Enantioselective one-carbon expansion of aromatic rings by simultaneous formation and chromoselective irradiation of a transient coloured enolate

Enantioenriched seven-membered carbocycles are motifs in many molecules of structural and biological interest. We report a simple, practical, transition metal-free and mechanistically unusual method for the enantioselective synthesis of substituted cycloheptatrienes. By forming a coloured enolate with an appropriate absorption band and selectively irradiating in situ, we to initiate a tandem, asymmetric anionic and photochemical ring expansion of readily accessible N-benzylbenzamides. The cascade of reactions leading to the products entails enantioselective benzylic deprotonation with a chiral lithium amide, dearomatizing cyclization of the resulting configurationally defined organolithium to give an extended amide enolate, and photochemically induced formal [1,7]-sigmatropic rearrangement and 6π-electrocyclic ring-opening – the latter all evidently being stereospecific – to deliver enantioenriched cycloheptatrienes with embedded benzylic stereocentres.

Irradiation of a mixture of aromatic amide and chiral base leads to a tandem reaction sequence in which dearomatization forms a chromophore capable of photochemical rearrangement leading to overall asymmetric expansion of the aromatic ring.     

Ring-opening and ring-expansion reactions of carborane-fused borirane

Though the reaction chemistry of three-membered ring molecules such as cyclopropanes and their heteroatom-containing analogues has been extensively studied, the chemical properties of their boron analogues, boriranes, are little known thus far. This work describes the diverse reactivity patterns of carborane-fused borirane 2. This borirane engages in ring-opening reactions with different types of Lewis acids, such as BBr₃, GeCl₂, GaCl₃, BH₃(SMe₂) and HBpin, affording a series of ring-opening products, in which M–X or B–H bonds add across the B–C(cage) bond of the three-membered ring in 2. On the other hand, borirane 2 can undergo ring-expansion reactions with unsaturated molecules such as PhCHO, CO₂ and PhCN to give ring-expansion products, five-membered boracycles, via a concerted reaction mechanism as supported by DFT calculations. The results of this work not only enrich the reaction chemistry of boriranes, but also offer new routes to boron-containing compounds and heterocycles.

Carborane-fused borirane can not only engage in ring-opening reactions with different types of Lewis acids, but also undergo ring-expansion reactions with unsaturated molecules such as PhCHO, CO₂ and PhCN to give five-membered boracycles.     

Cobalt-catalyzed multisubstituted allylation of the chelation-assisted C–H bond of (hetero)arenes with cyclopropenes

Cyclopropenes are highly strained three-membered carbocycles, which offer unique reactivity in organic synthesis. Herein, Cp*Co^III-catalyzed ring-opening isomerization of cyclopropenes to cobalt vinylcarbene has been utilized for the synthesis of multisubstituted allylarenes via directing group-assisted functionalization of C–H bonds of arenes and heteroarenes. Employing this methodology, various substituents can be introduced at all three carbons of the allyl moiety with high selectivity. The important highlights are excellent functional group tolerance, multisubstituted allylation, high selectivity, gram scale synthesis, removable directing group, and synthesis of cyclopenta[b]indoles. In addition, a potential cobaltocycle intermediate was identified and a plausible mechanism is also proposed.

Cp*Co^III-catalyzed ring-opening isomerization of cyclopropenes to cobalt vinylcarbene has been utilized for the synthesis of multisubstituted allylarenes via directing group-assisted functionalization of C–H bonds of arenes and heteroarenes.     

A different polynorbornene backbone by combination of two polymer growth pathways: vinylic addition and ring opening via β-C elimination

A new polynorbornene skeleton has been found that contains bicyclic norbornane units and cyclohexenyl methyl linkages. The polymers have been synthesized using a nickel catalyst in the presence of a controlled amount of ligands with low or moderate coordination ability. The backbone structure is the result of a vinylic addition polymerization, via sequential insertions of norbornene into a Ni–C bond (bicyclic units) combined with an unusual ring opening of the norbornene structure by a β-C elimination (cyclohexenyl methyl units) to give a new Ni–C(alkyl) bond that continues the polymerization. The ring opening events are favored when the rate of propagation of the vinylic addition polymerization decreases, and this can be modulated by making the coordination of norbornene to the metal center less favorable using additional ligands.

A new polynorbornene skeleton that contains a mixture of bicyclic norbornane units and cyclohexenylmethyl moieties can be obtained using a nickel catalyst.     

Skeletal remodeling of chalcone-based pyridinium salts to access isoindoline polycycles and their bridged derivatives

Simultaneous deconstructive ring-opening and skeletal reconstruction of an inert, aromatic pyridinium ring is of great importance in synthetic communities. However, research in this area is still in its infancy. Here, a skeletal re-modeling strategy was developed to transform chalcone-based pyridinium salts into structurally intriguing polycyclic isoindolines through a dearomative ring-opening/ring-closing sequence. Two distinct driving forces for the deconstruction of the pyridinium core were involved in these transformations. One was the unprecedented harnessing of the instability of in situ generated cyclic β-aminoketones, and the other was the instability of the resultant N,N-ketals. The desired isoindoline polycycles could undergo the Wittig reaction with various phosphorus ylides to achieve structural diversity and complexity. Notably, by tuning the Wittig conditions by addition of one equivalent of base, an additional bridged ring was introduced. A plausible mechanism was proposed on the basis of control experiments and theoretical calculations.

A novel skeletal remodeling strategy to transform chalcone-based pyridinium salts into structurally intriguing polycyclic isoindolines was achieved through a dearomative ring-opening/ring-closing sequence.     

Highly effective and chemoselective hydrodeoxygenation of aromatic alcohols

Effective hydrodeoxygenation (HDO) of aromatic alcohols is very attractive in both conventional organic synthesis and upgrading of biomass-derived molecules, but the selectivity of this reaction is usually low because of the competitive hydrogenation of the unsaturated aromatic ring and the hydroxyl group. The high activity of noble metal-based catalysts often leads to undesired side reactions (e.g., saturation of the aromatic ring) and excessive hydrogen consumption. Non-noble metal-based catalysts suffer from unsatisfied activity and selectivity and often require harsh reaction conditions. Herein, for the first time, we report chemoselective HDO of various aromatic alcohols with excellent selectivity, using porous carbon–nitrogen hybrid material-supported Co catalysts. The C–OH bonds were selectively cleaved while leaving the aromatic moiety intact, and in most cases the yields of targeted compounds reached above 99% and the catalyst could be readily recycled. Nitrogen doping on the carbon skeleton of the catalyst support (C–N matrix) significantly improved the yield of the targeted product. The presence of large pores and a high surface area also improved the catalyst efficiency. This work opens the way for efficient and selective HDO reactions of aromatic alcohols using non-noble metal catalysts.

Porous carbon–nitrogen hybrid material-supported Co catalysts can effectively promote the chemoselective hydrodeoxygenation reaction of a various of aromatic alcohols in ethanol and hydrogen atmosphere, under relatively mild conditions.     

Activation of Si–H and B–H bonds by Lewis acidic transition metals and p-block elements: same,but different

In this Perspective we discuss the ability of transition metal complexes to activate and cleave the Si–H and B–H bonds of hydrosilanes and hydroboranes (tri- and tetra-coordinated) in an electrophilic manner, avoiding the need for the metal centre to undergo two-electron processes (oxidative addition/reductive elimination). A formal polarization of E–H bonds (E = Si, B) upon their coordination to the metal centre to form σ-EH complexes (with coordination modes η¹ or η²) favors this type of bond activation that can lead to reactivities involving the formation of transient silylium and borenium/boronium cations similar to those proposed in silylation and borylation processes catalysed by boron and aluminium Lewis acids. We compare the reactivity of transition metal complexes and boron/aluminium Lewis acids through a series of catalytic reactions in which pieces of evidence suggest mechanisms involving electrophilic reaction pathways.

In this Perspective we compare the ability of transition metals and p-block Lewis acids to activate electrophilically hydrosilanes and hydroboranes. The mechanistic similarities and dissimilarities in different catalytic transformations are analyzed.     

Rhodium-catalysed ortho-alkynylation of nitroarenes

The ortho-alkynylation of nitro-(hetero)arenes takes place in the presence of a Rh(iii) catalyst to deliver a wide variety of alkynylated nitroarenes regioselectively. These interesting products could be further derivatized by selective reduction of the nitro group or palladium-catalysed couplings. Experimental and computational mechanistic studies demonstrate that the reaction proceeds via a turnover-limiting electrophilic C–H metalation ortho to the strongly electron-withdrawing nitro group.

Rh(iii)-catalyzed ortho-alkynylation of nitro-(hetero)arenes leads to a wide variety of alkynylated nitroarenes via a turnover-limiting electrophilic C–H ortho-metalation.     

Benzoates as photosensitization catalysts and auxiliaries in efficient,practical, light-powered direct C(sp3)–H fluorinations

Of the methods for direct fluorination of unactivated C(sp³)–H bonds, photosensitization of SelectFluor is a promising approach. Although many substrates can be activated with photosensitizing catalysts, issues remain that hamper fluorination of complex molecules. Alcohol- or amine-containing functional groups are not tolerated, fluorination regioselectivity follows factors endogenous to the substrate and cannot be influenced by the catalyst, and reactions are highly air-sensitive. We report that benzoyl groups serve as highly efficient photosensitizers which, in combination with SelectFluor, enable visible light-powered direct fluorination of unactivated C(sp³)–H bonds. Compared to previous photosensitizer architectures, the benzoyls have versatility to function both (i) as a photosensitizing catalyst for simple substrate fluorinations and (ii) as photosensitizing auxiliaries for complex molecule fluorinations that are easily installed and removed without compromising yield. Our auxiliary approach (i) substantially decreases the reaction''s induction period, (ii) enables C(sp³)–H fluorination of many substrates that fail under catalytic conditions, (iii) increases kinetic reproducibility, and (iv) promotes reactions to higher yields, in shorter times, on multigram scales, and even under air. Observations and mechanistic studies suggest an intimate ‘assembly’ of auxiliary and SelectFluor prior/after photoexcitation. The auxiliary allows other E_nT photochemistry under air. Examples show how auxiliary placement proximally directs regioselectivity, where previous methods are substrate-directed.

Benzoates serve as catalysts or auxiliaries for photochemical E_nT radical C(sp³)–H fluorinations. The auxiliary markedly increases scope and efficiency, enabling reactions of free alcohols, amines, and allowing rapid gram-scale fluorinations in air.     

Dimerizing cascades of enallenamides reveal the visible-light-promoted activation of cumulated C–C double bonds

The visible-light-promoted activation of conjugated C–C double bonds is well developed, while that of cumulated systems is underexplored. We present the feasibility of this challenging approach. The localization of a triplet on an allenamide arm can be favored over that on a conjugated alkene. Allenamides with an arylacryloyl arm dimerize at room temperature in the presence of visible light and an iridium(iii) photocatalyst. Two orthogonal polycyclizations took place and their outcome is entirely dictated by the substitution of the alkene partner. Both cascades afford complex molecular architectures with high selectivity. Products form through the ordered rearrangement of twelve π electrons, providing a [3.2.0] bicyclic unit tethered to a fused tricycle, whose formation included an aryl C–H functionalization step, using disubstituted alkenes. The outcome was reverted with trisubstituted ones, which gave rise to taxane-like bridged tricycles that had two six-membered lactams flanking a cyclooctane ring, which was established through the creation of four alternate C–C bonds.

Visible-light promoted activation of allenamides allowed us to disclose original dimerizing cascades that provide highly elaborate molecular architectures in a concise and mild fashion.     

Vinylazaarenes as dienophiles in Lewis acid-promoted Diels–Alder reactions

Described are the first examples of Lewis acid-promoted Diels–Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels–Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.

Vinyl-substituted azaarenes are rare and challenging substrates as dienophiles in Diels–Alder reactions; by employing Lewis acid activation, high yielding and highly selective cycloadditions with unactivated dienes are enabled.     

Stereodivergent synthesis via iridium-catalyzed asymmetric double allylic alkylation of cyanoacetate

Methods that enable the rapid construction of multiple C–C bonds using a single catalyst with high diastereo- and enantio-control are particularly valuable in organic synthesis. Here, we report an Ir-catalyzed double allylic alkylation reaction in which bisnucleophilic cyanoacetate reacted successionally with electrophilic π-allyl-Ir species, producing various pseudo-C₂-symmetrical cyanoacetate derivatives in high yield with excellent stereocontrol. More challenging sequential allylic alkylation/allylic alkylation with two distinct allylic carbonates that can deliver the corresponding products bearing three contiguous tertiary–quaternary–tertiary stereocenters was also developed by using a modified catalytic system, which is revealed to be associated with the quasi-dynamic kinetic resolution of the initially formed diastereomeric monoallylation intermediates. Notably, stereodivergence for this sequential process depending on a single iridium catalyst was successfully realized, and up to six stereoisomers could be predictably prepared by combining the appropriate enantiomer of the chiral ligand for the iridium catalyst and adjusting the adding sequence of two distinct allylic precursors.

Ir-catalyzed asymmetric double AAA reaction of cyanoacetate was developed, affording cyanoacetate derivatives in high yield with excellent stereocontrol. Notably, quasi-DKR is involved in the sequential protocol with two distinct allylic carbonates.     

Torsional strain inversed chemoselectivity in a Pd-catalyzed atroposelective carbonylation reaction of dibenzothiophenium

A palladium-catalyzed enantioselective ring-opening/carbonylation of cyclic diarylsulfonium salts is reported. In comparison to thioethers, the sulfonium salts displayed high reactivity and enabled the reaction to be performed under mild conditions (room temperature). The steric repulsion of the two non-hydrogen substituents adjacent to the axis led cyclic diarylsulfonium salts to be distorted, which enabled the ring-opening reaction to proceed with significant preference for breaking the exocyclic C–S bond.

Torsional strain inversed chemoselectivity: from bond a to bond b.     

Pd(ii)-catalyzed meta-C–H bromination and chlorination of aniline and benzoic acid derivatives

The classic electrophilic bromination leads to ortho- and para-bromination of anilines due to their electron-rich properties. Herein we report the development of an unprecedented Pd-catalyzed meta-C–H bromination of aniline derivatives using commercially available N-bromophthalimide (NBP), which overcomes the competing ortho/para-selectivity of electrophilic bromination of anilines. The addition of acid additives is crucial for the success of this reaction. A broad range of substrates with various substitution patterns can be tolerated in this reaction. Moreover, benzoic acid derivatives bearing complex substitution patterns are also viable with this mild bromination reaction, and meta-C–H chlorination is also feasible under similar reaction conditions. The ease of the directing group removal and subsequent diverse transformations of the brominated products demonstrate the application potential of this method and promise new opportunities for drug discovery.

An unprecedented Pd-catalyzed meta-C–H bromination and chlorination of highly substituted aniline and benzoic acid derivatives using N-bromophthalimide is reported.     

Heteroarylation of unactivated C–H bonds suitable for late-stage functionalization

The late-stage introduction of diverse heterocycles onto complex small molecules enables efficient access to new medicinally relevant compounds. An attractive approach to such a transformation would utilize the ubiquitous aliphatic C–H bonds of a complex substrate. Herein, we report a system that enables direct C–H heteroarylation using a stable, commercially available O-alkenylhydroxamate with heterocyclic sulfone partners. The C–H heteroarylation proceeds efficiently with a range of aliphatic substrates and common heterocycles, and is a rare example of heteroarylation of strong C–H bonds. Importantly, the present approach is amenable to late-stage functionalization as the substrate is the limiting reagent in all cases.

The late-stage introduction of diverse heterocycles onto complex small molecules enables efficient access to new medicinally relevant compounds.     

Organic amine mediated cleavage of Caromatic–Cα bonds in lignin and its platform molecules

The activation and cleavage of C–C bonds remains a critical scientific issue in many organic reactions and is an unmet challenge due to their intrinsic inertness and ubiquity. Meanwhile, it is crucial for the valorization of lignin into high-value chemicals. Here, we proposed a novel strategy to enhance the C_aromatic–C_α bond cleavage by pre-functionalization with amine sources, in which an active amine intermediate is first formed through Markovnikov hydroamination to reduce the dissociation energy of the C_aromatic–C_α bond which is then cleaved to form target chemicals. More importantly, this strategy provides a method to achieve the maximum utilization of the aromatic nucleus and side chains in lignin or its platform molecules. Phenols and N,N-dimethylethylamine compounds with high yields were produced from herbaceous lignin or the p-coumaric acid monomer in the presence of industrially available dimethylamine (DMA).

Pre-functionalization with amine sources mediated the cleavage of C_aromatic–C_α bonds to produce two valuable chemicals with high yields, for the full utilization of the aromatic rings and side-chains in lignin and its platform molecules.     

Copper-catalyzed radical cascade reaction of simple cyclobutanes: synthesis of highly functionalized cyclobutene derivatives

Cyclobutenes as versatile and highly valuable synthons have been widely applied in synthesis. Although various methods for their synthesis have been well established, new strategies for the construction of the cyclobutene skeleton from simple substrates are still highly desirable. Starting from simple cyclobutanes, the construction of the cyclobutene skeleton especially introducing multiple functional groups simultaneously had never been achieved. Here, we developed a novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare cleavage of four or five C–H bonds and formation of two C–N/C–S or three C–Br bonds. With copper as catalyst and N-fluorobenzenesulfonimide (NFSI) as oxidant, a wide range of diaminated, disulfonylated and tribrominated cyclobutene derivatives were efficiently synthesized.

A novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare four or five C–H bonds cleavage and two C–N/C–S or three C–Br bonds formation has been successfully developed.     

A new twist for Stork-Danheiser products enabled by visible light mediated trans-cyclohexene formation; access to acyclic distal enones

Herein, we investigate the use of visible light to indirectly drive ring opening in unstrained 6- and 7-membered ring systems via reaction with a transiently generated trans-cycloalkene. Identification of conditions that capture visible light energy in the form of ring strain was key to success. Under mildly acidic conditions, cycloalkenols were shown to undergo formally endothermic ring-opening isomerization to give acyclic exo-methylene and distal ketones or aldehydes in high yields. Ultimately, this work demonstrates the ability of cycloalkenes to capture visible light energy and its use to drive both kinetically and thermally unfavorable rearrangements.

In this work, visible light drives a contrathermodynamic isomerization of the classic Stork-Danheiser products through an energy transfer process to yield acyclic distal enone(al) isomers. This is possible because the photochemical energy is transiently captured as ring strain as a trans-, or twisted, cyclohexene.     

Three-component carboacylation of alkenes via cooperative nickelaphotoredox catalysis

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis. A wealth of ketones with high levels of structural complexity was rapidly obtained via direct functionalization of C(sp²)/C(sp³)–H bonds in a modular manner. Furthermore, a regioselective late-stage modification of natural products showcased the practical utility of the strategy, generally featuring high resource economy and ample substrate scope.

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis.