Aryl versus Alkyl Redox-Active Diazoacetates — Light-Induced C–H Insertion or 1,2-Rearrangement

Diazo compounds with redox-active leaving groups are versatile reagents for orthogonal functionalizations, previously utilized in the Rh-catalyzed synthesis of highly substituted cyclopropanes. Photochemical activation of aryl-substituted diazoacetates generates carbenes, whereas redox-active esters can furnish C-radicals via the photoexcitation of EDA complexes. However, the photochemical behavior of these two functionalities, while present in one molecule, remains to be defined. We demonstrate that under light irradiation, reactions occur only on the diazo moiety, leaving the NHPI functionality intact. Not only aryl- but also alkyl-substituted NHPI diazoacetates are activated by blue light; either C–H insertion or the hydrogen/carbon 1,2-rearrangement occurs depending on the aryl/alkyl group.


GENERAL INFORMATION
All solvents and commercially available reagents were purchased from Sigma-Aldrich, TCI, Acros Organics as reagent grade and were used without further purification, unless otherwise stated.
Dry solvents were taken from Solvent Purification System (SPS) or purchased from Sigma Aldrich.
Deuterated solvents used were purchased from Eurisotop.
All the photochemical reactions were performed in 10 mL glassy vials sealed with aluminum caps containing a rubber septa. Reactions were monitored by thin layer chromatography (TLC), using 0.20 mm Merck silica plates (60F-254) and visualized using UV-light, potassium permanganate, cerium molybdate or anisaldehyde stain, with heat as a developing agent. Unless otherwise noted, reactions were performed without the exclusion of air or moisture. Colum chromatography was performed on Merck silica gel 60 (230-400 mesh). All yields determined by 1 H NMR analysis were obtained using 1,3,5-trimethoxybenzene as the internal standard. Isolated yields refer to spectroscopically ( 1 H NMR) homogeneous materials. UV-Vis absorption spectra were recorded on UV-3600i Plus UV-Vis-NIR Spectrophotometer.
Fluorescence measurements were performed on Edinburgh Instruments FS5 Spectrofluorometer.
GC-MS analyses were performed using Shimadzu GCMS-QP2010 SE gas chromatograph with FID detector and Zebron ZB 5MSi column.

Constructed photoreactor setup with an aluminum cooling block
The LED plates are commercially available radiators (Fischer Electronic part no. SK 105 100 SA) with 6 epoxy-glued star-cased 3 W LEDs connected in series (constant current 0.7 A power supply).
Reactions were performed under blue light irradiation on a single diode (LT-2855 royal blue, λmax: 446 nm, 7W) per vial with 6 mm distance from the plate. The temperature of LED block was controlled with Huber MiniChiller 300 (T= 29-31 °C) ( Figure S1). Figure S1 -Constructed photoreactor setup with an aluminum cooling block

UOSlab Miniphoto photoreactor -Commercially available
Blue (maximum at 450 nm) light was supplied to each reaction vial with the use of 7 LUMINUS LED units (of overall 25 W intensity for 100% power applied). The temperature of LED block was controlled with Huber MiniChiller 300. photoreactor chiller S6

SYNTHESIS OF REDOX-ACTIVE NHPI DIAZOACETATES
Strategy for the synthesis of NHPI Diazoacetates

General procedure for the synthesis of Glyoxylic acid intermediates (GP1)
To a 100 mL round-bottom flask containing a solution of diethyl oxalate (1.46 g, 10 mmol) in dry Et2O (50 m) was added a solution of alkylmagnesium chloride (11 mmol, 1.1 equiv., 1.3 M in ether) dropwise over a period of one hour at -78° C. The mixture was stirred at -78 °C for the next 1.5 h and then poured into a vigorously stirred solution of cold water (40 mL), diethyl ether (50 mL) and concentrated HCl (9 mL). The aqueous phase was separated, and the organic phase was washed with water (50 mL), dried over Na2SO4, filtered, and concentrated to furnish viscous oil. To the 25 mL round-bottom flask with the crude from the previous step was added water (4.0 mL), then solution was cooled to 0 °C. Next, LiOH (470 mg, 20 mmol, 2 equiv.) was added in portions, then the reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with 2N HCl aqueous solution (14 mL) and extracted with Et2O (2x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to furnish glyoxylic acid derivative, which was used in the next step without further purification.

st step
To 25 mL round-bottom flask were added the glyoxylic acid derivative (6.3 mmol, 1.0 equiv.) and water (6.3 mL). The solution was heated to 60 °C and then p-toluenesulfonyl hydrazine (1.17 g, 6.3 mmol, 1.0 equiv.) was added in portions 2 portions over 5 minutes. Next, an aqueous solution of HCl (3.2 mL, 7.9 mmol, 2.5 M) was added dropwise and the reaction was stirred for another 30 minutes. A white precipitate formed* 1 and the reaction mixture was cooled down to room. The white solid was filtered off and washed with cold water. After drying overnight under vacuum, pure N-tosylhydrazone was then submitted to the next step without purification.

nd step
To 150 mL round-bottom flask containing the N-tosylhydrazone (6.3 mmol) was added DCM (45 mL) under argon atmosphere. The solution was cooled to 0 °C with an ice-water bath, DMF (19.5 µL, 0.25 mmol, 0.04 equiv.) was added, followed by the dropwise addition of oxalyl chloride (0.65 mL, 7.4 mmol, 1.2 equiv.) over 30 min (Caution: gas extrusion). The reaction was then allowed to warm-up to room temperature and was stirred overnight at room temperature. After that time, the crude reaction mixture was concentrated under vacuum furnishing a brown oil that was submitted to the next step. The solution of the crude in dry DCM (32.0 mL) was cooled down to 0 °C in an ice-water bath, then a briefly sonicated solution of N-hydroxyphtalimide (12.6 mmol, 2.0 equiv.) and 2,6-lutidine (2.2 mL, 19 mmol, 3.0 equiv.) in dry DCM (16.0 mL) was added dropwise over a period of 15 min. The reaction was then allowed to warm-up to room temperature and then was stirred overnight at room temperature. After this period, the crude reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel) using hexanes/ethyl acetate, gradually from 98:2 to 85:15 Hex/EA to afford the final product as a yellow solid.
*When the precipitate did not form after 30 min, the reaction mixture was cooled down and extracted with DCM (3 x 15 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated to furnish the Ntosylhydrazone in quantitative yield as a viscous oil.

General procedure for C-H insertion (GP3)
A glass vial equipped with a stirring bar was charged with NHPI diazoacetate 3a (31 mg, 0.1 mmol), then sealed with an aluminum cap with a rubber septum. Dry DCM (0.5 mL) and cyclohexane (0.5 ml) were added into the vial under the argon atmosphere, followed by the oxygen removal from the solution by freeze-pump-thaw technique. The reaction vial was placed in a photoreactor and was irradiated with blue LED (450 nm, 7 W) for 16 h. After that time, the crude reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel) using hexanes/ethyl acetate to afford the final product.

General procedure for O-H insertion (GP5)
A glass vial equipped with a stirring bar was charged with NHPI diazoacetate 3a (31 mg, 0.1 mmol) and benzoic acid (24.4 mg, 0.2 mmol, 2.0 equiv) then sealed with an aluminum cap with a rubber septum.
Dry DCM (1.0 mL) was added into the vial under the argon atmosphere, followed by the oxygen removal from the solution by freeze-pump-thaw technique. The reaction vial was placed in a photoreactor and was irradiated with blue LED (450 nm, 7 W) for 16 h. After that time, the crude reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel) using hexanes/ethyl acetate to afford the final product.