Blue LED-Mediated N–H Insertion of Indoles into Aryldiazoesters at Room Temperature in Batch and Flow: Reaction Kinetics, Density Functional Theory, and Mechanistic Study

Abstract

Mild blue light-mediated N–H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted indoles with electron-withdrawing groups such as −CN and −CHO facilitated the product formation, whereas the electron-donating group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the C3 position of indoles with the rate of the N–H insertion reaction. The strategy was utilized to synthesize a key intermediate for the natural product (−)-psychotrimine.

Lightening Diazo Compounds?

“…Photochemical generation of carbenes from diazo compounds proved also useful in N -alkylation of indoles 72 . This strategy has been lately developed by Sen et al who studied this reaction in both batch and flow conditions . The above transformation is feasible for several indoles 72 and diazo compounds 1 simply under blue light irradiation with yields of products being usually higher under flow conditions (Scheme ).…”

“…This strategy has been lately developed by Sen et al who studied this reaction in both batch and flow conditions. 58 The above transformation 59 In this context, avoiding the use of a metal as toxic as palladium is an obvious advantage of Sen's work. However, it is impossible to miss that transition metal catalysis, also in this case, may enable enantioselective transformations.…”

Visible Light-Promoted Transformation of Diazo Compounds via the Formation of Free Carbene as Key Intermediate

“…实验过程中发现, 芳基重氮酯 仅在可见光照射下无法直接完成对苯并三氮唑 N 环. 最近, Sen 课题组 [28] 也实现了光促条件下芳基重氮 酯对吲哚 N-H 的插入, 并且在连续流动光化学的条件 下依然可以顺利进行. 对于氨基酸或者多肽的选择性修饰是生物化学以 及药物化学中需要解决的关键科学问题.…”

Orthogonal Syntheses of γ-Carbolinone and Spiro[pyrrolidinone-3,3′]indole Derivatives in One Pot through Reaction Telescoping

“…Photochemical reactions of indoles and other substrates with aryl diazo acetates have been well reported by us and many others. , For example, diverse strategies for C–H functionalization and cyclopropanation of N-free or protected indoles have been demonstrated both under inter- and intramolecular fashion. , Additionally blue LED mediated ring expansion, cross coupling, carbene transfer, and NH-insertion have been reported with aryl diazoacetate in various substrates such as tetrahydrofuran, propargyl alcohol, indoles, carbazoles, pyrazoles, imidazoles, and etc. ,,,, . Recently, photochemical Doyle-Kirmse reactions have also been reported with aryl diazoacetates in blue LED. , We envisaged that our telescoping procedure will consist of cyclopropanation of indole derivatives followed by the in situ lactam formation of the resulting cyclopropane intermediate 4a and finally selective cyclopropane ring opening of 5a to afford the desired products (Table , Scheme a).…”