Regioselective construction of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives via cascade reaction of quinolines with heterocyclic ketene aminals: a joint experimental-computational approach.
A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China. yansj@ynu.edu.cn linjun@ynu.edu.cn.
Yi-Chuan
YC
Zhang
Zhi-Cheng
ZC
Liu
Rui
R
Yang
Ji-Hong
JH
Zhang
Sheng-Jiao
SJ
Yan
Jun
J
Lin
D003198:Computer Simulation; D005030:Ethylenes / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009287:Naphthyridines / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity
D005030:Ethylenes; D007659:Ketones; D009287:Naphthyridines; D011804:Quinolines; C008223:ketene