Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones

Abstract

Silicon amine protocol (SLAP) reagents for photocatalytic cross-coupling with aldehydes and ketones to form N-unprotected piperazines have been developed. This blue light promoted process tolerates a wide range of heteroaromatic, aromatic, and aliphatic aldehydes and structurally and stereochemically complex SLAP reagents. It provides a tin-free alternative to SnAP (tin amine protocol) reagents for the synthesis of substituted piperazines.

Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis

“…12 Previously, we could demonstrate that the combination of TPP and Bi(OTf) 3 as the Lewis acid additive were effective for the formation of a few morpholines from aldehydes and the SLAP M reagent 1 (see Supporting Information for batch experiments). 4 These were not general conditions, however, as they did not work well for heteroaromatic aldehydes and gave low yields when performed on larger scale.…”

Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic Photocatalyst

“…9 Photoredox catalysis has been instrumental in furthering this radical-based approach by enabling regulated radical generation under milder conditions. 10 Recent reports in this vein have accomplished the radical alkylation process elegantly and even with some degree of stereocontrol. 10a Although these methods furnish attractive diamines or amino alcohols, the focus of these strategies was on the installation of α-heteroatom-stabilized radicals.…”

Copper Promoted Oxidative Coupling of SnAP Hydrazines and Aldehydes to Form Chiral 1,4,5‐Oxadiazepanes and 1,2,5‐Triazepanes

“…However, the orbital overlap of the generated nitrogen‐centered radical with adjacent heteroatom renders this intermediate hydrazine radical more nucleophilic, making it more susceptible to be oxidized through abundant Cu(II) than reduced through the Cu(I) formed in the first step . Furthermore, we believe that a possible protonation of the intermediate hydrazine radical through HFIP negatively affects the oxidation needed to afford the desired product . ]…”

“…A number of modern methods are devoted to their construction and impressive progress in hydroamination, C–H functionalization, α ‐lithiation, or annulation methodologies have improved access to these structures. To this end, our group has introduced SnAP (Sn (tin) amine protocol) reagents, and SLAP (silicon amine protocol) reagents for the one‐step transformation of aldehydes and ketones to saturated, substituted, N‐unprotected aza‐heterocycles as thiomorpholines, morpholines, piperazines, piperidines, pyrrolidines, medium‐sized rings, and spirocycles. These processes tolerate a broad range of functional groups and are well suited to lead development and the preparation of libraries of saturated nitrogen heterocycles ( Fig .…”