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Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.

A [3 + 2] cycloaddition reaction of unstable difluoromethylphosphonate-containing diazoalkanes with vinyl sulfones under simple reaction conditions is developed, which provides an efficient route toward functionalized fluorinated pyrazolines derivatives in good chemical yields. The difluoro diazoalkanes are generated in situ using t-BuONO for the diazotization of (β-amino-α,α-difluoroethyl)phosphonates, and their stabilities and reactivities were carefully investigated.

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

Orthogonal frequency division multiplexing (OFDM) is an important technology that has been widely used in broadband wireless communications. However OFDM has some drawbacks, one of which is the high peak-to-average power ratio (PAPR) problem. Many techniques for reducing PAPR thus have been proposed in the literatures, where clipping and companding are effective techniques and have gained a lot of research interest. Based on the study of clipping and companding, this paper proposes a hybrid approach to reduce the PAPR of OFDM signals. An iterative clipping and filtering (ICF) technique and an enhanced nonlinear companding (ENC) scheme are used as the typical clipping and companding techniques in this paper. The results of the analysis show that the computational complexity of the proposed method is slightly higher than that of ENC, but much lower than that of ICF. And the simulation results show that the proposed method has better performance on PAPR reduction and bit error rate (BER) in contrast to ICF. On the other hand, compared to ENC with equal PAPR reduction, the proposed method still achieves better performance on BER.

An unprecedented transition-metal-free oxidative reaction of disulfides and amines with Selectfluor as a mild oxidant under aerobic conditions was developed. This reaction was conducted under mild conditions and tolerated a wide range of coupling partners including disulfides and amines, affording the corresponding sulfinamide products in good chemical yields. Furthermore, this reaction could be used in gram-scale synthesis. This reaction enriches the research content of Selectfluor and provides a valuable vista for the convenient synthesis of sulfinamides.

International audience; Herein, we report a general method for quantitative measurement of the con-figurational stability of the stereogenic nitrogen coordinated to M (II) in the corresponding square planar complexes. This stereochemical approach is quite sensitive to steric and electronic effects of the substituents and shown to work well for Ni(II), Pd(II), and Cu(II) complexes. Structural simplicity of the compounds used, coupled with high sensitivity and reliability of experimental procedures, bodes well for application of this approach in evaluation of chemical stability and stereochemical properties of newly designed chiral ligands for general asymmetric synthesis of tailor-made amino acids. KEYWORDS amino acids, chiral HPLC, kinetic of racemization, metal(II) complexes, Schiff bases, stereogenic nitrogen 1 | INTRODUCTION Tailor-made amino acids (AAs), 1 are essential structural features of numerous modern pharmaceuticals. 2 Application of AA residues in drug design allows for fairly accurate 3-D positioning of pharmacophoric moieties and mimicking the targeted biogenic peptide−receptor interactions. 3 Thus, over the past decade, about 20% of newly introduced drugs contained at least one tailor-made AA residue. 2 Consequently, the development of synthetic methodology for preparation of tailor-made AAs is currently in very high demand. 4 Following our long-standing interest in synthesis of sterically constrained 5 and fluorine-containing AAs, 6 we were actively contributing to the general asymmetric synthesis of α-AAs via Ni(II) complexes of AA Schiff bases (Scheme 1). 7

Here we disclose a practical asymmetric synthesis of an enantiomerically 97.8% ee pure N-Fmoc derivative of (S)-2-amino-4,4,4-trifluorobutanoic acid performed on >10 g scale of the target product. The method is based on alkylation (CF3–CH2–I) of a new generation of a chiral nucleophilic equivalent conducted at ambient temperature with an excellent stereochemical outcome. The developed protocol does not require any chromatographic separations and includes only one purification step via recrystallization of the final product.

This review article comprehensively profiles all literature reports (2015-2018) related to the detrifluoroacetylative in situ generation of fluorine-containing enolates and their reactions with electrophilic reagents. The innovative facets of this unconventional methodology and its synthetic generality for the preparation of fluorine-containing compounds of high medicinal value are highlighted.

The development of synthetic methodology allowing for a strategic incorporation of fluorine into target compounds is in a high demand in many areas of the chemical and pharmaceutical industries. In this regard, application of fluorinated chiral sulfinimine reagents, in particularly, N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine, is one of the most general and practical approaches for preparation of compounds containing pharmacophoric fluoro-amino-keto/hydroxy moieties. This article provides a timely and comprehensive overview of the recent synthetic applications of fluorinated chiral sulfinimine reagents for asymmetric synthesis of fluoro-containing polyfunctional amino-compounds of biological interest. Where it is possible, we emphasize the synthetic versatility and practicality of the reported methods.

A photoredox and copper catalyzed asymmetric cyanoalkylation reaction of alkenes has been developed, which uses alkyl N-hydroxyphthalimide esters as alkylation reagents. In this radical cyanoalkylation reaction, the photoredox induced alkyl radical adds to styrene, and the generated benzylic radical couples with a chiral Box/CuII cyanide complex to achieve the enantioselective cyanation. This reaction features mild conditions, operational simplicity, broad substrate scope, high yields, and high enantioselectivities, which represents an efficient method for the asymmetric radical difunctionalization of alkenes.

Owing to the innovative applications of fluorinated compounds in many areas of technology and medicine, methods for the preparation of C-F quaternary fluorine containing compounds are in extremely high demand. Here, we report the discovery of a general procedure for an SN 2 reaction catalyzed by Pd/Ding-SKP-type ligands, and that occurs between Colby pro-enolates with MBH carbonates to afford the corresponding products featuring two consecutive stereogenic carbons, including a C-F quaternary stereogenic center. The reactions readily occur at ambient temperatures with high chemical yields and in excellent chemo-, diastereo- and enantioselective manners. This practically attractive stereochemical outcome, coupled with the operational simplicity and structural generality, bodes well for the synthetic application of this process in the preparation of a novel class of biologically relevant fluorine-containing compounds.

Aryl alkynoate is an important intermediate and powerful synthetic tool in organic chemistry, because it contains acetylene bond which can be easily introduced of different functional groups. During the past decades, several types of reactions and coupling partners have been developed for the functionalization of aryl alkynoates. In this review, we summarize the recent advances on the reactions of aryl alkynoates, including direct cyclization, ester group migration/cyclization, aryl migration/decarboxylation, ipsocyclization/dearomatization, and other reactions in the past decade.

An electrochemical dehydrogenative homo-coupling reaction of imidazopyridine-based heterocycles has been developed, which affords biheteroaryls with good chemical yields and high regioselectivities. This reaction is conducted in a simple undivided cell at room temperature, which avoids the use of any metal-catalysts, additives and oxidants. This reaction tolerates a wide scope of substrates, which provides an easy and green strategy for the preparation of important bioactive biheteroaryl compounds.

Oxydifunctionalization of olefins represents a powerful tool and yet poses a challenging task. Previous methods have usually required a stoichiometric amount of a strong oxidant and an expensive transition-metal catalyst. This work describes the first example of the electrochemical oxysulfuration reaction of olefins with thiols and nucleophilic oxygen sources. This electrochemical difunctionalization reaction is conducted under catalyst- and oxidant-free conditions, and shows good substrate generality, affording thio-substituted alcohols, ethers and γ-lactones in good chemical yields and with excellent regioselectivities. This work represents a new and green strategy for the difunctionalization of olefins, and also provides a complementary and highly valuable prospect for current methodologies for the synthesis of thio-substituted compounds.

The first example of the SN2′ reaction type of the detrifluoroacetylatively in situ generated tertiary fluoro-enolates in the uncatalyzed reactions with Morita–Baylis–Hillman derivatives has been described. The SN2′ substitution takes place in a highly chemoselective manner as no corresponding SN2 products were observed in the reaction mixtures. Due to the excellent stereochemical outcome, the reactions seem to have an apparent synthetic value for the preparation of structurally new fluorinated oxindoles.

We report a new reaction cascade allowing preparation of synthetically important isatin-hydrazones by the reaction of detrifluoroacetylatively in situ generated 3-fluoroindolin-2-one enolates with diethyl azodicarboxylates. The reactions take place under operationally convenient conditions featuring synthetically attractive chemical yields. Plausible mechanistic rationale is discussed.

It was found that properly protected glycinates (Schiff base, alkyl/aryl ester) cleanly react with chiral sulfinyl derived phosphoryldifluoro-aldimines at ambient conditions in THF in the presence of catalytic amounts of Cs2CO3. The procedure is operationally simple providing the target addition products with respected (60-80%) yields and excellent (99/1) diastereoselectivity. This approach allows preparation of novel structural type of biologically interesting molecules representing at the same time the structural features of α-,β-amino, vicinal-diamino, carboxylic and phosphonic acids. Chemo-selective operation of α- and β-amino functional groups is demonstrated by the preparation of all α- and mixed α-/β-amino acid derived dipeptides.

The development of synthetic methodology for preparation of structurally novel and biologically relevant fluorine-containing compounds is currently one of the major areas of research activity. Here we provide a comprehensive summary of the recent advances in detrifluoroacetylative generation and chemistry of fluorine containing tertiary enolates, methodologically promising intermediates for preparation of structurally complex compounds bearing quaternary stereogenic C-F centers along with other known pharmacophoric groups.

The development of new asymmetric methods for preparation of chiral fluorine-containing compounds is in extremely high demand in many areas of chemical research and industry. Herein, we describe a new cascade reaction approach, exemplified by the reactions of, in situ generated fluoro-enolates, with ortho-phthalaldehyde. The reactions proceed through the sequence of detrifluoroacetylation, aldol addition, intramolecular cyclization and oxidation, under convenient conditions with synthetically attractive stereochemical outcome and good structural generality. We demonstrate that these cascade reactions can be performed in catalytic asymmetric mode affording diastereomerically pure products with up to 86% ee.

A copper(II) acetate-catalyzed aerobic thiolation of C=C double bonds, oxygenation, and intramolecular cyclization reactions of unsaturated carboxylic acids with thiols has been explored. The reaction proceeds through a new hydroxysulfenylation-initiated lactonization pathway with carboxyl as electrophilic group, which provides an efficient access to assembly highly valuable thio-substituted lactone derivatives with good yields under mild conditions. Several control experiments, as well as an isotope labelling experiment disclose that oxygen acts as both oxidant and reactant being transferred into the final product. The mechanistic studies support the discovery of a new strategy through difunctionalization of alkenes based on unsaturated carboxylic acids to construct the diversely substituted lactones.

A transition-metal-free oxidative coupling reaction for the synthesis of sulfonohydrazides from two types of hydrazines and potassium metabisulfite under air has been developed. This highly selective reaction used one arylhydrazine as an aryl coupling partner and potassium metabisulfite as a sulfur dioxide precursor, which provides a new and green strategy to sulfonohydrazides.

The first metal-free nitroxyl-radical-mediated β-amination of saturated ketones by using heteroaryl halides as amide precursors has been developed. This reaction proceeds through a cascade α-aminoxylation/Cope-like elimination/aza-Michael addition sequence to afford β-amino ketone derivatives with excellent yields. TEMPO plays multiple roles in the current β-amination process, including those of an oxidant, an α-aminoxylation reagent, a β-hydrogen acceptor, an in situ base, and an oxygen source.

A Cu-catalyzed highly selective aerobic oxidative coupling reaction of hydrazines and amines has been achieved with the use of 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) as sulfonyl group source. The hydrazines were explored as aryl precursors for the coupling reaction with DABSO, which directly reacted with amines without use of any additional additives. The cascade reaction was performed under mild conditions, and tolerated a wide range of substrates affording the corresponding sulfonamides with good chemical yields. This conceptually new method proceeds with the release of nitrogen, which provides an easy and practical strategy for the preparation of sulfonamides.

In this work we report a convenient asymmetric synthesis of Fmoc-(S)-6,6,6-trifluoro-norleucine via alkylation reaction of chiral glycine equivalent. The target amino acid of 99% enantiomeric purity was prepared with 82.4% total yield (three steps).

An eco-friendly and efficient method for the synthesis of organophosphinates via an electrochemical cross-dehydrogenative-coupling reaction between alcohols and secondary phosphine oxides has been developed. This electrochemical reaction was conducted at room temperature without the addition of any oxidant, metal catalyst, or additive, which provides a new strategy for the synthesis of organophosphinates.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

A thiolation initiated cascade reaction of aryl alkynoates has been developed with thiol as a coupling partner. This radical process has been demonstrated to proceed through S-H bond cleavage, thiolation of alkynoate, aryl migration, and decarboxylation. This reaction tolerates a wide scope of substrates resulting in good chemical yields, which provides an easy and practical strategy for preparation of trisubstituted vinyl sulfides.

This work is solely focused on the development of optimized procedures for preparation of various (S)-N-tert-butanesulfinyl-aldimines bearing CHF2, CClF2, CBrF2, CIF2, C2F5, C3F7, C4F9, C4HF8, C5F11 and C6HF12 groups, synthetically valuable reagents for preparation of fluorinated amino-compounds of high pharmaceutical potential.

Synthetic methods for the preparation of compounds containing trifluoromethyl groups are in extremely high demand in nearly every sector of the chemical industry. Over the last several years the chemistry of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine has undergone particular development. Currently, it is commonly used as a versatile reagent for general asymmetric synthesis of trifluoromethyl-containing amines and amino acids of pharmaceutical potential. This review provides a critical and comprehensive overview of synthetic applications of this reagent as well as of several relevant analogues, such as aldimines containing –CHF2, –CClF2, –CBrF2, and –CF2P(O)(OEt)2 groups and N-tert-butylsulfinyl-3,3,3-trifluoromethyl-substituted ketimines. Where it is possible, we emphasize the structural novelty and pharmaceutic value of the products obtainable by application of these reagents.

Herein is reported an N-iodosuccinimide-initiated spirocyclopropanation reaction of styrenes with 1,3-dicarbonyl compounds in the presence of white LED light. The reaction proceeds via two C-H and two C-I bond cleavage event, along with two C-C bond formation event, and formation of quaternary centers. These reactions could be carried out at room temperature and tolerated a wide range of substrates, resulting in good to excellent chemical yields. This developed radical reaction provides easy and practical access to spiro[2.4]heptane-4,7-dione derivatives.

We demonstrate, that the reactions of in situ generated fluoro-enolates with a range of aliphatic aldehydes can be successfully performed using asymmetric catalyst derived from chiral ligand and Cu(OTf) 2 . The enantioselectivity of the formation of two contiguous stereogenic carbons in these additions was excellent, rendering the developed approach as an important methodological advance in asymmetric catalytic reactions of detrifluoroacetylatively generated fluoro-enolates. This process allows preparation of structurally new pharmaceutically interesting class of 1,3-hydroxy ketones containing C-F quaternary stereogenic center adjacent to secondary hydroxy group.

An oxidative reaction for the synthesis of 4-alkyl-substituted dihydroisoquinolin-1(2H)-ones with N-allylbenzamide derivatives as starting materials has been developed. The radical alkylarylation reaction proceeds through a sequence of alkylation and intramolecular cyclization. The substituent on the C–C double bond was found to play a key role for the progress of the reaction to give the expected products with good chemical yields. Additionally, N-methacryloylbenzamides were also suitable substrates for the current reaction and provided the alkyl-substituted isoquinoline-1,3(2H,4H)-diones in good yield.

A sunlight-initiated radical conversion of aryl alkynoates to 3-iodocoumarins has been achieved using N-iodosuccinimide as the iodine source without the use of a catalyst or additive. Experimental, X-ray analysis, and computational studies indicate that the reaction under sunlight proceeds through iodination, spirocyclization and ring expansion to form the kinetic product. The sunlight-driven reaction provides a green pathway to especially valuable 3-halocoumarins derivatives.

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.

An efficient electrochemical 1,2-sulfonylation/alkynylation of alkenes via radical 1,4-alkynyl migration of alkynyl-substituted tertiary alcohols is described, which used sodium sulfinates as sulfonyl sources affording the corresponding α-sulfonyl-β-alkynylated products in moderate to excellent yields. This electrochemical reaction proceeds smoothly without the use of any metal catalyst, additive and oxidant and thus represents a new and eco-friendly strategy for the difunctionalization of unactive olefins, and also the first example of the electrochemical distal radical migration reaction.

An efficient photocatalytic oxidative/reductive cyclization reaction of N-cyanamide alkenes with arylsulfinic acids or arylsulfonyl chlorides, which proceeds through C–S, C–C, and C–N bond formations, is reported. This photocatalytic reaction was carried out under mild conditions, which provides a new strategy for the synthesis of sulfonated quinazolinones. Furthermore, a one-pot procedure to achieve terminal alkenes has been explored via elimination of the obtained sulfonated quinazolinones under basic conditions.

A cascade visible-light photocatalytic difluoroalkylation and intramolecular cyclization reaction has been developed for the synthesis of difluoroalkylated oxygen heterocycles. The reaction was carried out under very mild conditions, affording fluorinated isobenzofuran-1-ones, lactone, and cyclic ethers with up to 97% chemical yields. Furthermore, several types of bromofluoroalkane precursors bearing ester, keto, amido, and phosphate groups could all work very well in this reaction, which provides an easy method for the preparation of functionalized difluoroalkylated oxygen heterocycles.

This work describes, for the first time, Michael addition reactions of tertiary fluoro-enolates in situ generated by detrifluoroacetylation with 1-(1-(phenylsulfonyl) vinylsulfonyl)benzene. Excellent enantioselectivity and chemical yields were achieved with application of catalysts (10 mol %) derived from Cu(OTf)2 and (1S,2S)-1,2-diphenylethane-1,2-diamine. These reactions show a considerable degree of structural generality and allow the preparation of new types of biologically relevant molecules that contain quaternary C-F stereogenic carbon atoms and feature five-, six-, or seven-membered rings as well as heterocyclic 3-fluoro-2,3-dihydrochromen-4-one moieties.

A Ni-catalyzed reductive cross-coupling reaction between two electrophiles, amides and aryl iodides, has been developed. This work is the first example using amide as an electrophile to couple with another electrophile, instead of using highly basic and pyrophoric nucleophiles. Furthermore, the Ni catalyst chemoselectively inserting the C–N bond of amide triggered the reductive cross-coupling reaction, which solves the problem that the Ni catalyst preferentially inserts the more reactive C–I bond to form a self-coupling product.

Reported herein is a Cu(I)/bisoxazoline ligand-catalyzed aldol reaction of unprotected tertiary enolates generated in situ from 3-(1,1-dihydroxy-2,2,2-trifluoroethyl)-substituted derivatives of 3-fluoro-2-oxindoles. A range of α-fluoro-β-aryl/hetaryl/alkyl-β-hydroxy-indolin-2-ones containing C–F quaternary stereogenic centers of high pharmaceutical importance were furnished in good yields and satisfactory diastereo- and enantioselectivities. The reactions were conducted under operationally convenient conditions and displayed wide substrate/functional group generality including unprotected N–H on the tertiary enolates, and aromatic, hetero-aromatic and aliphatic aldehydes.

This review comprehensively profiles perfluoro-3-ethyl-2,4-dimethyl-3-pentyl persistent radical (PPFR) as a new reagent for radical trifluoromethylation, trifluoromethylation/fluorination and polymer initiation. The PPFR is perfectly stable at ambient conditions, but at temperatures above 80 °C undergoes β-scission to generate trifluoromethyl radical. This property can be used to initiate various chain-polymerization or trifluoromethylation reactions. The unique feature of this process, distinguishing it from all other known methods for ·CF3-radical generation, is that the radical is produced under neutral, inert and additive-free conditions. Hopefully, the mild reaction conditions and commercial availability of PPFR will generate research interest for practical applications of this novel perfluorination reagent for fluorination and polymerization processes.

An unexpected Cu-catalyzed deoxygenative C2-sulfonylation reaction of quinoline N-oxides in the presence of radical initiator K2S2O8 was developed that used sodium sulfinate as a sulfonyl coupling partner. The mechanism studies indicate that the reaction proceeds via Minisci-like radical coupling step to give sulfonylated quinoline with good chemical yields.

The first asymmetric catalytic aldol–cyclization reaction of detrifluoroacetylatively in situ generated enolates with methyl 2-formylbenzoate is reported. This reaction tolerates a wide range of substrates, affording fluorinated quaternary stereogenic α,α-dialkyl/cyclo-alkyl-β-ketoesters with good yields, high diastereo- (94% de) and enantioselectivity (96% ee) at room temperature.

A new chiral reagent has been developed for generalized installation of pharmacophoric (S)- or (R)-2-(alkoxyphosphono)-1-amino-2,2-difluoroethyl group into organic compounds. The original synthetic application of this new reagent is exemplified by Friedel-Crafts reactions with indoles, which proceed efficiently with excellent diastereoselectivity to give enantiomerically pure products.

An efficient cascade trifunctioalization reaction of alkynoates with N-iodosuccinimide has been developed which proceeds through iodination, aryl migration, decarboxylation, and second iodination. This reaction represents an example of 1,1-difunctionalization of the acetylene bond and also provides a new strategy for the preparation of 1,1-diiodoalkenes.