Fluorinated Building Blocks Research Articles

Synthetic approaches to monofluoroalkenes

Monofluoroalkenes are an important fluorinated class of compounds with applications in medicinal chemistry, material sciences and organic chemistry. An overview of methods allowing synthetic access to these fluorinated building blocks is provided. In particular, this critical review, which covers publications up to October 2010, will be divided according to the substitution pattern of the monofluoroalkenes, i.e. di-, tri- or tetra-substituted. Within each group, the various synthetic approaches will be divided according to the reaction type (282 references).

ChemInform Abstract: Synthesis of Difluorinated β‐Ketosulfones and Novel gem‐Difluoromethylsulfone‐Containing Heterocycles as Fluorinated Building Blocks.

Abstract A series of new heterocyclic β-ketosulfides was prepared by the reaction of the corresponding heterocyclic thiols with α-bromoacetophenone and its derivatives. Oxidation of the products using m-CPBA gave the corresponding heterocyclic β-ketosulfones, which, on treatment with Selectfluor™ under anhydrous condition underwent electrophilic fluorination resulting in new heterocycles with difluoromethylene moiety adjacent to the sulfur atom and the carbonyl group. Base-induced cleavage of the five types of the resulting products, with different heterocyclic moieties as model compounds, afforded the difluoromethyl sulfones attached to the corresponding heterocycles. They can be considered as interesting fluorinated building blocks for further elaborations.

Enantiomerically Pure and Highly Substituted Alicyclic α,α‐Difluoro Ketones: Potential Inhibitors for Malarial Aspartic Proteases, the Plasmepsins

AbstractThe design and synthesis of novel fluorinated building blocks is of major interest in the development of new pharmaceuticals and agrochemicals. A quantitative search in the Protein Data Bank (PDB) manifests the use of di‐ and trifluoro hydrates for binding to hydrophilic enzyme active sites. Hydrated alicyclic α,α‐difluorinated ketones attract attention since they provide suitable functionalities for binding to the pair of catalytically active aspartate (Asp) side chains at the active site of aspartic proteases. This article expands the synthetic availability of this novel class of binding elements. Enantiomerically pure alicyclic α,α‐difluoro ketones are efficiently accessed by a straightforward route involving the separation of diastereoisomeric Mosher esters. The transformation into Mosher esters also enables the determination of the absolute configuration of the enantiomeric α,α‐difluoro ketones. The synthetic protocol was further expanded to the preparation of highly substituted cyclohexyl‐based α,α‐difluoro ketones bearing two exit vectors to fill the corresponding side pockets in the malarial aspartic proteases, the plasmepsins. Moderate biological activities toward these enzymes were determined, with IC50 (median inhibitory concentration) values in the lower micromolar range.

Selective fluorination of substituted trichloromethyl benzenes by HF in liquid phase: Preparation of fluorinated building blocks

The selective fluorination by successive Cl/F exchanges of α,α,α-trichlorotoluene, substituted or not by a chlorine atom, 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 control the fluorination was also investigated. In mild conditions (50 °C and after 1 h of reaction), HF in excess was required in order to obtained the trifluoromethylation by Cl/F exchanges. The presence of SbCl 5 in small amount activated the Cl/F exchanges and only a stoichiometric amount of HF was required whatever the chlorinated molecules. Selective mono and difluorination could be obtained by using basic solvents.

ChemInform Abstract: 3-Bromo-2-fluoropropene (V) - A Fluorinated Building Block. 2-Fluoroallylation of Glycine and Alanine Ester Imines.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Rearrangement Routes to Selectively Fluorinated Compounds

Abstract Fluoroallylic alcohols are easy to synthesise by a variety of routes using one or two carbon fluorinated building blocks. Sigmatropic rearrangement then transforms these intermediates into species in which the fluorine atom (or atoms) is borne on an sp3-hybridised carbon. Alternatively, allylic alcohols can be transformed into fluorinated vinyl ether derivatives; rearrangement then affords products in which the fluorine atoms occupy a different and complementary location with respect to a carbonyl function.

ChemInform Abstract: HFC-134a as a Fluorinated Building Block: Short Syntheses of α-Fluoroenones.

Abstract 1,1,1,2-Tetrafluoroethane (HFC-134a) has been transformed into a range of α-fluoroenones via a direct route. Dehydrofluorination/metallation allowed trifluorovinylsilanes to be prepared; these could be converted in situ, or isolated and treated further, with alkyllithium reagents to give difluorovinylsilanes. Fluoride-catalysed addition to aldehydes followed by acidic work-up allowed the isolation of a range of α-fluoroenones in two- or three-pots.

Preparation and Reactions of (β-Trifluoromethyl)vinyl Sulfonium Salt

(Beta-trifluoromethyl)vinyl sulfonium salt as a novel three-carbon fluorinated building block was conveniently prepared from easily available (beta-trifluoromethyl)vinyl sulfide and diphenyl iodonium salt in excellent yield. This easily handled crystalline reagent displayed two types of useful transformation involving aziridination and vinylation to afford the corresponding trifluoromethylated compounds in excellent yields.

Synthesis of difluorinated β-ketosulfones and novel gem-difluoromethylsulfone-containing heterocycles as fluorinated building blocks

A series of new heterocyclic β-ketosulfides was prepared by the reaction of the corresponding heterocyclic thiols with α-bromoacetophenone and its derivatives. Oxidation of the products using m-CPBA gave the corresponding heterocyclic β-ketosulfones, which, on treatment with Selectfluor™ under anhydrous condition underwent electrophilic fluorination resulting in new heterocycles with difluoromethylene moiety adjacent to the sulfur atom and the carbonyl group. Base-induced cleavage of the five types of the resulting products, with different heterocyclic moieties as model compounds, afforded the difluoromethyl sulfones attached to the corresponding heterocycles. They can be considered as interesting fluorinated building blocks for further elaborations.

α-Fluorovinyl Weinreb Amides and α-Fluoroenones from a Common Fluorinated Building Block

Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones to give alpha-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are > or = 98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give alpha-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of alpha-fluorovinyl Weinreb amides and alpha-fluoroenones has been demonstrated. Application of the Weinreb amide to alpha-fluoro allyl amine synthesis is also shown.

Nitrogen-Containing Organofluorine Derivatives: An Overview

Fluorinated organic compounds, in particular those containingnitrogen atoms, are popular targets in medicinal chemistry. Theyare obtained through chemical synthesis, usually by employing small,fluorinated molecules as starting building blocks. This accountfocuses on the reactivity and synthetic applications of differenttypes of fluorinated building blocks. It summarizes recent methodologiesdeveloped in our and other laboratories for the synthesis of a varietyof nitrogen-containing organofluorine compounds. 1 Introduction 2 Fluorinated Imidoyl Halides 2.1 Reaction of Fluorinated Imidoyl Chlorides with Enolates: Synthesisof Fluorinated β-Amino Acids 2.2 Reaction of Fluorinated Imidoyl Chlorides with Sulfoxides 3 Fluorinated α-Imino Esters and Imines 3.1 Fluorinated α-Imino Esters 3.2 Fluorinated Aldimines and Ketimines 4 Fluorinated Acrylic Acid Derivatives 5 Fluorinated GEM-Difluoroalkynes 6 Fluorinated Nitriles 6.1 Synthesis of Fluorinated Uracils 6.2 Synthesis of Fluorinated Pyrimidin-2(1 H)-ones 7 Fluorinated β-Dicarbonylic Compounds 8 Miscellaneous 8.1 Tandem Ring-Closing Metathesis-Isomerization 8.2 β-Amino-α-trifluoromethyl Alcohols 9 Conclusion

Highly Diastereoselective Zn/SnCl2-Mediated gem-Difluoroallylation of Chiral Hydrazones

gem-Difuoroallylic zinc reacts with chiral hydrazones 1 in the presence of SnCl(2) to afford the versatile and chiral fluorinated building blocks, gem-difluorohomoallylic amines, in good yields and high diastereoselectivities.

ChemInform Abstract: Recent Progress in One‐Pot Syntheses of Fluorinated Building Blocks

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Aromatization via a Dibromination-Double Dehydrobromination Sequence: A Facile and Convenient Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols

An efficient and reliable method to synthesize 2,6- bis(trifluoroacetyl)phenols bearing various substituents in the 4-po- sition was developed. These valuable fluorinated building blocks were obtained from the corresponding cyclohexanones in a facile and convenient procedure, demonstrated to be superior to the tradi- tional approaches. The application of this methodology to cyclohex- ane-1,4-dione opened access to 2,5-bis(polyfluoroacyl)-1,4- hydroquinones. Structural peculiarities of the obtained phenols as well as their 1,3-dicarbonyl or 1,3,5-tricarbonyl precursors are dis- cussed on the basis of multinuclear NMR spectroscopy.

HFPO Trimer-Based Alkyl Triflate, a Novel Building Block for Fluorous Chemistry. Preparation, Reactions and 19F gCOSY Analysis

Triflate 4, CF3(CF2)2O-CF(CF3)CF2O-CF(CF3)CH2-OTf (RFOCH2OTf), of the HFPO trimer-based alcohol 3 (RFOCH2OH) is a novel highly fluorinated building block for fluorous chemistry. In analogy to similar polyfluorinated triflates with methylene spacer, its reactivity is limited to strong and soft nucleophiles. Whereas reactions with cyanide anion, phenolate anion, enolate of diethyl malonate or lithium salt of benzaldehyde bis(phenylsulfanyl)acetal were unsuccessful, the corresponding imidazole 5, iodide 6 or azide 7 were prepared in good yields. Reaction of imidazole 5 with (perfluorohexyl)methyl triflate (9) afforded highly fluorinated non-crystalline imidazolium salt 8, TfO-RFOCH2-(C3H3N2)+-CH2C6F13-n, which could be employed as fluorous ionic liquid or intermediate for fluorous carbenes. Complete assignment of complex 19F NMR spectra of all compounds employed was accomplished using 19F gCOSY NMR method.

Synthesis of 3‐Fluorofuran‐2(5H)‐ones Based on Z/E Photoisomerisation and Cyclisation of 2‐Fluoro‐4‐hydroxybut‐2‐enoates

AbstractMixtures of some (E)‐ and (Z)‐2‐fluoroalk‐2‐enoates prepared from the corresponding 2‐hydroxycarbonyl compounds and ethyl 2‐(diethoxyphosphoryl)‐2‐fluoroacetate have been transformed in high conversions into the target 3‐fluorofuran‐2(5H)‐ones by an efficient Z/E photoisomerisation of noncyclisable Z isomers followed by acid‐catalysed cyclisation. In contrast, the acid‐catalysed deprotection of ethyl (E)‐ and (Z)‐4‐[tert‐butyl(dimethyl)silyloxy]‐2‐fluoro‐4‐phenylbut‐2‐enoates resulted in the displacement of vinylicfluorine, affording ethyl (E)‐2‐oxo‐4‐phenylbut‐3‐enoate. 3‐Fluoro‐4‐phenylfuran‐2(5H)‐one was transformed into 2‐[tert‐butyl(dimethyl)silyloxy]‐3‐fluoro‐5‐methylfuran as a novel fluorinated building block.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Recent Progress in One-Pot Syntheses of Fluorinated Building Blocks

Recent Progress in One-Pot Syntheses of Fluorinated Building Blocks

Asymmetric Synthesis of New β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives

The synthesis of new β,β-difluorinated cyclic quaternary α-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated α-amino acids as single enantiomers.

Asymmetric Synthesis of New β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives

The synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated alpha-amino acids as single enantiomers.

Synthesis of Novel Enantiopure Fluorinated Building Blocks from Acyclic Chiral Allylsilanes.

AbstractFor Abstract see ChemInform Abstract in Full Text.