Construction of Pyranoisoquinolines via Ru(II)-Catalyzed Unsymmetrical Double Annulation of N-Methoxybenzamides with Unactivated Alkynes

Abstract

A ruthenium (Ru)-catalyzed double annulation of easily accessible N-methoxybenzamide derivatives with unactivated alkynes for the synthesis of unusual 6,6-fused pyranoisoquinolines is described. Both ortho-C–H bonds of arenes and the N- and O-moieties of N-methoxybenzamides are involved in the construction of four [(C–C)–(C–N) and (C–C)–(C–O)] bonds in one step under single catalytic conditions. The unsymmetrical annulation of N-methoxybenzamides with two distinct alkynes is also demonstrated. The oxidizable directing group N-methoxyamine (NHOMe) assists the unsymmetrical double annulations of arenes [that use both N- and O-heteroatoms] in a single operation. This synthetic method features excellent substrate scope and tolerates a wide range of functional groups. Peripheral modification of pyranoisoquinolines for the construction of complex heterocyclic compounds is also demonstrated.

Redox-Neutral [4 + 2] Annulation of N-Methoxybenzamides with Alkynes Enabled by an Osmium(II)/HOAc Catalytic System

“…It was worth emphasizing that the subsequent alkyne coordination and migratory insertion into the C–Os rather than the N–Os bond were involved (Δ G ⧧ = 26.0 kcal/mol for TS-3 vs Δ G ⧧ = 33.1 kcal for TS-3′ ) to generate INT-6 . From then on, a relatively high energy barrier of 24.5 kcal/mol (from INT-6 to TS-4′ ) was involved for the following C–N bond reductive elimination process, which had been proved as the key step in precedent transition-metal-catalyzed C–H/N–H annulation of N -methoxybenzamides. − , Alternatively, an oxidative addition of osmium into the N–O bond proceeded via TS-4 (Δ G ⧧ = 14.0 kcal/mol) with the assistance of HOAc, producing the osmium­(IV) species INT-7 with a free energy of −7.6 kcal/mol. Thereafter, the facile reductive elimination occurred via the transition states TS-5 and TS-6 with the free energy of −2.7 kcal/mol and −3.3 kcal/mol, respectively, followed by the protonlysis and the ligand exchange in the presence of HOAc to deliver the final isoquinolone product along with extrusion of the active osmium­(II) catalyst.…”

“…Preliminarily, in a search for appropriate DGs that enable osmium­(II)-catalyzed diversified C–H functionalization, we turned our attention to N–OR-substituted benzamides, which represent a type of versatile ODG for the construction of various heterocycles via transition-metal-catalyzed transformations. ,− To our delight, the treatment of the simple N -methoxybenzamide 3a with diphenylacetylene 4a in the presence of [Os­( p -cymene)­Cl 2 ] 2 (5 mol %) and NaOAc (0.5 equiv) in methanol led to the formation of isoquinolone product 5aa in 21% isolated yield along with the disappearance of most of the starting materials, which confirmed our aforementioned inference. Encouraged by this result, we next screened the experimental parameters systematically to figure out the optimal conditions for the catalytic C–H functionalization (see Table S1 in the Supporting Information for a detailed optimization).…”

Isoquinolone Syntheses by Annulation Protocols

“…Although [RuCl 2 (p-cymene)] 2 -catalyzed annulations of N-alkoxybenzamides (R' = alkoxy) with internal alkynes occur with dealkoxylation reactions via activation of N-O bond to give N-H isoquinolones [37][38][39][40], with the use of Cu(OAc) 2 •H 2 O as the terminal oxidant and t-AmOH as the solvent, the oxidative annulation of N-alkyl/arylbenzamides (R' = alkyl, aryl) with internal alkynes gives efficient access to N-alkyl/aryl-substituted isoquinolones by highly selective cleavage of N-H bond [54,55].…”

Rh(III)-Catalyzed Dual C–H Functionalization/Cyclization Cascade by a Removable Directing Group: A Method for Synthesis of Polycyclic Fused Pyrano[de]Isochromenes

“…Also, Cheng developed a Rh­(III)-catalyzed dual ortho -C–H functionalization/annulation cascade of ethylbenzimidates with sulfur ylides to equip effectively pyrano­[4,3,2- ij ]­isoquinoline skeleton in moderate to good yields and good functional group compatibility (Scheme b). Similarly, Sahoo and co-workers achieved two intriguing Ru­(II)-catalyzed unsymmetrical double annulation to construct pyranoisoquinoline skeleton with benzamide equipping different N-directing groups and unactivated alkynes (Scheme c), respectively. However, to the best of our knowledge, the facile synthesis of pyrano­[ de ]­isochromenes with two oxygen atoms on its core scaffold was still unreported heretofore.…”