Fluorinated Building Blocks Research Articles

Efficient synthesis of new fluorinated building blocks by means of hydroformylation.

Hydroformylation of fluorinated alkenes is an efficient method for the preparation of fluorinated functionalized building blocks for the synthesis of biologically active target structures. In this article we summarize known hydroformylation reactions of fluorinated olefins and we add new results from our research groups. Particular attention is paid to the remarkable influence of organofluorine substituents on catalyst activity, regio- and stereoselectivity of the hydroformylation reaction.

ChemInform Abstract: The Synthesis of Gemcitabine

AbstractReview: 68 refs.

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

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).

Fries rearrangement: scalable synthesis of key fluoro building blocks 3-fluoro-4-methoxybenzoyl chloride and 1,2-diethoxy-3-fluorobenzene

Lewis acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3) was performed on kg scale. The ortho5 and para4 isomers obtained were separated in an industrially feasible way. Compound 4 was then converted into fluorinated building block 3-fluoro-4-methoxybenzoyl chloride (1) while compound 5 was converted into 1,2-diethoxy-3-fluorobenzene (2) in high yields.

Vicinal bis(trifluoroacetimidoyl chloride)s: novel building blocks for the synthesis of benzo-fused eight-membered rings via [2 + 2 + 2] cycloadditions

Vicinal bis(trifluoroacetimidoyl chloride)s, a novel kind of fluorinated building block, were obtained from o-phenylenediamines in the presence of TFA, triethylamine, triphenylphosphine and tetrachloromethane. Based on these blocks, a new synthesis involving [2 + 2 + 2] cycloaddition reactions for trifluoromethylated benzo-fused eight-membered rings was disclosed.

Copper(I)‐Catalyzed Intermolecular Cyclization of Methyl Perfluoroalk‐2‐ynoates with o‐Aminophenyl Ketones: Access to 2‐Perfluoroalkylated Quinolines

AbstractOne‐pot, two‐step cyclization of o‐aminophenyl ketones 1 and methyl perfluoroalk‐2‐ynoates 2 takes place in the presence of copper(I) as catalyst and diisopropylethylamine as base, leading to 2‐perfluoroalkylated quinolines. Compared with previous methods that have been used to generate quinoline skeletons, this technique uses inexpensive copper salt as catalyst, methyl perfluoroalk‐2‐ynoate as fluorinated building block and proceeds smoothly under mild conditions, which makes the transformation both sustainable and practical.

Ortho-Perfluoroalkylation and Ethoxycarbonyldifluoromethylation of Aromatic Triazenes

A robust protocol for perfluoroalkylation and ethoxycarbonyldifluoromethylation of functionalized aromatic triazenes is described. Using silver(I)-fluoride and different fluorinated (trimethyl)silyl substituted species, it was possible to synthesize various ortho-fluorinated triazenes in good yields via simple CH-substitution. Initial reactions under solvent-free (neat) conditions indicate a stabilizing interaction between "AgRf" and the triazene moiety, which may be responsible for the good yields and regioselectivity. The transformation possibilities of the triazene moiety make these reactions interesting for the synthesis of fluorinated building blocks. In addition, quantum chemical calculations suggest that the stabilization of the radical intermediate in the ortho-position is distinctly more favored for aromatic triazenes than for other aromatic substrates.

ChemInform Abstract: Synthesis of Fluorinated Building Blocks by Transition‐Metal‐Mediated Hydrodefluorination Reactions

AbstractReview: ca. 200 refs.

Synthesis of Fluorinated Building Blocks by Transition‐Metal‐Mediated Hydrodefluorination Reactions

The activation and functionalization of carbon-fluorine bonds can be considered as a major challenge in organometallic chemistry. The growing demand for means to introduce fluorine into new materials or into biologically active molecules has inspired the development of diverse synthetic strategies. Hydrodefluorination is regarded as a promising approach to access partially fluorinated building blocks from readily available perfluorinated bulk chemicals. We provide an overview of transition-metal-based complexes and catalysts that were developed to mediate hydrodefluorination reactions. Special emphasis will be placed on discussing the underlying mechanistic patterns and their impact on scope and selectivity. In addition, future requirements for further developing this field will be highlighted.

ChemInform Abstract: Suzuki—Miyaura Coupling Reactions of Iodo(difluoroenol) Derivatives, Fluorinated Building Blocks Accessible at Near‐Ambient Temperatures.

AbstractThe iodides (II) and (X), which are available in good yields, efficiently undergo Suzuki—Miyaura coupling with a number of aromatic trifluoroborates and some arylboronic acids.

ChemInform Abstract: Preparation of (E)‐4‐Aryl‐1,1,1‐trifluoro‐3‐tosylbut‐3‐en‐2‐ones as Fluorinated Building Blocks and Their Application in Ready and Highly Stereoselective Routes to trans‐2,3‐Dihydrofurans Substituted with Trifluoromethyl and Sulfonyl Groups.

AbstractThe arsonium‐ylide assisted ring‐closure reaction proceeds with excellent diastereoselectivity, leading to exclusive formation of the thermodynamical stable trans‐isomers.

Suzuki–Miyaura Coupling Reactions of Iodo(difluoroenol) Derivatives, Fluorinated Building Blocks Accessible at Near-Ambient Temperatures

A recently developed method for the near-ambient generation of difluorovinylzinc reagents has facilitated the preparation of 1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene and 2,2-difluoro-1-iodo-1-(2'-methoxyethoxymethoxy)ethene. The utility of these reagents has been investigated in Suzuki-Miyaura couplings with a range of potassium trifluoroborate coupling partners, with the scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from i-PrOH to t-BuOH suppressed the pathway to these species and improved coupling yields.

Preparation of (E)‐4‐Aryl‐1,1,1‐trifluoro‐3‐tosylbut‐3‐en‐2‐ones as Fluorinated Building Blocks and Their Application in Ready and Highly Stereoselective Routes to trans‐2,3‐Dihydrofurans Substituted with Trifluoromethyl and Sulfonyl Groups

Abstract(E)‐4‐Aryl‐1,1,1‐trifluoro‐3‐tosylbut‐3‐en‐2‐one fluorinated building blocks were prepared through a two‐step process. Treatment of these (E)‐4‐aryl‐1,1,1‐trifluoro‐3‐tosylbut‐3‐en‐2‐ones with arsonium bromides in the presence of Cs2CO3 in CH2Cl2 at reflux resulted in highly stereoselective ring closure to provide 4‐tosyl‐5‐trifluoromethyl‐trans‐2,3‐dihydrofurans in good to excellent yields.

Fluorophosphonylated Nucleoside Derivatives as New Series of Thymidine Phosphorylase Multisubstrate Inhibitors

The synthesis of new class of potential TPase inhibitors containing a difluoromethylphosphonate function as phosphate mimic is reported. This new series was prepared from a readily available fluorinated building block in few steps. Two series were evaluated as potential inhibitors: a linear series and a conformational constrained series. The activity of these multisubstrate inhibitors depends on the size of the spacer introduced between the pyrimidine ring and the phosphonate function. Best results were observed from triazolyl derivatives, easily obtained from propargylthymine and corresponding azides.

Practical Synthesis of 1,1-Difluoro- or 1-Fluoroalkenes from 2,2,2-Trifluoroacetophenone Derivatives

Since the discovery of the fact that compounds bearing a vinylic fluoride moiety often exhibit remarkable biological activities such as enzyme inhibitors, many synthetic methods for fluorine-substituted vinylic compounds have been developed. The synthesis of selectively fluorinated building blocks, such as arylsubstituted fluoro-alkenes, also has become an area of interest in recent years. Herein we describe a novel and practical method for the synthesis of 1,1-difluoro- and 1-fluoroalkenes starting from easily accessible trifluoroacetophenone derivatives. Various 1,1-difluoro- and 1-fluoroalkenes were prepared by the reaction of the corresponding tosyl hydrazones that were derived from trifluoroacetophenone derivatives by treating with alkyl or aryllithium reagents via addition-elimination and single electron transfer (SET) mechanism.

Catalytic fluorination of dichloromethylbenzene by HF in liquid phase. Preparation of fluorinated building blocks

The selective fluorination by successive Cl/F exchanges of the dichloromethylbenzene, was studied in the presence of HF as the fluorinating agent. The influence of the presence of a catalyst or a basic solvent (such as dioxane, pyridine, tributylphosphate) in order to favour the fluorination was investigated. In mild conditions, (50 °C and after 1 h of reaction), the fluorination of the dichloromethylbenzene was observed and the polymerization reaction inhibited. The best results were obtained in the presence of the HF-dioxane system and antimony trifluoride as catalyst.

Cleavage of Carbon−Carbon Bonds through the Mild Release of Trifluoroacetate: Generation of α,α-Difluoroenolates for Aldol Reactions

The selective cleavage of carbon-carbon bonds is a significant challenge in synthetic chemistry, yet this strategy can be a powerful way to generate reactive intermediates. We have discovered that, through the facile release of trifluoroacetate which occurs by C-C bond scission, difluoroenolates can be generated under very mild reaction conditions. Unlike existing reactions, this method is not limited to a small group of fluorinated building blocks. We have applied this process to the aldol reaction to install difluoromethylene groups.

ChemInform Abstract: C—F Bond Activation of Highly Fluorinated Molecules at Rhodium: From Model Reactions to Catalysis

AbstractReview: ca. 100 refs.

ChemInform Abstract: Selective Fluorination of Substituted Trichloromethyl Benzenes by HF in Liquid Phase: Preparation of Fluorinated Building Blocks.

AbstractSelective trifluoromethylation of the corresponding chlorinated compounds is achieved by successive Cl/F exchange under mild conditions using HF as the fluorinating agent.

C–F Bond Activation of Highly Fluorinated Molecules at Rhodium: From Model Reactions to Catalysis

AbstractRhodium complexes are excellent tools for the activation of aromatic and olefinic carbon–fluorine bonds. C–F bond cleavage reactions are key steps for the derivatization of highly fluorinated compounds via stoichiometric or catalytic reaction pathways. The reaction routes involve hydrodefluorinations, but also the selective introduction of functional groups at distinctive positions, to provide access to new fluorinated building blocks. One can identify two general types of rhodium precursors that can induce the C–F activation step. Cyclopentadienyl compounds have been applied for thermal and photochemical C–F bond cleavage reactions of aromatics in solution, but oxidative addition steps have also been investigated in matrix isolation studies at low temperature. Square‐planar hydrido, silyl, and boryl complexes are often involved in unique stoichiometric and catalytic processes for the derivatization of aromatics and olefins.