Allocolchicinoids, with a distinct polyoxygenated dibenzocycloheptane skeleton, attract much attention as potential candidate anticancer drugs. In this study, eight C‐ring fluorinated analogues of allocolchicinoids, seven C‐ring oxygen‐substituted analogues, and known compounds N‐acetylcolchinol and NSC 51046 were synthesized as racemates from a single common intermediate by using either the deoxyfluorination/migration domino reaction or acid‐promoted migration as the key step. Among the products obtained, some of the fluorinated derivatives strongly inhibited the growth of prostate DU145 and pancreas Panc 1 cancer cell lines with efficacy comparable to or better than those of N‐acetylcolchinol and NSC 51046. They were also less toxic against a non‐cancerous cell line than the known compounds were.

We herein report a regioselective preparation of 6-and 7-fluoro-1,2,3,4-tetrahydroquinolines by applying the deoxyfluorination strategy, developed by the authors. This method includes the cyclization of catecholamines bearing an N-protecting group to form 7-hydroxy-1-azaspiro[4.5]deca-6,9-dien-8ones and 6,7-dihydroxy-1,2,3,4-tetrahydroquinolines followed by deoxyfluorination, in which the nature of the N-protecting group has a significant effect on both the cyclization and the regioselectivity of the deoxyfluorination reaction. INTRODUCTIONDue to the unique properties of fluorine, including its high electronegativity, very small atomic radius close to that of hydrogen, and its ability to form strong bonds with carbon, the installation of fluorine atoms into bioactive molecules can increase their lipophilicity, bioavailability, and metabolic stability, and so this strategy is frequently used in the discovery of new pharmaceuticals and agrochemicals. 1Fluorine is also of interest since it frequently used as a biological equivalent (i.e., a bioisostere) of either hydrogen or oxygen in drug discovery research. 2 In addition, radioactive [ 18 F]fluorine is useful for positron emission tomography. 3 Among the wide range of fluorinated pharmaceuticals reported to date, aromatic moieties bearing fluorine atoms are particularly common. In terms of their preparation, the classical electrophilic aromatic fluorination reaction employed for the synthesis of fluorobenzene units generally produces a mixture of regioisomers. On the other hand, the ipso-nucleophilic substitution of pre-functionalized aromatic compounds with fluorine, such as via the Halex (halogen exchange) and Balz-Schiemann reactions, proceeds with an excellent regioselectivity, but requires harsh reaction conditions. Recently, an ipso-fluorination method has been devised via arylsulfonium intermediates. 4Transition-metal-catalyzed carbon-fluorine bond forming reactions of pre-functionalized aromatics have also been developed, where copper, palladium, and silver serve as efficient catalysts, 5 while aromatic C-H fluorination is another rapidly growing protocol. 6 The deoxyfluorination of phenolic hydroxy groups is also intriguing for the regio-controlled fluorination of bioactive aromatic molecules due to the ready availability of different phenolic structures as natural products and synthetic compounds. 7Scheme 1. (A) The regio-complementary deoxyfluorination of bridged biaryls and (B) the outline of this work.