Abstract
As a privileged structural motif, tetrahydroquinoline skeletons widely exist in biologically active natural products and pharmaceuticals. In this protocol, a highly diastereoselective [4 + 2] annulation of ortho-tosylaminophenyl-substituted p-QMs and cyanoalkenes to construct tetrahydroquinoline derivatives has been successfully achieved. This strategy proceeds efficiently under mild condition, offering straightforward route to a variety of 4-aryl-substituted tetrahydroquinolines with high yields, excellent diastereoselectivities, broad functional group tolerance as well as gram-scale capacity. Moreover, a one-pot reaction sequence utilizing in situ generated p-QMs under the similar condition to build tetrahydroquinoline framework is smoothly conducted with good reaction performance as well as step and atom economy.
Highlights
As privileged structural motifs, nitrogen-containing heterocycles widely exist in biologically active natural products and pharmaceuticals (Noolvi et al, 2011; Solomon and Lee, 2011; Afzal et al, 2015; Murlykina et al, 2018; Harikandei et al, 2019; Staskiewicz et al, 2021)
A one-pot reaction sequence utilizing in situ generated p-QMs under the similar condition to build tetrahydroquinoline framework is smoothly conducted with good reaction performance as well as step and atom economy
In order to further explore the robustness of this methodology, a preliminary attempt of one-pot synthesis of functionalized tetrahydroquinoline compound starting from precursor 1a was successfully conducted, producing target molecule 3a in 63% yield (Scheme 3C, Wang et al, 2018)
Summary
Nitrogen-containing heterocycles widely exist in biologically active natural products and pharmaceuticals (Noolvi et al, 2011; Solomon and Lee, 2011; Afzal et al, 2015; Murlykina et al, 2018; Harikandei et al, 2019; Staskiewicz et al, 2021). The group of Hu and Zhao pioneered the design of in situ generated ortho-tosylaminophenyl-substituted p-QMs and transformations of this class of substrates in [4 + 1] (Wang et al, 2019; Wang et al, 2020a) and [4 + 2] (Wang et al, 2018; Si et al, 2020) annulation reactions, providing a straightforward access to construct valuable tetrahydroquinoline and 2,3-dihydroindole derivatives, respectively (Scheme 1B). Those transformations avoid the utilization of presynthesized p-QMs, which greatly enhance the step and atom economy of this strategy. This reaction features high yield (up to 96% yield), excellent diastereoselectiveties (>20:1 dr), broad functional group tolerance as well as gram-scale capacity (Scheme 1C)
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