Accelerated and Scalable C(sp³)-H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs

[Image: see text] Carbon–nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C–H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp(2))–H bonds, only few examples have been reported for the direct amination of aliphatic C(sp(3))–H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp(3))–H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines

EntF*-D15

molecular dynamics simulation of the EntF* peptide, residue 15 in D form -starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide -topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 -md settings md.mdp  time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.groframe rate 10 ps, water and ions removed, box centered on peptide -analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)

EntF*-D10

molecular dynamics simulation of the EntF* peptide, residue 10 in D form -starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide -topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 -md settings md.mdp time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)

EntF*-D1

Molecular dynamics simulation of the EntF* peptide, residue 1 in D form -starting coordinates posre.gro energy minimized and water+ions equilibrated around peptide -topology topol.top force field AMBER99SB-ILDB, TIP3P water protonation states at pH = 3 (E,K protonated) [NaCl] = 25 mM disulfide bond generated between residues 14 and 6 -md settings md.mdp time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files frame rate 1 ps radius of gyration, solvent accessible surface area (hydrophilic parts (backbone + hydrophilic side chains), hydrophobic parts (hydrophobic side chains)

EntF*-D12

molecular dynamics simulation of the EntF* peptide, residue 12 in D form -starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide -topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 -md settings md.mdp  time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.groframe rate 10 ps, water and ions removed, box centered on peptide -analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)

EntF*-D14

molecular dynamics simulation of the EntF* peptide, residue 14 in D form starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 md settings md.mdp: time step 2 fs, temperature = 298 K, pressure = 1 bar 1 microsecond trajectory dry.xtc, dry.groframe rate 10 ps, water and ions removed, box centered on peptide analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)

EntF*-D7

molecular dynamics simulation of the EntF* peptide, residue 7 in D form -starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide -topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 -md settings md.mdptime step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)

EntF*-D6

Molecular dynamics simulation of the EntF* peptide, residue 6 in D form -starting coordinates posre.gro energy minimized and water+ions equilibrated around peptide -topology topol.top force field AMBER99SB-ILDB, TIP3P water protonation states at pH = 3 (E,K protonated) [NaCl] = 25 mM disulfide bond generated between residues 14 and 6 -md settings md.mdp time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files frame rate 1 ps radius of gyration, solvent accessible surface area (hydrophilic parts (backbone + hydrophilic side chains), hydrophobic parts (hydrophobic side chains)

EntF*-D5

Molecular dynamics simulation of the EntF* peptide, residue 5 in D form -starting coordinates posre.gro energy minimized and water+ions equilibrated around peptide -topology topol.top force field AMBER99SB-ILDB, TIP3P water protonation states at pH = 3 (E,K protonated) [NaCl] = 25 mM disulfide bond generated between residues 14 and 6 -md settings md.mdp time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files frame rate 1 ps radius of gyration, solvent accessible surface area (hydrophilic parts (backbone + hydrophilic side chains), hydrophobic parts (hydrophobic side chains)

EntF*-D9

molecular dynamics simulation of the EntF* peptide, residue 9 in D form -starting coordinates posre.gro: energy minimized and water+ions equilibrated around peptide -topology topol.top: force field AMBER99SB-ILDB, TIP3P water, protonation states at pH = 3 (E,K protonated), [NaCl] = 25 mM, disulfide bond generated between residues 14 and 6 -md settings md.mdp time step 2 fs, temperature = 298 K, pressure = 1 bar -1 microsecond trajectory dry.xtc, dry.gro frame rate 10 ps, water and ions removed, box centered on peptide -analysis files: radius of gyration, solvent accessible surface area (hydrophilic (backbone + hydrophilic side chains), hydrophobic (hydrophobic side chains)