Divergent Reaction Pathways of Homologous and Isosteric Propargyl Amides in Sequential Ru/Pd-Catalyzed Annulations for the Synthesis of Heterocycles

Abstract

Cu-catalyzed three-component coupling of imines with benzoyl chloride and terminal arylalkynes followed by enyne ring-closing metathesis (RCM) and Heck cyclization afforded medicinally relevant benzoindolines, cyclopropane-fused indenopyridines, pyrroloquinolines, or 1,7-tetrahydrophenanthrolines via divergent cyclization pathways. Unexpectedly, the Pd-catalyzed cyclization of heterocyclic dienes proceeded via regiodivergent 5-exo or 6-endo pathways depending on the ring size (n = 1, 2) or the presence of isosteric groups (CH vs N). A one-pot protocol for the enyne-RCM/Heck annulation featuring a sequential addition of the Ru and Pd catalysts was developed maximizing the synthetic efficiency.

Acyclic Twisted Amides

“…Structurally characterized N-pyramidalized N-heterocycle-activated amides with χ N values >40° are summarized in Figure . ,,,,− In general, these amides can be divided into the following classes of amides: (1) conformationally constricted N -acyl-7-azabicyclo­[2.2.1]­heptanes ( 5.4 , 5.5 , 5.7 , 5.9 – 5.20 ) ,, and related derivatives, such as N -acyl-8-azabicyclo­[3.2.1]­octanes ( 5.2 ) and N -acyl-2-azabicyclo­[2.1.1]­hexanes ( 5.8 ), (2) N -acyl-pyrrolidines ( 5.1 , 5.3 ), , and (3) N -acyl-oxazolidin-5-ones ( 5.6 , 5.21 ). , N -Acyl-azetidines and N -acyl-azridines are not included because the ring strain of the small ring significantly contributes to the properties of these amides. , …”

“…305,312 Similar to 7-azabicyclo[2.2.1]heptane amides, N-acyl-pyrrolidines 5.1 and 5.3 contain predominantly N-pyramidalized amide bonds cf. twist (5.1: χ N = 40.2°, τ = 13.2°; 5.3: χ N = 43.7°, τ = 13.2°), 536,538 which originates from the steric interactions between amide bond substituents and pyrrolidine ring. The nitrogen pyramidalization leads to an increased electron density at the nitrogen and more electrophilic carbonyl groups in these amides.…”

Recent Advances in One-Pot Enyne Metathesis Processes for the Preparation of Biologically and Medicinally Relevant Compounds

“…82 In 2013, Malinakova and Raikar reported a one-pot RCEYM/Heck annulation sequence for the synthesis of benzoindolines 166, indenopyridines 167, pyrroloquinoline 168, 1,7-phenanthrolines 169 and related heterocycles, which represent drug-like scaffolds potentially endowed with valuable medicinal properties (Scheme 34). 83 Cu(I)catalyzed coupling of properly designed imines, acyl chlorides, and alkynes afforded enyne derivatives of the type 164 that were subjected to the one-pot RCEYM/Heck annulation process. The Pd-catalyzed cyclization of dienes 165 proceeded via regiodivergent 5-exo or 6-endo pathways depending on the ring size (n = 1, 2) or the presence of isosteric groups (CH vs N).…”

Recent advances in the discovery and design of multicomponent reactions for the generation of small-molecule libraries

“…The more recent work highlights the possibility to uncover divergent reaction pathways via structural variations in one of the substrates (reaction B; Figure 9). 64 Thus, the CuCl-catalyzed coupling of N-allyl or N-homoallyl imines derived from 2-bromoarylcarbaldehydes or pyridine-2-bromo-3-carbaldehyde with terminal aromatic alkynes and benzoyl chloride afforded a total of 15 highly functionalized acyclic enynes, generally in practical 49%-53% yields. The products of the first step were isolated and characterized.…”

“…61 (B) Sequential MCR/cyclizations strategy. 64 cyclization products of the reversible carbopalladation. The kinetic product can either react further (n=2) or revert back (n=1) to the substrates, which then proceed to undergo the 6-endo carbopalladation.…”