Photoinduced Remote Functionalisations by Iminyl Radical Promoted C−C and C−H Bond Cleavage Cascades

Abstract A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp3)−(sp3) and C(sp3)−H bond cleavage gives access to distal carbon radicals that undergo SH2 functionalisations. These mild, visible‐light‐mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.


cyclopenta[a]phenanthren-17-yl)hexan-2-one (S31)
A solution of lithocolic acid (0.5 g, 1.3 mmol, 1.0 equiv.) in THF (15 mL), cooled to 0 ºC and treated with MeLi (4.2 mL, 6.5 mmol, 5.0 equiv., 1.6 M in diethyl ether) by dropwise. The reaction mixture was stirred for 8 h at room temperature, and then quenched with TMSCl (6 mL). The crude was diluted with EtOAc (20 mL), washed with HCl 1M (20 mL) and water (20 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated. The crude was purified by column chromatography on silica gel, eluting with CH 2 Cl 2 -MeOH (95:5), to give S31 as an oil (290 mg, 60%). 1  Data in accordance with the literature. [ A solution of the ketone (1.0 equiv.) in MeOH (0.2 M) was treated with 1-carboxy-1methylethoxyammonium chloride (1.5 equiv.), anhydrous NaOAc (3 equiv.) and heated to reflux until complete by TLC analysis (1-6 h). The mixture was allowed to cool to room temperature and an aqueous K 2 CO 3 solution was added. The solution was extracted with Et 2 O and the organic layer washed with aqueous K 2 CO 3 solution (x 2). The combined aqueous extractions were then acidified with conc. HCl solution (30% H 2 O) and extracted with CH 2 Cl 2 (x 3). The combined organic fractions were dried (MgSO 4 ), filtered and evaporated.  In this case not all 13 C NMR signals could be assigned between the major (M) and the minor component owing to partial overlap.

General Procedure for the Reaction Optimization -GP5
A dry tube equipped with a stirring bar was charged with 1a (21 mg, 0.1 mmol, 1.0 equiv.), 2 (2 mg, 0.005 mmol, 5 mol%), the base (0.1 mmol, 1.0 equiv.), and the F-source (0.2 mmol, 2.0 equiv.). The reaction vessel was sealed, evacuated and back-filled with nitrogen three times, then sealed with parafilm. The solvent (0.5 mL) was added, the blue LEDs were switched on and the reaction was stirred under irradiation for the given amount time. H 2 O (1 mL), EtOAc (1 mL) and 1,3-Dinitrobenzene (4 mg, 0.025 mmol, 0.5 equiv.) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. CDCl 3 (0.4 mL) was added and the mixture was analysed by 1 H NMR spectroscopy to determine the NMR yield.
The optimum reaction conditions identified by this optimisation study were: The following  The optimum reaction conditions identified by this optimisation study were: The following

General Procedure for the Reaction Optimization -GP7
A dry tube equipped with a stirring bar was charged with 1a (21 mg, 0.1 mmol, 1.0 equiv.), 2 (2 mg, 0.005 mmol, 5 mol%), the base (0.1 mmol, 1.0 equiv.), and the azide source (0. The optimum reaction conditions identified by this optimisation study were: The following
The solvent (1 mL) was added, the blue LEDs were switched on and the reaction was stirred under irradiation, under a constant flow of nitrogen for the given amount of time. H 2 O (1 mL), EtOAc (1 mL) and 1,3-Dinitrobenzene (4 mg, 0.025 mmol, 0.5 equiv.) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. CDCl 3 (0.4 mL) was added and the mixture was analysed by 1 H NMR spectroscopy to determine the NMR yield.
The optimum reaction conditions identified by this optimisation study were: The following  The optimum reaction conditions identified by this optimisation study were: The following

General Procedure for the Reaction Optimization -GP10
A dry tube equipped with a stirring bar was charged with the oxime (1.0 equiv.), 2 (5 mol%),

General Procedure for the Reaction Optimization -GP11
A dry tube equipped with a stirring bar was charged with the oxime (1.0 equiv.), 2 (5 mol%),
The tube was sealed, evacuated and back-filled with nitrogen three times. CH 3

Quantum Yield Determination
The quantum yield determination was performed following the procedure reported by Yoon [19] and are the average of two runs.

Reaction
Quantum

Ring-Opening: DFT Reactivity Scales
The following radical ring-openings were not found experimentally successful: We have performed DFT studies aimed at determine the reaction parameters and reported them graphically in the following scales.

1,5-H Abstraction: DFT Reactivity Scales
The following 1,5-H abstraction were not found experimentally successful: We have performed DFT studies aimed at determine the reaction parameters and reported them graphically in the following scales.

Role of Ag(I) in the 1,5-H Abstraction Fluorination
We have performed preliminary mechanistic studies to understand the role of Ag(I) in the 1,5-H abstraction fluorination cascade. We propose that the Ag(I) species acts at as dual cocatalyst facilitating both the radical fluorination and the final SET reduction.

A)
Selectfluor is a strong oxidant (E red = +0.25 V vs SCE) [20] that can provide to formation of Ag(III)-F species. [21] B) Ag(III)-F species are known to be strong oxidants [21a] and we propose that they can close the photoredox cycle by direct SET with the reduced photoredox catalyst (B1) and can also sustain productive radical chain propagations by oxidation of the DABCO species S32 (B2) and/or the deprotonated oxime 6a (B3).

SI-87
C) This SET would deliver a Ag(II)-F species which is a very powerful radical F-transfer agent. [21a, 21c, 21d] In this way, following 1,5-H abstraction, the C-radical S35 would undergo F-transfer to give the product and regenerate the catalytically active Ag(I) species.
At this stage, the presence of multinuclear Ag-complexes [22] cannot be excluded.
In order to provide some evidence for this reactivity scenario we have run some control experiments with several Ag(I) sources. The successful formation of 8a in the presence of AgF 2 , with and without selectfluor, supports our proposed mechanistic picture.
The unsuccessful reaction outcome when using NFSI can be result by the fact that NFSI being a weaker oxidant than selectfluor, [21d] does not enable the efficient generation of the Ag(III)-F species to sustain the photoredox cycle and/or the productive radical chain pathways operating under our reaction conditions.
We have also evaluated the possibility of the 1,5-abstraction and fluorination to take place following oxidative fragmentation from the oxime. We feel this is not the case because when ketone S10 was exposed to identical reaction conditions, 8a could not be detected and S10 was quantitatively recovered.

Computational Methods
Density functional theory (DFT) [23] calculations were performed using Gaussian 09 (revision E.01) [24] and the Gaussview [25] 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 [26] was used with the UB3LYP/6-31+G(d,p) basis set. [27] 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. Representative transition states were also linked to their corresponding minima through the intrinsic reaction coordinate (IRC) [28] calculations, which confirm the connection of transition structures with the reactants and products. For substrates having more than one conformations, low energy conformation of the transition state could possibly be different from the low energy ground state. [