Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

Abstract

We report herein the first examples of ap alladiumcatalyzede nantioselective Cacchir eaction for the synthesis of indoles bearing ac hiral C2-aryl axis.I nt he presence of ac atalytic amount of Pd(OAc) 2 and (R,R)-QuinoxP* ligand, reaction of N-aryl(alkyl)sulfonyl-2-alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3-disubstituted indoles in high yields and enantioselectivity.The indole ring is constructed de novo in this process and ac omplexation-induced chirality transfer is proposed to account for the observed enantioselectivity. Scheme 1. Axially chiral indoles:occurrence and synthesis.Scheme 3. Synthesis and X-ray structural characterization of (L6)PdArX complexes 7a (X = OAc) and 8a (X = I). Scheme 4. Results of control experiments using QuinoxP*(=O) and QuinoxP*(=O) 2 as ligands. Angewandte Chemie Communications 2107

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…[31] Later in 2019, Zhou and co-workers reported as tepwise strategy to synthesize chiral 2,3-diarylbenzoindoles 52 featuring two stereogenic axes with a1,2-arrangement in good yield and excellent stereoselectivity (Scheme 15). [32] Thec hiral phosphoric acid (CPA) VI catalyzed the formal (3+ +2) cycloaddition of 1-styrylnaphthols 49 with azonaphthalenes 50 to construct the enantiomerically enriched dihydropyrrole precursors 51 in good yield and excellent diastereo-and enantioselectivity.N ext, the oxidative aromatization with dichlorodicyanobenzene (DDQ) under mild conditions efficiently afforded the diarylbenzoindoles 52 through central-toaxial chirality conversion after the protection of phenolic hydroxyl group with p-toluene sulfonyl (Ts) group.N otably, this well-designed process was the first example of the conversion of two adjacent stereogenic centers into two ortho-stereogenic axes.…”

Catalytic Asymmetric Construction of Axially Chiral Indole‐Based Frameworks: An Emerging Area

“…Very recently, Zhu's group reported an elegant approach for the catalytic asymmetric construction of axially chiral C2‐arylindole frameworks via the de novo synthesis of the indole ring (Scheme 14). [35] They utilized the Cacchi reaction, [36] and realized its catalytic asymmetric version by reacting N ‐aryl(alkyl)sulfonyl‐2‐alkynyl anilides 49 with arylboronic acids 50 in the presence of Pd/ L6 , which afforded axially chiral C2‐arylindoles 51 in good yields with high enantioselectivities. Notably, this protocol could be used to generate a variety of axially chiral C2‐arylindole frameworks, such as C2‐naphthylindole 51 a , C2‐phenylindole 51 b , C2‐quinolinylindole 51 c and 2,3’‐bisindole 51 d , with moderate to excellent enantioselectivities, which opens a new avenue for the future expansion of this protocol in constructing axially chiral indole‐based frameworks.…”

Tuneable access to indole, indolone, and cinnoline derivatives from a common 1,4-diketone Michael acceptor

“…Several routes have been reported to access these key compounds, the most developed being for the indole [14] derivatives using the Fischer indole synthesis involving sigmatropic rearrangements [15][16][17][18], nucleophilic and electrophilic cyclizations [19][20][21][22][23][24][25], reductive and oxidative cyclizations [26,27], and transition-metal catalysis [28][29][30][31][32][33][34][35][36][37]. There are fewer ways to [9], indolone [10], and cinnoline [11] derivatives).…”

“…Several routes have been reported to access these key compounds, the most developed being for the indole [ 14 ] derivatives using the Fischer indole synthesis involving sigmatropic rearrangements [ 15 – 18 ], nucleophilic and electrophilic cyclizations [ 19 – 25 ], reductive and oxidative cyclizations [ 26 – 27 ], and transition-metal catalysis [ 28 – 37 ]. There are fewer ways to access indolone derivatives, mainly based on the use of di- [ 12 , 38 – 39 ] or triketones [ 10 , 13 ] and enaminones [ 40 – 43 ] as starting materials.…”