Chemoselective bond activation by unidirectional and asynchronous PCET using ketone photoredox catalysts

The triplet excited states of ketones are found to effect selective H-atom abstraction from strong amide N–H bonds in the presence of weaker C–H bonds through a proton-coupled electron transfer (PCET) pathway. This chemoselectivity, which results from differences in ionization energies (IEs) between functional groups rather than bond dissociation energies (BDEs) arises from the asynchronicity between electron and proton transfer in the PCET process. We show how this strategy may be leveraged to achieve the intramolecular anti-Markovnikov hydroamidation of alkenes to form lactams using camphorquinone as an inexpensive and sustainable photocatalyst.


A. General Considerations
All manipulations were performed with the rigorous exclusion of air and moisture unless otherwise stated.Commercial reagents were stored in a N2-filled glovebox and used without further purification.All liquid reagents and deuterated solvents were degassed by three cycles of freezepump-thaw and stored over activated 3Å molecular sieves prior to use.All non-deuterated solvents were purified by the method of Grubbs and stored over activated 3Å molecular sieves. 1 Camphorquinone, tributylmethylammonium dibutyl phosphate, triethylamine, tetrabutylammonium chloride (TBACl) and potassium hydrogen fluoride (KHF2) were purchased from Sigma Aldrich.The Ir photooxidant, (

B. Synthesis of New Amide Precursors and Products
The known amide substrates were either purchased or prepared as previously described, 2 whereas the new ones were synthesized according to the procedures reported below.

Cyclohex-2-en-1-yl (4-(Bpin)phenyl)carbamate (13).
In a 20 mL scintillation vial equipped with a PTFE-coated stir bar, 2-cyclohexen-1ol (0.404 g, 4.08 mmol, 1.00 equiv) and triethylamine (1.75 mL, 12.7 mmol, 3.20 equiv) were combined and CH2Cl2 was added (2 mL).4-Isocyanatobenzeneboronic acid pinacol ester (1.00 g, 4.11 mmol, 1.00 equiv) was added as a solid and more CH2Cl2 (3 mL) was used to effect quantitative transfer.After stirring the yellow solution at room temperature for 18 h, an aliquot was removed, dried, and subjected to 1 H NMR analysis, which showed complete consumption of the starting materials.The sample was brought back and recombined with the reaction.Volatiles were removed from the solution in vacuo and the residual solid was redissolved with minimum CH2Cl2 and subjected to a chromatographic column (0 → 30% EtOAc in hexanes; the desired product elutes first).After removing the solvents in vacuo a white solid remained and was dried for 18 h.Yield after drying: 0.360 g (26%).

3-(4-(Bpin)phenyl)hexahydrobenzo[d]oxazol-2(3H)-one (8).
In the glovebox, compound 13 (0.176 g, 0.518 mmol, 1.00 equiv), camphorquinone (17.6 mg, 0.106 mmol, 0.200 equiv) and phenyl disulfide (12.4 mg, 0.057 mmol, 0.100 equiv) were combined as solids in a 20 mL scintillation vial containing a PTFE-coated stir bar.CH2Cl2 (5 mL) was added, the vial was capped, and sealed with electrical tape.The reaction was then brought outside the glovebox and irradiated using a Kessil A160WE Tuna Blue LED lamp under fan cooling.After 24 h, the reaction was brought back to the glovebox and an aliquot was retrieved for NMR analysis, which showed still the presence of starting material.More camphorquinone (13.0 mg, 0.08 mmol, 0.20 equiv) and phenyl disulfide (12.0 mg, 0.06 mmol, 0.10 equiv) were added to the reaction, which was stirred under blue LED for another 14 h.After that, another aliquot was retrieved and analyzed by 1 H NMR, which showed complete consumption of the starting material.The reaction had its volatiles removed and the residue was redissolved with minimum CH2Cl2.After that, the crude material was subjected to a chromatographic column (100% hexanes, 1 CV; 0 → 70% EtOAc in hexanes, 10 CV; 70% EtOAc, 2 CV).The volatiles were removed under reduced pressure, yielding a faint-yellow solid, which was further dried for 18 h.Yield after drying: 0.140 g (80%).
After 5 min, the reaction was removed from the ice bath and allowed to stir at room temperature for 2 h.After that, the volatiles were evaporated using a rotavap.To help remove most of the pinacol side-product, the crude material was redissolved with MeOH (10 mL) and water (5 mL) and the volatiles were evaporated.This process was repeated once more.To the resulting material, acetone (10 mL) was added to create a white cloudy suspension, which was stirred for 30 min.
After that, the reaction was filtered through a PTFE filter (0.45 µm) into a 20 mL scintillation vial.
To the stirring colorless solution, tetrabutylammonium chloride was added (0.166 g, 0.597 mmol, 1.00 equiv), immediately forming a white precipitate.The reaction was stirred at room temperature for 30 min, after which it was filtered through a small pad of silica.The silica was further washed with acetone (ca. 3 mL) and the resulting filtrate had its volatiles removed in the rotavap, resulting in a sticky colorless oil.Et2O (5 mL) was added to the crude material and stirred vigorously for 5 min.The supernatant was carefully removed with a pipette and the process was repeated once more with hexanes (5 mL).After pulling vacuum, a white solid remained, which was dried for a further 18 h.Yield after drying: 0.210g (68%).

Tetrabutylammonium trifluoro(4-(2-oxohexahydrobenzo[d]oxazol-3(2H)yl)phenyl)borate (12).
In the glovebox, compound 14 (0.206 g, 0.391 mmol, 1.00 equiv), camphorquinone (19.4 mg, 0.177 mmol, 0.500 equiv) and phenyl disulfide (16.0 mg, 0.073 mmol, 0.200 equiv) were combined as solids in a 20 mL scintillation vial containing a PTFE-coated stir bar.CH2Cl2 (5 mL) was added, the vial was capped, and sealed with electrical tape.The reaction was brought outside the glovebox and irradiated using a Kessil A160WE Tuna Blue LED lamp under fan cooling.After 24 h, the reaction was brought back into the glovebox and an aliquot was retrieved for NMR analysis, which showed complete consumption of the starting material.The reaction had its volatiles removed, CH2Cl2 (2 mL) and hexanes (5 mL) were added and the reaction was stirred vigorously for ca. 5 min, after which the supernatant was removed.To the crude residue, CH2Cl2 (3 mL) was added and the suspension was filtered through a silica plug.After washing the silica with more CH2Cl2 (3 mL), hexanes (3 mL) was added to the filtrate and the solution was stirred for 5 min.Then, the supernatant was removed and the orange sticky solid was dried for 18 h.Yield after drying: 0.150g (73%).

D. Single-Wavelength Kinetic Studies and Transient Absorption Spectroscopy
The nanosecond transient absorption (TA) spectroscopy setup was described previously in detail. 3A Quanta-Ray Nd:YAG laser (SpectraPhysics) provides 3 rd harmonic laser pulses at 355 nm with a repetition rate of 10 Hz and pulse width of ~10 ns (FWHM).A MOPO (SpectraPhysics) was used to provide tunable laser pulses in the visible region.Typical excitation energy was adjusted to ~4 mJ/pulse @460 nm.Solutions were prepared in the glovebox and placed through a 1.0 cm flow cell (Starna) with a peristaltic pump for spectral acquisition.To extract the rate constants for HAT (kH) and back reaction (kBR), we use the following rate equation to model the TA trace: As shown in Figure 4 (A B) of the main text, the signal at 430 nm is due to the amidyl radical exclusively, 4 therefore, the signal can be written as S430nm = ε[1´•] where ε = 4100 M -1 cm -1 is the extinction coefficient of the amidyl radical at 430 nm, determined from previous studies. 4

E. NMR Study of the Ground-State Association Between CQ and 1
Solutions of 1 (2 mM) and varying amounts of CQ (0, 20, 30, 40, and 50 mM) were prepared in anhydrous DCM-d2.The association constant (Ka) between CQ and 1 in DCM-d2 was determined using 1 H NMR spectroscopy by plotting [CQ]/Δδ against [CQ] and calculating Ka = slope/intercept, where Δδ = δ1 -δobs is the difference in chemical shifts of the N-H proton of 1 by itself (δ1) and 1 in the presence of added CQ (δobs). 4,5

F. Steady-State Stern-Volmer Studies
Fluorescence was monitored on a QM4 fluorometer (Photon Technology International).Different samples were obtained by sequentially diluting a stock solution of the quencher and photocatalyst with a solution containing only the photocatalyst and transferred into 1 cm quartz cuvettes (Starna) for measurement.Steady-state quenching studies were performed by using the peak phosphorescence intensity with excitation at 450 nm.Samples were exposed to air after the measurements in order to fully quench the phosphorescence.The resulting fluorescence spectrum was subtracted from the total emission spectra in order to obtain the phosphorescence-only spectra.

G. Photochemical CQ-and Ketone-Mediated Intramolecular Hydroamidation
A mixture of CQ (100 µL of a stock solution of 0.100 g CQ in 3 mL CD2Cl2, 0.02 mmol, 20 mol%), disulfide (0.01 mmol, 10 mol%), 1,4-bis(trifluoromethyl)benzene or 1,3,5-tris(trifluoromethyl)benzene as an internal standard, and amide substrate (0.10 mmol) was diluted with 0.88 mL CD2Cl2 to give a final concentration of 100 mM substrate.The reaction solution was transferred to a J-Young NMR tube, which was taken to the spectrometer to establish the starting ratio of substrate to internal standard.The reaction was then irradiated using a Kessil A160WE Tuna Blue LED lamp under fan cooling.After 24 h, the reaction yield was determined by 1 H NMR spectroscopy.

H. Quantum Yield Measurements
Determination of the photon flux at 467 nm.A 0.15 M solution of ferrioxalate was prepared by dissolving potassium ferrioxalate hydrate (2.210 g) in H2SO4 (30 mL of a 0.05 M solution).A buffered solution of 1,10-phenanthroline was prepared by dissolving 1,10-phenanthroline (0.050 g) and sodium acetate (11.25 g) in H2SO4 (50.0 mL of a 0.5 M solution).Both solutions were stored in the dark.To determine the photon flux of the LED (Kessil PR160-467nm), the ferrioxalate solution (3.0 mL) was placed in a cuvette and irradiated for 20 seconds at λmax = 467 nm.After irradiation, the phenanthroline solution (0.53 mL) was added to the cuvette and the mixture was allowed to stir in the dark for 1 h to allow for complete coordination of ferrous ions to the phenanthroline.The absorbance of the solution was measured at 510 nm.A non-irradiated sample was also similarly prepared, and its absorbance measured at 510 nm.The difference in absorbance between the irradiated solution and the dark solution (Δ) was calculated and used to determine the yield of Fe 2+ according to: where  is the total volume (0.00353 L) of the solution after addition of phenanthroline, Δ is the difference in absorbance at 510 nm between the irradiated and non-irradiated solutions containing added 1,10-phenantroline,  is the path length (1.00 cm), and ε is the molar absorptivity of the ferrioxalate actinometer at 510 nm (11100 L mol -1 cm -1 ).
The fraction of light absorbed (f) at 467 nm by pure ferrioxalate actinometer was calculated using equation ( 2 where Φ is the quantum yield of ferrioxalate actinometer at 467 nm and  is the time the actinometer was irradiated. Quantum yield measurement for hydroamidation of 1 with camphorquinone.A reaction mixture of 1 (0.148 g, 0.500 mmol), camphorquinone (17.2 mg, 0.103 mmol, 20 mol%), diphenyl disulfide (13.2 mg, 0.0604 mmol, ca. 10 mol%) and 1,4-bis(trifluoromethyl)benzene as an internal standard was dissolved in CD2Cl2 (5 mL).An aliquot (1 mL) was transferred to a J-Young NMR tube, which was taken to the spectrometer to establish the starting ratio of substrate to internal standard.The remaining solution (4 mL) was transferred to a cuvette containing a stir bar, which was caped, sealed with electrical tape and brought outside the glovebox to a darkroom.The reaction was then irradiated using a Kessil PR160-467nm LED lamp for 30 min.The reaction yield was determined by 1 H NMR spectroscopy against internal standard.The reaction quantum yield was measured using equation ( 4 Where  is the reaction time and ′ is the fraction of light absorbed by camphorquinone at 467 nm (calculated as in equation 2; A467nm = 0.85).

Figure S6. 1 H
Figure S6. 1 H NMR (400 MHz, CDCl3) spectrum for N-phenylacetamide-N-d (15).Inset shows the aromatic region for protic (bottom) vs deuterated (top) compounds.Red arrows indicate the disappearance of the N-H signal in the deuterated version.

Figure S7 .
Figure S7.Comparison of the IR spectra for proteo-acetanilide (▬ black trace) and Nphenylacetamide-N-d (▬ green trace) showing a redshift of the N-D stretching frequency relative to the N-H stretching frequency.

Figure S8 .
Figure S8.Electrochemical studies on CQ. (A) Cyclic voltammogram of 2 mM CQ in DCM with 0.1 M [TBA][PF6] as the supporting electrolyte.(B) Spectroelectrochemistry on 2 mM CQ in DCM with 0.1 M [TBA][PF6] as the supporting electrolyte in a 0.5 mm pathlength cell using a Pt mesh working electrode.

Figure S9 .
Figure S9.TA spectra of CQ (10 mM) and phenol (20 mM) in DCM showing the evolution from an initial spectrum dominated by CQ* (▬ orange trace) to one dominated by PhO• (▬ blue trace).λexc = 460 nm.

Figure S11. 1 H
Figure S11. 1 H NMR study of association between amide 1 and CQ.(A) Stacked 1 H NMR spectra showing the change in the amide N-H signal of 1 (marked by *) with varying concentrations of added CQ. (B) Plot of [CQ]/Δδ against [CQ] for solutions of 1 with varying amounts of CQ (black circle) and linear fit (solid line).

Figure S13 .
Figure S13.Time traces for the cycloamidation reaction.Time traces for the yield of cyclized product 4 (dashed lines) and % remaining of CQ (solid lines).Black traces are for the reaction performed with PhSSPh and red traces are with (TripS)2.

3 Figure S14 .
Figure S14.Photoredox intramolecular cycloamidation using various ketones as the photocatalyst.Yields as determined by1 H NMR spectroscopy are denoted in parentheses.*For ketones that absorb poorly in the visible region, a 370 nm LED light source (Kessil) was used in place of the standard blue LEDs.

Table S1 .
Correlation of the quenching rate (kq) of *CQ in DCM with different thermodynamic parameters of the quenchers.Calculated from the Stern-Volmer constant (KSV) using a value of τ = 30.6(0.1) µs for the lifetime of the CQ triplet state, as determined from time-resolved emission spectroscopy (see FigureS12for Stern-Volmer plots). a