Stereoselective cacchi reaction catalyzed by angelw: PD for asymmetric synthesis of axially chiral 2,3-disubstituted indoles

Indole, as a kind of heterocyclic compounds, widely exists in natural products, drug molecules and agricultural chemicals Although indole itself does not have chirality, the introduction of ortho substituted aryls at the N1, C2 and C3 positions of indole can effectively restrict the rotation of C-N and / or C-C bonds, resulting in the generation of axially chiral compounds In fact, axially chiral diindoles exist in nature and are used as chiral ligands for asymmetric synthesis The synthesis of six aryl and heteroaryl compounds with axial chirality has attracted great interest of many chemists Recently, the catalytic asymmetric synthesis of five heterocyclic (especially indole) axial chirality compounds has also attracted great attention Because of the lower rotational energy barrier of five six or five five five biaryl compounds, the synthesis of these compounds has always been a challenge N-protected 2-alkynylaniline compounds can react with aryl, alkenyl or alkynyl halides to form 2,3-disubstituted indoles under PD catalysis This reaction was first discovered by cacchi team and is now widely used in the synthesis of indoles In addition, this reaction can also be carried out under the oxidation condition with the divalent Pd catalyst, so that both arylboric acid and terminal alkyne can be used as coupling reagents in the reaction In 2010, Kitagawa team reported the stereoselective hydroamination reaction catalyzed by PD to synthesize axially chiral indoles with N1 aryl substitution In this reaction, the oxidation state of PD remains unchanged, so no oxidant is needed Although the stereoselectivity of the reaction is low, it can be proved that the chirality of the ligand can induce the axial chirality of n-arylindole Recently, Li group has developed cpxrh (III) - catalyzed C-H activation, ammonia rhodium reduction and elimination to synthesize indoles with C3 aryl axis chirality However, stereoselective cacchi reaction has not been reported Recently, a series of chiral 2,3-disubstituted indoles were synthesized by asymmetric oxidation of cacchi, which was reported for the first time by the research group of Jieping Zhu, Institute of chemical science and engineering, Lausanne, Switzerland The product has good yield and EE value The relevant research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201914049) (source: angelw Chem Int ed.) first of all, the author used 1a and boric acid compound 2A as template substrate to optimize the conditions (Table 1) By optimizing the reaction conditions of ligands, alkali, solvent, PD source, etc., the author determined the optimal reaction conditions as follows: palladium acetate as metal salt, L6 The target product was obtained with 88% yield and 87% ee value at room temperature for 16 h under the condition of ligand, potassium phosphate as base, methanol as solvent and substrate in oxygen atmosphere (source: angelw Chem Int ed.) after determining the optimal reaction conditions, the author expanded the substrate range of the reaction (scheme2) The or group of naphthalene ring in substrate 1 has a great influence on the reaction efficiency, and the OBN group gives the best result The boric acid substituted by electron donor and electron acceptor can reach the target product with high yield and high EE value Heterocyclic compounds, such as furan, quinoline and indole, are compatible with the reaction conditions In addition, 2-phenyl substituted indole can also be obtained in high yield, but the EE value is slightly reduced When there is methyl substitution in the 2-position of boric acid, there will be two axial chirality (DR 2:1), but the EE values are all low (27%, 33%) In the separation process, it is found that there is an equilibrium process between the two compounds, which may be due to the lower rotational energy barrier (source: angelw Chem Int ed.) when boric acid is not added to the reaction, hydrogen amination product (scheme 3) will be produced But the EE value was very low (7%) This is different from the EE value when boric acid is involved Therefore, the author speculates that the transition metal process may occur prior to amine palladization Subsequently, the presence of (L6) PDPH (OAC) complex in the reaction system was confirmed by phosphine spectrum (source: angelw Chem Int ed.) according to the control experiment and simple mechanism experiment, the author proposed a possible catalytic cycle (scheme 5): firstly, L6 PD (Ⅱ) interacts with boric acid compound to form L6 arpdx complex 7; then it coordinates with substrate n-sulfonyl-2-alkynylaniline to form 11, and then through intermolecular cyclization to form 12 At the same time, the zero valent PD was oxidized to bivalent PD in oxygen atmosphere, and entered the next cycle (source: angelw Chem Int ed.) Summary: the research group of Jieping Zhu has developed stereoselective cacchi reaction for the first time, and synthesized a series of axially chiral 2,3-disubstituted indoles with good yield and enantioselectivity This study provides a good method for the synthesis of axial chiral indoles.