N-Heteroaromatic Fluoroalkylation through Ligand Coupling Reaction of Sulfones

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N-heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N-heteroaryl sulfur(IV) and N-heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N-heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis. Here we present a ligand coupling-enabled formal SO₂ extrusion of fluoroalkyl 2-azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N-heteroaromatic fluoroalkylation.     

Modified natural substances—fluorinated and fluoroalkylated monosaccharides and inositols

The review summarizes the results of our research group in the field of fluorinated sugar and inositol derivatives using direct fluorination methods and using fluorinated “building blocks”. Contributions of other German working groups are included, as far as the synthesis of fluorinated carbohydrates was target of these reports.     

Recent advance in radical fluoroalkylation with sulfinate salts

In the last few years, the incorporation of a fluoroalkyl moiety into an organic molecule has been extensively studied. Especially, radical fluoroalkylation, involving the formation of CC and Cheteroatom bonds, presents its valuable synthetic potential to achieve fluoroalkylated compounds. This digest paper highlights recent progress on fluoroalkylation with sulfinate salts, and focuses on radical tri-/di-/monofluoromethylation during the last five years.     

Stereoselective synthesis of fluorobis(phenylsulfonyl)methyl-substituted alkenes using free radical fluoroalkylation

(PhSO₂)₂CFI was prepared in quantitative yield by the iodination of fluorobis(phenylsulfonyl)methane and utilized in facile radical bis(phenylsulfonyl)monofluoromethylation of various terminal alkenes. The synthetic methodology was further extended for the preparation of monofluoromethyl-substituted alkenes.     

Microwave accelerated three-component fluoroalkylations: expeditious routes to fluoropharmaceuticals and PET ligands

One-pot three-component coupling methods have been developed to allow in situ preparation of fluoroalkylated arenes and hydrocarbon chain analogs. The methods, which are accelerated under microwave irradiation gives access to ω-fluorinated alkyl, alkenyl, and alkynyl substituted arenes from readily available precursors. The methods involve late stage introduction of the fluorine and are well suited to application in the synthesis of ¹⁸F labeled PET imaging agents.     

Sodium dithionite initiated fluoroalkylation of trimethoxybenzenes, mesitylene and pyrroles with BrCF2CF2Br

Sodium dithionite initiated reaction of 1,2-dibromotetrafluoroethane with 1,3,5-trimethoxybenzene (1a) in an acetonitrile-water mixture proceeded efficiently at ambient temperature to give 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) almost quantitatively. Similar reaction with 1,2,3-trimethoxybenzene (1b) gave only reasonable yield of regioisomers of (2-bromotetrafluoroethyl)-trimethoxybenzenes 3 and 4 and small amount of a substitution product of the central trimethoxy group, 1-(2-bromotetrafluoroethyl)-2,6-dimethoxybenzene (5). The reaction with mesitylene (6) gave complex mixtures from which, depending on the temperature and a mesitylene/BrCF₂CF₂Br ratio, the expected (2-bromotetrafluoroethyl)mesitylene (8) or a dimeric product, 4,4′-bis(2-bromo-1,1,2,2-tetrafluoroethyl)-1,3,5,1′,3′,5′-hexamethylbicyclohexyl-2,5,2′,5′-tetraene (7), were isolated in a yield of 18 and 13%, respectively. The reactions of BrCF₂CF₂Br with pyrrole (9) and 1-methylpyrrole (11) gave the respective alkylated compounds, 2-(2-bromotetrafluoroethyl)pyrrole (10) and 2-(2-bromotetrafluoroethyl)-1-methylpyrrole (12) in over 70% yields; the former was found to be fairly unstable. The reactivity of the terminal bromine atom in 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) was also investigated.     

Nucleophilic Fluoroalkylation of α,β‐Unsaturated Carbonyl Compounds with α‐Fluorinated Sulfones: Investigation of the Reversibility of 1,2‐Additions and the Formation of 1,4‐Adducts

A detailed investigation of the reactions of PhSO₂CF₂H and PhSO₂CH₂F with (E)‐chalcone (=(E)‐1,3‐diphenylprop‐2‐en‐1‐one) at low temperatures revealed that these two reactions were kinetically controlled, and the ratios of 1,2‐ vs. 1,4‐adducts, which did not change much over time at these temperatures, reflect the relative rates of the two reaction pathways. The controlled experiments of converting the PhSO₂CF₂‐ and PhSO₂CHF‐substituted 1,2‐adducts to 1,4‐adducts showed that these isomerizations are not favored due to the low stability and hard‐soft nature of PhSO₂CF and PhSO₂CHF^? anions. Moreover, taking advantage of the remarkable stability and softness of (PhSO₂)₂CF^? anion, an efficient thermodynamically controlled isomerization of (PhSO₂)₂CF‐substituted 1,2‐adduct to 1,4‐adduct was achieved for the first time.     

Radical additions to fluoroolefins. Photochemical fluoroalkylation of alkanols and alkane diols with perfluoro vinyl ethers; photo-supported O-alkylation of butane-1,4-diol with hexafluoropropene

Butane-1,4-diol was fluoroalkylated by its photoaddition reactions with hexafluoropropene and perfluoro (propyl vinyl) ether under atmospheric pressure, by which monofluoroalkylated and bis-fluoroalkylated products were obtained. 1,3-Diols were completely unreactive under the conditions. 2,2,2-Trifluoroethanol, tert.butyl alcohol and methyl tert.butyl ether appeared to be inert solvents for the additions while acetonitrile quenched the reactions. The reactivity of perfluoro vinyl ethers was studied (tested) in their photoaddition reactions with alkanols that were less regioselective (up to 7% rel.of regioisomer) in comparison with hexafluoropropene. Surprisingly, photo-supported base-induced nucleophilic monoand bis-addition of butane-1,4-diol onto hexafluoropropene was observed in acetonitrile.     

A Common Sugar as Model for Many‐Sided Natural Product Modification. From D‐Fructose via D‐Tagatose to 2‐C‐Chlorodifluoro‐methylated D‐Arabinopyranos‐5‐ulose Derivatives

Abstract

Starting with 3,4‐O‐[(R)‐2,2,2‐trichloroethylidene]‐1,2‐O‐isopropylidene‐β‐D‐tagatopyranose 2 obtained from 1,2‐O‐isopropylidene‐β‐D‐fructopyranose 1 by a non‐classical one‐step acetalization with chloral/DCC, the fluoroalkylated glycosyl donors 15 and 17 were synthesised in 3–4 steps. By this sequence, one stereogenic center was inverted, one new chiral center was introduced, and one stereogenic center, for the time being eliminated, was later re‐introduced. The glycals 11 and 12, key intermediates of the synthesis sequence, were accessible from triflate precursors (e.g., 10) by treatment with DBU. Corresponding halogeno‐(6, 7), tosyl‐(5, 8), or mesyl‐(9) precursors were unsuitable. The stereoselective introduction of a chlorodifluoromethyl group was realised by dithionite‐mediated CF₂ClBr‐addition to the glycal double bond. Subsequently, either the chlorodifluoromethylated glycosyl bromide (13) or the corresponding pyranoses (14 and 16) were isolated. The latter were still acetylated to the 1‐O‐acetyl derivatives 15 and 17, respectively. An x‐ray analysis is given for the 5‐O‐tosylate 8.