Radical cyanomethylation via vinyl azide cascade-fragmentation

The cyanomethylation of radicals with a vinyl azide reagent is described, via a cascade-fragmentation mechanism.


General procedure A: cyanomethylation of radicals derived from bromides, chlorides and iodides
An 8 mL vial equipped with a PTFE septum and a magnetic stirrer bar was charged with the halide radical precursor (1.00 mmol), 3-azido-2-methylbut-3en-2-ol (1) (191 mg, 1.50 mmol) and photocatalyst (0.010 mmol). MeCN (5.0 mL) and then 2,6-lutidine (161 mg, 175 µL, 1.5 mmol) were added and the mixture was sparged with Ar for 10 min with stirring. After sparging was complete the septum was additionally sealed with paraffin film and the reaction was irradiated with a 60 W blue LED floodlight (5 cm away) for 4 h, with stirring and cooling from a small fan to maintain an ambient temperature. The mixture was partitioned between EtOAc (3 x 50 mL) and 1 N HCl (50 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with the solvents indicated to afford the cyanomethylated product.

General procedure B: cyanomethylation of radicals derived from Othiocarbamates
An 8 mL vial equipped with a PTFE septum and a magnetic stirrer bar was charged with the O-thiocarbamate radical precursor (1.00 mmol), 3-azido-2methylbut-3-en-2-ol (1) (191 mg, 1.50 mmol) and photocatalyst (0.010 mmol). MeCN (5.0 mL) was added and the mixture was sparged with Ar for 10 min with stirring. After sparging was complete the septum was additionally sealed with paraffin film and the reaction was irradiated with a 60 W blue LED floodlight (5 cm away) for 4 h, with stirring and cooling from a small fan to maintain an ambient temperature. The mixture was partitioned between EtOAc (3 x 50 mL) and 1 N HCl (50 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with the solvents indicated to afford the cyanomethylated product.

General procedure C: cyanomethylation of radicals derived from Nhydroxyphthalimido esters
An 8 mL vial equipped with a PTFE septum and a magnetic stirrer bar was charged with the N-hydroxyphthalimido ester (1.00 mmol), 3-azido-2methylbut-3-en-2-ol (1) (191 mg, 1.50 mmol), (+)-sodium L-ascorbate (297 mg, 1.5 mmol) and tris[5-fluoro-2-(2-pyridinyl-kN)phenyl-kC]iridium(III) Ir(5-Fppy) 3 (7.1 mg, 0.010 mmol). MeCN (5.0 mL) was added and the mixture was sparged with Ar for 10 min with stirring. After sparging was complete the septum was additionally sealed with paraffin film and the reaction was irradiated with a 60 W blue LED floodlight (5 cm away) for 4 h, with stirring and cooling from a small fan to maintain an ambient temperature. The mixture was partitioned between EtOAc (3 x 50 mL) and water (50 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. To aid with the removal of the phthalimide byproduct, crude products were suspended in hexanes or toluene as appropriate, filtered through a plug of cotton and the filtrate concentrated under reduced pressure.
x The residue was purified by silica gel flash column chromatography, eluting with the solvents indicated to afford the cyanomethylated product.

General procedure D: cyanomethylation of radicals derived from aryldiazonium tetrafluoroborates
An 8 mL vial equipped with a PTFE septum and a magnetic stirrer bar was charged with the aryldiazonium tetrafluoroborate (1.00 mmol) and 3-azido-2methylbut-3-en-2-ol (1) (191 mg, 1.50 mmol). MeCN (5.0 mL) was added and the mixture was sparged with Ar for 10 min with stirring. After sparging was complete, 2,6-lutidine was added drop-wise and the septum was additionally sealed with paraffin film and the reaction was stirred at rt for 4 h. The mixture was partitioned between EtOAc (3 x 50 mL) and 1 N HCl (50 mL) and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with the solvents indicated to afford the cyanomethylated product.

Images of LED experimental setup
Sparging xi

Reaction in progress
xii Substrate scope

Quantum Yield Measurements
The photon flux of the LED set up was determined by standard ferrioxalate actinometry, 28 following the procedure outlined previously by Yoon 44 and the calculations at λ = 455 nm by Xia. 45 Cuvettes were placed 10 cm from the LED light source.