Flexible access to 2,3,5,6-tetrasubstituted dehydropiperidines by Ni- or Co-catalyzed site-selective cross-coupling using Vilsmeier-Haack-derived α-chloro-β-formyltetrahydropyridines

Modular synthesis and transition metal-free alkynylation/alkenylation of Castagnoli–Cushman-derivedN,O- andN,S-heterocyclic vinyl chlorides

“…We initiated studies toward the transition metal-free coupling of N,O-and N,S-heterocyclic vinyl chlorides by attempting to nd general Vilsmeier-Haack conditions for preparing precursor 4. In the event, we found that under reaction conditions analogous to those previously optimized on the more stable piperidine system, 24 morpholinones bearing electronrich-, electron-neutral-and electron-decient N-aryl substituents as well as alkyl and benzyl substituents underwent productive lactam-selective Vilsmeier-Haack functionalization (Scheme 1). In all cases, satisfactory yields were obtained (see 4a1-4a18).…”

“…In all cases, satisfactory yields were obtained (see 4a1-4a18). As we have previously noted, 24 the silica/Et 3 N system employed in these studies for mild hydrolysis of the intermediate chloromethylene iminium salts is desirable given that the use of conventional bases such as NaOH, KOH or NH 4 OAc led to poor yields, undesirable epimerization, and ring-opened side products.…”

“…With an assorted wardrobe of N,O-and N,S-heterocyclic vinyl chlorides in hand, we next sought efficient conditions for transition metal-free a-alkynylation. Despite the many merits of transition metal-catalyzed coupling of inert substrates of this class, 24 one of our objectives was to avoid the drawbacks, including toxicity, cost, need for substrate-dependent designer ligands, and risk of product contamination. We also desired to utilize a sustainable solvent as the reaction medium for the alkynylation.…”

Introducing a sulfone-embedded anhydride to the anhydride-imine reaction for the modular synthesis of N-heterocyclic sulfones bearing vicinal stereocenters

“… 33 We were therefore pleased to find that Ni-catalyzed coupling of iodoarylated sulfones 8a10 and 8a16 with terminal alkynes proceeds smoothly to afford the alkynylated sulfones depicted in Scheme 5 (see 14a–e). These directing group-free 34 conditions employ Cs 2 CO 3 as the base and 1,4-dioxane as the reaction medium. The copper co-catalyst, CuI, is desirable seeing as the reaction does not proceed under copper-free conditions.…”