ACS catalyst: NHC enantioselective catalytic functionalization of indole N-H

At present, the selective functionalization of most (hetero) aromatic molecules is realized by transition metal catalysis However, there are few reports on the use of organic catalysts to activate and functionalize aromatic molecules Macmillan, melchiorre, Phipps and other research groups have successively reported the free radical reaction combining photo oxidation reduction with organic catalysis The functionalization of another aromatic molecule catalyzed by small amines has been reported by J? Rgensen, Chen and Xu The N-heterocyclic carbene (NHC) organic catalysis has also achieved great success in the asymmetric reactions of aldehydes, esters and related carbonyl compounds Recently, Professor Yonggui Robin Chi of Nanyang University of technology in Singapore reported the enantioselective [4 + 2] addition reaction of indolealdehyde and ketone catalyzed by chiral NHC (Figure 1) Relevant research results were published on ACS catalyst (DOI: 10.1021 / acscan 9b03163) (source: ACS catalyst.) the author used indole-7-formaldehyde 1a and trifluoroacetone 2A as model substrates to optimize the conditions (Table 1) The precatalyst C with electron deficient trichlorophenyl on nitrogen can promote the formation of target product 3a, the yield is 8%, er value is 90:10 Then the author investigated a variety of N-heterocyclic carbene catalysts, and found that D was the best, and the cyclization product 3A could be obtained with 90% yield and 95.5:4.5 er When the organic base diea was used instead of CS 2CO 3, the yield was further increased to 99%, and the enantioselectivity was excellent (source: ACS catalyst.) after determining the best reaction conditions, the author inspected the universality of the method (Table 2) First of all, the author investigated the range of substrate application of aryltrifluoromethylketone The substratum with the electron acceptor or electron acceptor in the ortho or para position of benzene ring can reach the corresponding ring product 3B - 3I with excellent yield and ER value Other heteroaryl or alkyltrifluoromethylketone can also react smoothly, and the target product 3j - 3M can be obtained with good yield and excellent Er value In addition, difluoromethylketone and α - ketoacid ester are also suitable substrates (3N, 3O) (source: ACS catalyst.) then, the author investigated the substrate range of indole-7-formaldehyde-1 (Table 3) Indole-7-formaldehyde with different substituents at different positions can be compatible with the reaction, and the target product 3a-3w can be obtained with excellent yield and optical purity (source: ACS catalyst.) in order to further prove the universality and practicability of this method, the author continued to investigate the substrate range of indigo derivatives (Table 4) Under the optimized reaction conditions, a variety of indigo derivatives can obtain spiro compound 5A - 5p with good yield and excellent enantioselectivity (source: ACS catalyst.) the author speculates that the mechanism of [4 + 2] cyclization is shown in Figure 2 NHC and aldehyde 1A are added to form Breslow intermediate, which is oxidized to form acyl azole intermediate I Intermediate I is deprotonated to form intermediate II similar to aza-o-qms Finally, intermediate II and trifluoroacetone 2A were cyclized to form the desired product 3a and regenerated NHC catalyst (source: ACS catalyst.) in conclusion, the enantioselective functionalization of indole N-H has been realized by NHC catalyst for the first time The addition of NHC catalyst to indole remote aldehyde group initiated the reaction and controlled the stereoselectivity The results show that under the catalysis of NHC, the nitrogen atoms in heteroaromatic molecules can undergo asymmetric cycloaddition reaction In addition, a series of polycyclic n, o-acetals and amines can be prepared with high yield and good enantioselectivity.