Carbon–Fluorine Bond Formation

We present a selection of carbon–fluorine bond formations that have been developed in the recent past. An overview of the most common fluorination reagents is followed by fluorination reactions organized by reactivity. We have distinguished between nucleophilic and electrophilic fluorinations as well as aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for syntheses of pharmaceuticals, $^{18}$F-radiolabeling, and mechanistic investigations are provided.Chemistry and Chemical Biolog

Ionic liquids: A pharmaceutical perspective

In the last decades, ionic liquids (ILs) progressed from chemical curiosities to interesting biological compounds apprehending the attention of researchers of distinct areas, from chemistry to pharmacology. Initially, ILs were explored as materials for diverse applications due to the possibility of synthesize compounds with targeted chemical properties combined with selected physical properties. More recently, the emergence of ILs with biological activity revolutionized the scientific focus of these compounds and opened interesting perspectives regarding their pharmaceutical application. From the pharmaceutical point of view, an IL approach, in the design of novel active pharmaceutical ingredients (APIs), appears to be appropriate as it enables the chemical manipulation of the compounds with specific objectives related with the manufacturing process, the stability of the formulation, bioavailability and eventual adverse effects. Furthermore, even though crystallinity confers advantages during isolation, processing and storage of the drug, it is known that solid forms of APIs often suffer from low solubility and polymorphic conversion which can influence negatively the bioavailability of the drug and ultimately its therapeutic effect. On a distinct perspective, the possibility of engineering the properties of ILs by manipulating anion-cation combinations, in association with their solvent properties and in some cases water-miscibility, are considered promising characteristics regarding the applicability of ILs as solvents or carriers of pharmaceutical drugs. In this chapter it is intended to expose the pharmaceutical potential of ILs through the discussion of their utilization either as APIs or solvents/carriers of pharmaceutical drugs. The discussion will be centered on the benefits of the IL approach for the development of novel drug candidates considering not only physico-chemical aspects but also the pharmaceutical profile of the developed active pharmaceutical ingredients with IL properties. Considering the utilization of ILs as solvents of drugs or as part of drug delivery systems, it is anticipated that the discussion will be focused on the efficiency and toxicity of the systems and on their influence on the pharmacokinetics and pharmacodynamics of the vehiculated drugs. It is also planned to debate the motivations for the pharmaceutical usage of ILs as well as their peculiar properties that launched them in this context. Currently, the pharmaceutical utilization of ILs is one of the most relevant applications of these solvents, with impact on the safety and effectiveness of the involved processes and with benefits in terms of pharmaceutical formulations and pharmacological activity. It is our belief that this chapter is adequate for the book in project and can greatly enhance its acceptance and interest by readers in distinct research areas

Advances in Functionalized Ionic Liquids as Reagents and Scavengers in Organic Synthesis

Functionalized ionic liquids (FILs) synthesized with specific desired chemical properties have shown promising results in various areas of organic synthesis. In supported organic synthesis, FILs have become known as a new alternative to commonly used PEG and fluorous soluble supports. This review summarizes the progress of recent development in the synthesis of functionalized ionic liquids with emphasis on their applications as reagents and scavengers in organic synthesis

Synthesis of Pyrazolo-Fused 4-Azafluorenones in an Ionic Liquid. Mechanistic Insights by Joint Studies Using DFT Analysis and Mass Spectrometry

A series of pyrazolo-fused 4-azafluorenones (indeno[1,2-b]pyrazolo[4,3-e]pyridines, IPP) were synthesized via the three-component reaction between arylaldehydes, 3-methyl-1H-pyrazol- 5-amine and 1,3-indanedione in an ionic liquid as a catalyst at room temperature. The applied synthetic route has the advantages of easy work-up under mild reaction conditions presenting moderate yields and an environmentally benign procedure. A theoretical study based on conceptual-density functional theory has been done, bond reactivity indices have been calculated and an electrophilic and nucleophilic character of localized orbitals has been determined to analyze the possible electronic mechanisms

Recent Advances in the Synthesis of Carboxylic Acid Esters

In this chapter, recent advances in the synthesis of carboxylic acid esters are summarized based on the utilization of carboxylic acids as electrophiles or nucleophiles in reactions. Condensation reagents or catalysts connect the carboxylic acids with the alcohols to afford the corresponding esters, together with the formation of 1 equiv. of H2O, in which the carboxylic acids can be regarded as the electrophile. In contrast, the carboxylate ion intermediates derived from the carboxylic acids react with alkyl halides, carbocations, or their equivalents to produce the esters, in which the carboxylate ions from the carboxylic acids can be regarded as the nucleophile. This chapter mainly introduces the recent progress in this field of the formation of esters, based on the classification of the role of carboxylic acids in reactions

Microwave-Assisted Esterification of N-Acetyl-L-Phenylalanine Using Modified Mukaiyama's Reagents: A New Approach Involving Ionic Liquids

Inspired by the concept of ionic liquids (ILs), this study modified the original Mukaiyama's reagent, 2-chloro-1-methylpyridinium iodide (m.p. 200-dec), from ionic solid into liquids by changing its anion. The esterification of N-acetyl-L-phenylalanine was investigated as a model reaction. The microwave irradiation was more effective in esterifying N-acetyl-L-phenylalanine than the conventional reflux method. The original Mukaiyama's reagent was modified into ILs through manipulating its anion. However, only non-nucleophilic anions (such as EtSO4– and Tf2N–) were favorable since nucleophilic ones (such as CF3COO– and CH3COO–) could exchange with chlorine resulting in non-reactive coupling reagents. Two modified Mukaiyama's compounds (i.e. hydrophilic [2-ClMePy][EtSO4] and hydrophobic [2-ClMePy][Tf2N]) have been identified as the best ILtype coupling reagents. The esterification reaction was greatly enhanced by using 1- methylimidazole as the base instead of conventional toxic tertiary amines, and by using excess amount of alcohols as solvents instead of dichloromethane. Overall, the method reported is effective and ‘greener’

On the real catalytically active species for CO2 fixation into cyclic carbonates under near ambient conditions: dissociation equilibrium of [BMIm][Fe(NO)2Cl2] dependant on reaction temperature

An imidazolium based iron-containing ionic liquid [BMIm][Fe(NO)2Cl2] (BMIm = 1-n-butyl-3-methyl-imidazolium) has been synthesized for the first time and fully characterized employing a wide range of techniques. The iron-based containing ionic liquid was found to be an active catalyst for the cycloaddition of CO2 to epoxides, giving high conversions for various substrates under near ambient conditions. In addition, the catalytic system showed a good recycling performance for five consecutive reaction cycles. Key mechanistic studies demonstrated that a bifunctional catalytic system is generated in situ by the partial dissociation of the iron-based ionic liquid into [BMIm][Cl], which results in a very efficient catalyst without the need of any additive or co-catalyst. The metal center plays a role as Lewis acid and activate the epoxide group, and the chloride anion, as part of [BMIm][Cl] moiety, acts as nucleophile and leads to the ring opening through a nucleophilic attack on the less sterically-hindered Cβ. The process is favoured by an interaction via H-bonding between the substrate and the H–C2 of the imidazolium ring, as was demonstrated by additional experiments. Kinetic studies indicated that the process followed first-order kinetics with respect to epoxide concentration and proved the existence of a reversible coordination/de-coordination equilibrium in which the active species are generated from the [BMIm][Fe(NO)2Cl2] complex

Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13