Visible-light-induced indole synthesis via intramolecular C–N bond formation: desulfonylative C(sp2)–H functionalization

Despite significant advances made on the synthesis of indole derivatives through photochemical strategies during the past several years, the requirement of equivalent amounts of oxidants, bases or other additional additives has limited their practical applications in the synthesis of natural products and pharmaceuticals as environment-friendly processes. Herein, we report LED visible-light-induced redox neutral desulfonylative C(sp²)–H functionalization for the synthesis of N-substituted indoles with a broad scope through γ-fragmentation under mild conditions in the absence of any additional additive. The reaction mechanism paradigm has been investigated on the basis of deuterium labeling experiments, kinetic analysis, Hammett plotting analysis and DFT calculations.

LED visible-light-induced redox neutral desulfonylative C(sp²)–H functionalization for the synthesis of N-substituted indoles in the absence of any additional additive has been established on the basis of KIE, Hammett plotting and DFT calculations.     

An economical approach for peptide synthesis via regioselective C–N bond cleavage of lactams

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed. The method not only eliminates the need for condensation agents and their auxiliaries, which are essential for conventional peptide synthesis, but also exhibits high atom economy. The reaction is versatile because it can tolerate side chains bearing a range of functional groups, affording up to >99% yields of the corresponding peptides without racemisation or polymerisation. Moreover, the developed strategy enables peptide segment coupling, providing access to a hexapeptide that occurs as a repeat sequence in spider silk proteins.

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed.     

A general method for site-selective Csp3–S bond formation via cooperative catalysis

Herein, we report a copper-catalysed site-selective thiolation of Csp³–H bonds of aliphatic amines. The method features a broad substrate scope and good functional group compatibility. Primary, secondary, and tertiary C–H bonds can be converted into C–S bonds with a high efficiency. The late-stage modification of biologically active compounds by this method was also demonstrated. Furthermore, the one-pot preparation of pyrrolidine or piperidine compounds via a domino process was achieved.

A copper-catalyzed site-selective thiolation of Csp³–H bonds of aliphatic amines was developed. The method features a broad substrate scope and good functional group tolerance.     

Selective editing of a peptide skeleton via C–N bond formation at N-terminal aliphatic side chains

The applications of peptides and peptidomimetics have been demonstrated in the fields of therapeutics, diagnostics, and chemical biology. Strategies for the direct late-stage modification of peptides and peptidomimetics are highly desirable in modern drug discovery. Transition-metal-catalyzed C–H functionalization is emerging as a powerful strategy for late-stage peptide modification that is able to construct functional groups or increase skeletal diversity. However, the installation of directing groups is necessary to control the site selectivity. In this work, we describe a transition metal-free strategy for late-stage peptide modification. In this strategy, a linear aliphatic side chain at the peptide N-terminus is cyclized to deliver a proline skeleton via site-selective δ-C(sp³)–H functionalization under visible light. Natural and unnatural amino acids are demonstrated as suitable substrates with the transformations proceeding with excellent regio- and stereo-selectivity.

We have developed a visible light-promoted selective editing of a peptide skeleton via C–N bond formation at N-terminal aliphatic side chains. A proline skeleton was constructed in peptides under such transition metal free conditions.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Aryl diazonium intermediates enable mild DNA-compatible C–C bond formation for medicinally relevant combinatorial library synthesis

Forging carbon–carbon (C–C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate scope and exquisite functional group tolerance. Here we reported the palladium-catalyzed Suzuki–Miyaura, Heck and Hiyama type cross-coupling via DNA-conjugated aryl diazonium intermediates for DNA-encoded chemical library (DEL) synthesis. Starting from commodity arylamines, this synthetic route facilely delivers vast chemical diversity at a mild temperature and pH, thus circumventing damage to fragile functional groups. Given its orthogonality with traditional aryl halide-based cross-coupling, the aryl diazonium-centered strategy expands the compatible synthesis of complex C–C bond-connected scaffolds. In addition, DNA-tethered pharmaceutical compounds (e.g., HDAC inhibitor) are constructed without decomposition of susceptible bioactive warheads (e.g., hydroxamic acid), emphasizing the superiority of the aryl diazonium-based approach. Together with the convenient transformation into an aryl azide photo-crosslinker, aryl diazonium''s DNA-compatible diversification synergistically demonstrated its competence to create medicinally relevant combinatorial libraries and investigate protein–ligand interactions in pharmaceutical research.

Taking advantage of aryl diazonium intermediates, this work reported a DNA-compatible C–C bond formation strategy, achieving broad substrate scope, exquisite functional group tolerance, and orthogonality to aryl halide-based coupling reactions.     

Utilizing 2‐phenylpropanal as coupling partner for C‐S bond formation via sequential thioarylation and decarbonylation process: A novel strategy for the synthesis of aryl alkyl sulfides

In this study, first direct access to aryl alkyl sulfides employing 2‐phenylpropanal as coupling partner is reported. Diaryl disulfides react with this aldehyde in the presence of morpholine and produce the corresponding sulfide products in high yields. In another part, disulfides are in situ generated in the reaction mixture from aryl halides/CuI/Cyanodithioformate and coupled with 2‐phenylpropanal to access aryl alkyl sulfides.     

An effective and versatile strategy for the synthesis of structurally diverse heteroarylsilanes via Ir(iii)-catalyzed C–H silylation

A versatile silylation of heteroaryl C–H bonds is accomplished under the catalysis of a well-defined spirocyclic NHC Ir(iii) complex (SNIr), generating a variety of heteroarylsilanes. A significant advantage of this catalytic system is that multiple types of intermolecular C–H silylation can be achieved using one catalytic system at α, β, γ, or δ positions of heteroatoms with excellent regioselectivities. Mechanistic experiments and DFT calculations indicate that the polycyclic ligand of SNIr can form an isolable cyclometalated intermediate, which leaves a phenyl dentate free and provides a hemi-open space for activating substrates. In general, favorable silylations occur at γ or δ positions of chelating heteroatoms, forming 5- or 6-membered C–Ir–N cyclic intermediates. If such an activation mode is prohibited sterically, silylations would take place at the α or β positions. The mechanistic studies would be helpful for further explaining the reactivity of the SNIr system.

A versatile silylation of heteroaryl C–H bonds is accomplished under the catalysis of a well-defined spirocyclic NHC Ir(iii) complex (SNIr), generating a variety of heteroarylsilanes.     

Intramolecular Csp3–H/C–C bond amination of alkyl azides for the selective synthesis of cyclic imines and tertiary amines

The intramolecular Csp³–H and/or C–C bond amination is very important in modern organic synthesis due to its efficiency in the construction of diversified N-heterocycles. Herein, we report a novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines through selective Csp³–H and/or C–C bond cleavage. Two C–N single bonds or a C N double bond are efficiently constructed in these transformations. The carbocation mechanism differs from the reported metal nitrene intermediates and therefore enables metal-free and new transformation.

A novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines has been developed. The aliphatic C–H or C–C bond was selectively cleaved with the efficient formation of two C–N single bonds or a C N double bond.     

A versatile method for carbon-nitrogen bond formation via ene reactions of acylnitroso compounds

The use of acylnitroso compounds of the general formula RCONO as enophiles in the formation of carbon-nitrogen bonds is described. Both inter- and intramolecular ene reactions have been studied. For the intermolecular examples, nitrosocarbonylmethane, thermally liberated from its Diels-Alder adduct with 9,10-dimethylanthracene, is reacted with various olefins giving the corresponding N-alkylhydroxamic acids in moderate to high yields, providing an efficient method for allylic amidation. The regiochemistry of the intermolecular reaction is observed to be the result of kinetic control, and the direction of addition is consistent with attack by the olefin on electron-deficient nitrogen. Several examples of intramolecular ene cyclization are demonstrated, providing efficient entry into both spiro and fused bicyclic nitrogen containing systems which can be viewed as derived from annulation of 5- and 6- membered nitrogen containing rings onto 5- and 6-membered carbocycles, respectively. Various examples of this hetero-annulation scheme are described. Experimental details are also privided describing typical reaction procedures.     

Modular synthesis of α-arylated carboxylic acids,esters and amides via photocatalyzed triple C–F bond cleavage of methyltrifluorides

α-Arylated carboxylic acids, esters and amides are widespread motifs in bioactive molecules and important building blocks in chemical synthesis. Thus, straightforward and rapid access to such structures is highly desirable. Here we report an organophotocatalytic multicomponent synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles. This operationally simple strategy features a unified access to functionally diverse α-arylated carboxylic acids, esters, and primary, secondary, and tertiary amides through backbone assembly from simple starting materials enabled by consecutive C–F bond functionalization at room temperature. Preliminary mechanistic investigations reveal that the reaction operates through a radical-triggered three-step cascade process, which involves distinct mechanisms for each defluorinative functionalization of the C–F bond.

Here we report an organophotocatalytic synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles.     

Palladium-catalyzed synthesis of β-hydroxy compounds via a strained 6,4-palladacycle from directed C–H activation of anilines and C–O insertion of epoxides

A palladium-catalyzed C–H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides using O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized β-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of the ortho-C(sp²) atom of O-coordinating directing groups with a C(sp³) carbon of chiral epoxides offers diverse substrate scope in good to excellent yields. In addition, further transformations of the synthesized compound led to biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged in this work is significantly more strained (>10 kcal mol⁻¹) than the literature known 5,4 palladacycles.

The combined experimental and computational study on palladium-catalyzed regioselective C–H functionalization of O-coordinating directing groups with epoxides is described.     

Oxidative regulation of the mechanical strength of a C–S bond

The mechanical strength of individual polymer chains is believed to underlie a number of performance metrics in bulk materials, including adhesion and fracture toughness. Methods by which the intrinsic molecular strength of the constituents of a given polymeric material might be switched are therefore potentially useful both for applications in which triggered property changes are desirable, and as tests of molecular theories for bulk behaviors. Here we report that the sequential oxidation of sulfide containing polyesters (PE-S) to the corresponding sulfoxide (PE-SO) and then sulfone (PE-SO2) first weakens (sulfoxide), and then enhances (sulfone), the effective mechanical integrity of the polymer backbone; PE-S ∼ PE-SO2 > PE-SO. The relative mechanical strength as a function of oxidation state is revealed through the use of gem-dichlorocyclopropane nonscissile mechanophores as an internal standard, and the observed order agrees well with the reported bond dissociation energies of C–S bonds in each species and with the results of CoGEF modeling.

The mechanical strength of individual polymer chains is believed to underlie a number of performance metrics in bulk materials, including adhesion and fracture toughness.     

A rare earth metallocene containing a 2,2′-azopyridyl radical anion

Introducing spin onto organic ligands that are coordinated to rare earth metal ions allows direct exchange with metal spin centres. This is particularly relevant for the deeply buried 4f-orbitals of the lanthanide ions that can give rise to unparalleled magnetic properties. For efficacy of exchange coupling, the donor atoms of the radical ligand require high-spin density. Such molecules are extremely rare owing to their reactive nature that renders isolation and purification difficult. Here, we demonstrate that a 2,2′-azopyridyl (abpy) radical (S = 1/2) bound to the rare earth metal yttrium can be realized. This molecule represents the first rare earth metal complex containing an abpy radical and is unambigously characterized by X-ray crystallography, NMR, UV-Vis-NIR, and IR spectroscopy. In addition, the most stable isotope ⁸⁹Y with a natural abundance of 100% and a nuclear spin of ½ allows an in-depth analysis of the yttrium–radical complex via EPR and HYSCORE spectroscopy. Further insight into the electronic ground state of the radical azobispyridine-coordinated metal complex was realized through unrestricted DFT calculations, which suggests that the unpaired spin density of the SOMO is heavily localized on the azo and pyridyl nitrogen atoms. The experimental results are supported by NBO calculations and give a comprehensive picture of the spin density of the azopyridyl ancillary ligand. This unexplored azopyridyl radical anion in heavy element chemistry bears crucial implications for the design of molecule-based magnets particularly comprising anisotropic lanthanide ions.

Unambiguous characterization of the first 2,2′-azobispyridine radical-containing rare earth metal complex through X-ray crystallography, DFT computations, EPR and HYSCORE spectroscopy.     

Correction: Cu-catalyzed C–C bond formation of vinylidene cyclopropanes with carbon nucleophiles

Correction for ‘Cu-catalyzed C–C bond formation of vinylidene cyclopropanes with carbon nucleophiles’ by Jichao Chen et al., Chem. Sci., 2019, 10, 10601–10606.

We regret that in the original article the structure of compound 1 in Tables 1–3 was incorrect. The correct structure is given below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Diazaphosphinyl radical-catalyzed deoxygenation of α-carboxy ketones: a new protocol for chemo-selective C–O bond scission via mechanism regulation

C–O bond cleavage is often a key process in defunctionalization of organic compounds as well as in degradation of natural polymers. However, it seldom occurs regioselectively for different types of C–O bonds under metal-free mild conditions. Here we report a facile chemo-selective cleavage of the α-C–O bonds in α-carboxy ketones by commercially available pinacolborane under the catalysis of diazaphosphinane based on a mechanism switch strategy. This new reaction features high efficiency, low cost and good group-tolerance, and is also amenable to catalytic deprotection of desyl-protected carboxylic acids and amino acids. Mechanistic studies indicated an electron-transfer-initiated radical process, underlining two crucial steps: (1) the initiator azodiisobutyronitrile switches originally hydridic reduction to kinetically more accessible electron reduction; and (2) the catalytic phosphorus species upconverts weakly reducing pinacolborane into strongly reducing diazaphosphinane.

Diazaphosphinyl radical-catalyzed chemo-selective deoxygenation of α-carboxy ketones with pinacolborane was achieved through the mechanism switch from direct to stepwise hydride transfer of diazaphosphinane.

The importance of reductive deoxygenation can be gauged by the wide use of Barton–McCombie deoxygenation in organic syntheses.¹ Such C–O bond cleavage is also a crucial step in the degradation of natural polymers (e.g., sugars and lignins) to recycle sustainable resources.² Consequently, a great variety of methodologies were explored for activation of these strong C–O bonds.³ Among them, deoxygenation of α-acyloxy ketones^3b,c,4 (represented by benzoin derivatives, stemming from simple aldehydes via benzoin condensation⁵) has attracted considerable attention, because it may provide a facile way for accessing commonly useful building blocks (aryl ketones).⁶ As known, benzoin derivatives bear two types of C–O bonds—the carbonyl π-C O bond and the benzyl σ-C–O bond (Scheme 1). While reduction of the carbonyl π-C O bonds has been well established through transition metal-⁷ or Lewis acid-mediated⁸ hydride transfers, chemo-selective cleavage of the benzyl σ-C–O bonds is challenging and has seldom been achieved.⁹ The later process is occasionally seen, however, in some radical or electron reductions, but toxic tin hydrides^1c or aggressive metal reagents (like Raney nickel,¹⁰ zinc dust,¹¹etc.) are inevitably employed.Open in a separate windowScheme 1Possible reactive sites for benzoin reduction.The recent successful development of super electron donors (SEDs),^4,12 which are defined as ground-state organic electron-donors capable of reducing aryl halides to aryl radicals or aryl anions,¹³ and photocatalytic systems^3b,c may provide alternative protocols for reductive cleavage of the σ-C–O bonds in O-acetylated benzoin. However, these electron transfer-initiated reductions also suffer from some drawbacks, such as, excessive use of SEDs and their tedious synthetic procedures, expensive photoredox catalysts and ligands, and group-tolerance issues. In fact, there have been few reports to date on metal-free systems for efficiently catalytic deoxygenation with commercially available inexpensive reductants.^3h Given the ubiquity of C–O bonds in nature, it is still an unmet need for development of efficient and economical methods for their degradation. N-Heterocyclic phosphines (NHPs)^8c,14 have recently found plentiful applications in hydridic reductions^8b,15 owing to their outstanding hydricity.¹⁶ However, this seems to blind one to search for their other promising reaction patterns, like radical and electron transfer reactivities. Up to now, the catalytic potential of NHPs in radical or electron reductions has never been explored. Given the logical understanding that a deliberately manipulated mechanism variation usually leads to diverse reactivity and selectivity, we anticipate that an intended mechanism switch for NHP-based reactions from the conventional hydride transfer to an alternative electron transfer might provide a chance for originally inaccessible chemo-selectivity in the reduction of the substrates bearing multiple reactive sites. As known from previous studies, NHPs could transfer a hydride ion to carbonyl C O bonds to deliver the corresponding alcohol counterparts (Scheme 2a).^8b This is indeed what we have seen. When NHPs are mixed with O-acetylated benzoins, an exclusive hydridic reduction of the carbonyl π-C O bonds is observed, leaving the benzyl σ-C–O bonds intact. How could we make the propensity of NHP reduction to switch from the original hydridic path to a radical one? Inspired by our recent findings that NHPs are also capable of serving as good hydrogen-atom donors (by P–H bond homolysis) and their corresponding phosphinyl radicals are excellent electron donors¹⁷ (Scheme 2b, bottom), we envisioned that if phosphinyl radicals can be in situ generated, their super electron-donicity may promote the initial electron transfer to benzoin, and trigger the subsequent benzyl σ-C–O bond scission. If this is realizable, chemo-selective deoxygenation of benzoin derivatives with NHPs may be achieved via such a mechanism switch.Open in a separate windowScheme 2Chemical transformations of N-heterocyclic phosphines NHPs in reduction reactions.It is noted that the phosphorus species NHP-OR′ is produced in either the hydride or electron reduction of benzoin derivatives (Scheme 2c). Based on the previous knowledge that NHP-OR′ can be recycled back to NHP through a σ-bond metathesis between its exocyclic P–O bond and the B–H bond of pinacolborane (HBpin),^8b we envisioned that the present deoxygenation may operate in a catalytic fashion with readily available HBpin as the terminal reductant to avoid the use of stoichiometric NHP. To verify this plot, we chose dimethyl 4,4′-(1-acetoxy-2-oxoethane-1,2-diyl)dibenzoate X as the testing substrate, and 1,3-di-tert-butyl-1,3,2-diazaphosphinane 1a as the catalyst based on its compatible reducing capacity (Scheme 3, for structure of 1a, cf.Table 1).^17a It is observed that, under the previously established catalytic conditions for carbonyl reduction (20 mol% of 1a and 1.2 equiv. HBpin),^8b the product X1 of hydridic reduction was obtained in 86% yield and 1 : 0.69 of diastereomer ratio in 12 h. On the other hand, when 10% azodiisobutyronitrile (AIBN) was added as a radical initiator, the σ-C–O bonds were, indeed, selectively cleaved to give the anticipated product X2 in 87% yield. This distinct chemo-selectivity did echo our proposed mechanism switch from the direct hydridic pathway to an electron reduction. In the following, we report this catalytic transformation in a more inclusive fashion. To our best knowledge, this is the first example of catalytic electron reduction mediated by NHPs.Optimization of reaction conditions for C–O bond cleavage

Practical synthesis of 4,4,4-trifluorocrotonaldehyde: a versatile precursor for the enantioselective formation of trifluoromethylated stereogenic centers via organocatalytic 1,4-additions

The practical synthesis of 4,4,4-trifluorocrotonaldehyde (1) and its application to enantioselective 1,4-additions are described. The organocatalytic 1,4-addition of 1 with several nucleophiles such as heteroaromatics, alkylthiols and aldoximes afforded the corresponding products, each bearing a trifluoromethylated stereogenic center with high optical purity. A resulting product was converted into an MAO-A inhibitor, befloxatone.     

Metal-stabilized thiyl radicals as scaffolds for reversible alkene addition via C-S bond formation/cleavage

The one-electron oxidation of metal thiolates results in an increased oxidation state of the metal ion or the formation of a sulfur-based, thiyl radical in limiting extremes. For complexes with highly covalent M-S bonds, the unpaired electron may be delocalized over the metal and the sulfur, yielding a metal-stabilized thiyl radical. Oxidation of the metal thiolate precursors [Ru(DPPBT)(3)](-), [Ru-1](-), and Re(DPPBT)(3), Re-1 (DPPBT = diphenylphosphinobenzenethiolate), generates metal-stabilized thiyl radicals that react with alkenes to yield dithioether-metal products. Alkene addition to [Ru-1](+) and [Re-1](+) is symmetry-allowed due to the meridional arrangement of the DPPBT chelates. Combined bulk electrolysis and cyclic voltammetry experiments reveal the addition of alkenes to [Ru-1](+) as an irreversible process with experimentally determined rate constants ranging from 4.6(5) × 10(7) M(-1) s(-1) for electron-rich alkenes to 2.7(2) × 10(4) M(-1) s(-1) for electron-poor alkenes. Rate constants for cyclic alkenes range from 4(2) × 10(7) to 2.9(3) × 10(3) M(-1) s(-1). Chemical oxidation of [Ru-1](-) by ferrocenium hexafluorophosphate (FcPF(6)) in the presence of m-methylstyrene or p-methylstyrene yields the dithioether complexes [Ru-1·m-methylstyrene](+) and [Ru-1·p-methylstyrene](+), respectively. Each complex was crystallized and the structure determined by single-crystal X-ray diffraction. (31)P NMR of the samples reveals a major and minor product, each displaying a second-order spectrum. The oxidized intermediate [Re-1](+) binds alkenes reversibly with equilibrium binding constants that vary with the complex charge from 1.9 × 10(-11) M(-1) for n = 0 to 4.0 M(-1) for n = +1 to 2.5 × 10(9) M(-1) for n = +2. The three binding regimes are separated by 240 mV. Crystalline samples of [Re-1·C(2)H(4)](2+) are obtained upon chemical oxidation of Re-1 with silver hexafluorophosphate (AgPF(6)) in the presence of ethylene. Strategies for the addition of alkenes to other metal-stabilized thiyl radicals are suggested.