Switchable photocatalysis for the chemodivergent benzylation of 4-cyanopyridines

We report a photocatalytic strategy for the chemodivergent radical benzylation of 4-cyanopyridines. The chemistry uses a single photoredox catalyst to generate benzyl radicals upon N–F bond activation of 2-alkyl N-fluorobenzamides. The judicious choice of different photocatalyst quenchers allowed us to select at will between mechanistically divergent processes. The two reaction manifolds, an ipso-substitution path proceeding via radical coupling and a Minisci-type addition, enabled selective access to regioisomeric C4 or C2 benzylated pyridines, respectively. Mechanistic investigations shed light on the origin of the chemoselectivity switch.


C.1 Experimental set-up -Set-up 1: 3D printed reactor with blue LED strip
For reactions performed using a blue LED strip as the light source, a 3D-printed photoreactor was used, consisting of a 9 cm diameter crystallizing dish with a 3D printed support of 6 positions, and a hole of 22 mm in the middle to allow ventilation ( Figure S2, left). A commercial 1-meter LED strip was wrapped around the crystallizing dish, while a fan was used to cool down the reactor (the reaction temperature was measured to be 35-40 ºC). Each of the positions could be used to fit a standard 16 mm diameter vial with a Teflon screw cap. Experiments at 465 nm were conducted using a 1 m strip, 14.4 W "LEDXON MODULAR 9009083 LED, SINGLE 5050" purchased from Farnell, catalog number 9009083. The emission spectrum of these LEDs is shown in Figure S2, right panel.

C.2 General procedure (A): Ipso subtitution
Reactions performed using set-up 1 in Figure S2. In an oven dried vial with a Teflon septum screw cap, 2-alkyl N-fluorobenzamide 2 (0.1 mmol, 1 equiv.) was added and dissolved in 1,2-DCE (2 mL, synthesis grade solvent). Cyano-pyridine 1 (0.3 mmol, 3 equiv.), 4DPAIPN (photocatalyst A, 0.8 mg, 0.01 mmol, 0.01 equiv.), and DIPEA (52 µL, 0.3 mmol, 3 equiv.) were then added. The resulting yellow mixture was degassed with argon sparging for 60 seconds. The vial was irradiated under stirring for 16 hours, unless otherwise specified. Volatiles were evaporated and the residue purified by column chromatography on silica gel to afford the corresponding product in the stated yield with >95% purity according to 1 H-NMR analysis. The exact conditions for chromatography are reported for each compound.

C.4 General procedure (B): Minisci reaction
Reactions performed using set-up 1 in Figure S2. In an oven dried vial with a Teflon septum screw cap, 2-alkyl N-fluorobenzamide 2 (0.1 mmol, 1 equiv.) was added and dissolved in 1,2-DCE (2 mL, synthesis grade solvent). Cyanopyridine 1 (0.3 mmol, 3 equiv.), 4DPAIPN catalyst A (0.8 mg, 0.01 mmol, 0.01 equiv.), and PPh3 (79 mg, 0.3 mmol, 3 equiv.) were added. Finally, water is added (9 uL, 0.5 mmol, 5 equiv.). The resulting yellow mixture was irradiated under stirring for 12 hours. The mixture was transferred to an extraction funnel, saturated aqueous NaHCO3 was added and the organic layer was extracted with EtOAc. The organic layer was washed with brine twice. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue purified by column chromatography on silica gel to afford the corresponding product in the stated yield with >95% purity according to 1 H-NMR analysis. The exact conditions for chromatography are reported for each compound.

E.1 Optimization studies: Ipso substitution
All reactions performed under inert atmosphere using the illumination set-up 1 in Figure S2. Yield determined by 1 H NMR analysis of the crude mixture using trimethoxybenzene as the internal standard.  All reactions performed under inert atmosphere using the illumination set-up 1 in Figure S2. Yield determined by 1 H NMR analysis of the crude mixture using 1,3,5-trimethoxybenzene as the internal standard.

F. pH measurements
We measured the pH of the reaction mixture upon complete conversion of the both DIPEA-and PPh3-enabled processes. Upon reaction completion, 4 mL of H2O was added. The aqueous phase of the biphasic mixture was transferred to a clean vial. The pH was measured using a Mettler Toledo FG2-Kit FiveGo™ Portable pH Meter ( Figure S5). A sample for crude pH measurement was taken using standard pH universal indicator paper.
Ipso-substitution process of 1a and 2a to afford 3a enabled by DIPEA conditions as in entry 1 of Figure 2b in the main manuscript pH = 9.8 Minisci reaction of 1a and 2a to afford 3a enabled by PPh3 -water conditions as in entry 7 of Figure 2b in the main manuscript pH = 3.1 These measurements indicate that the C2-selective reaction operates under a typical Minisci mechanistic regime, whereby protonation of the N-heterocycle leads to radical addition at the C2 position. In contrast, the basicity of the aqueous solution derived from the reaction with DIPEA indicates that any protons generated during the process are quenched by the excess of DIPEA. This implies that protonation of the pyridine substrate is not feasible, and therefore a Minisci pathway is unavailable. Figure S5. pH measurements.

G.1 Proposed mechanism for the ipso substitution
Experimental evidence prompted us to propose the mechanism depicted in Figure S6, since product 3a is not formed when using quenchers other than tertiary amines (see Figure 2b in the manuscript). The mechanism would start with the reductive quenching of the photoredox catalyst A (4-DPAIPN) by DIPEA (see section J.1 for Stern-Volmer quenching studies). The SET event would generate a highly reducing catalyst PC n-1 (E 1/2 (PC/PC -) = -1.65 vs SCE) 11 capable of activating 4-cyanopyridine 1a (E ox (1a/1a •-) = -1.60 V vs SCE) 14 by SET reduction, leading to the radical anion I. The catalyst reductive quenching would also generate the radical cation of DIPEA, which is known to undergo rapid deprotonation to deliver an α-amino radical b. The latter intermediate b has recently been reported to be a good SET reductant. 15 In the context of this socalled reductant upconversion process, 16 17 Alternatively, reduction of the N-F bond of 2a could be achieved via an atom transfer mechanism (XAT), again from α-amino radical b. This event would afford an N-centered amidyl radical, which upon1,5-HAT would lead to the benzylic radical III. Radical-radical coupling between III and I, followed by decyanation, would deliver the desired product 3. Figure S6. Plausible mechanism for the ipso substitution pattern.

G.2 Probing α-amino radicals as SET reductants for N-F bond activation
The main feature of the mechanism proposed in Figure S6 is that the photocatalyst would reduce the cyanopyridine 1, while the transiently generated α-amino radical b would activate the N-F fluoramide 2. To gain evidence that the intermediate α-amino radical may perform the N-F bond reduction, we performed the mechanistic experiment detailed in Figure S7. This method, which is based on a protocol recently reported by Ritter and coworkers, 15 generates the α-amino radical in situ using a stoichiometric oxidant. Sodium persulfate is known to oxidize tertiary amines, delivering α-amino radicals. Treatment of the N-fluoroamide 2b with Na2S2O8 in the presence of DIPEA resulted in 20% of the corresponding hydrodefluorinated product 2b'. This result suggests that SET reduction of 2b by the α-amino radical b is feasible.
In addition, also the quantum yield measurement of the ipso-substitution (see section H.1 for details), which was found to be as low as 0.01, hints to a close catalytic cycle being operational, which is congruent with the mechanistic scenario depicted in Figure S6.

G.3 Minisci-type reaction, plausible mechanism
A plausible mechanism for the Minisci-type reaction is depicted in Figure S8.

G.4 Minisci reaction: probing the phopshoranyl radical as SET reductant for N-F activation
The main feature of the mechanism proposed in Figure S8 is that, upon reductive quenching of the photocatalyst by PPh3, the resulting phopshoranyl radical f would activate the N-F fluoramide 2. Recent studies reported that phopshoranyl radicals can serve as strong SET reducing agents (e.g., Eox (Ph3POMe + /Ph3POMe • ) = -1.63 vs SCE). 18 We surmised that, since SET reduction of 2b by a phosporanyl radical is thermodyanamically feasible, stoichiometric generation of such a radical should give the hydrodefluorinated amide 2b'. We therefore treated 2b with an excess of triphenylphosphine and persulfate as the stoichiometric oxidant in the presence of water. As shown in Figure 9, this control experiment afforded the reduced product 2b' in 40% yield. Figure S9. Benzyl radical generation upon SET from f.

G.5 Oxygen isotope experiment
Following the general procedure B, the standard Minisci reaction was performed using H2 18 O in place of H2O. The formation of labelled triphenylphosphine oxide was detected by HR-MS ( Figure S10). 19 Mols of Fe(II) = 1× 3× ∆ (510 nm)/10 3 × 2× × (510 ) (Eq. 1) where V1 is the irradiated volume (1 mL), V2 is the aliquot of the irradiated solution taken for the determination of the ferrous ions (1 mL), V3 is the final volume after complexation with phenanthroline (10 mL), l is the optical path-length of the irradiation cell (1 cm), ΔA(510 nm) is the optical difference in absorbance between the irradiated solution and the one stored in the dark, ε(510 nm) is the extinction coefficient the complex Fe(phen)3 2+ at 510 nm (11100 L mol -1 cm 1 ). The moles of Fe2+ formed (x) are plotted as a function of time (t). The slope of this line was correlated to the moles of incident photons by unit of time (q0 n,p) by the use of the following Equation 2: where dx/dt is the rate of change of a measurable quantity (spectral or any other property), the quantum yield (Φ) for Fe 2+ at 458 nm is 1.1, 21 [1-10 -A(λ) ] is the ratio of absorbed photons by the solution, and A(λ) is the absorbance of the actinometer at the wavelength used to carry out the experiments (460 nm). The absorbance at 460 nm A(460) was measured using a Shimadzu 2401PC UV-Vis spectrophotometer in a 10 mm path quartz cuvette, obtaining an absorbance of 0.182. q 0 n,p, which is the photon flux, was determined to be 4,14*10 -08 .

H.2 Minisci reaction
While the reaction mixture for the ipso substitution remains homogenous during irradiation, the Minisci reaction mixture becomes heterogenous and blurry upon irradiation. Light scattering prevented a precise quantum yield determination. In addition, the induction time observed in the kinetic studies reported in section I below further complicated our efforts to precisely measure the quantum yield of the C2-selectvie process.

I. Kinetic profile analyses
The kinetic profile of both the ipso-substitution and the Minisci reaction have been followed for 75 minutes. The two reactions have been conducted under inert conditions using the illumination set-up 2 in Figure S3. Product yield was determined by GC-FID analysis upon calibration with trimethoxybenzene as the internal standard. The three processes in Figure S14 has been analyzed: a) the DIPEA-enabled ipso-substitution; b) the PPh3-enabled Minisci reaction; c) and the same PPh3-enabled Minisci reaction adding TFA. As shown in Figure S15, the PPh3-enabled Minisci reaction (reaction b, red line) exhibits an induction period with low product 4m formation. After about 45 minutes, the reaction rate rapidly increases, reaching 62% yield after 75 minutes. The induction time is not observed when the Minisci reaction is performed in the presence of a catalytic amount of trifluoroacetic acid (TFA, reaction c, blue line). In contrast, the ipso-substitution reaction exhibits a slow but steady kinetic rate profile, delivering 5% of product after 75 minutes (reaction a, grey line).

J.2 Stern-Volmer quenching studies with PPh3
A 2M solution of PPh3 was added via Hamilton syringe in portions 5 µL, 10 µL, 20 µL, 40 µL and between each addition the fluorescence spectra was measured. The emission intensity was recorded at 527 nm. After each addition, an absorption spectrum and an emission spectrum of the solution were recorded. The excitation wavelength was fixed at 390 nm (incident light slit regulated to 2 mm); the emission light was acquired from 410 nm to 650 nm (emission light slit regulated to 2 mm).   The Stern-Volmer plot, reported in Figure S23, shows a linear correlation between the amounts of NF and the ratio I0/I. On the basis of the following Equation