Visible light promotes the synthesis of benzo [a] quinolinidine derivatives

Benzo [a] quinoline is the core structural unit of many natural alkaloids and therapeutic drugs (scheme 1) For example, emetine is a natural product isolated from the root of cephailis acuminate, which has a good curative effect on lymphoid leukemia The commercial drugs based on benzo [a] quinoricidine structure are mainly Rotundine, an analgesic, and bubenazine, which is used to treat motor disorders and central nervous system disorders On the other hand, fluorine-containing drugs account for a considerable proportion in clinical drugs The introduction of fluorine atoms into small molecule drugs is one of the important strategies for the chemical structure transformation of drugs Although there have been many studies on the synthesis of benzo [a] quinolicidine, there are few reports on the efficient synthesis of its fluorinated derivatives, especially on the construction of fluoroazabicycles Scheme I The natural products and drugs containing benzo [a] quinolicidine structure recently, the research group of Professor Zhou Lei of Sun Yat sen University has realized the synthesis of benzo [a] quinolicidine 3 by using visible light oxidation-reduction catalysis, starting from simple a-trifluoromethylolefin 1 and tetrahydroisoquinoline alkyl acid 2, and through the two-step carbon fluorine bond cutting of trifluoromethyl group The mechanism of the reaction is shown in Figure 2: first, the trivalent iridium photocatalyst transitions to the excited state under the visible light and transfers with the substrate 2 to generate a carboxyl radical, at the same time, the catalyst is reduced to divalent; the radical removes a part of CO 2 to obtain a-aminoalkyl autoradical a The introduction of carboxyl group in substrate 2 not only makes it easier to be oxidized by photocatalyst, but also selectively leads to a-aminoalkyl radical a outside the ring Then free radical a is added to a-trifluoromethylolefin 1 to obtain free radical B, which is then reduced to a-trifluoromethylcarboanion C by a single electron of iridium divalent, and then eliminated by b-fluoride anion to form a-trifluoromethylolefin 4 In the same photocatalysis system, the second single electron transfer between the nitrogen atom and the catalyst takes place, and the nitrogen radical ion D is obtained In the presence of alkali, the intermediate can remove the protons at the a-position of nitrogen to obtain a-aminoalkyl radical E There may be two ways to change the intermediate e into the final product 3: one is the process of free radical addition and elimination (path a), that is, a-aminoalkyl radical e is added to the molecule of amido difluoride to get free radical F, which is reduced by iridium divalent to get carbon anion g, and then the product 3 is eliminated by b-fluoride anion Because there are two fluorine atoms with strong electron absorption on the double bond of difluoroethylene, it is very likely that it will be directly reduced by iridium divalent to obtain free radical anion, which will occur first to eliminate the fluoride anion and generate free radical h, so we can not completely exclude the possibility of obtaining target product 3 (path B) by coupling the intramolecular double radicals After optimizing the reaction conditions, the author investigated the application scope of a-trifluoromethylolefin-1 and tetrahydroisoquinoline alkyl acid-2 (scheme 3) The results show that the substituents on the aromatic ring of tetrahydroisoquinoline have little effect on the reaction Both the substituents of electron absorption (3b) and electron donor (3C) can be transformed well The substituent R 3 of carboxyl a-position can be methyl, n-propyl, long chain n-heptyl, isopropyl and other alkyl groups When R 4 is hydrogen atom, these substrates almost get 5:1 non corresponding selectivity When the carboxyl A-site has no substituent (3D) or is linked with dimethyl (3e), the yield of the reaction decreases slightly However, when R3 = pH, the reaction did not detect the expected product When a phenyl was introduced into the 4-position of 2-tetrahydroisoquinoline, the product 3F had three chiral centers, but only three of them were detected, and the Dr selectivity was 8:1:1 When R 2 was substituted by phenyl methyl, only two non corresponding isomers were produced These non corresponding isomers can be efficiently separated by sepabean intelligent purification system of Changzhou Santai Technology Co., Ltd., and the product configuration is also determined by their NOESY It is worth mentioning that when R4 is changed from "H" to "me" (3L), or "pH" (3m), the yield of the product is not only increased, but also the non corresponding selectivity is further increased to > 20:1 Finally, we investigated the substrate range of a-trifluoromethylolefin, and found that all kinds of a-trifluoromethylstyrene can participate in the reaction well, and the corresponding product 3n-3s can be obtained in medium to better yield However, when the phenyl in alkene is replaced by other substituents, such as alkyl, ester, bromine, etc., the expected product cannot be obtained Reactionconditions: 1 (0.24 mmol), 2 (0.2 mmol), photocatalyst (2 mol%), K 2 CO 3 (2equiv), MeCN (1 mL), 5 W blue LED, rt, 48 h, In this reaction, a simple a-trifluoromethylene was used as raw material, and under the conditions of visible light and room temperature, two carbon fluorine bonds of trifluoromethyl group were cut off to prepare monofluoro compounds, which provided a new method and idea for the preparation of fluorine-containing heterocyclic compounds This achievement was published on advanced synthesis & catalysis The first author of this paper is Chen haoguo, a master's degree candidate of School of chemistry, Sun Yat sen University Haoguo Chen, tiebo Xiao, Linyong Li, devideddy Anand, Yuwei he, and Lei Zhou, adv synth Catalyst 2017, 359, 3642-3647 full text download link: http://onlinelibrary.wiley.com/doi/10.1002/adsc.201700852/abstract Professor Zhou Lei research group information: http://ce.sysu.edu.cn/zhoulab/index.html contributor: Chen haoguo