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Herein, we report the metal-free synthesis of polyfluoroalkyl aryl ethers via nucleophilic substitution of fluorosulfonates, obtained in one pot by bubbling of sulfuryl fluoride (SO 2 F 2 ). Polyfluoroalkyl aryl ethers are present in a variety of biologically active compounds, but previous methods for accessing them required metal catalysts or harsh conditions. With this method, their synthesis is possible under mild conditions and with a short reaction time (30 min) from commercially available starting materials and in yields of ≤97%. Various fluorinated alcohols could be used as electrophiles, and a diversity of electron-withdrawing groups on the aryl or heteroaryl group were tolerated.

Here we report an efficient access to high-value N-polyfluoroalkyl anilines, primary polyfluoroalkylamines and N,N-bis(polyfluoroalkyl)amines, via N-polyfluoroalkylation of sulfonamides and phthalimide derivatives using sulfuryl fluoride (SO 2 F 2 ). The in situ formation of polyfluoroalkyl fluorosulfonates from commercially available fluorinated alcohols and economical sulfuryl fluoride is highly advantageous given that some polyfluoroalkyl halides are ozone-depleting substances (ODS) regulated by the Montreal protocol. This general method is applied to the polyfluoroalkylation of a variety of sulfonamides, N-sulfonyl carbamates and phthalimide with a wide tolerance of functional groups. The process thus provides viable access for industry to N-(polyfluoroalkyl)anilines as well as primary and secondary N-(polyfluoroalkyl)amines, which are very valuable but not easily accessible building blocks for life science applications., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The N -alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of nontoxic, economic, and commercially available alcohol derivatives on exposure to SO 2 F 2 gas. The use of electron-withdrawing groups and DMAc as solvent affords a ( Z )- and N -endocyclic selectivity for the easy introduction of a variety of alkyl and polyfluoroalkyl chains.

In the context of new scaffolds obtained by photochemical reactions, Paternò-Büchi reactions between heteroaromatic, trifluoromethylphenyl ketone and electron rich alkenes to give oxetanes are described. A comprehensive study has then been carried out on the reaction of aromatic ketones with fluorinated alkenes. Depending on the substitution pattern at the oxetane ring, a metathesis reaction is described as a minor side process to give mono fluorinated alkenes. Overall, this last reaction corresponds to a photo-Wittig reaction and yield amid isosteres. In order to explain the uncommon regioselectivity of the Paternò-Büchi reaction with these alkenes, electrostatic-potential derived charges (ESP) have been determined. In a second computational study, the relative stabilities of the typical 1,4-diradical intermediates of the Paternò-Büchi reaction have been determined. The results well explain the regioselectivity. Further transformations of the oxetanes or previous functionalization of the fluoroalkenes open perspectives for oxetanes as core structures for biologically active compounds., (© 2021 Wiley-VCH GmbH.)

Several approaches were developed for the preparation of phosphorus-substituted 5- and 6-membered benzophostams. Carbodiimide-promoted cyclization of zwitterionic aminophosphinates derived from a nitrobenzene precursor accomplished the cyclization in good yields. Alternatively, a novel copper-catalyzed cross-coupling between a phosphonamide and a bromobenzene precursor produced the heterocycles in moderate to good yields. Three different methods are compared for the synthesis of the P -ethoxy-substituted 5-membered benzophostam.

A synthesis to access rarely described 3-amino-5-fluoroalkylfurans has been developed by cyclization of easily accessible fluorovinamides. This method is rapid and simple and affords the desired furans as hydrochloride salts in quantitative or nearly quantitative yields. It is compatible with four different fluorinated groups (-CF 3 , -CF 2 CF 3 , -CHF 2 , and -CF 2 Cl) and a wide range of substituents on the amine.

The synthesis of glycopyranosyl nucleosides modified in the sugar moiety has been less frequently explored, notably because of the lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.

New phosphorous-containing lead structures against drought stress in crops interacting with RCAR/(PYR/PYL) receptor proteins were identified starting from in-depth SAR studies of related sulfonamide lead structures and protein docking studies. A converging 6-step synthesis via phosphinic chlorides and phosphono chloridates as key intermediates afforded envisaged tetrahydroquinolinyl phosphinamidates and phosphonamidates. Whilst tetrahydroquinolinyl phosphonamidates 13a,b exhibited low to moderate target affinities, the corresponding tetrahydroquinolinyl phosphinamidates 12a,b revealed confirmed strong affinities for RCAR/ (PYR/PYL) receptor proteins in Arabidopsis thaliana on the same level as essential plant hormone abscisic acid (ABA) combined with promising efficacy against drought stress in vivo (broad-acre crops wheat and canola)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The functionalization of 3-(difluoromethyl)pyridine has been developed via direct deprotonation of -CHF 2 with a lithiated base and subsequent trapping with various electrophiles in THF. In situ quenching gives access to 3-pyridyl-CF 2 -SiMe 2 Ph as a new silylated compound, which can be postfunctionalized with a fluoride source to obtain a larger library of 3-(difluoroalkyl)pyridines that could not be accessed via direct deprotonation.

The xanthate-mediated addition of tertiary alkyl radicals to heteroarenes enabled the easy functionalization of heteroaromatic rings as well as more decorated structures, such as marketed drugs or agrochemicals. This work provides a synthetic tool for efficiently exploring the chemical space by allowing late-stage diversification with a high tolerance toward functional groups.

A new strategy was developed using fluorinated acetoacetates, malononitrile, and fluoroalkyl amino reagents (FARs) to access unprecedented 4,6-bis(fluoroalkyl)pyrimidine-5-carboxylates, their carboxylic acid analogues, and 4-amino-6-(fluoroalkyl)pyrimidine-5-carbonitriles. An efficient cyclization step using suitable amidines was developed under microwave irradiation, providing the desired pyrimidines rapidly and efficiently. Standard saponification conditions were applied from carboxylate derivatives to access to the corresponding carboxylic acids. These new valuable building blocks, bearing either a single or two emergent fluorinated substituents, hold strong potential for medicinal and agrochemical research., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fluoroalkyl amino reagents 1a and 2a have been developed from commercially available trifluoromethyl trifluorovinyl ether via a hydroamination reaction with diethylamine or dimethylamine. These reagents can be activated by treatment with a Lewis acid and subsequently used as a mono- or dielectrophile for the introduction of the fluoro(trifluoromethoxy)methyl group, either in Vilsmeier-type acylations of aromatic substrates or in the synthesis of fluorinated pyrazoles from CH-acidic substrates and of bis-fluorinated pyrazoles, all being important building blocks for medicinal and agricultural chemistry.

Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)-a class of chemicals that was slightly forgotten over the last decades-has emerged again recently and proved to be a powerful tool for the introduction of various fluorinated groups onto (hetero)aromatic derivatives., Competing Interests: The authors declare no conflict of interest.

A novel approach towards highly functionalized fluoroalkyl pyrazoles was developed by using fluoroalkyl amino reagents in combination with a variety of fluorinated ketimines. Tuneable introduction of fluoroalkyl groups in the 3- and 5-positions was possible by using vinamidinium intermediates or the corresponding enamino ketones after hydrolysis. These high-value building blocks can give rise to a large number of analogues for bioactivity screening and discovering new heterocyclic bioactive ingredients in various life science fields., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The use of TFEDMA, a fluoroalkyl amino reagent, for the difluoromethylation and difluoroacylation of arenes, heteroarenes, and C-H acidic compounds is reported. This approach allows for an efficient access to difluoromethylated products of high added value in good to excellent yields and with scale-up possibilities.

An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.

A range of valuable 1-indanols and 1-indanamines containing a tertiary C1 atom were synthesized by intramolecular palladium(0)-catalyzed C(sp(3))-H arylation, despite unfavorable steric interactions. The efficiency of the reaction was found to correlate with the degree of substitution at C2, as expected from the Thorpe-Ingold effect. Additionally, the nature of the heteroatomic substituent at C1 had a marked influence on the diastereoselectivity at C1 and C2; indeed, 1-indanols and 1-indanamines were obtained with the opposite relative configuration. Analysis of the X-ray and DFT-optimized structures of the corresponding reactive intermediates provided useful insights into the subtle conformational effects induced by these substituents., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon-fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of -CFH2, -CF2H, -C n F2 n +1 and -SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.

A palladium-catalyzed cross-coupling between 3-, 4-, and 5-halo-pyrazoles and H-phosphonates, H-phosphinates, and secondary phosphine oxides has been developed. This coupling reaction constitutes the first general method allowing the introduction of a great diversity of phosphorus substituents on the different carbons of the pyrazole ring in a one-step process.

Nowadays, the easy access of tetra-N-acetyl-chitopentaose and its counterparts is highly interesting since such chemical compounds are precursors of biological signal molecules with a strong agro-economic impact. The chemical synthesis of tetra-N-acetyl-chitopentaose by controlled N-acetylation of the glucosamine pentamer hydrochloride under mild conditions is described herein. A systematic study on the influence of the different parameters involved in this reaction, such as the solvent, the acetylating agent, and the base used for the deprotonation of ammonium groups of the starting material was carried out. The characterization of final reaction products by HPLC and MALDI-TOF mass spectrometry showed that each of these parameters affects differently the acetylation reaction. Whereas the solvent plays an important role in the N- or O-acetylation selectivity, the acetylating agent and the base were found to influence both the degree of N-acetylation and the distribution of the partially N-acetylated derivatives in the product mixtures. Based on these results, optimized reaction conditions have been established allowing tetra-N-acetyl-chitopentaose to be synthesized in a one-pot deprotonation/N-acetylation of the glucosamine pentamer hydrochloride in a moderate yield (ca 30%)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The N-cyclopropylation of aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, has been accomplished using a simple and cheap copper system. The corresponding tertiary acyclic amides, which constitute a wide family of biologically active compounds, have been obtained in good to excellent yields.

A new general access to A-ring aromatic strigolactones, a new class of plant hormones, has been developed. The key transformations include in sequence ring-closing metathesis, enzymatic kinetic resolution and a radical cyclization with atom transfer to install the tricyclic ABC-ring system. The activity as plant hormones for the inhibition of shoot branching in pea of various analogues synthesized by this strategy is reported., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters., (© 2011 American Chemical Society)

The N-arylation of aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, has been accomplished using a simple and cheap copper catalytic system. The corresponding tertiary acyclic amides, which can be found in numerous biologically active compounds, have been obtained in good to excellent yields.

A palladium-catalyzed oxidative carbo-heterofunctionalization of aniline derivatives involving concomitant direct C-H functionalization and C-X bond formation was developed. By simply changing the reaction conditions (solvent and catalyst), either 3,3'-disubstituted oxindole or spirooxindole was accessible from the same starting material.

Aluminum-based Lewis acids are effective promoters of the condensation of alpha-chloroglycinates with isonitriles or with cyanide ion, leading to the formation of 5-amino-oxazoles.

The [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes opens a straightforward access to 3,5-dihalopyrazoles, valuable scaffolds for the elaboration of unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions. For instance, the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus was achieved in a one-pot operation via sequential reactions with various boronic acids.

Avenues to bi- and tricyclic building blocks for the elaboration of sordaricin and its analogues are described. The target molecules were obtained through inter- and intramolecular Diels-Alder reactions of a number of previously unknown cyclopentadienes. Unusual properties of 3-cyanoenones and 1-cyanocyclopentadienes have been unveiled and circumvented.

After nitrogen, fluorine is probably the next most favorite hetero-atom for incorporation into small molecules in life science-oriented research. This review focuses on a particular fluorinated substituent, the trifluoromethoxy group, which is finding increased utility as a substituent in bioactives, but it is still perhaps the least well understood fluorine substituent in currency. The present review will give an overview of the synthesis, properties and reactivity of this important substituent.

We describe a synthesis of ketones 3 (X = O-R or CN; Y = H or alkyl), which are useful building blocks for the preparation of analogs of the potent antifungal agent sordarin, 1. Congeners of 1 constructed from 3 should permit detailed SAR investigations of the terpenoid core of the natural product.

3,5-Dihalogeno-4-methoxy-N-methylpyridin-2(1H)-ones have been shown to undergo single Suzuki coupling reactions in a site-selective fashion. Monoarylations occur at the C-5 position preferentially, thus leaving the remaining C-3 halide free for further functionalization, to finally access differentially 3,5-disubstituted 2-pyridones. This two-step strategy has been applied to the elaboration of the 3-acyl-5-aryl-4-oxy-2-pyridone subunit that is prevalent in numerous bioactive natural products. [reaction: see text].

[reaction: see text] We describe a convergent approach to soraphen A, 1, that involves coupling of two fragments by an aldol condensation-olefin metathesis sequence. This route permits rapid access to congeners of 1.

A unified strategy for the synthesis of mauritines A (5), B (6), C (7), and F (10) has been developed based on a key intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) for the formation of the strained 14-membered paracyclophane. It was demonstrated that the outcome of the cycloetherification is independent of the stereochemistry of the peptide backbone and that both (1R)-16 and (1S)-16 cyclized smoothly to provide the corresponding macrocycle. On the other hand, dehydration of the secondary benzylic alcohol, via the phenylselenide intermediate, is configuration dependent. (1R)-25 underwent the two-step syn-elimination much more easily than (1S)-22. A modified reductive deamination procedure via the diazonium intermediate was developed. A complete assignment of proton and carbon NMR spectroscopy signals for these natural products is reported for the first time.

[structure: see text] Three tetrapeptides incorporating a 14-membered (R(i+1), S(i+2)) cycloisodityrosine at the i + 1 and i + 2 positions were designed and synthesized. Conformational analysis by (1)H NMR and CD spectra as well as molecular modeling indicated that they all adopt a beta-turn conformation. While the CD spectrum of compound 2 is characteristic of the typical type-II beta-turn (maximum at approximately 200 nm and a minimum at approximately 220 nm), that of 1a (atropisomer of 2) is opposite in sign to the expected spectrum of the type-II beta-turn.

An efficient synthesis of the three halogenated naturally occurring products, pterulone (2), pterulone B (3) and alcohol 5, and of a wide range of related unnatural analogues has been achieved starting from the two readily available 1-benzoxepine sulfonyl-containing intermediates 6a and 6b. The biological activities of pterulone and some of the synthesized analogues were tested against a wide spectrum of phytopathogenic fungi.

[reaction: see text] From readily accessible starting materials, macrocycles with an endo aryl-aryl ether bond are synthesized in only two operations by combination of the Ugi four-component reaction and an intramolecular S(N)Ar reaction. The nitro group serves as an activator for the macrocyclization and provides a handle for the introduction of functional group diversity. A Ugi reaction promoted by ammonium chloride in aprotic solvent is documented for the first time.