Photoredox‐Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition–Polar Cyclization Cascade

Abstract Photoredox‐catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single‐electron transfer induced deboronative radical addition to an electron‐deficient alkene followed by single‐electron reduction and polar 4‐exo‐tet cyclization with a pendant alkyl halide. Key to the success of the methodology was the use of easily oxidizable arylboronate complexes. Structurally diverse cyclobutanes are shown to be conveniently prepared from readily available alkylboronic esters and a range of haloalkyl alkenes. The mild reactions display excellent functional group tolerance, and the radical addition‐polar cyclization cascade also enables the synthesis of 3‐, 5‐, 6‐, and 7‐membered rings.


3
Melting points were recorded in degrees Celsius (°C), using a Kofler hot-stage microscope apparatus and are reported uncorrected.
Optical rotations ([α]D T ) were measured on a Bellingham and Stanley Ltd. ADP220 polarimeter and are quoted in (° mL)(g dm) -1 .

Photochemical Equipment and Setup
The blue LED lamps were either 40 W Kessil A160WE Tuna Blue LED Aquarium Lights (used with the colour dial turned fully anticlockwise and the intensity dial turned fully clockwise) or 40 W Kessil PR160-427 nm LED Photoredox Lights (used with the intensity dial set to 100).
All photoredox reactions were carried out at room temperature (r.t.). Fan assisted cooling was used to maintain this temperature.

Reaction set-up:
The reaction flasks were positioned 5 cm from a single 40 W Kessil LED lamp ( Figure S1).

General Procedures
General Procedure A (for reactions of alkyl boronic esters with iodide 7a, see Table 2): To a stirred solution of boronic ester (0.44 mmol, 1.1 equiv.) in THF (1.75 mL) under N2 at 0 °C was added phenyllithium (1.9 M in dibutyl ether, 0.48 mmol, 1.2 equiv.) dropwise. The solution was then stirred for 1 h at 0 °C, warmed to r.t. and stirred for a further 10 min before removing the solvent under vacuum. Degassed dry DMSO (5 mL) was added to the system. The mixture was irradiated with a 40 W Kessil LED lamp with fan cooling. A degassed solution of iodide-tethered alkene 7a (0.40 mmol, 1.0 equiv.) and 4CzIPN (5.0 mol%) in DMSO (3.0 mL) was added under irradiation. The N2 inlet was removed and the flask sealed with parafilm. The reaction mixture was stirred vigorously overnight (20 h) under constant irradiation. The reaction mixture was diluted with DCM (60 mL) and the solution washed with saturated aqueous NH4Cl (30 mL), water (30 mL) and brine (30 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography.
General Procedure B (for reactions of boronic ester 35 with halide-tethered alkenes, see Table 3): To a stirred solution of N-Boc-piperidine-4-boronic acid pinacol ester (35) (0.440 mmol, 137 mg, 1.1 equiv.) in THF (1.75 mL) under N2 at 0 °C was added phenyllithium (1.9 M in dibutyl ether, 0.48 mmol, 1.2 equiv.) dropwise. The solution was then stirred for 1 h at 0 °C, warmed to r.t. and stirred for a further 10 min before removing the solvent under vacuum. Degassed dry solvent (DMSO or DMF, 5 mL) was added to the system. The mixture was irradiated with a 40 W Kessil LED lamp with fan cooling. A degassed solution of the halide-tethered alkene (0.40 mmol, 1.0 equiv.) and 4CzIPN (2.0-5.0 mol%) in DMSO or DMF (3.0 mL) was added under irradiation. The N2 inlet was removed and the flask sealed with parafilm. The reaction mixture was stirred vigorously overnight (20 h) under constant irradiation. 5 The reaction mixture was diluted with DCM (60 mL) and the solution washed with saturated aqueous NH4Cl (30 mL), water (30 mL) and brine (30 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography. 6

Evaluation of Other Photoredox-catalyzed Deboronative Giese Protocols
Reaction without phenyllithium activation of 6: To a 7 mL vial equipped with a magnetic stir bar was added 2-cyclohexyl-4,4,5,5-tetramethyl-1,3,2dioxaborolane (6) (23 mg, 0.11 mmol, 1.1 equiv.), 4CzIPN (3.9 mg, 5.0 mol%) and anhydrous DMSO (0.05 M), followed by the iodide-tethered alkene 7a (25 mg, 0.10 mmol, 1.0 equiv.). The vial was sealed with a septum and the reaction mixture degassed by sparging with nitrogen for 10 min. The nitrogen inlet was removed, and the vial further sealed with parafilm. The reaction mixture was stirred at 800 rpm and irradiated with a 40 W Kessil LED lamp with fan cooling for 20 h. The reaction mixture was diluted with DCM (20 mL) and the solution washed with saturated aqueous NH4Cl (20 mL), water (2 × 20 mL) and brine (30 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. Yields were determined by 1 H NMR using diethyl phthalate as internal standard.
Reaction using the corresponding trifluoroborate salt: To a 7 mL vial equipped with a magnetic stir bar was added the potassium cyclohexyltrifluoroborate (21 mg, 0.11 mmol, 1.1 equiv.), 4CzIPN (3.9 mg, 5.0 mol%) and anhydrous DMSO (0.05 M), followed by the iodide-tethered alkene 7a (25 mg, 0.1 mmol, 1.0 equiv.). The vial was sealed with a septum and the reaction mixture degassed by sparging with nitrogen for 10 min. The nitrogen inlet was removed, and the vial further sealed with parafilm. The reaction mixture was stirred at 800 rpm and irradiated with a 40 W Kessil LED lamp with fan cooling for 20 h. The reaction mixture was diluted with DCM (20 mL) and the solution washed with saturated aqueous NH4Cl (20 mL), water (2 × 20 mL) and brine (30 mL). The resulting organic phase was dried (MgSO4), filtered and concentrated in vacuo. Yields were determined by 1 H NMR using diethyl phthalate as internal standard.
Reactions using previously reported deboronative Giese conditions: Submitting iodide-tethered alkene 7a to Akita and co-workers' optimized conditions for Giese reactions of trifluoroborate salts (Adv. Synth. Catal. 2012, 354, 3414) gave no desired product. This was also the case when using Ley and co-workers' optimized conditions for Giese reactions of Lewis base-activated pinacol boronic esters (Angew. Chem. Int. Ed. 2017, 56, 15136

Boronic Esters
The following boronic esters were purchased from commercial suppliers: The syntheses of the following boronic esters have been previously reported by our group: 2
The reaction mixture was heated to 100 °C for 24 h before cooling to r.t. and concentrating in vacuo.

HRMS (ESI
The carbon attached to boron could not be observed due to quadrupolar relaxation.  (Table 3)

Unsuccessful Substrates
During our studies, we found that halide-tethered alkenes bearing β-substitution (SI-1a and SI-2a) failed to undergo the desired radical addition-polar cyclization cascade with boronic ester 35.

Cyclic Voltammetry Measurement
Cyclic voltammograms were recorded using an Autolab potentiostat. The sample was prepared using 0.025 mmol of boronate complex 5 in 5 mL of a 0.1 M solution of N(nBu)4PF6 in dry, degassed MeCN.
Measurements used a glassy carbon working electrode, a platinum counter electrode, and a Ag/Ag + reference electrode with scan rates of 100 and 250 mV/s. Oxidation potentials were normalised to the ferrocene/ferrocenium redox couple and then converted to saturated calomel electrode (SCE) by adding 0.38 V. Figure S2. Cyclic voltammograms of boronate complex 5 in MeCN.

Anion Trapping Experiments
When the reaction of boronate complex 36 with iodide-tethered alkene 7a was performed in the presence of H2O a dramatic solvent effect was observed on the selectivity of the reaction. In MeCN, only Giese product 54 was observed (see entries 1-3, (54) To a stirred solution of N-Boc-piperidine-4-boronic acid pinacol ester (137 mg