified with HCl (0.1 M) to pH < 2 and diluted with CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (x 3). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. The residue purified by column chromatography on silica gel eluting with petrol-EtOAc (9:1→1:1).
Step 2) The crude methyl ester was dissolved in MeOH-H 2 O (0.1 M, 16:1) and LiOH (5.0 equiv.) was added. The reaction was stirred and monitored by TLC analysis until no starting material was observed (4-24 h). The mixture was acidified with HCl (0.1 M) to pH < 2 and diluted with CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (x 3). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. The residue purified by column chromatography on silica gel eluting with petrol-EtOAc (9:1→1:1).

GP6 -General Procedure for Remote Functionalization i
A dry tube equipped with a stirring bar was charged with the starting material (0.1 mmol, 1.0 equiv.), the photocatalyst (2b, c) (5 µmol, 5 mol%), the base (0.1 mmol, 1.0 equiv.) and the SOMOphile (3a-e) (0.2 mmol, 2.0 equiv.) The reaction vessel was sealed, evacuated and back-filled with N 2 (x 3), then sealed with parafilm. The degassed solvent was added, the blue LEDs were switched on and the reaction was stirred under irradiation for the given amount of time. The mixture was diluted with H 2 O (1 mL) and EtOAc (1 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (x 2). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. The crude was purified by column chromatography on silica gel.
The two diastereomers were separated by column chromatography on silica gel.
The two diastereomers were separated by column chromatography on silica gel.

Emission Quenching Experiments
Emission intensities were recorded using a Steady State emission spectra were recorded on an Edinburgh Instrument FP920 Phosphorescence Lifetime Spectrometer equipped with a 5 watt microsecond pulsed xenon flash lamp and a 450 watt steady state xenon lamp and a red sensitive photomultiplier in peltier (air cooled) housing, (Hamamatsu R928P) spectrophotometer.
The 2b solutions were excited at 435 nm and the emission intensity was collected at 473 nm.
The 2c solutions were excited at 435 nm and the emission intensity was collected at 543 nm.

Experimental procedures:
A screw-top quartz cuvette was charged with a 1.6 x 10 -5 M solution of 2b in MeCN (2.0 mL) and the initial emission was collected then the appropriate amount of the quencher as a 1.6 x 10 -2 M solution in MeCN was added. The sample was shaken for 1 min and then the emission of the sample was collected.

Experimental procedures:
A screw-top quartz cuvette was charged with a 1.6 x 10 -5 M solution of 2c in CH 2 Cl 2 (2.0 mL) and the initial emission was collected then the appropriate amount of the quencher as a SI-47 1.6 x 10 -2 M solution in CH 2 Cl 2 was added. The sample was shaken for 1 min and then the emission of the sample was collected.
The quenching constants were obtained using the Stern-Volmer relationship:

Quantum Yield Determination
The quantum yield determination was performed following the procedure reported by Yoon [2] and are the average of two runs.

Computational Methods
Density functional theory (DFT) [3] calculations were performed using Gaussian 09 (revision E.01) [4] and the Gaussview [5] was used to generate input geometries and visualize output structures. Geometry optimizations and frequency calculations for the ring-opening and 1,5-H atom abstraction reactions, B3LYP functional [6] was used with the UB3LYP/6-31+G(d,p) basis set. [7] All stationary points were characterized as minima or transitions states based on normal vibrational mode analysis. Thermal corrections were computed from unscaled frequencies, assuming a standard state of 298.15 K and 1 atm.
Electronic properties of radicals, global and local electrophilicity index were calculated at the UB3LYP/6-311+G(d,p) level of theory, followed by frequency calculations at the same level. [8] Hirshfeld charges were also computed at the same level of theory. [9] For substrates having more than one conformations, low energy conformation of the transition state could possibly be different from the low energy ground state. [10] The structures described herein are the lowest energy-optimized conformers.