Regiodivergent Intramolecular Nucleophilic Addition of Ketimines for the Diverse Synthesis of Azacycles

Abstract

Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as aflexible approach to access Nfunctionalizedindoles and tetrahydroquinolines,bythe control of reaction at the N-terminus and C-terminus,r espectively. Using ketimines derived from 2-(2-nitroethyl)anilines with isatins or a-ketoesters,t he regioselective N-attackr eaction gives N-functionalized indoles,w hile the catalytic enantioselective C-attackr eaction affords chiral tetrahydroquinolines featuring an a-tetrasubstituted stereocenter.M echanistic studies reveal that hydrogen-bonding interactions may greatly facilitate such unusual N-attackreactions of imines.The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (À)-psychotrimine,and the construction of various fused aza-heterocycles. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201910864. Angewandte Chemie Research Articles Scheme 1. Reaction design and development. M.S. = moleculars ieves, Ts = 4-toluenesulfonyl.Figure 8. Synthetic applicationsofN-functionalized indole derivatives. X-ray structure for 21 shown. [36] AIBN = 2,2'-azobis(isobutyronitrile), LAH = lithium aluminumhydride, Ns = 4-nitrobenzenesulfonyl, TEA = triethylamine.

Tandem imine generation/N-cyclization/C-alkylation sequence to access N-functionalized indoles featuring an aza-quaternary carbon

“…With the above working hypothesis, we first tried to integrate an alkylation reaction to trap the enolate formed in situ to develop a one-pot tandem sequence for the facile synthesis of N-functionalized indoles with the nitrogen connected to a tetrasubstituted carbon. First, based on our previous studies, 10 we conducted a one-pot reaction of isatin-derived functionalized imine 1a and benzyl bromide 2a in MeOH using 2.0 equivalents of Na 2 CO 3 , and we were pleased to find that the desired quaternary oxindole 3a could be obtained in 29% yield (Scheme 1A). This result, along with our previous finding that the base greatly influenced the imine/N-alkylation reaction, 10 encouraged us to carefully optimize the base and other conditions, such as the temperature, and the amounts of the base and alkylating reagent.…”

“…Accordingly, a regioselective N-attack reaction of ketimines derived from 2-(2-nitroethyl)anilines with isatins or α-keto-esters was developed, allowing facile access to N-functionalized indoles. 10 Based on these results, along with the current interest in medical research studies to employ quaternary carbons to improve the drug-like properties of organic compounds, 11 we envisioned coupling this process with alkylation to develop a one-pot tandem sequence for the creation of an aza-quaternary carbon, given that the enolate formed in situ could be effectively trapped by a suitable electrophile (Fig. 1C).…”

Stereoselective synthesis and applications of spirocyclic oxindoles

“…375 Also, due to the number of bioactive compounds containing the spirodihydropyridine oxindole scaffold, there has been a significant amount of work aimed at racemic synthesis, 376 of note is Shi's enantioselective [3 + 3] annulation. 377 Very recent advances include a copper catalysed aza-Henry reaction by Wang and Zhou 378 and HFIP mediated C(sp 3 )-H functionalisation by hydride transfer. 379 Stepwise strategies.…”

Enantioselective synthesis and selective functionalization of 4‐aminotetrahydroquinolines as novel GLP‐1 secretagogues

“…The chemistry of tetrahydroquinolines has attracted substantial attention in recent years due to the activity profile of this privileged scaffold in biological assays, [1][2][3] and various organocatalytic 4 and metal-catalyzed [5][6][7][8] synthesis methods have been reported. In particular, the 4-aminotetrahydroquinoline (4-ATQ) motif is present in a large number of natural products and pharmaceutical agents, such as martinellic acid, martinelline, I-BET726, and compound 4D (Figure 1).…”