Amination of Isonitriles in Water: Urea Synthesis under Biocompatible Conditions

Bioorthogonal reactions have been widely used to track biomolecules in living systems. Due to stringent requirements of physiological conditions, enriching the toolkit of bioorthogonal reactions remains the most important and challenging issue. Herein, the biocompatible ligation of isonitriles and amines to ureas in neutral aqueous medium was developed for the first time. The ligation showed benign nature of biocompatibility, broad substrate scope, and specific chemoselectivity. Meanwhile, urea as a natural linkage, its derivatives played an important role in medicinal chemistry. The second-order reaction rate constant (k₂) was determined, which was higher or comparable to that of Staudinger ligation and strain-promoted azide-alkyne cycloaddition (SPAAC). Direct labeling of Ac₄GlcN has been achieved in Hep G2 cells.     

Terminal Alkenes as Versatile Chemical Reporter Groups for Metabolic Oligosaccharide Engineering

The Diels–Alder reaction with inverse electron demand (DAinv reaction) of 1,2,4,5‐tetrazines with electron rich or strained alkenes was proven to be a bioorthogonal ligation reaction that proceeds fast and with high yields. An important application of the DAinv reaction is metabolic oligosaccharide engineering (MOE) which allows the visualization of glycoconjugates in living cells. In this approach, a sugar derivative bearing a chemical reporter group is metabolically incorporated into cellular glycoconjugates and subsequently derivatized with a probe by means of a bioorthogonal ligation reaction. Here, we investigated a series of new mannosamine and glucosamine derivatives with carbamate‐linked side chains of varying length terminated by alkene groups and their suitability for labeling cell‐surface glycans. Kinetic investigations showed that the reactivity of the alkenes in DAinv reactions increases with growing chain length. When applied to MOE, one of the compounds, peracetylated N‐butenyloxycarbonylmannosamine, was especially well suited for labeling cell‐surface glycans. Obviously, the length of its side chain represents the optimal balance between incorporation efficiency and speed of the labeling reaction. Sialidase treatment of the cells before the bioorthogonal labeling reaction showed that this sugar derivative is attached to the glycans in form of the corresponding sialic acid derivative and not epimerized to another hexosamine derivative to a considerable extent.     

Synthesis and Reactivity of Fluoro(Organyl)Phosphanes

Abstract

A new method for producing fluoro(organyl) phosphanes is presented. They are prepared by Cl/F-exchange from the corresponding chloro compounds using Et₃N.nHF as a fluorinating agent. Phosphanyl fluorophospharanes, R₂P-PR₂F₂, are found to be intermediates of the disproportionation of Fluoro (diorganyl) phosphanes. R₂PF react with aldehydes to form phosphinito phosphoranes, R₂PF₂-CHR'-OPR₂. Oxaphospholenes are formed in their reaction with α, β- unsaturated aldehydes. Furthermore, the reactions with 1.2-diketones, carboxylic acid derivatives, and covalent azides are described.     

Anodic benzylic fluorination of toluene,ethylbenzene, and cumene derivatives

Anodic fluorination of toluene, ethylbenzene, and cumene derivatives was comparatively studied using Et₄NF-4HF as a supporting electrolyte and a fluorine source. Anodic benzylic fluorination occurred except for some cumene derivatives and the yields of the fluorinated products greatly depended on the stability of benzylic cations.     

A convenient method for the preparation of oxazaborolidine catalyst in situ using (S)-α,α-diphenylpyrrolidinemethanol,tetrabutylammonium borohydride,and methyl iodide for the asymmetric reduction of prochiral ketones

An oxazaborolidine catalyst is readily prepared in situ at 25 °C in THF using (S)-α,α-diphenylpyrrolidinemethanol and borane generated from tetrabutylammonium borohydride/CH₃I reagent system. The oxazaborolidine/BH₃ reagent system prepared in this way is useful for the reduction of prochiral ketones to the corresponding alcohols with up to 99% ee.     

Selective α‐Monomethylation by an Amine‐Borane/N,N‐Dimethylformamide System as the Methyl Source

A new and practical α‐monomethylation strategy using an amine‐borane/N,N‐dimethylformamide (R₃N‐BH₃/DMF) system as the methyl source was developed. This protocol has been found to be effective in the α‐monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R₃N‐BH₃ donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH₂‐, CD₂H‐, and CD₃‐ units using Me₂NH‐BH₃/d₇‐DMF, Me₃N‐BD₃/DMF and Me₃N‐BD₃/d₇‐DMF systems, respectively. Further application of this method to the facile synthesis of anti‐inflammatory flurbiprofen and its varied deuterium‐labeled derivatives was demonstrated.     

Borane and Borohydride Complexes of the Rare‐Earth Elements: Synthesis,Structures, and Butadiene Polymerization Catalysis

The reaction of potassium 2,5‐bis[N‐(2,6‐diisopropylphenyl)iminomethyl]pyrrolyl [(dip₂‐pyr)K] with the borohydrides of the larger rare‐earth metals, [Ln(BH₄)₃(thf)₃] (Ln=La, Nd), afforded the expected products [Ln(BH₄)₂(dip₂‐pyr)(thf)₂]. As usual, the trisborohydrides reacted like pseudohalide compounds forming KBH₄ as a by‐product. To compare the reactivity with the analogous halides, the dimeric neodymium complex [NdCl₂(dip₂‐pyr)(thf)]₂ was prepared by reaction of [(dip₂‐pyr)K] with anhydrous NdCl₃. Reaction of [(dip₂‐pyr)K] with the borohydrides of the smaller rare‐earth metals, [Sc(BH₄)₃(thf)₂] and [Lu(BH₄)₃(thf)₃], resulted in a redox reaction of the BH₄^? group with one of the Schiff base functions of the ligand. In the resulting products, [Ln(BH₄){(dip)(dip‐BH₃)‐pyr}(thf)₂] (Ln=Sc, Lu), a dinegatively charged ligand with a new amido function, a Schiff base, and the pyrrolyl function is bound to the metal atom. The by‐product of the reaction of the BH₄^? anion with the Schiff base function (a BH₃ molecule) is trapped in a unique reaction mode in the coordination sphere of the metal complex. The BH₃ molecule coordinates in an η² fashion to the metal atom. The rare‐earth‐metal atoms are surrounded by the η²‐coordinated BH₃ molecule, the η³‐coordinated BH₄^? anion, two THF molecules, and the nitrogen atoms from the Schiff base and the pyrrolyl function. All new compounds were characterized by single‐crystal X‐ray diffraction. Low‐temperature X‐ray diffraction data at 6 K were collected to locate the hydrogen atoms of [Lu(BH₄){(dip)(dip‐BH₃)‐pyr}(thf)₂]. The (DIP₂‐pyr)^? borohydride and chloride complexes of neodymium, [Nd(BH₄)₂(dip₂‐pyr)(thf)₂] and [NdCl₂(dip₂‐pyr)(thf)]₂, were also used as Ziegler–Natta catalysts for the polymerization of 1,3‐butadiene to yield poly(cis‐1,4‐butadiene). Very high activities and good cis selectivities were observed by using each of these complexes as a catalyst in the presence of various cocatalyst mixtures.     

18F‐Labeling of Aryl‐SCF3, ‐OCF3 and ‐OCHF2 with [18F]Fluoride

We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic ¹⁸F‐fluorination of aryl‐OCHFCl, ‐OCF₂Br and ‐SCF₂Br precursors under mild conditions. This Ag^I‐mediated process allows for the first time access to a range of ¹⁸F‐labeled aryl‐OCHF₂, ‐OCF₃ and ‐SCF₃ derivatives, inclusive of [¹⁸F]riluzole. The ¹⁸F‐labeling of these medicinally important motifs expands the radiochemical space available for PET applications.     

Beiträge zur Chemie des Phosphors. 240 [1]. Zum reaktiven Verhalten von Diphosphan-boran,P2H4 · BH3

Contributions to the Chemistry of Phosphorus. 240. On the Reactive Behaviour of Diphosphane-borane, P₂H₄ · BH₃ Under mild temperature conditions, the thermal decomposition of diphosphane-borane ( 1 ) gives rise to the formation of phosphane-borane, PH₃ · BH₃, and triphosphane-2-borane, PH₂? PH(BH₃)? PH₂ ( 2 ). In the presence of diphosphane-1,2-bis(borane), triphosphane-1,3-bis(borane), BH₃? PH₂? PH? PH₂? BH₃ ( 3 ), is formed additionally. The thermolysis product at room temperature is a polymeric solid of varying composition which contains phosphorus, boron, and hydrogen. Compound 1 reacts with metalating agents such as n-BuLi, LiBH₄, and NaBH₄ to furnish the borane-trihydrogendiphosphide ion, [PH₂? PH? BH₃]^?, which immediately disproportionates to give the corresponding mono-and triphosphane derivatives. In the presence of an excess of THF-borane and in the case of a 1 : 1 molar ratio of 1 : NaBH₄, the disproportionation does not occur and the new diphosphide derivative sodium-1,1,2-tris(borane)-1,2,2-trihydrogendiphosphide, Na[(BH₃)₂PH? PH₂BH₃] ( 4 ) can be obtained. The action of additional NaBH₄ yields the diphosphide dianion with four coordinated BH₃ groups.     

Alkene–Tetrazine Ligation for Imaging Cellular DNA

5‐Vinyl‐2′‐deoxyuridine (VdU) is the first reported metabolic probe for cellular DNA synthesis that can be visualized by using an inverse electron demand Diels–Alder reaction with a fluorescent tetrazine. VdU is incorporated by endogenous enzymes into the genomes of replicating cells, where it exhibits reduced genotoxicity compared to 5‐ethynyl‐2′‐deoxyuridine (EdU). The VdU–tetrazine ligation reaction is rapid (k≈0.02 M ^?1 s^?1) and chemically orthogonal to the alkyne–azide “click” reaction of EdU‐modified DNA. Alkene–tetrazine ligation reactions provide the first alternative to azide–alkyne click reactions for the bioorthogonal chemical labeling of nucleic acids in cells and facilitate time‐resolved, multicolor labeling of DNA synthesis.     

Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho-Dithiophenols

A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho-dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho-dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3-b]quinoxaline with strong built-in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ-DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans-tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k₂≈1.3 m ⁻¹ s⁻¹), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein-fishing applications and in-gel fluorescence analysis.     

Developing organoboranes as phase transfer catalysts for nucleophilic fluorination using CsF

Despite the general high fluorophilicity of boron, organoboranes such as BEt₃ and 3,5-(CF₃)₂C₆H₃–BPin are shown herein for the first time, to our knowledge, to be effective (solid to solution) phase-transfer catalysts for the fluorination of certain organohalides with CsF. Significant (up to 30% e.e.) chiral induction during nucleophilic fluorination to form β-fluoroamines using oxazaborolidine (pre)catalysts and CsF also can be achieved. Screening different boranes revealed a correlation between calculated fluoride affinity of the borane and nucleophilic fluorination reactivity, with sufficient fluoride affinity required for boranes to react with CsF and form Cs[fluoroborate] salts, but too high a fluoride affinity leading to fluoroborates that are poor at transferring fluoride to an electrophile. Fluoride affinity is only one component controlling reactivity in this context; effective fluorination also is dependent on the ligation of Cs⁺ which effects both the phase transfer of CsF and the magnitude of the [Cs⋯F-BR₃] interaction and thus the B–F bond strength. Effective ligation of Cs⁺ (e.g. by [2.2.2]-cryptand) facilitates phase transfer of CsF by the borane but also weakens the Cs⋯F–B interaction which in turn strengthens the B–F bond – thus disfavouring fluoride transfer to an electrophile. Combined, these findings indicate that optimal borane mediated fluorination occurs using robust (to the fluorination conditions) boranes with fluoride affinity of ca. 105 kJ mol⁻¹ (relative to Me₃Si⁺) under conditions where a signficant Cs⋯F–B interaction persists.

Simple boranes with the optimal fluoride ion affinity are effective as catalysts for phase transfer nucleophilic fluorination with CsF.     

Metallboranate und Boranato-metallate. VI. Zur Reaction von Oniumboranaten mit Trimethylamin-Alan: Trimethylamin-boranato-alanat,BH4 · AlH3 · N(CH3) und Onium-alanate

Trimethylamine-alane adds to tetrabutylammonium tetrahydroborate in benzene to yield tetrabutylammonium trimethylamine-tetrahydroborato-trihydroaluminate. The BH₄ group of this novel complex hydrido-anion is bound via a single hydrogen bridge to the aluminium atom. Although there is ir-spectroscopic evidence for the formation of a similar tetraphenylphosphonium salt in the reaction of tetraphenylphosphonium tetra-hydroborate and trimethylamine-alane (employed in excess), the products are tetraphenylphosphonium tetrahydroaluminate and trimethylamine-tetrahydroborato-alane. However, tetraphenylarsonium tetrahydroborate yields triphenylarsine and (CH₃)₃N · AlH₂BH₄ under similar conditions. Tetrabutylammonium, tetraphenylphosphonium and tetraphenylarsonium tetrahydro-aluminates were prepared from the respective tetrahydroborate and LiAlH₄.     

Encapsulating Inorganic Acetylene,HBNH, Using Flanking Coordinative Interactions

A stable donor–acceptor coordination complex of the elusive parent inorganic iminoborane HBNH (a structural analogue of acetylene) is reported. This species was generated via thermally induced N₂ elimination/1,2‐H migration from a hydrido(azido)borane adduct NHC?BH₂N₃ (NHC=N‐heterocyclic carbene) in the presence of a fluorinated triarylborane. The mechanism of this process was also investigated by computational and isotopic labeling studies. This transformation represents a new and potentially modular route to unsaturated inorganic building blocks for advanced material synthesis.     

Bioorthogonal organic chemistry in living cells: novel strategies for labeling biomolecules

The chemical labeling of biomolecules continues to be an important tool for the study of their function and cellular fate. Attention is increasingly focused on labeling of biomolecules in living cells, since cell lysis introduces many artefacts. In addition, with the advances in biocompatible synthetic organic chemistry, a whole new field of opportunity has opened up, affording high diversity in the nature of the label as well as a choice of ligation reactions. In recent years, several different two-step labeling strategies have emerged. These rely on the introduction of a bioorthogonal attachment site into a biomolecule, then ligation of a reporter molecule to this site using bioorthogonal organic chemistry. This Perspective focuses on these techniques, their implications and future directions.     

A novel method for regioselective ring-opening reduction of 4,6-O-benzylidene hexopyranoside derivatives using CoCl2 and BH3·THF

A novel and facile reductive ring-opening reaction for 4,6-O-benzylidene acetal derivatives of hexopyranosides using CoCl₂/BH₃·THF gave the corresponding 4-O-benzyl-6-OH derivatives selectively in good yields. This convenient method should allow large-scale synthesis at low cost.     

Metallboranate und Boranatometallate. VIII. Darstellung und Eigenschaften von dimeren Halogeno-titan (III)- bis (boranaten) [XTi (BH4)2]2

Metal Tetrahydroborates and Tetrahydroboratometallates. VIII. Preparation and Properties of Dimeric Halogenotitanium(III) Bis(tetrahydroborates) [XTi(BH₄)₂]₂ Chlorotitanium(III)bis(tetrahydroborate) is produced besides Ti(BH₄)₃ in the reaction of TiCl₄ vapour with solid LiBH₄. It forms in 72% yield by using n-pentane as reaction medium. BrTi(BH₄)₂ and ITi(BH₄)₂ were prepared similarly. All these compounds are dimerized via halogen bridges. The bridge opens by addition of tetrahydrofurane to ClTi(BH₄)₂ with disproportionation to yield Ti(BH₄)₃ · nOC₄H₈ and TiCl₃ · mOC₄H₈ contrary to diethylether. The ir, ¹¹B-nmr and electronic spectra of the halogenotitanium(III) bis(tetrahydroborates) are discussed.     

Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho‐Dithiophenols

A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho‐dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho‐dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3‐b]quinoxaline with strong built‐in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ‐DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans‐tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k₂≈1.3 m ^?1 s^?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein‐fishing applications and in‐gel fluorescence analysis.     

Phosphineborane analogs of trimethylsilyl amides

The reaction of (CH₃)₂(BH₃)PCl with the lithium salts of acetamide, N-methyl acetamide, and N-methyl formamide produced the N(CH₃)₂(BH₃)P-monosubstituted amides. Attempts to employ the same procedure for the preparation of the bis-acetamide, the acetanilide and the N-methyl benzamide derivatives were unsuccessful. Variable temperature NMR spectroscopy revealed the presence of rotational isomers for the formamide with a population of 0.85 for the major rotamer which on the basis of the ³¹P-formyl proton coupling constants was assigned the structure where the (CH₃)₂(BH₃)P group is trans to carbonyl oxygen. The free energies of activation were determined to be 16.2 and 17.3 kcal/mol. For the other derivatives only one isomer could be detected down to—60°C. The compounds are similar to the trimethylsilyl analogs in structure and rotational populations, but the lower rotational barrier in the phosphineborane formamide derivative suggests a greater destabilization of the polar ground state amide resonance structure by the formal positive charge on phosphorus.     

Vinylboronic Acids as Fast Reacting,Synthetically Accessible,and Stable Bioorthogonal Reactants in the Carboni–Lindsey Reaction

Bioorthogonal reactions are widely used for the chemical modification of biomolecules. The application of vinylboronic acids (VBAs) as non‐strained, synthetically accessible and water‐soluble reaction partners in a bioorthogonal inverse electron‐demand Diels–Alder (iEDDA) reaction with 3,6‐dipyridyl‐s‐tetrazines is described. Depending on the substituents, VBA derivatives give second‐order rate constants up to 27 m ^?1 s^?1 in aqueous environments at room temperature, which is suitable for biological labeling applications. The VBAs are shown to be biocompatible, non‐toxic, and highly stable in aqueous media and cell lysate. Furthermore, VBAs can be used orthogonally to the strain‐promoted alkyne–azide cycloaddition for protein modification, making them attractive complements to the bioorthogonal molecular toolbox.