Advances in organic synthesis

Photocatalytic selective C(sp³)–H activation/cross-coupling reactions are appealing in organic synthesis. Here the authors describe the development of excited-state Pd-catalyzed dehydrogenative β-sulfonylation reactions using amines and aryl sulfonyl chlorides via intermolecular hydrogen atom transfer and C−S cross-coupling processes at room temperature.

The direct and selective coupling between unactivated C(sp2)-H and C(sp3)-H bonds is widely recognized as one of the most challenging tasks in organic synthesis. Here, the authors present an iron halidepromoted photochemical aerobic oxidation strategy for achieving such transformations.

Spirocyclic tetrahydronaphthyridines (THNs) are valuable structural motifs in medicinal chemistry, but the modular and scalable synthesis of this specific motif remains challenging. Here, the authors develop an automated and continuous flow synthesis of 1,8-THN and 1,6-THN analogues based on photoredox-catalysed hydroaminoalkylation, demonstrating the concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669.

Performing enantioselective photocatalytic reactions with visible light is a challenging task that has seen substantial advances with the development of new catalysts. Although many approaches utilize dual-catalytic systems in which the photocatalyst is separate from the chirality-inducing moiety, in this Review bifunctional photocatalysts that perform both roles are discussed.

The 1,2 migration reaction on tetracoordinate boron species have been well investigated but less work looked on 1,2-boryl radical shift for the construction of organoborons. Here, the authors demonstrate a visible-light-induced photoredox neutral decarboxylative radical cross-coupling reaction, which undergoes a radical 1,2-boron shift to give a translocated C-radical for further capture of versatile radical acceptors

Cross-dehydrogenative coupling is an efficient route for C–C bond formation by direct C–H functionalization, however, this protocol usually requires stoichiometric oxidants under harsh reaction conditions. Here, the authors report a cross-dehydrogenative Minisci-alkylation using a heterogeneous Rh₂O₃/GaN photocatalyst and a benzophenone photosensitizer under oxidant-free conditions.

Developing reaction conditions for radical–radical cross-dehydrogenative amination reactions is challenging. Now a nickel-catalysed asymmetric electrochemical cross-dehydrogenative amination reaction between acylimidazoles and nitrogen nucleophiles is developed to access structurally diverse α-amino carbonyls that can be used to synthesize (+)-γ-secretase inhibitor, (+)-flamprop-methyl and (+)-flamprop-isopropyl.

Ethylene glycol is an important commodity chemical and its production results in millions of tons of CO2 emissions annually. Here, the authors report a paired electrocatalytic strategy to produce ethylene glycol from methanol with a high Faradaic efficiency at industrial scale current density.

Hydrocarbons are challenging to functionalize. Here, the authors present an electrochemical oxo-functionalization of cyclic alkanes and alkenes to ketones and dicarboxylic acids via mediating nitrate-based supporting electrolyte and molecular oxygen.

The synthesis of biaryls by transition metal-free coupling is an important challenge. Here, the authors describe an electrochemical approach to the synthesis of biaryls, in which aniline derivatives are coupled through the temporary formation and reduction of ureas.

The combination of nickel-catalysis and sensitized electron transfer is underdeveloped. Now, a nickel-catalysed sensitized electron transfer method for the synthesis of methyl thioesters from carboxylic acids is reported. Mechanistic investigations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this thioesterification reaction.

(1H-indol-3-yl)methyl electrophiles are potential precursors for the synthesis of indole derivatives, however, their preparation remains challenging and only a few syntheses have been reported so far. Here, the authors examine previously reported preparations, clarify inconsistencies within the literature, and develop a highly versatile nucleophilic substitution at the indole 3’-position using microflow technologies.

1,6 enynes are a useful synthetic building block, but their use asymmetric intramolecular reductive couplings with cobalt catalysts have not been well-explored. Here, the authors describe an enantioselective intramolecular reductive coupling of enynes via the combination of electrochemistry and cobalt catalysis.

Functional-group transfer strategies using surrogates to avoid handling hazardous reagents are often limited to monofunctionalization reactions. Now, an operationally simple and mechanistically distinct photocatalytic transfer strategy for vicinal dihalogenation of carbon–carbon multiple bonds, such as in alkenes, alkynes and allenes, using readily synthesized oxime-based dihalogen surrogates is reported.

Enantioselective synthesis of medium-sized rings by organocatalytic cycloadditions offers opportunities that are complementary to metal-catalysed cycloadditions. This Review discusses the ability of organocatalytic cycloadditions to synthesize stereodefined medium-sized ring architectures, critically evaluates current synthetic strategies, and highlights avenues for further development.

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Now, 2,3-azacyclic and 2,3-oxacyclic allenes are generated and trapped using cycloaddition reactions, generating complex heterocycles that bear a large fraction of sp³-hybridized atoms.

Arynes are often generated using strong bases or fluoride sources, limiting functional group tolerance. Now, stable triaryloxonium salts are transformed into arynes and subsequently trapped using cycloaddition reactions by treatment with potassium phosphate at room temperature. This functional group-tolerant method proceeds by an elimination, unimolecular, conjugate base-like elimination mechanism to form the aryne.

One-carbon insertion into N–O bonds is widely exploited in organic synthesis, but synthetic protocols for this rely on hazardous diazo precursors that are difficult to access. Here, copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles is shown to facilitate one-carbon insertion into heterocyclic N–O bonds without the need for diazo precursors.

The lack of efficient and diverse synthesis strategy has hindered the study of perifused cycles. Here, the authors report a metal-catalyzed cascade electrocyclization to access 5,6,7-perifused cycles, and demonstrated the versatility of this protocol in the late-stage modification of pharmaceuticals.

Catalytic glycosylation provides access to oligosacchairdes with minimal amount of promoters. Here, the authors developed a new catalytic glycosylation reaction using an ester type donor driven by ring-strain release.

Cycloisomerization/cyclization cascade reactions for yne-enones and enyamides can be used to construct diverse fused furans, however, the corresponding (2 + n) reaction remains challenging. Here, the authors report cycloisomerization/(2 + 3) cycloadditions catalyzed by silver acetate and a modified chiral pyrrolidinopyridine relay system, to generate bispirocyclopentene pyrazolone products with isoform-selective phosphodiesterase 1 (PDE1) inhibitory activity.

Piperidine heterocycles are widely prevalent in drug molecules; however, their synthesis remains challenging. Now, a general approach for N-(hetero)aryl piperidine synthesis using isolable iminium salts is reported. A variety of substituents are installed at the C2 and C3 positions, giving access to densely functionalized piperidines that are challenging to obtain using other methods.

The asymmetric inverse-electron-demand oxa-Diels–Alder reaction (IODA) between activated α,β-unsaturated carbonyl compounds with highly polarized alkenes has been reported before but acroleins or simple alkenes were so-far rarely employed as substrates. Here, the authors study the catalytic asymmetric intermolecular IODA reaction between acroleins and simple alkenes.

Substituted pyridines are important structural motifs present in various bioactive molecules, however their multi-functionalization remains challenging. Here, the authors report a facile approach for introducing various functional groups on the pyridine scaffold by remodeling of 3-formyl (aza)indoles/benzofurans via a ring cleavage reaction.

Preparation of functionalized analogues of 1,2-benzdiyne, from heavily substituted as well as benzofused scaffolds, is challenging. Here, the authors develop an array of 3-sulfonyloxyaryl(mesityl)iodonium triflates as 1,2-benzdiyne precursors, triggered from ortho-deprotonative elimination.

Lawsones and indenopyrazoles harbor an interesting benzo-fused cyclic ketone scaffold as an essential structural motif in diverse bioactive molecules, however, their synthesis remains challenging. Here, the authors report an efficient synthesis of lawsones and indenopyrazolones via the solvent-controlled regioselective ring-expansion of indantriones involving a 1,2-carbonyl shift.

Bicyclobutanes are among the most highly strained organic compounds and are intriguing building blocks in organic synthesis. This review provides an overview of the recent developments in bicyclobutane synthesis, their synthetic utility and their modes of reactivity.

Nucleophilic addition reactions of propargyl cations can result in diverse synthetically useful compounds, however, dehydrative propargylation through α-alkyl-propargyl cations remains challenging. Here, the authors utilize a highly oxophilic indium cation to generate α-alkyl-propargyl cations from secondary alcohols and apply them to S_N1-propargylation.

Catalytic enantioselective synthesis of all-carbon quaternary stereocentres is a long-term challenge in organic synthesis because of substantial steric repulsion and dissimilarities between the substituents around the stereocentre. This Review presents how the desymmetrization strategy plays an important role in constructing these types of motifs.

Saturated α-alkyl aza-heterocycles are found in a wide array of bioactive molecules. Here, the authors disclosed a one-pot, catalytic enantioselective synthesis of pyrrolidine, piperidine and indolizidine alkaloids from amides and alkynes.

Molecules with axial chirality are of intense focus to the synthetic organic community, but the axes most commonly explored are carbon–carbon and carbon–heteroatom. Here the authors report the syntheses of diaxially chiral biaryls containing N-N and C-N/C-C axes, achieved via rhodium catalysis.

Chiral monodentate biaryl phosphines (MOPs) have attracted intense attention as chiral ligands over the past decades. Here, the authors show diversity-oriented synthesis of structurally diverse MOPs containing both phosphorus and axial chirality.

The ability to selectively functionalize different sites on simple starting materials is a constant pursuit in organic chemistry. Here, the authors report a catalytic system to regioselectively differentiate and alkynylate different positions on azaarenes via rhodium catalysis.

The development of catalysts for practical asymmetric hydrogenation of ketones remains an important goal of synthetic organic chemistry. Here, an anionic iridium catalyst with excellent activity is reported and used in a hundred-kilogram-scale reduction as part of a route to chiral nicotine.

The development of selective multifunctionalization of alkynes is essential for organic synthesis with alkyne units as building blocks. Here the authors report a gold-catalyzed, four-component reaction that achieves the oxo-arylfluorination or oxo-arylalkenylation of internal aromatic or aliphatic alkynes

The selective transformation of a less reactive carbonyl moiety in the presence of more reactive ones can realize straightforward and environmentally benign chemical processes but such a transformation is highly challenging. Here, the authors report an Ir catalyst for the selective hydrogenolysis of urea derivatives, which are the least reactive carbonyl compounds, affording formamides and amines even in the presence of more reactive carbonyl groups such as ester.

Allylic substitution reactions have emerged as a powerful tool for the construction of C − C/X bonds. Here, the authors develop a migratory strategy of allylic arylation under the catalysis of nickel and lanthanide triflate.

Enantioselective α-allylic allenylation of carbonyls is a straightforward approach to access chiral allenes that are of significant relevance as synthons and bio-active products. Here, the Luo group describe an asymmetric α-allylic allenylation of β-ketocarbonyls and aldehydes with 1,3-enynes, via a combined chiral primary amine and palladium catalyst system.

Catalytic redox transformations of C–O bonds are pertinent to the valorization of oxygenated hydrocarbons, but typically rely on hazardous redox agents which bring about numerous drawbacks ranging from safety hazards to waste management. Here, the authors demonstrate that such reagents can be rendered redundant by catalytically harnessing internal C–H bonds as redox equivalents.

Asymmetric alkylation of enolates is an important method for the formation of α-stereogenic carbonyls but generally requires the introduction and then removal of chiral auxiliaries. Here, the authors report a copper-catalyzed asymmetric alkylation of α-amino esters.

The stereoselective synthesis of olefins from alkynes is a long-standing challenge in organic synthesis. Here, the authors report the chromium-catalyzed alkyne hydrogenation; E- or Z-olefins are obtained depending on the carbene ligand used.

Traditional peptide synthesis iteratively elongates the chain from the C-terminus to the N-terminus (C-to-N), however, this process requires excess N-carbamate-protected amino acids and condensation reagents to minimize epimerization. Here, the authors report an alternative N-to-C elongation strategy by catalytic peptide thioacid formation and oxidative peptide bond formation without requiring condensation reagents and excessive protecting group manipulations.

While a variety of well-established methods enable the control of a stereogenic center, a catalytic method for controlling a stereogenic axis in one substrate is typically unavailable for controlling axial chirality in other substrates with a similar structure. Here, the authors report o-amidobiaryl as a flexible platform for chiral phosphoric acid catalyzed atroposelective dynamic kinetic resolution.

Adenosylcobalamin (AdoCbl) is an essential vitamin whose production is limited to bacterial fermentation. Here, the authors report an alternative method for the synthesis of AdoCbl based on a cell-free reaction system integrating more than 30 biocatalytic reactions to produce AdoCbl from 5-aminolevulinic acid.

The isoperfluoropropyl group (i-C₃F₇) is an analogue of the trifluoromethyl group (CF₃) featuring a stronger electron-withdrawing effect and more steric hindrance, giving it a unique role in synthetic chemistry, however, direct isoperfluoropropylation remains challenging. Here, the authors develop a highly reactive electrophilic hypervalent-iodine based i-C₃F₇ reagent and demonstrate its use for the efficient isoperfluoropropylation of aromatic C–H bonds.

Suzuki-type cross-coupling for C(sp²)–C(sp³) bond formation with aliphatic halides remains challenging with tertiary aliphatic halides and under transition-metal-free conditions. Now, a transition-metal-free C(sp²)–C(sp³) cross-coupling of α-(pseudo)halo aliphatic ketones with boronic acids via a 1,4-metallate shift is reported which is compatible with tertiary aliphatic halides, allowing for 1,3-disubstituted products.

Alkyl boronic esters are commonly used building blocks in organic synthesis, causing efficient C-H borylation methods to be in high demand. Here, the authors develop a method for the photoredox-catalyzed borylation of unreactive C(sp³)-H bonds, mediated by amidyl radicals to achieve C-H borylation at the λ position of carbonyl compounds.

Stereogenic phosphorous compounds play a crucial role in asymmetric catalysis in organic chemistry, and thus access to P-stereogenic motifs is highly desirable. Here, the authors develop a camphor-derived 2,3-diol as a chiral template to afford diverse P(III) and P(V) chiral compounds.

gem-Difluorinated motifs are prevalent in numerous leading pharmaceuticals. Here the authors merge I(I)/I(III)-catalysed fluorination and C(sp3)-F bond activation to generate these motifs directly from 1,3-diaryl cyclobutanols in a single operation.

Amide dehydration is an important reaction to access organonitrile compounds harboring high synthetic value, however, the reaction relies on harsh dehydrating reagents or transition metals. Here, the authors develop an oxygen transfer reaction to generate hydroxyalkyl nitriles from sequential dehydration and hydrolysis of haloalkyl amides catalyzed by phenylboronic acid.

Catalytic enantioselective phosphinylation of imines with diarylphosphine oxides is a powerful approach to access chiral α-amino diarylphosphine oxides. Here, the authors report the asymmetric phosphinylation of 3,4-dihydroisoquinolines at the C1 position using diarylphosphine oxides, catalyzed by chiral phosphoric acids.