Cooperative copper-squaramide catalysis for the enantioselective N–H insertion reaction with sulfoxonium ylides

The first examples of a highly efficient and enantioselective carbene-mediated insertion reaction, from a sulfur ylide, are described. By way of a catalytic asymmetric insertion reaction into N–H bonds from carbonyl sulfoxonium ylides and anilines, using a copper-bifunctional squaramide cooperative catalysis approach, thirty-seven α-arylglycine esters were synthesized in enantiomeric ratios up to 92 : 8 (99 : 1 after a single recrystallization) and reaction yields ranging between 49–96%. Furthermore, the protocol benefits from quick reaction times and is conducted in a straightforward manner.

The first examples of a highly efficient and enantioselective carbene-mediated insertion reaction, from a sulfur ylide, are described.     

Tandem sequential catalytic enantioselective synthesis of highly-functionalised tetrahydroindolizine derivatives

An isothiourea-catalysed enantioselective synthesis of novel tetrahydroindolizine derivatives is reported through a one-pot tandem sequential process. The application of 2-(pyrrol-1-yl)acetic acid in combination with either a trifluoromethyl enone or an α-keto-β,γ-unsaturated ester in an enantioselective Michael addition–lactonisation process, followed by in situ ring-opening and cyclisation, led to a range of 24 tetrahydroindolizine derivatives containing three stereocentres in up to >95 : 5 dr and >99 : 1 er.

The isothiourea-catalysed enantioselective synthesis of tetrahydroindolizine derivatives containing three stereocentres is reported through a one-pot tandem sequential process.     

Catalytic asymmetric synthesis of 3,2′-pyrrolinyl spirooxindoles via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles

A catalytic asymmetric conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles was realized. It afforded a variety of optically active 3,2′-pyrrolinyl spirooxindoles with high yields (up to 98%), and excellent diastereo- and enantioselectivities (up to 98% ee, >19 : 1 dr), even at the gram-scale in the presence of a chiral N,N′-dioxide–nickel(ii) complex. In addition, a possible catalytic cycle and transition state model were proposed to rationalize the stereoselectivity.

Lewis acid catalyzed asymmetric synthesis of 3,2′-pyrrolinyl spirooxindole skeletons via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles.     

N2Phos – an easily made,highly effective ligand designed for ppm level Pd-catalyzed Suzuki–Miyaura cross couplings in water

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki–Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000–2500 ppm or 0.10–0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N₂Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand–Pd(0) complex more for N₂Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand–Pd^o complex that is more reactive in oxidative addition to aryl chlorides.

A new, biaryl phosphine-containing ligand, N₂Phos, forms a 1 : 1 complex with Pd resulting in an active catalyst at the ppm level for Suzuki–Miyaura couplings in water, enabled by an aqueous micellar medium. Notably, aryl chlorides are shown to be amenable substrates.     

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.     

Fe-catalyzed Fukuyama-type indole synthesis triggered by hydrogen atom transfer

Fe, Co, and Mn hydride-initiated radical olefin additions have enjoyed great success in modern synthesis, yet the extension of other hydrogen radicalophiles instead of olefins remains largely elusive. Herein, we report an efficient Fe-catalyzed intramolecular isonitrile–olefin coupling reaction delivering 3-substituted indoles, in which isonitrile was firstly applied as the hydrogen atom acceptor in the radical generation step by MHAT. The protocol features low catalyst loading, mild reaction conditions, and excellent functional group tolerance.

A mild and efficient method has been developed to synthesize 3-substituted indoles via an Fe-catalyzed radical isonitrile–olefin coupling reaction initiated by MHAT to isonitriles.     

Catalytic enantioselective synthesis of macrodiolides and their application in chiral recognition

New types of C₂-symmetric chiral macrodiolides are readily obtained via chiral N,N′-dioxide-scandium(iii) complex-promoted asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles. This protocol provides an array of enantioenriched macrodiolides with 16, 18 or 20-membered rings in moderate to good yields with high diastereoselectivities and excellent enantioselectivities through adjusting the length of the tether at the C3 position of indoles. Density functional theory calculations indicate that the formation of macrocycles is more favorable than that of 9-membered-ring lactones in terms of kinetics and thermodynamics. The potential utility of these intriguing chiral macrodiolide molecules is demonstrated in the enantiomeric recognition of aminols and chemical recognition of metal ions.

An asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles was achieved by using a chiral N,N′-dioxide-scandium(iii) complex.     

Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones

Indole-tethered ynones form an intramolecular electron donor–acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C–S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor–acceptor complex in synthesis.

Indole-tethered ynones form an intramolecular electron donor–acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols.     

Exploiting single-electron transfer in Lewis pairs for catalytic bond-forming reactions

A single-electron transfer (SET) between tris(pentafluorophenyl)borane (B(C₆F₅)₃) and N,N-dialkylanilines is reported, which is operative via the formation of an electron donor–acceptor (EDA) complex involving π-orbital interactions as a key intermediate under dark conditions or visible-light irradiation depending on the structure of the aniline derivatives. This inherent SET in the Lewis pairs initiates the generation of the corresponding α-aminoalkyl radicals and their additions to electron-deficient olefins, revealing the ability of B(C₆F₅)₃ to act as an effective one-electron redox catalyst.

Radical–ion pair generation from common Lewis pairs and its application to catalytic carbon–carbon bond formation.     

The simplest Diels–Alder reactions are not endo-selective

There is a widespread perception that the high level of endo selectivity witnessed in many Diels–Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels–Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo : exo ratios close to 1 : 1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo : exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels–Alder reactions are not endo-selective. Trends in behaviour are traced to steric and electronic effects in Diels–Alder transition structures, giving new insights into these fundamental processes.

Cycloadditions of deuterium-labeled 1,3-butadiene with monosubstituted alkenic dienophiles challenge the widespread assumption of endo-selectivity in prototypical Diels–Alder reactions.     

Cobalt-catalyzed intramolecular decarbonylative coupling of acylindoles and diarylketones through the cleavage of C–C bonds

We report here cobalt–N-heterocyclic carbene catalytic systems for the intramolecular decarbonylative coupling through the chelation-assisted C–C bond cleavage of acylindoles and diarylketones. The reaction tolerates a wide range of functional groups such as alkyl, aryl, and heteroaryl groups, giving the decarbonylative products in moderate to excellent yields. This transformation involves the cleavage of two C–C bonds and formation of a new C–C bond without the use of noble metals, thus reinforcing the potential application of decarbonylation as an effective tool for C–C bond formation.

A method for cobalt–N-heterocyclic carbene catalytic systems for the intramolecular decarbonylative coupling of ketones was achieved.     

Regiocontrol in the oxidative Heck reaction of indole by ligand-enabled switch of the regioselectivity-determining step

Efficient control of regioselectivity is a key concern in transition-metal-catalyzed direct C–H functionalization reactions. Various strategies for regiocontrol have been established by tuning the selectivity of the C–H activation step as a common mode. Herein, we present our study on an alternative mode of regiocontrol, in which the selectivity of the C–H activation step is no longer a key concern. We found that, in a reaction where the C–H activation step exhibits a different regio-preference from the subsequent functionalization step, a ligand-enabled switch of the regioselectivity-determining step could provide efficient regiocontrol. This mode has been exemplified by the Pd(ii)-catalyzed aerobic oxidative Heck reaction of indoles, in which a ligand-controlled C3-/C2-selectivity was achieved for the first time by the development of sulfoxide-2-hydroxypyridine (SOHP) ligands.

Ligand-enabled switch of the regioselectivity-determining step allowed for efficient regiocontrol in the aerobic oxidative Heck reaction of indole.     

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.     

Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base

Hydrogen bonding-assisted polarization is an effective strategy to promote bond-making and bond-breaking chemical reactions. Taking inspiration from the catalytic triad of serine protease active sites, we have devised a conformationally well-defined benzimidazole platform that can be systematically functionalized to install multiple hydrogen bonding donor (HBD) and acceptor (HBA) pairs in a serial fashion. We found that an increasing number of interdependent and mutually reinforcing HBD–HBA contacts facilitate the bond-forming reaction of a fluorescence-quenching aldehyde group with the cyanide ion, while suppressing the undesired Brønsted acid–base reaction. The most advanced system, evolved through iterative rule-finding studies, reacts rapidly and selectively with CN⁻ to produce a large (>180-fold) enhancement in the fluorescence intensity at λ_max = 450 nm.

Biomimetic cascade hydrogen bonds promote covalent capture of a nucleophile by polarizing the electrophilic reaction site, while suppressing non-productive acid–base chemistry as the competing reaction pathway.     

Three-component three-bond forming cascade via palladium photoredox catalysis

A highly modular radical cascade strategy based upon radical cyclisation/allylic substitution sequence between alkyl/aryl bromides, 1,3-dienes and nucleophiles ranging from sulfinates to amines, phenols and 1,3-dicarbonyls is described (>80 examples). Palladium phosphine complexes – which merge properties of photo- and cross coupling-catalysts – allow to forge three bonds with complete 1,4-selectivity and stereocontrol, delivering highly value added carbocyclic and heterocyclic motifs that can feature – inter alia – vicinal quaternary centers, free protic groups, gem-difluoro motifs and strained rings. Furthermore, a flow chemistry approach was for the first time applied in palladium–photocatalysed endeavors involving radicals.

Highly modular three-bond three-component cascade featuring palladium as dual photoredox/cross coupling catalyst.     

Cobalt-catalyzed aminocarbonylation of (hetero)aryl halides promoted by visible light

The catalytic aminocarbonylation of (hetero)aryl halides is widely applied in the synthesis of amides but relies heavily on the use of precious metal catalysis. Herein, we report an aminocarbonylation of (hetero)aryl halides using a simple cobalt catalyst under visible light irradiation. The reaction extends to the use of (hetero)aryl chlorides and is successful with a broad range of amine nucleophiles. Mechanistic investigations are consistent with a reaction proceeding via intermolecular charge transfer involving a donor–acceptor complex of the substrate and cobaltate catalyst.

An aminocarbonylation of (hetero)aryl halides using a simple cobalt catalyst under visible light irradiation is presented.     

Enthalpic and entropic contributions to the basicity of cycloalkylamines

Large-ring cycloalkylamines are slightly less basic than other cycloalkylamines such as cyclohexylamine, even though all have tetrahedral carbons and are strain-free. To understand why, enthalpy and entropy for protonation of a series of cycloalkylamines were accurately determined by isothermal titration calorimetry in 3 : 1 methanol–water. The study required resolving a discrepancy between these measurements and those in pure water. The data show that the lower basicity of large-ring cycloalkylamines is not due to enthalpy but to a more negative entropy of protonation. Computations show that this can be attributed in part to an entropy of conformational mixing, but the dominant contribution is steric hindrance to solvation, also corroborated by computation.

Large-ring cycloalkylamines are slightly less basic than other cycloalkylamines such as cyclohexylamine, even though all have tetrahedral carbons and are strain-free.     

Organophotoredox/palladium dual catalytic decarboxylative Csp3–Csp3 coupling of carboxylic acids and π-electrophiles

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed. The new process is mild, operationally simple, and has greatly improved upon the efficiency and generality of previous methodology. In addition, new insights into the reaction mechanism have been realized and provide further understanding of the harnessed reactivity.

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed.