Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Small peptide diversification through photoredox-catalyzed oxidative C-terminal modification

A photoredox-catalyzed oxidative decarboxylative coupling of small peptides is reported, giving access to a variety of N,O-acetals. They were used as intermediates for the addition of phenols and indoles, leading to novel peptide scaffolds and bioconjugates. Amino acids with nucleophilic side chains, such as serine, threonine, tyrosine and tryptophan, could also be used as partners to access tri- and tetrapeptide derivatives with non-natural cross-linking.

A photoredox approach for the generation of N-acyliminiums derived from peptides enabling diversification via Friedel–Crafts reactions.     

A new hypervalent iodine(iii/v) oxidant and its application to the synthesis of 2H-azirines

The reaction of o-nitroiodobenzene and mCPBA in acetic acid was found to afford a novel hypervalent iodine compound, in the structure of which both iodine(iii) and iodine(v) moieties coexist. The nitro groups at the ortho phenyl positions were found to be crucial in stabilizing this uncommon structure. This novel hypervalent iodine(iii/v) oxidant is proved to be effective in realizing the synthesis of 2-unsubstitued 2H-azirines via intramolecular oxidative azirination, which could not be efficiently achieved by the existing known hypervalent iodine reagents.

The reaction of o-nitroiodobenzene and mCPBA in AcOH was found to afford a novel hypervalent iodine compound which both iodine(iii) and iodine(v) moieties coexist. This new reagent is proved to be effective in realizing the synthesis of 2H-azirines.     

A chiral cobalt(ii) complex catalyzed enantioselective aza-Piancatelli rearrangement/Diels–Alder cascade reaction

A chiral N,N′-dioxide/cobalt(ii) complex catalyzed highly diastereoselective and enantioselective tandem aza-Piancatelli rearrangement/intramolecular Diels–Alder reaction has been disclosed. Various valuable hexahydro-2a,5-epoxycyclopenta[cd]isoindoles bearing six contiguous stereocenters have been obtained in good yields with excellent diastereo- and enantio-selectivities from a wide range of both readily available 2-furylcarbinols and N-(furan-2-ylmethyl)anilines.

An asymmetric aza-Piancatelli rearrangement/Diels–Alder cascade reaction between 2-furylcarbinols and N-(furan-2-ylmethyl)anilines was realized by using a chiral N,N′-dioxide/cobalt(ii) complex catalyst.     

C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles by tuning Pd catalytic modes: Pd(i)–Pd(ii) catalysis vs. Pd(ii) catalysis

Efficient C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles have been developed. The former route enables C4-arylation in a highly efficient and mild manner and the latter route provides an alternative straightforward protocol for synthesis of C2/C4 disubstituted indoles. The mechanism studies imply that the different reaction pathways were tuned by the distinct acid additives, which led to either the Pd(i)–Pd(ii) pathway or Pd(ii) catalysis.

C4-arylation via Pd(i)–Pd(ii) catalysis and domino C4-arylation/3,2-carbonyl migration of indoles via Pd(ii) catalysis tuning by acids have been developed.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

The role of hypervalent iodine(iii) reagents in promoting alkoxylation of unactivated C(sp3)–H bonds catalyzed by palladium(ii) complexes

Although Pd(OAc)₂-catalysed alkoxylation of the C(sp³)–H bonds mediated by hypervalent iodine(iii) reagents (ArIX₂) has been developed by several prominent researchers, there is no clear mechanism yet for such crucial transformations. In this study, we shed light on this important issue with the aid of the density functional theory (DFT) calculations for alkoxylation of butyramide derivatives. We found that the previously proposed mechanism in the literature is not consistent with the experimental observations and thus cannot be operating. The calculations allowed us to discover an unprecedented mechanism composed of four main steps as follows: (i) activation of the C(sp³)–H bond, (ii) oxidative addition, (iii) reductive elimination and (iv) regeneration of the active catalyst. After completion of step (i) via the CMD mechanism, the oxidative addition commences with an X ligand transfer from the iodine(iii) reagent (ArIX₂) to Pd(ii) to form a square pyramidal complex in which an iodonium occupies the apical position. Interestingly, a simple isomerization of the resultant five-coordinate complex triggers the Pd(ii) oxidation. Accordingly, the movement of the ligand trans to the Pd–C(sp³) bond to the apical position promotes the electron transfer from Pd(ii) to iodine(iii), resulting in the reduction of iodine(iii) concomitant with the ejection of the second X ligand as a free anion. The ensuing Pd(iv) complex then undergoes the C–O reductive elimination by nucleophilic attack of the solvent (alcohol) on the sp³ carbon via an outer-sphere S_N2 mechanism assisted by the X⁻ anion. Noteworthy, starting from the five coordinate complex, the oxidative addition and reductive elimination processes occur with a very low activation barrier (ΔG^‡ 0–6 kcal mol⁻¹). The strong coordination of the alkoxylated product to the Pd(ii) centre causes the regeneration of the active catalyst, i.e. step (iv), to be considerably endergonic, leading to subsequent catalytic cycles to proceed with a much higher activation barrier than the first cycle. We also found that although, in most cases, the alkoxylation reactions proceed via a Pd(ii)–Pd(iv)–Pd(ii) catalytic cycle, the other alternative in which the oxidation state of the Pd(ii) centre remains unchanged during the catalysis could be operative, depending on the nature of the organic substrate.

This work uses DFT calculations to explore Pd(ii)-catalysed iodine(iii)-mediated alkoxylation of unactivated C(sp³)–H bonds and reveals how important the isomerization is in triggering the oxidative addition of ArIX₂ to Pd(ii).     

Catalytic asymmetric multiple dearomatizations of phenols enabled by a cascade 1,8-addition and Diels–Alder reaction

A direct catalytic asymmetric multiple dearomatization reaction of phenols was disclosed, which provides expedient access to a series of architecturally complex polycyclic compounds bearing four stereogenic centers in high enantiopurity. The key to achieve such a transformation is the combination of a dearomative 1,8-addition of β-naphthols to para-quinone methides generated in situ from propargylic alcohols and a subsequent intramolecular dearomative Diels–Alder reaction. Noteworthily, this protocol enrichs not only the diversity of dearomatized products but also the toolbox of dearomatization strategies.

The first chiral phosphoric acid catalyzed asymmetric multiple dearomatizations of phenols for the synthesis of bridged polycyclic compounds are reported.     

Design of pure heterodinuclear lanthanoid cryptate complexes

Heterolanthanide complexes are difficult to synthesize owing to the similar chemistry of the lanthanide ions. Consequently, very few purely heterolanthanide complexes have been synthesized. This is despite the fact that such complexes hold interesting optical and magnetic properties. To fine-tune these properties, it is important that one can choose complexes with any given combination of lanthanides. Herein we report a synthetic procedure which yields pure heterodinuclear lanthanide cryptates LnLn*LX₃ (X = NO₃⁻ or OTf⁻) based on the cryptand H₃L = N[(CH₂)₂N CH–R–CH N–(CH₂)₂]₃N (R = m-C₆H₂OH-2-Me-5). In the synthesis the choice of counter ion and solvent proves crucial in controlling the Ln–Ln* composition. Choosing the optimal solvent and counter ion afford pure heterodinuclear complexes with any given combination of Gd(iii)–Lu(iii) including Y(iii). To demonstrate the versatility of the synthesis all dinuclear combinations of Y(iii), Gd(iii), Yb(iii) and Lu(iii) were synthesized resulting in 10 novel complexes of the form LnLn*L(OTf)₃ with LnLn* = YbGd 1, YbY 2, YbLu 3, YbYb 4, LuGd 5, LuY 6, LuLu 7, YGd 8, YY 9 and GdGd 10. Through the use of ¹H, ¹³C NMR and mass spectrometry the heterodinuclear nature of YbGd, YbY, YbLu, LuGd, LuY and YGd was confirmed. Crystal structures of LnLn*L(NO₃)₃ reveal short Ln–Ln distances of ∼3.5 Å. Using SQUID magnetometry the exchange coupling between the lanthanide ions was found to be anti-ferromagnetic for GdGd and YbYb while ferromagnetic for YbGd.

We present a synthetic strategy to prepare the first heterodinuclear lanthanide(iii) cryptate complexes. The cryptate design ensures that the complexes are stable in solution for days. The exchange coupling in YbYb, GdGd and YbGd is investigated.     

Chiral N,N′‐Dioxide–Scandium(III) Complex‐Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction of ortho‐Hydroxybenzyl Alcohols with C3‐Substituted N‐Protected Indoles

The first Lewis acid catalyzed asymmetric Friedel–Crafts alkylation reaction of ortho‐hydroxybenzyl alcohols with C3‐substituted indoles is described. A chiral N,N′‐dioxide Sc(OTf)₃ complex served not only to promote formation of ortho‐quinone methides (o‐QMs) in situ but also induced the asymmetry of the reaction. This methodology enables a novel activation of ortho‐hydroxybenzyl alcohols, thus affording the desired chiral diarylindol‐2‐ylmethanes in up to 99 % yield and 99 % ee. A range of functional groups were also tolerated under the mild reaction conditions. Moreover, this strategy gives concise access to enantioenriched indole‐fused benzoxocines.     

Rh(i)- and Rh(ii)-catalyzed C–H alkylation of benzylamines with alkenes and its application in flow chemistry

The Rh-catalyzed C–H alkylation of benzylamines with alkenes using a picolinamide derivative as a directing group is reported. Both Rh(i) and Rh(ii) complexes can be used as active catalysts for this transformation. In addition, a flow set up was designed to successfully mimic this process under flow conditions. Several examples are presented under flow conditions and it was confirmed that a flow process is advantageous over a batch process. Deuterium labelling experiments were performed to elucidate the mechanism of the reaction, and the results indicated a possible carbene mechanism for this C–H alkylation process.

Rh(i)- and Rh(ii)-catalyzed C–H alkylation of benzylamines with alkenes using a picolinamide derivative as a directing group is reported under both batch and flow.     

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines

Hexahydropyrazinoindoles were prepared in a single step from N-sulfonyl triazoles and imidazolidines. Under dirhodium catalysis, α-imino carbenes were generated and formed nitrogen ylide intermediates that, after subsequent aminal opening, afforded the pyrazinoindoles predominantly via formal [1,2]-Stevens and tandem Friedel–Crafts cyclizations. Of mechanistic importance, a regiodivergent reactivity was engineered through the use of a specific unsymmetrically substituted imidazolidine that promoted the exclusive formation of 8-membered ring 1,3,6-triazocines. Based on DFT calculations, an original Curtin–Hammett-like situation was demonstrated for the mechanism. Further derivatizations led to functionalized tetrahydropyrazinoindoles in high yields.

Hexahydropyrazinoindoles are prepared in a single step from N-sulfonyl triazoles and imidazolidines. Of mechanistic importance, a regiodivergent reactivity can be engineered towards the exclusive formation of 8-membered ring 1,3,6-triazocines.     

Advances in anion binding and sensing using luminescent lanthanide complexes

Luminescent lanthanide complexes have been actively studied as selective anion receptors for the past two decades. Ln(iii) complexes, particularly of europium(iii) and terbium(iii), offer unique photophysical properties that are very valuable for anion sensing in biological media, including long luminescence lifetimes (milliseconds) that enable time-gating methods to eliminate background autofluorescence from biomolecules, and line-like emission spectra that allow ratiometric measurements. By careful design of the organic ligand, stable Ln(iii) complexes can be devised for rapid and reversible anion binding, providing a luminescence response that is fast and sensitive, offering the high spatial resolution required for biological imaging applications. This review focuses on recent progress in the development of Ln(iii) receptors that exhibit sufficiently high anion selectivity to be utilised in biological or environmental sensing applications. We evaluate the mechanisms of anion binding and sensing, and the strategies employed to tune anion affinity and selectivity, through variations in the structure and geometry of the ligand. We highlight examples of luminescent Ln(iii) receptors that have been utilised to detect and quantify specific anions in biological media (e.g. human serum), monitor enzyme reactions in real-time, and visualise target anions with high sensitivity in living cells.

This minireview highlights advances in anion binding and sensing using luminescent lanthanide(iii) complexes.     

Protected amino acids as a nonbonding source of chirality in induction of single-handed screw-sense to helical macromolecular catalysts

Chiral nonbonding interaction with N-protected amino acid methyl esters used as chiral additives in achiral solvents allows dynamic induction of single-handed helical conformation in poly(quinoxaline-2,3-diyl)s (PQX) bearing only achiral substituents. Ac-l-Pro-OMe, for instance, allows induction of energy preference of 0.16 kJ mol⁻¹ per monomer unit for the M-helical structure over the P-helix in t-butyl methyl ether (MTBE). With this new mode of screw-sense induction, homochiral screw-sense has been induced in virtually achiral poly(quinoxaline-2,3-diyl)s 1000-mer containing phosphine pendants (PQXphos). Use of PQXphos as a helically dynamic ligand along with Ac-Pro-OMe (l or d) as a chiral additive in MTBE allowed a highly enantioselective Suzuki–Miyaura coupling reaction with up to 95% enantiomeric excess.

Achiral poly(quinoxaline-2,3-diyl) containing Ar₂P groups undergo dynamic induction of M-helical conformation through nonbonding interaction with protected AA such as Ac-l-Pro-OMe, serving as a chiral ligand in asymmetric cross-coupling with up to 95% ee.     

Prebiotic access to enantioenriched glyceraldehyde mediated by peptides

A prebiotically plausible route to enantioenriched glyceraldehyde is reported via a kinetic resolution mediated by peptides. The reaction proceeds via a selective reaction between the l-peptide and the l-sugar producing an Amadori rearrangement byproduct and leaving d-glyceraldehyde in excess. Solubility considerations in the synthesis of proline–valine (pro–val) peptides allow nearly enantiopure pro–val to be formed starting from racemic pro and nearly racemic (10%) ee val. (ee = enantiomeric excess = (|d − l|)/(d + l)) Thus enantioenrichment of glyceraldehyde is achieved in a system with minimal initial chiral bias. This work demonstrates synergy between amino acids and sugars in the emergence of biological homochirality.

A prebiotically plausible route to enantioenriched glyceraldehyde is reported via a kinetic resolution mediated by peptides.     

Heterobimetallic Eu(iii)/Pt(ii) single-chain nanoparticles: a path to enlighten catalytic reactions

We introduce the formation and characterization of heterometallic single-chain nanoparticles entailing both catalytic and luminescent properties. A terpolymer containing two divergent ligand moieties, phosphines and phosphine oxides, is synthesized and intramolecularly folded into nanoparticles via a selective metal complexation of Pt(ii) and Eu(iii). The formation of heterometallic Eu(iii)/Pt(ii) nanoparticles is evidenced by size exclusion chromatography, multinuclear NMR (¹H, ³¹P{¹H}, ¹⁹F, ¹⁹⁵Pt) as well as diffusion-ordered NMR and IR spectroscopy. Critically, we demonstrate the activity of the SCNPs as a homogeneous and luminescent catalytic system in the amination reaction of allyl alcohol.

A bifunctional terpolymer containing two orthogonal ligand moieties was synthesized, giving way to the facile formation of heterometallic Eu(iii)/Pt(ii) single-chain nanoparticles, which display both catalytic and luminescent properties.     

Time-resolved luminescence detection of peroxynitrite using a reactivity-based lanthanide probe

Peroxynitrite (ONOO⁻) is a powerful and short-lived oxidant formed in vivo, which can react with most biomolecules directly. To fully understand the roles of ONOO⁻ in cell biology, improved methods for the selective detection and real-time analysis of ONOO⁻ are needed. We present a water-soluble, luminescent europium(iii) probe for the rapid and sensitive detection of peroxynitrite in human serum, living cells and biological matrices. We have utilised the long luminescence lifetime of the probe to measure ONOO⁻ in a time-resolved manner, effectively avoiding the influence of autofluorescence in biological samples. To demonstrate the utility of the Eu(iii) probe, we monitored the production of ONOO⁻ in different cell lines, following treatment with a cold atmospheric plasma device commonly used in the clinic for skin wound treatment.

Reactivity-based europium(iii) probe displays excellent selectivity for peroxynitrite (ONOO⁻), enabling its time-resolved luminescence detection in living cells.     

Palladium catalyzed carbonylative generation of potent,pyridine-based acylating electrophiles for the functionalization of arenes to ketones

We describe here the design of a palladium catalyzed route to generate aryl ketones via the carbonylative coupling of (hetero)arenes and aryl- or vinyl-triflates. In this, the use of the large bite angle Xantphos ligand on palladium provides a unique avenue to balance the activation of the relatively strong C(sp²)–OTf bond with the ultimate elimination of a new class of potent Friedel–Crafts acylating agent: N-acyl pyridinium salts. The latter can be exploited to modulate reactivity and selectivity in carbonylative arene functionalization chemistry, and allow the efficient synthesis of ketones with a diverse array of (hetero)arenes.

A palladium catalyzed approach to the overall carbonylative functionalization of arenes to form ketones with aryl- and vinyl-triflates is described.     

Exceptionally fast radiative decay of a dinuclear platinum complex through thermally activated delayed fluorescence

A novel dinuclear platinum(ii) complex featuring a ditopic, bis-tetradentate ligand has been prepared. The ligand offers each metal ion a planar O^N^C^N coordination environment, with the two metal ions bound to the nitrogen atoms of a bridging pyrimidine unit. The complex is brightly luminescent in the red region of the spectrum with a photoluminescence quantum yield of 83% in deoxygenated methylcyclohexane solution at ambient temperature, and shows a remarkably short excited state lifetime of 2.1 μs. These properties are the result of an unusually high radiative rate constant of around 4 × 10⁵ s⁻¹, a value which is comparable to that of the very best performing Ir(iii) complexes. This unusual behaviour is the result of efficient thermally activated reverse intersystem crossing, promoted by a small singlet–triplet energy difference of only 69 ± 3 meV. The complex was incorporated into solution-processed OLEDs achieving EQE_max = 7.4%. We believe this to be the first fully evidenced report of a Pt(ii) complex showing thermally activated delayed fluorescence (TADF) at room temperature, and indeed of a Pt(ii)-based delayed fluorescence emitter to be incorporated into an OLED.

Efficient thermally activated delayed fluorescence (TADF) in a brightly luminescent diplatinum(ii) complex results in significant enhancement of the radiative decay rate.     

Electrochemical studies of tris(cyclopentadienyl)thorium and uranium complexes in the +2, +3, and +4 oxidation states

Electrochemical measurements on tris(cyclopentadienyl)thorium and uranium compounds in the +2, +3, and +4 oxidation states are reported with C₅H₃(SiMe₃)₂, C₅H₄SiMe₃, and C₅Me₄H ligands. The reduction potentials for both U and Th complexes trend with the electron donating abilities of the cyclopentadienyl ligand. Thorium complexes have more negative An(iii)/An(ii) reduction potentials than the uranium analogs. Electrochemical measurements of isolated Th(ii) complexes indicated that the Th(iii)/Th(ii) couple was surprisingly similar to the Th(iv)/Th(iii) couple in Cp′′-ligated complexes. This suggested that Th(ii) complexes could be prepared from Th(iv) precursors and this was demonstrated synthetically by isolation of directly from UV-visible spectroelectrochemical measurements and reactions of with elemental barium indicated that the thorium system undergoes sequential one electron transformations.

Electrochemical determination of the reduction potentials for a variety of tris(cyclopentadienyl)uranium and thorium complexes, including data on U(ii) and Th(ii) complexes.