The selective activation of sp3 carbon-hydrogen bonds in presence of multiple C¬-H bonds is challenging and remains of supreme importance in chemical research. Herein, we describe the activation of a C(sp3) H bond in α position to an amine via a carbanion intermediate. In the presence of several α amine sites, only one specific position is selectively activated. Applying this protocol, the proposed carbanion intermediate was effectively trapped with different electrophiles such as deuterium (D+), tritium (T+), or carbonyl compounds compiling over 50 examples. Further, this methodology was used to install deuterium or tritium in different drug derivatives (> 10 drugs) at a selected position in a late-stage functionalization. In addition, the protocol is suitable for a gram-scale synthesis and a detailed mechanistic investigation has been carried out to support our hypothesis.
Photoredox Catalyzed Site-Selective Generation of Carbanions from C(sp3)-H bonds in Amines
1. General information 2. Synthetic procedure 2.1 General procedure for the synthesis of starting materials (GP1) 2.2 General procedure for the synthesis of starting materials (GP2) 2.3 General procedure for the synthesis of starting materials (GP3) 2.4 General procedure for the photocatalytic deuterium labelling 2.5 General procedure for the photocatalytic tritium labelling 2.5 General procedure for the photocatalytic amino alcohol synthesis 2.6 General procedure for gram-scale reaction of deuterium labelling 2.7 General procedure for gram-scale reaction of amino alcohol synthesis 2.8 General procedure for N-PMP-deprotection 3. Reaction optimization 4. Mechanistic Investigation 4.1 UV-Visible spectra of photocatalyst and substrate 4.2 1H NMR of N-(4-methoxyphenyl)-N-methylglycinate and photocatalyst (3DPA2FBN) 4.3 Emission quenching studies 4.4 Mechanistic experiments 4.5 In situ NMR Kinetics 4.6 Cyclic Voltammetry measurement 5. Characterization of prepared compounds 6. NMR and HRMS spectra 7. References