Frédéric R. Leroux

Recent advances in transition metal-catalyzed Csp2-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

Summary 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, –CnF2 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.

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

Summary 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.

Trifluoromethyl Ethers and –Thioethers as Tools for Medicinal Chemistry and Drug Discovery

The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.

Atropisomerism, biphenyls, and fluorine: a comparison of rotational barriers and twist angles.

Axially chiral biaryl compounds are attracting more and more attention. One reason is the growing number of known biologically active natural products that contain the biaryl motif (for example, vancomycin, steganone, and michellamine). Furthermore, the stereogenic axes provide rigid molecular frameworks for highly efficient tools in asymmetric synthesis, such as chiral ligands like BINAP and Meo-BIPHEP, just to mention two of the most prominent ones. The biaryl core is also commonly encountered in the liquid-crystal field, where its derivatives have found commercial application. Moreover, the biphenyl unit belongs to the group of six or seven privileged structures, reputated to be TMsafe bets∫ in pharmaceutical research because they guarantee versatility and high hit rates. The stretched and slim shape of this aromatic unit enables it to intercalate in the empty space between transmembrane-receptor helices and to be recognized as an unnatural ligand. For example, the biaryl unit is a key feature in the sartan family of drugs for high blood pressure: losartan (Merck, Sharpe and Dohme trademarks: Cozaar, Lorzaar), valsartan (Novartis trademark: Diovan), irbesartan (Bristol±Myers Squibb trademark: Aprovel), or candesartan (Astra trademark: Atacand). Similarly, the biaryl unit can dive into deep pockets or long clefts of enzymes. In this way, 3’and 4’-substituted biphenyl derivatives were recognized as extremely potent 17a-hydroxylase-C17,20-lyase (P-45017) inhibitors. [9] They could become promising substances for the treatment of steroidal-hormonedependent cancers, in particular prostate cancer. In view of the increasing importance of axially chiral biaryls, attention has to be paid to the stereoisomerism, called atropisomerism, that arises from the hindered rotation about the sp±sp carbon±carbon single bond. In this article, the influence of fluorine, the only element capable of mimicking hydrogen by virtue of comparable size (TMisosterism∫), will mainly be considered, in particlular how it alters the electronic and geometric properties of the biaryl unit.

The “Aryne” Route to Biaryls Featuring Uncommon Substituent Patterns†

The reaction of 1-bromo-3-halo-2-iodobenzene (I; X = Cl) with butyllithium gives 62% (II; X = Cl) similarly reaction of [I; X = F(III)] gave 64% II (X = F). These reactions involve the immediate intermediacy of the halolithiobiphenyl (IV) and the penultimate intermediate (V); V decomps. to give the corresponding benzyne VI which then reacts with addnl. V to give IV. Similarly, reaction of III with butyllithium and gives 79% VII (R = Br) via intermediacy of labile 2-BrC6H4Li (VIII) and V (X = F); VIII decomps. to VI (X = F), at temps. > -125 Deg, which then combines with the more stable V (X = F) to give the immediate intermediate to VII (R = Br), namely VII (R = Li). [on SciFinder (R)]

α-Fluorinated Ethers as “Exotic” Entity in Medicinal Chemistry

After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacologic drugs, neurological drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chemistry.

Switchable reactivity: the site-selective functionalization of trifluoromethyl-substituted pyrazoles

Modern organometallic methods enable the regioflexible conversion of simple heterocyclic starting materials into families of isomers and congeners. Depending on the choice of the reagent, 1-methyl-5-(trifluoromethyl)pyrazole undergoes deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached Me group. Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole and 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole are selectively attacked by lithium diisopropylamide at the heterocyclic 4-position and by butyllithium concomitantly at the 4-position and the ortho position of the Ph ring. In contrast, metalation of 1-methyl-3-(trifluoromethyl)pyrazole occurs only at the 5-position, whatever the organometallic or metal amide base. Further sites become accessible to functionalization if bromine is introduced into the heterocyclic or arom. ring. This has been demonstrated with 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole, 4-bromo-1-methyl-3-(trifluoromethyl)pyrazole, 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole and 1-(2-bromophenyl)-5-(trifluoromethyl)pyrazole. [on SciFinder (R)]

Efficient synthesis of quaternary and P-stereogenic phosphonium triflates.

An efficient and general method for the preparation of achiral and chiral phosphonium salts is reported. This synthesis is based on the quaternization of phosphines and their derivatives with arynes generated in situ from 2-(trimethylsilyl)aryl triflates. This methodology is successfully applied to the synthesis of new valuable P-stereogenic phosphonium triflates.

Stereoselective Synthesis of o-Bromo (or Iodo)aryl P-Chirogenic Phosphines Based on Aryne Chemistry

The efficient synthesis of chiral or achiral tertiary phosphines bearing an o-bromo (or iodo)aryl substituent is described. The key step of this synthesis is based on the reaction of a secondary phosphine borane with the 1,2-dibromo (or diiodo)arene, owing to the formation in situ of an aryne species in the presence of n-butyllithium. When P-chirogenic secondary phosphine boranes were used, the corresponding o-halogeno-arylphosphine boranes were obtained without racemization in moderate to good yields and with ee up to 99%. The stereochemistry of the reaction, with complete retention of the configuration at the P atom, has been established by X-ray structures of P-chirogenic o-halogenophenyl phosphine borane complexes. The decomplexation of the borane was easily achieved without racemization using DABCO to obtain the free o-halogeno-arylphosphines in high yields.

Palladium-catalyzed intramolecular direct arylation of 2-bromo-diaryl sulfoxides via C-H bond activation.

Efficient access to dibenzothiophene-S-oxides from differently substituted 2-bromo-diarylsulfinyl moieties using ligandless Pd(OAc)2 as the catalyst and KOAc as the base in dimethylacetamide at 130 °C is reported. Various dibenzothiophene-S-oxides were obtained in excellent yields.