Expanding Radical Chloropentafluorosulfanylation of Alkynes.

The chloropentafluorosulfanylation of alkynes is a delicate but crucial operation for accessing SF5-alkynes that serve as substrates in numerous transformations. Dolbier's procedure using Et3B/O2 was the most efficient approach, while recent efforts make use of other initiators and light activation. We found that THF, as a single stimulus, is sufficient to trigger the reaction of SF5Cl with alkynes. We determined the configuration of Cl/SF5 products and clarified the structure of side-products.

Palladium-Catalyzed Regioselective Synthesis of 2-SF5 -Indenols and Further Derivatizations.

A palladium-catalyzed synthesis of 2-SF5 -indenols has been developed by reacting commercially available boronic acid derivatives and readily accessible SF5 -alkynes. The present methodology is fully regioselective thanks to the intrinsic polarization of SF5 -alkynes. A selection of downstream functionalizations has been performed to highlight the versatility of 2-SF5 -indenols and indenones as platforms for the design of more complex SF5 -containing molecules.

Divergent Synthesis of 6- or 7-Aza-Indazoles via Intramolecular Diels-Alder Cascade of Pyrazines.

Pyrazines are reactive 4π partners in intermolecular Diels-Alder cycloaddition with exceptionally activated dienophiles or in an intermolecular version at elevated temperatures. Herein, it is shown that an intramolecular cascade could occur even at room temperature, delivering a collection of 6- or 7-aza-indazoles. An interesting substituent effect of the cycloaddition precursor on the product distribution was uncovered, and in situ NMR studies were conducted to gain insights into this unexpected selectivity.

Tracking SF5 I in the Iodopentafluorosulfanylation of Alkynes.

In the vibrant field of SF5 chemistry, SF5 X reagents (X=F, Cl, Br) are at the heart of current investigations in radical pentafluorosulfanylation reactions. SF5 I is the missing link whose existence has not been reported despite its potential as SF5 donor. This study reports the formal addition of the hitherto unknown SF5 I reagent to alkynes by means of a combination of SF5 Cl/KI/18-crown-6 ether. The exclusive regio- and stereoselective synthesis of unprecedented (E)-1-iodo-2-(pentafluoro-λ6 -sulfanyl) alkenes was achieved. A consensus was reached through computational and mechanistic studies for the realistic formation of SF5 - anion but not SF5 I in solution and the rational involvement of SF5 ⋅ and iodine radicals in the iodo pentafluorosulfanylation reaction.

Copper-Catalyzed, Ligand-Controlled N(sp3)- or N(sp)-Selective Arylation of Cyanamides.

Cyanamides possess both nucleophilic and electrophilic centers, and their arylation reactions are known to proceed at N(sp3) and C(sp) sites, leading to N-aryl cyanamides or amidines. N(sp) selectivity has also been reported only in the presence of amines, thus leading to guanidines. Herein, we report a general copper-catalyzed ligand-controlled Chan-Lam-Evans arylation of cyanamides proceeding regioselectively at the N(sp3) or N(sp) atoms and leading to either N-aryl cyanamides or dissymmetric carbodiimides. The nature of the ligand, either a bipyridine or a diamine, controls the product distribution and thus offers a divergent entry to useful building blocks from readily available cyanamides.

Regio- and Stereoselective Hydroelementation of SF5 -Alkynes and Further Functionalizations.

Herein is described a fully regio- and stereoselective hydroelementation reaction of SF5 -alkynes with N, O and S-nucleophiles and further functionalization of the corresponding Z-(hetero)vinyl-SF5 intermediates, a suitable platform to access α-SF5 ketones and esters, ß-SF5 amines and alcohols under mild reaction conditions. Experimental and computational comparative studies between SF5 - and CF3 -alkynes have been performed to highlight and explain the difference of reactivity and selectivity observed between these two fluorinated motifs.

Synthesis and Physicochemical Properties of 2-SF5-(Aza)Indoles, a New Family of SF5 Heterocycles.

Structural diversity in heterocyclic chemistry is key to unlocking new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promise. Herein is described a strategy to access 2-SF5-(aza)indoles for the first time. The sequence relies on the radical addition of SF5Cl to the alkynyl π-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed, making this strategy very appealing and reproducible on a gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, pK a, log P, and differential scanning calorimetry measurements of several fluorinated 2-Rf-indoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as an indole.

Ligand-Controlled Regiodivergent Palladium-Catalyzed Hydrogermylation of Ynamides.

Ynamides are fascinating small molecules with complementary reactivities under radical, ionic, and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydrometalation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent α,E- or ß,E-selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metalated enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans-geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, these calculations support the prevalence of a hydro-palladation pathway over a metal palladation of the π system of the ynamide.

Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions.

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoroacetylation of 2-hydrazonylpyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.

Acid Fluorides in Transition-Metal Catalysis: A Good Balance between Stability and Reactivity.

Several recent reports outlined the singular reactivity of acid fluorides as excellent electrophiles in transition-metal catalysis. These species undergo oxidative addition of the metal into the C-F bond; then, retention or release of the CO moiety can occur and be controlled by tuning the catalytic system and the reaction parameters. Acid fluorides, which can be derived from carboxylic acids, show good stability and high reactivity in a wide range of possible functionalizations with nucleophiles. Their use provides an interesting alternative to that of the parent carboxylic acid derivatives (acid chlorides, esters, amides, acids, or aldehydes).

Palladium-Catalyzed Enantioselective Intermolecular Carboetherification of Dihydrofurans.

A novel enantioselective Pd-catalyzed intermolecular carboetherification of dihydrofurans is reported. The in situ generation of chiral bis-phosphine mono-oxide ligands is crucial, and a general catalytic system has been identified based on this approach. It provides access to a variety of fused tetrahydrofurobenzofurans in consistently high yield and enantiomeric excess.

Sulfur imidations: access to sulfimides and sulfoximines.

Being mono-aza analogues of sulfoxides and sulfones, sulfimides and sulfoximines, respectively, are important compounds in asymmetric synthesis, crop protection and medicinal chemistry. For their preparation various methods have been developed. In the search for the optimal synthetic approach for a given target compound, several parameters have to be considered which also include safety issues and availability of starting materials. In this tutorial review, we present an overview of sulfur imidation methods, classified by imidating agents and compounds with a related behaviour. The aim of this survey is to provide a practical "tool box" for the synthetic chemist by mapping the advantages and disadvantages associated with the use of these compounds.

Access to enantioenriched 2,3- and 2,5-dihydrofurans with a fully substituted C2 stereocenter by Pd-catalyzed asymmetric intermolecular Heck reaction.

A palladium-catalyzed intermolecular asymmetric Heck reaction with dihydrofurans with a trisubstituted double bond is reported. The use of two different chiral ligands provides access to valuable 2,3- and 2,5-dihydrofurans with a fully substituted C2 stereocenter with high levels of regio- and enantiocontrol.

Fluorine as a control element in asymmetric synthesis.

The installation of fluorine atoms in reactants or catalysts has a dramatic impact on reactivity, regioselectivity and stereoselectivity. Several effects account for the modified stereochemical outcome of reactions with fluorinated versus non-fluorinated molecules. These effects are inherent to the specific properties of fluorine such as the size, the electronegativity, the chelation with metal cations, the hydrogen-bonding ability, the electrostatic and stereoelectronic interactions with neighbouring groups. The use of the effects of fluorine for a desirable goal in asymmetric synthesis is exemplified hereafter.

Light-induced ruthenium-catalyzed nitrene transfer reactions: a photochemical approach towards N-acyl sulfimides and sulfoximines.

1,4,2-Dioxazol-5-ones are five-membered heterocycles known to decarboxylate under thermal or photochemical conditions, thus yielding N-acyl nitrenes. Described herein is a light-induced ruthenium-catalyzed N-acyl nitrene transfer to sulfides and sulfoxides by decarboxylation of 1,4,2-dioxazol-5-ones at room temperature, thus providing direct access to N-acyl sulfimides and sulfoximines under mild reaction conditions. In addition, a one-pot sulfur imidation/oxidation sequence catalyzed by a single ruthenium complex is reported.

Fluorinated sulfoximines: syntheses, properties and applications.

The interest in fluorinated sulfoximines has rapidly increased over the past twenty years. As sulfoximines are analogues of sulfones where one of the two S[double bond, length as m-dash]O units has been replaced by an S[double bond, length as m-dash]N moiety, they can confer new reactivities and properties never observed for the respective sulfones. In this tutorial review, we present the specific properties of fluorinated sulfoximines (including important bioactivities) and describe the syntheses and the applications of fluoromethyl transfer agents such as Johnson's reagent. Furthermore, we highlight the exceptional electronic effects induced by the presence of strongly electron-withdrawing fluoro-bearing sulfonimidoyl moieties, which allowed the development of remarkable super-acidifiers and super-acceptors with relevance in materials sciences.

Recent progress in asymmetric fluorination and trifluoromethylation reactions.

All domains of society are impacted by fluorine chemistry. In particular, fluorine plays a key role in medicinal, pharmaceutical and agrochemical sciences in which the synthesis and evaluation of molecules featuring one or more fluorine atoms is nowadays routine in every new discovery and development program. Since the beginning of this century, enantiopure fluorinated molecules are at the forefront of innovation of the tremendous achievements in fluorine chemistry. This review introduces the reader to the recent progress in asymmetric installation of one fluorine and a trifluoromethyl group via nucleophilic, electrophilic and radical diastereo- and enantioselective reactions.

The influence of fluorine in asymmetric catalysis.

All domains of chemistry are increasingly impacted by organofluorine molecules, often favorably. In asymmetric synthesis of fluorinated compounds, significant achievements are the result of extensive research efforts toward appropriate experimental conditions rather than of the rationalization of fluorine effects. Most of the time, the influence of fluorine is inspected retrospectively. When elaborating a synthetic plan, the question should not be only when and how to introduce fluorine but also how to use the effects of fluorine for a desirable result. The subtle effects of fluorine atom(s) on the course of asymmetric reactions are outlined in this tutorial review. We present some selected examples of asymmetric reactions that involve fluorinated components either as reactants, catalysts, solvents or additives, and a comparative study of the stereochemical outcomes with reactions carried out in the presence of non-fluorinated analogues.

Ruthenium-catalyzed redox isomerization of trifluoromethylated allylic alcohols: mechanistic evidence for an enantiospecific pathway.

Transfer news: A synthetic approach to chiral ß-CF(3)-substituted saturated carbonyl compounds has been developed in which ruthenium complexes efficiently catalyze the redox isomerization of CF(3)-bearing allylic alcohols by an intramolecular suprafacial enantiospecific 1,3-hydrogen transfer (see scheme). This method was used for the enantioselective synthesis of (S)-CF(3)-citronellol.

Synthesis of α-CF3-substituted carbonyl compounds with relative and absolute stereocontrol using electrophilic CF3-transfer reagents.

Evans-type chiral lithium imide enolates undergo diastereoselective α-trifluoromethylation with a hypervalent iodine-CF(3) reagent with up to 91% combined isolated yield and 97:3 dr. The resulting isolated diastereopure products can be further transformed into valuable products without racemization.