Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

Abstract

Die Einführung einer CH2F‐Gruppe in organische Moleküle ist in den letzten Jahren zweifellos zu einem sehr wichtigen Forschungsgebiet geworden. Aufgrund der vorteilhaften Eigenschaften von Organofluorverbindungen – wie ihre metabolische Stabilität – ist der Einbau der CH2F‐Gruppe als bioisosterer Ersatz für verschiedene funktionelle Gruppen eine attraktive Strategie, um z. B. neue Medikamente zu entwickeln. Darüber hinaus findet die Monofluormethyleinheit auch in der Agrochemie, in der pharmazeutischen Chemie und in der Feinchemie einen breiten Einsatz. Aufgrund des menschengemachten Klimawandels und des wachsenden Bedarfs an umweltfreundlichen industriellen Prozessen sind Alternativen zu den häufig verwendeten Fluormethylierungsmitteln auf FCKW‐ und HFBKW‐Basis (CH2FCl und CH2FBr) dringend erforderlich und im Montrealer Protokoll auch gefordert. Dies hat in letzter Zeit viele Forscher dazu veranlasst, die Entwicklung umweltfreundlicher Fluormethylierungsmittel zu entwickeln. Dieser Kurzaufsatz umfasst sowohl die klassischen als auch die neue Generation von Fluormethylierungsmitteln. Es werden Reagenzien und deren Vorläuferverbindungen diskutiert, die sowohl direkt als auch indirekt über elektrophile und nukleophile als auch radikalische Wege reagieren.

N‐Fluoromethylated (Amino)Tetrazoles: Manipulating Thermal and Energetic Properties

“…The corresponding N1–C2 and N2–C2 bond lengths of 1.429(4) and 1.439(2) Å, respectively, compare well to each other and are shortened compared to the known [Me 3 NCH 2 F] +[23a] moiety. The C2–F1 distance of 1.382(3) Å ( 2a ) and 1.380(2) Å ( 2b ) compare well with those reported for a FCH 2 P phosphonium salt [1.379(5) Å], [ 19c ] FCH 2 I [1.380(17) Å] [ 23b ] and FCH 2 Br [1.377(4) Å]. [ 23b ] Noteworthy is the different thermal behavior observed for 2a and 2b .…”

“…However, until very recently this year, the first and only fluoromethyl containing tetrazole, 5‐fluoromethyl‐tetrazole [ 17 ] and one non‐energetic complex [ 18 ] were reported. Since a large number of fluoromethylating agents for various nucleophiles are available until now [ 19 ] and only N ‐methylated but no N ‐fluoromethylated tetrazoles are known up to date, this prompted us to synthesize fluoromethylated tetrazoles und investigate their thermal‐, energetic‐ and complexation behavior.…”

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

“…Simple aliphatic alkenes were smoothly hydrofluoroalkylated, affording the desired monofluoroalkanes (3,4) in high yields. It should be mentioned that a series of transformable functional groups including chloro (5), protected alcohol (6, 7, 15), ester (16), cyano (18,19) and amine (20) were well tolerated in this catalytic method. Meanwhile, alkenes bearing different protecting groups such as ether (9), benzoate (14) and tosylate (20) also behave well in this…”

“…In particular, the fluorine replacement could tremendously improve the metabolic stability, lipophilicity, and bioavailability of the original compounds, thus offering highly appealing solutions to design and development of pharmaceuticals, agriculture chemicals, and special materials (Figure 1a). [1][2][3][4][5][6][7][8][9][10][11][12] Significant advances have been made in developing novel methods for accessing various organofluorine compounds, [13][14][15][16][17][18] especially monofluorinated arenes and alkanes which have seen increasing presence in fluorine-containing drugs, etc. over the past few decades.…”

The Reactivity of α‐Fluoroketones with PLP Dependent Enzymes: Transaminases as Hydrodefluorinases

“…Thus, the increasing interest around this halogen has gone in hand with the development of very efficient and selective synthetic pathways to obtain fluorinated compounds. [4] Due to the inert nature of fluorinated compounds, many efforts have focused on their degradation, but since oxidative methods or incineration can produce toxic wastes, reductive alternatives are envisaged as safer methodologies. Among them, the cleavage of a CÀ X into a CÀ H bond, i. e. hydrodehalogenation [3,5] (hydrodefluorination, when X=F), [6,7] is one of the most promising chemical approaches to degrade these compounds.…”