Catalytic Synthesis of N‐Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents

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

“…In light of the fact that the oxidized hydrazone products 5 are isolated as sole products and based on our current mechanistic picture of the SnAP protocols as well as previous reports of copper mediated radical additions onto hydrazones, we continue to favor a radical mechanism for the overall transformation ( Scheme ). Initial Cu(II) mediated oxidation of the organotin species generates Cu(I) and a heteroatom stabilized carbon‐centered radical.…”

“…No special precautions were taken for the reaction set‐up, and all experiments were performed using identical conditions without substrate‐specific optimization. HFIP, an additive used in SnAP protocols involving the amino tin SnAP reagents, believed to activate the imines for radical additions, could be omitted without a decrease in isolated yields. An observation that we attribute to the well‐known characteristic of hydrazones as better radical acceptors than imines due to additional stabilization of the intermediate nitrogen centered radical through the lone pair of the adjacent heteroatom .…”

“…A salient feature of the general SnAP protocol is its high tolerance for functional groups; the cyclization with oxadiazepane reagent 1 is no exception. Electron‐rich, and electron‐poor aromatic ( 5a , 5d , 5e , 5i , 5j ), heteroaromatic ( 5m – 5p ), and aliphatic aldehydes ( 5h ) containing halides ( 5a , 5b ), esters ( 5k ), or nitriles ( 5l ) at various positions of the aromatic rings, all were excellent substrates ( Scheme ).…”

“…) . This is the first use of hydrazones, rather than imines, in SnAP chemistry and leads to oxidative cyclization – in contrast to overall redox neutral processes observed for all other examples . ]…”

“…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 .…”