Synthesis of Fluorinated Benzophenones, Xanthones, Acridones, and Thioxanthones by Iterative Nucleophilic Aromatic Substitution

Abstract

Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4, 4′ fluorines, and second by cyclization through substitution of the less reactive 2, 2′ fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones, and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds.

Fluorinated Boron‐Dipyrromethene (BODIPY) Dyes: Bright and Versatile Probes for Surface Analysis

“…Fluorine substitution is generally considered as rendering a certain dye considerably more photostable than its hydrogen-containing analogue, often also improving its spectroscopic characteristics. [49][50][51] For XPS, on the other hand, it is essential to increase the amount of a certain marker atom on a label as much as possible to achieve better limits of detection. Thus, the task for a dual XPS/fluorescence label is to increase the number of fluorine atoms on a dye while still allowing further attachment of reactive groups or its conjugation to surface functional groups.…”

Bromination of Aromatic Compounds using Bromine in a Microreactor

“…For the 1 H NMR spectrum see the Supporting Information. Generally, 2,4,5‐trifluorobromobenzene can be prepared from the diazo reaction of 2,4,5‐trifluoroaniline followed by the copper‐catalyzed Gatterman reaction 53–55. However, this route involves multisteps and the formation of potentially explosive diazonium compounds.…”

“…Therefore, the development of green, convenient, and practical methods for their preparation is of considerable importance and highly desirable. Our approach using Br 2 in a continuous‐flow system has primarily been designed for the synthesis of 2,4,5‐trifluorobromobenzene, an intermediate with important applications in the preparation of biologically active peptides 53 and fluorescent reagents 54. The present protocol features a continuous microflow of the volatile and irritating Br 2 into the reaction system with a crucially steady generation of the catalyst (FeBr 3 ), which enables the reaction to proceed in a safe manner with efficiency.…”

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

“…From salicylic acid and phenol in phosphorus pentoxide-methanesulfonic acid [144,170] Benzoxanthone FeCl 3 -Catalyzed, three-components, one-pot [171] Caged xanthones Regioselective Claisen/DielsÀ Alder cascade reaction [151,[172][173][174]175] Haloxanthones From 2-bromofluorobenzenes and salicylaldehydes via palladium-catalyzed acylation-SNAr [167,176,177] Hydroxyxanthone Classical one-step synthesis starting from two aryls induced by Mannich reaction and Eaton's reagents. [167,[178][179][180][181][182] Pyranoxanthones From 1,3-dihydroxyxanthone with different reagents [180] Pyridyl xanthones Ag 2 CO 3 mediated oxidative cyclization [183] Sulfonamides xanthones Eaton's reagent and chlorosulfonic acid [184] Thioxanthones Heteropoly acid, catalytic, under microwave [176,185,186] Toxyloxanthones Regioselective aryne addition and Claisen rearrangement [187] Triazole xanthone…”