A One-Pot Diazotation–Fluorodediazoniation Reaction and Fluorine Gas for the Production of Fluoronaphthyridines

Abstract

Several synthetic routes to 7-fluoro-2-methoxy-8-methyl-1,5-naphthyridine (1) are presented, and their suitability for scale-up is discussed. The way of introducing the fluorine atom is crucial. Early routes start from commercially available fluorinated building blocks or employ F+ reagents like SelectFluor and delivered up to 70 kg of 7-fluoro-2-methoxy-1,5-naphthyridine (18). To prepare for larger scales, the focus turned to the use of HF or elemental fluorine, both one of the cheapest sources of fluorine. The first method, a one-pot diazotation–fluorodediazoniation with 6-methoxy-1,5-naphthyridin-3-amine (9) in HF gave the fluorinated naphthyridine 18 in high yield and purity without isolation of the unstable diazonium salt, the latter being a severe drawback of the related Balz–Schiemann protocol. The second method relies on the use of fluorine gas for a surprisingly selective ortho-fluorination of 6-methoxy-1,5-naphthyridin-4-ol (10).

Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

“…Other a-diazocarbonyl substrates have typically been prepared using traditional batch procedures before investigating the subsequent reactivity of the diazo group in a flow reactor. Procedures in which a-diazocarbonyl compounds have been generated in continuous processes are the Bamford-Stevens reaction of arylsulfonylhydrazones precursor compounds or the Arndt-Eistert reaction of activated carboxylic acids with 1 [or the equivalent trimethylsilyldiazomethane (32)] to produce terminal a-diazomethylketones (10,35).…”

“…[81] In their system, trimethylsilyldiazomethane (32, TMSCHN 2 ) is used as a less explosive alternative to diazomethane (1). After the initial reaction between the acid chloride (33) and 32, which takes place at room temperature (R1), the TMS group is cleaved off by passage through a column containing an immobilised fluoride source (34, S1) to reveal the a-diazoketone intermediates (35). The ketones 35 generated in flow were telescoped into a second flow process where they mix with ortho-diaminoaro-Scheme 7.…”

“…Scheme 9. Use of trimethylsilyldiazomethane (32) in the generation of a-diazoketones (35). The telescoped flow procedure converted the reactive diazo intermediates 35 into quinoxalines (38).…”

“…[17][18][19][20][21][22] Diazo compounds are also important 1,3-dipoles for heterocycle-forming cycloaddition reactions. [23][24][25][26][27][28] The diazonium ion moiety is an important leaving group in Sandmeyer, [29][30][31] Meerwein, [32,33] Balz-Schiemann [34,35] and palladium-catalysed cross coupling [36][37][38] chemistry; it is also an essential reagent for the preparation of azo compounds, the backbone of the synthetic dye industry. [38,39] The versatility of the diazo and diazonium moieties is matched only by their fearsome reputation.…”

“…Diazo compounds are also important 1,3‐dipoles for heterocycle‐forming cycloaddition reactions 23–28. The diazonium ion moiety is an important leaving group in Sandmeyer,29–31 Meerwein,32, 33 Balz–Schiemann34, 35 and palladium‐catalysed cross coupling36–38 chemistry; it is also an essential reagent for the preparation of azo compounds, the backbone of the synthetic dye industry 38. 39…”