Highly Regioselective Remote Lithiation of Functionalized 1,3‐bis‐Silylated Arenes

Substituted arenes flanked by two bulky triethylsilyl groups were regiospecifically lithiated at the 5‐position with nBuLi?PMDTA at 25 °C. The resulting aryllithiums reacted with a broad range of electrophiles such as ketones, isocyanates, Weinreb amides, allyl bromides, and CO₂ at 25 °C. These bis‐silylated arenes were then converted in simple reaction sequences into silyl‐free tetrasubstituted arenes. This remote lithiation was extended to 2,6‐bis(triethylsilyl)pyridine as well as 3,3′‐bis(triethylsilyl)biphenyl.     

One‐Pot Halogen Dance/Negishi Coupling of Dibromothiophenes for Regiocontrolled Synthesis of Multiply Arylated Thiophenes

One‐pot halogen dance/Negishi cross‐coupling of readily available 2,5‐dibromothiophenes is described. A lithium diisopropylamide (LDA)‐mediated halogen dance reaction resulted in the formation of thermodynamically stable α‐lithiodibromothiophenes, which were transmetalated with ZnCl₂ and subjected to Negishi cross‐coupling to provide the corresponding arylated dibromothiophenes in one pot. The resultant β‐bromo group was much less reactive than the remaining α‐bromo group, which was used in a one‐pot double Suzuki–Miyaura cross‐coupling, enabling facile synthesis of multiply arylated thiophenes.     

Transforming LiTMP Lithiation of Challenging Diazines through Gallium Alkyl Trans‐Metal‐Trapping

This study establishes a new trans‐metal‐trapping (TMT) procedure based on a mixture of LiTMP (the base) and tris(trimethylsilylmethyl)gallium [Ga(CH₂SiMe₃)₃, GaR₃] (the trap) that, operating in a tandem manner, is effective for the regioselective deprotonation of sensitive diazines in hydrocarbon solution, as illustrated through reactions of pyrazine, pyridazine, and pyrimidine, as well as through the N‐S heterocycle benzothiazole. The metallo‐activated complexes of all of these compounds were isolated and structurally defined.     

Lithiation of optically active oxazolinyloxiranes: configurational stability

The α-lithiation reaction of optically active oxazolinyloxiranes has been investigated. The trapping reaction with D₂O, MeI and acetone affording substituted oxazolinyloxiranes proved that the corresponding lithiated species are configurationally unstable. A stereoconvergency was observed in the case of lithiation-deuteration sequence of two oxazolinyloxiranes.     

Continuous-Flow Synthesis of Arylthio-Cyclopropyl Carbonyl Compounds

The straightforward, continuous-flow synthesis of cyclopropyl carbaldehydes and ketones has been developed starting from 2-hydroxycyclobutanones and aryl thiols. This acid-catalyzed mediated procedure allows access to the multigram and easily scalable synthesis of cyclopropyl adducts under mild conditions, using reusable Amberlyst-35 as a catalyst. The resins, suitably ground and used for filling steel columns, have been characterized via TGA, ATR, SEM and BET analyses to describe the physical–chemical properties of the packed bed and the continuous-flow system in detail. To highlight the synthetic versatility of the arylthiocyclopropyl carbonyl compounds, a series of selective oxidation reactions have been performed to access sulfoxide and sulfone carbaldehyde cyclopropanes, oxiranes and carboxylic acid derivatives.     

Halogen Bonding Between Anions: Association of Anion Radicals of Tetraiodo-p-benzoquinone with Iodide Anions

Halogen bonding between two negatively charged species, tetraiodo-p-benzoquinone anion radicals (I₄Q^−.) and iodide anions, was observed and characterized for the first time. X-ray structural and EPR/UV–Vis spectral studies revealed that the anion–anion bonding led to the formation of crystals comprising 2D layers of I₄Q^−. anion radicals linked by iodides and separated by Et₄N⁺ counter-ions. Computational analysis suggested that the seemingly antielectrostatic halogen bonds in these systems were formed via a combination of several factors. First, an attenuation of the interionic repulsion by the solvent facilitated close approach of the anions leading to their mutual polarization. This resulted in the appearance of positively charged areas (σ-holes) on the surface of the iodine substituents in I₄Q^−. responsible for the attractive interaction. Finally, the solid-state associations were also stabilized by multicenter (4:4) halogen bonding between I₄Q^−. and iodide.     

Halogen bond versus hydrogen bond: The many‐body interactions approach

The analysis of interrelation between halogen bond and hydrogen bond in the (RX)(HNC)(HCN) complexes (R = CH₃, CF₃ and X = Cl, Br, I) was performed on the basis of DFT calculations. Both two‐body additive contributions and three‐body nonadditive contributions to the total interaction energy were discussed. QTAIM was used for topological analysis of electron density. Additionally, QTAIM analysis of electron density was performed for both two‐ and three‐body complexes. The electron charge transfer in trimers showed the dual character of the fragment with halogen atom involved into the investigated interactions—it acts as Lewis acid and Lewis base, depending on the type of interaction considered. The effect of cooperativity of X‐ and H‐bonding was assessed on the basis of many‐body interaction energy and electron density analysis. Additionally, an alternative two‐body model with the same situation (in the context of intermolecular interactions) is investigated. The anti‐cooperative effect was found also for this model.     

Benchmarking of Halogen Bond Strength in Solution with Nickel Fluorides: Bromine versus Iodine and Perfluoroaryl versus Perfluoroalkyl Donors

The energetics of halogen bond formation in solution have been investigated for a series of nickel fluoride halogen bond acceptors; trans-[NiF(2-C₅NF₄)(PEt₃)₂] ( A1 ), trans-[NiF{2-C₅NF₃(4-H)}(PEt₃)₂] ( A2 ), trans-[NiF{2-C₅NF₃(4-NMe₂)}(PEt₃)₂] ( A3 ) and trans-[NiF{2-C₅NF₂H(4-CF₃)}(PCy₃)₂] ( A4 ) with neutral organic halogen bond donors, iodopentafluorobenzene ( D1 ), 1-iodononafluorobutane ( D2 ) and bromopentafluorobenzene ( D3 ), in order to establish the significance of changes from perfluoroaryl to perfluoroalkyl donors and from iodine to bromine donors. ¹⁹F NMR titration experiments have been employed to obtain the association constants, enthalpy, and entropy for the halogen bond formed between these donor-acceptor partners in protiotoluene. For A2 – A4 , association constants of the halogen bonds formed with iodoperfluoroalkane ( D2 ) are consistently larger than those obtained for analogous complexes with the iodoperfluoroarene ( D1 ). For complexes formed with A2 – A4 , the strength of the halogen bond is significantly lowered upon modification of the halogen donor atom from I (in D1 ) to Br (in D3 ) (for D1 : 5≤K₂₈₅≤12 m ⁻¹, for D3 : 1.0≤K₁₉₃≤1.6 m ⁻¹). The presence of the electron donating NMe₂ substituent on the pyridyl ring of acceptor A3 led to an increase in −ΔH, and the association constants of the halogen bond complexes formed with D1 – D3 , compared to those formed by A1 , A2 and A4 with the same donors.     

Halogen Bonding Between Anions: Association of Anion Radicals of Tetraiodo‐p‐benzoquinone with Iodide Anions

Halogen bonding between two negatively charged species, tetraiodo‐p‐benzoquinone anion radicals (I₄Q^?.) and iodide anions, was observed and characterized for the first time. X‐ray structural and EPR/UV–Vis spectral studies revealed that the anion–anion bonding led to the formation of crystals comprising 2D layers of I₄Q^?. anion radicals linked by iodides and separated by Et₄N⁺ counter‐ions. Computational analysis suggested that the seemingly antielectrostatic halogen bonds in these systems were formed via a combination of several factors. First, an attenuation of the interionic repulsion by the solvent facilitated close approach of the anions leading to their mutual polarization. This resulted in the appearance of positively charged areas (σ‐holes) on the surface of the iodine substituents in I₄Q^?. responsible for the attractive interaction. Finally, the solid‐state associations were also stabilized by multicenter (4:4) halogen bonding between I₄Q^?. and iodide.     

Theoretical Insights into the Nature of Halogen Bonding in Prereactive Complexes

Benchmark quality geometries and interaction energies for the prereactive halogen‐bonded complexes of dihalogens and ammonia, including hypothetical astatine containing dihalogens, have been produced via explicitly correlated coupled cluster methods. The application of local electron correlation partitioning reveals dispersion, electrostatics and ionic substitutions all contribute significantly to the interaction energy, with a linear relationship between the ionic substitutions and the degree of charge transfer. Potential energy curves for H₃N???ClF show that as the relative orientations of the two subunits are manipulated appreciable interactions can be found at considerably angular displaced geometries, signifying lower directionality in halogen bonding than previously supposed.     

An All‐Halogen Bonding Rotaxane for Selective Sensing of Halides in Aqueous Media

The synthesis and anion binding properties of the first rotaxane host system to bind and sense anions purely through halogen bonding, is described. Through a combination of polarized iodotriazole and iodotriazolium halogen bond donors, a three‐dimensional cavity is created for anion binding. This rotaxane incorporates a luminescent rhenium(I) bipyridyl metal sensor motif within the macrocycle component, thus enabling optical study of the anion binding properties. The rotaxane topology was confirmed by single‐crystal X‐ray structural analysis, demonstrating halogen bonding between the electrophilic iodine atoms and chloride anions. In 50 % H₂O/CH₃CN solvent mixtures the rotaxane host exhibits strong binding affinity and selectivity for chloride, bromide, and iodide over a range of oxoanions.     

Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow

Ethyl diazoacetate (EDA) is one of the most prominent diazo reagents. It is frequently used in metal–carbene‐type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopropylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.     

Strategic Application of Residence-Time Control in Continuous-Flow Reactors

As a sustainable alternative for conventional batch-based synthetic techniques, the concept of continuous-flow processing has emerged in the synthesis of fine chemicals. Systematic tuning of the residence time, a key parameter of continuous-reaction technology, can govern the outcome of a chemical reaction by determining the reaction rate and the conversion and by influencing the product selectivity. This review furnishes a brief insight into flow reactions in which high chemo- and/or stereoselectivity can be attained by strategic residence-time control and illustrates the importance of the residence time as a crucial parameter in sustainable method development. Such a fine reaction control cannot be performed in conventional batch reaction set-ups.     

Continuous-Flow Chemistry and Photochemistry for Manufacturing of Active Pharmaceutical Ingredients

An active pharmaceutical ingredient (API) is any substance in a pharmaceutical product that is biologically active. That means the specific molecular entity is capable of achieving a defined biological effect on the target. These ingredients need to meet very strict limits; chemical and optical purity are considered to be the most important ones. A continuous-flow synthetic methodology which utilizes a continuously flowing stream of reactive fluids can be easily combined with photochemistry, which works with the chemical effects of light. These methods can be useful tools to meet these strict limits. Both of these methods are unique and powerful tools for the preparation of natural products or active pharmaceutical ingredients and their precursors with high structural complexity under mild conditions. This review shows some main directions in the field of active pharmaceutical ingredients’ preparation using continuous-flow chemistry and photochemistry with numerous examples of industry and laboratory-scale applications.     

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.     

Sydnone Ring as an ortho-Director of Lithiation, 3: One-Pot Regiospecific o-Acylation and Subsequent Sydnone 4-Substitution

Readily available 3-phenylsydnone (1) reacts with n-butyllithium/N,N,N′,N′-tetramethylethylenediamine (TMEDA) to form the dilithio species 2, which can be acylated regiospecifically at the ortho-aryl position using N-methoxy-N-methylamides (Weinreb's amides) followed by reaction with a second, more reactive electrophile at the sydnone C-4 position. Asymmetrically substituted arylsydnones 7 are obtained in 57–86% yield.     

Extremely Fast Gas/Liquid Reactions in Flow Microreactors: Carboxylation of Short‐Lived Organolithiums

Carboxylation of short‐lived organolithiums bearing electrophilic functional groups such as nitro, cyano, and alkoxycarbonyl groups with CO₂ to give carboxylic acids and active esters was accomplished in a flow microreactor system. The successful reactions indicate that gas/liquid mass transfer and the subsequent chemical reaction with CO₂ are extremely fast.