Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

Abstract

A base- and catalyst-free C(sp3)–H allylic alkylation of 2-alkylpyridines with Morita–Baylis–Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26–91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.

Catalyst-Free α-Allylation of Dihydroisoquinolines with Morita–Baylis–Hillman Carbonates and Its Applications in the Construction of Benzo[a]quinolizidines

“…In addition, although the reaction between 1,3,3-trimethyl-3,4-dihydroisoquinoline 1w and 2.5 equiv of 2a could occur to form the double-substituted product 3wa in 79% yield, the reaction became more sluggish, which may be attributed to the influence of steric hindrance. The above experimental results as well as previous reports from our and other groups clearly validate the possibility of the cascade S N 2′substitution/aza-Cope rearrangement mechanism as we proposed in Scheme . In the reaction, the electron-rich imine moiety of 3,4-dihydroisoquinolines acts as a nucleophilic base and initiates the reaction by attacking the MBH carbonates 2 in an S N 2′ manner, then undergoes an aza-Cope-type rearrangement to give the final products.…”

“…To examine the feasibility of our proposal, we initiated our investigation using 1-ethyl-3,4-dihydroisoquinoline 1a and MBH carbonate 2a as the model substrates. Following the condition in our previous work, 19 the allylation reaction between 1a (0.2 mmol) and 2a (1.5 equiv) was initially performed in anhydrous CH 3 CN at 80 °C under N 2 atmosphere. To our delight, the reaction proceeded smoothly and completed in 2 h, giving the desired α-allylation product 3aa in 87% yield (Table 1, entry 1).…”

“…In our previous work, we have developed a catalyst-free benzylic C(sp 3 )−H allylation reaction of 2-alkylpyridines with MBH carbonates. 19 In this reaction, the basic pyridine served as the nucleophilic agent, which triggered the allylation reaction via a tandem S N 2′ substitution/aza-Cope rearrangement sequence (Scheme 1d).…”

“…Then, under the activation of the strong electron-withdrawing iminium ion, the α-C­(sp 3 )–H proton is activated and deprotonated by the in situ generated t BuO – , generating the enamine intermediate B , which subsequently undergoes an aza-Cope rearrangement to give the α-C­(sp 3 ) allylation product 3 . Different from our previous work, the products generated from the imine α-C­(sp 3 ) allylation reaction contain reactive CN moiety, which provides flexible handle for further transformations. Herein, we will present the catalyst-free α-allylation reaction of 1-alkyl-3,4-dihydroisoquinolines with MBH carbonates and its further applications in the diverse synthesis of pharmacologically interesting benzo­[ a ]­quinolizidine derivatives.…”