SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines—An Alternative to Cross‐Coupling with Saturated Heterocycles

Abstract

It's a SnAP! The transformation of aldehydes into N‐unsubstituted 3‐thiomorpholines provides a convenient alternative to metal‐catalyzed cross‐coupling reactions, which are generally unsuited to the functionalization of saturated N‐heterocycles. A copper‐mediated radical cyclization is the key to the mild conditions, high functional group tolerance, and broad substrate scope offered by these reagents.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…The most important recent breakthrough in the synthesis of morpholines is probably the stannyl amine protocol (SnAP) developed by the Bode group (Figure A) . In this method a SnAP reagent (2‐((tributylstannyl)methoxy)ethan‐1‐amine or derivatives thereof) is used to react with an aldehyde, followed by a radical‐based stoichiometric Cu II mediated cyclization.…”

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

“…The tolerance of these conditions towards heterocyclic carboxaldehydes containing heteroatoms in the ortho-position (6e-6h) is noteworthy as no product was observed with the previously reported stoichometric conditions using 1.0 equiv Cu(OTf)2. [3][4][5][6] The catalytic conditions were unfortunately not applicable to the formation of larger rings, such as diazepanes, which work well under stoichiometric conditions. Ketones also did not prove to be viable substrates under these conditions and afforded the desired spirocycles in low yields.…”

“…This operationally simple process provides facile, one-step access to C-substituted thiomorpholines, [3] morpholines, piperazines, [4] diazepanes and other medium-ring heterocycles [ 5 ] and spirocyclic structures ( Figure 1). [ 6 ] Many of these SnAP reagents are now commercially available and SnAP chemistry is finding widespread use in industry.…”

“…With HFIP as the sole solvent, we were able to reduce the catalyst loading to 5 mol % (entry13). [11] Based on literature precedents, [3,7,12] we attribute the beneficial effect of increased HFIP, a solvent of broad utility due to strong hydrogen-bond donor abilities, [12,13] The catalytic conditions provided morpholines and thiomorpolines from the corresponding SnAP reagents, giving the majority of products in excellent yields from aromatic, heteroaromatic, and branched aliphatic aldehydes. We were pleased to find that -unlike the stoichiometric variant -all regioisomers of pyridinecarboxaldehydes and related heteroaromatic aldehydes were excellent substrates, an outcome that we attribute to the superior ligand and increased amount of HFIP.…”

“…The need for stoichiometric copper is also at odds with our current mechanistic hypothesis, which postulates an overall redox neutral reaction. [3,5] We attributed the need for stoichiometric copper to product inhibition -a common obstacle for metal catalyzed reactions in which the products are more basic than the starting materials. [ 7 ] Second, aldehydes with proximal heteroatoms do not undergo cyclization.…”