A unique method for highly enantioselective synthesis of N–C axially chiral compounds

In this issue of Chem, Zhou and co-workers report a new strategy for synthesizing optically active N–C axially chiral compounds. the presence norbornene-ester-Pd catalyst, Catellani reaction iodobenzene derivatives with N-(2-substituted-phenyl)-2-bromobenzamides proceeds in highly enantioselective manner to give N-aryl-phenanthridinone derivatives. Atropisomeric biaryl C–C axis have been widely used as ligands, organo-catalysts, selectors, functional materials fields chemistry science.1Lassaletta J.M. Atropisomerism Axial Chirality. World Scientific, 2019Crossref Google Scholar Furthermore, number natural products bioactive compounds bearing an atropisomeric skeleton are well known.1Lassaletta Because importance biaryls, their catalytic syntheses also reported by many groups.1Lassaletta Scholar,2Bringmann G. Price Mortimer A.J. Keller P.A. Gresser M.J. Garner J. Breuning M. Atroposelective synthesis compounds.Angew. Chem. Int. Ed. Engl. 2005; 44: 5384-5427Crossref PubMed Scopus (1001) On other hand, although analogous long known because rotational restriction around bond (N–C compounds), they attracted little attention until recently. Over last 10 years, considerable synthetic organic medicinal chemistry.3Alkorta I. Elguero Roussel C. Vanthuyne N. Piras P. axial chirality heteroaromatic compounds.Adv. Heterocycl. 2012; 105: 1-188Crossref (83) Scholar,4Kumarasamy E. Raghunathan R. Sibi M.P. Sivaguru Nonbiaryl heterobiaryl atropisomers: molecular templates promise atropselective chemical transformations.Chem. Rev. 2015; 115: 11239-11300Crossref (322) particular, asymmetric currently hot research topic explored groups.5Takahashi Suzuki Y. Kitagawa O. Asymmetric N‒C axis.Org. Prep. Proced. 2014; 46: 1-23Crossref (63) Scholar, 6Kitagawa Chiral Pd-catalyzed various N-C applications.Acc. Res. 2021; 54: 719-730Crossref (36) 7Thönnißen V. Patureau F.W. Enantioselective aromatic amination?.Chemistry. 27: 7189-7192Crossref (5) Various prepared high enantioselectivity via groups’ own original catalysts methodologies; nevertheless, construction bonds remains challenging from viewpoint efficiency, substrate scope, product diversity. unique elegant method simple substrates.8Liu Z. Xie Hua Wu Ma Chen et al.An axial-to-axial transfer atroposelective C–N chirality.Chem. 7: 1917-1932Abstract Full Text PDF (16) They previously found that norbornene-Pd-catalyzed, three-component coupling (asymmetric reaction) aryl iodide, 2,6-disubstituted bromide, alkene (or alkyne) substrates derivatives.9Liu Gao Q. Tang H. Shang Cheng Construction palladium/chiral norbornene cooperative catalysis.Nat. Catal. 2020; 3: 727-733Crossref (46) report, was applied axis. ester (NBE∗) Pd(OAc)2-TFP iodobenzenes 1 N-(2-substituted phenyl)-2-bromobenzamides 2 gave 3 excellent (87%–98% enantiomeric excess [ee]; Scheme 1). The stereochemical pathway present investigated detail density theory (DFT) study. That is, insertion aryl-Pd(II) species, formed Pd(0), into NBE∗ subsequent C–H activation proceeded regio- stereo-selective manners afford palladacycle(II) intermediate 1A. oxidative addition 2-bromobenzamide resulting 1A bis-aryl-NBE∗ palladacycle(IV) 1B. reductive elimination 1B stereo-control result 1B, leading 1C S-configuration selectivity. Subsequently, β-C substitution bromide ligand on Pd center amide nitrogen (ligand exchange) afforded 1D. This species is proposed exist two diastereomeric forms (1D-A 1D-B) axis, one diastereomer (1D-A) occurs more rapidly than (1D-B); hence, (R)-configuration constructed Meanwhile, 1D-A disappears association bond-forming (the formation 3) phenanthridinone only chirality. Thus, brought about efficient initially (axial-to-axial transfer). scope limitation were detail. N-(2-tert-butylphenyl)-2-bromo-3-methylbenzamides (R3 = Me, R4 t-Bu) substituents (R1 R2) N-(2-tert-butylphenyl)-10-methylphenanthridin-6-one enantioselectivities (90%–98% ee) regardless R1 R2. N-(2-tert-butylphenyl)-2-bromobenzamides (R4 several R3 (93%–98% ee). contrast, benzamides less bulky group i-Pr C(OH)Me2) instead tert-butyl yielded racemic instability N–Ar under conditions (70°C, 36 h). Interestingly, when ortho-unsubstituted H, R2 CF3) substrate, groups such i-Pr, C(OH)Me2, Br, I (90%–98%) ee. DFT study X-ray crystal-structural analysis revealed stability be significantly influenced group. at 4-position distorted ring steric repulsion destabilize ground-state structure. Hence, barrier ≠ H) substituent remarkably lower (7 kcal mol−1 lower) 4-unsubstituted H), racemization 3. double 2-bromobenzanilide 4,4′-diiodo-1,1′-biphenyl 1,5-diiodonaphthalene smoothly bis-lactam axes complete enantioselectivity. conclusion, authors succeeded through norbornene-Pd-catalyzed tandem reaction). Through reaction, ee obtained good yields readily available substrates. detailed conceptually induction will arouse curiosity chemists. addition, An chiralityLiu al.ChemMay 13, 2021In BriefC–N skeletons prevalent pharmaceuticals. However, formidable challenge. Herein, phenanthridinones catalysis reported. involves process, which has scarcely calculations performed elucidate mechanism providing broader implications future studies synthesis. Full-Text Open Archive