Direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines from propargyl sulfonylamides and allenamides

Multisubstituted pyrroles are important fragments that appear in many bioactive small molecule scaffolds. Efficient synthesis of multisubstituted pyrroles with different substituents from easily accessible starting materials is challenging. Herein, we describe a metal-free method for the preparation of pentasubstituted pyrroles and hexasubstituted pyrrolines with different substituents and a free amino group by a base-promoted cascade addition–cyclization of propargylamides or allenamides with trimethylsilyl cyanide. This method would complement previous methods and support expansion of the toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines. Mechanistic studies to elucidate the reaction pathway have been conducted.

This method is a toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines.

Pyrroles are molecules of great interest in a variety of compounds including pharmaceuticals, natural products and other materials. Pyrrole fragments for example are key motifs in bioactive natural molecules, forming the subunit of heme, chlorophyll and bile pigments, and are also found in many clinical drugs, including those in Fig. 1a.¹ Although many classical methods of pyrrole synthesis, including the Paal–Knorr condensation,² the Knorr reaction,³ the Hantzsch reaction,⁴ transition metal-catalyzed reactions,⁵ and multicomponent coupling reactions,⁶ have been developed over many years, the efficient synthesis of multisubstituted pyrroles is still challenging. In condensation syntheses of pyrroles, the major problems lie in the extended syntheses of complex precursors and limited substitution patterns that are allowed. Multicomponent reactions are superior when building pyrrole core structures with more substituents. Among these, the [2+2+1] cycloaddition reaction of alkynes and primary amines is attractive because of the readily available alkyne and amine substrates and the ability to construct fully substituted pyrroles.⁷ However, with the exception of some rare examples,⁸ most [2+2+1] cycloaddition reactions afford pyrroles with two or more identical substituents. The synthesis of multisubstituted pyrroles with all different substituents from simple starting materials therefore remains a major challenge.Open in a separate windowFig. 1Previous reports and this work on propargylamides transformation.Easily accessible propargylamides are classical, privileged building blocks broadly utilized for the synthesis of a large variety of heterocyclic molecules such as pyrroles, pyridines, thiazoles, oxazoles and other relevant organic frameworks.⁹ For example, Looper¹⁰et al. reported the synthesis of 2-aminoimidazoles from propargyl cyanamides and Eycken¹¹ reported a method starting from propargyl guanidines which undergo a 5-exo-dig heterocyclization as shown in Fig. 1b. Subsequently, Wan¹²et al. revealed the cyclization of N-alkenyl propargyl sulfonamides into pyrroles via sulfonyl migration. Inspired by these transformations and multi-substituted pyrrole synthesis, we report herein a direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines with all different substituents from propargyl sulfonylamides and allenamides.Previously, Zhu,¹³ Ji¹⁴ and Qiu^13b,15 reported efficient syntheses of 2-aminopyrroles from isocyanides. Ye¹⁶ and Huang¹⁷ independently developed gold-catalyzed syntheses of 2-amino-pentasubstituted pyrroles with ynamides. Despite the many advantages of these methods, they all afford protected amines, rather than free amines. The deprotection of these amines may cause problems in further transformations of the products. Our method delivers pyrroles with an unprotected free amino group and are often complementary to the previously well-developed classical methods.Initially, the cyclization reaction of N-(1,3-diphenylprop-2-yn-1-yl)-N-ethylbenzenesulfonamide (1a) with trimethylsilyl cyanide (TMSCN) was carried out with Ni(PPh₃)₂Cl₂ as a catalyst, a base (Cs₂CO₃) and DMF as a solvent. Different metal catalysts, such as Ni(PPh₃)₂Cl₂, Pd(OAc)₂, Cu(OAc)₂, and Co(OAc)₂ provided the desired product with similar yields (

Allylic alcohol synthesis by Ni-catalyzed direct and selective coupling of alkynes and methanol

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir. We herein report nickel-catalyzed direct coupling of alkynes and methanol, providing direct access to valuable allylic alcohols in good yields and excellent chemo- and regioselectivity. The approach features a broad substrate scope and high atom-, step- and redox-economy. Moreover, this method was successfully extended to the synthesis of [5,6]-bicyclic hemiacetals through a cascade cyclization reaction of alkynones and methanol.

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir.

To address the sustainability issues in the production of new chemicals, the development of new catalytic processes that are free of by-products and using abundant renewable feedstocks is one of the most important challenges facing chemists today. The simplest alcohol, methanol, is very abundant, with a total annual production capacity of approximately 110 million metric tons per year,¹ and is an important C1-feedstock in the chemical industry. Beller² and Milstein³ made fundamental developments in catalytic dehydrogenation reactions of methanol.⁴ Krische and coworkers pioneered the study of Ir-catalyzed direct C–C coupling of methanol with reactive π-unsaturated reactants (1,3-dienes, 1,3-enynes and allenes).⁵ The groups of Glorius,⁶ Donohoe,⁷ Obora,⁸ Andersson⁹ and others¹⁰ demonstrated the direct methylation of ketones or amines using methanol. Despite these achievements, the catalytic C–C bond coupling reactions with methanol are still extremely rare and are limited to the use of precious and noble metal-catalysts such as Ru, Rh or Ir.¹¹ The development and use of cheap and abundant metal catalysts for methanol activation is uphill and remains an important field that urgently needs to be developed.On the other hand, allylic alcohols are highly versatile building blocks in organic synthesis and the pharmaceutical industry, and much effort has been devoted to their synthesis. Among them, nickel-catalyzed reductive coupling of alkynes and aldehydes represents an effective and powerful method. However, this method generally requires the use of stoichiometric reducing reagents that are air-sensitive, metallic or pyrophoric (e.g. ZnR₂, BEt₃, and R₃SiH, Scheme 1a).¹² The direct cross-coupling of alcohols and alkynes to synthesize allylic alcohols without the use of any reductant or oxidant represents a significant advancement (Scheme 1b).¹³ However, this approach still poses many limitations that will require considerable effort to overcome. (1) Alkynes are limited to dialkyl alkynes, and poor regioselectivities were observed for unsymmetrical alkynes, which greatly limits the scope of application of the reaction. (2) Alcohols are restricted to active benzyl alcohols and higher alcohols. The direct cross-coupling of alkynes with methanol has not yet been reported.Open in a separate windowScheme 1Synthesis of allylic alcohols by Ni-catalyzed coupling reaction with alkynes.Although the alkyne–paraformaldehyde reductive coupling has been developed,¹⁴ the paraformaldehyde was itself prepared from synthesis gas (through methanol). Therefore, the development of a new strategy for the direct coupling of alkynes and methanol without the use of any reductant or oxidant is still of great value, but also extremely challenging: (1) alkynes are reactive and could rapidly dimerize to 1,3-dienes¹⁵ or cyclotrimerize to aromatic ring derivatives in the interaction with nickel.¹⁶ (2) Unsymmetric alkynes could result in a mixture of regioisomers that are difficult to separate. (3) The activation energy of methanol in the dehydrogenation process (ΔH = +84 kJ mol⁻¹) is significantly higher than that of higher alcohols or even ethanol (ΔH = +68 kJ mol⁻¹).¹⁷Herein we report the nickel-catalyzed direct and regioselective hydrohydroxymethylation of alkynes for the first time using methanol as a C1-feedstock, providing a broad and efficient approach for the synthesis of high added-value allylic alcohols in a high atom-, step- and redox-economic manner. In addition, a cascade cyclization reaction of alkynones and methanol has also been developed for the synthesis of [5,6]-bicyclic hemiacetals in good yields and excellent regio- and diastereoselectivity (Scheme 1c).In our initial experiments, we chose unsymmetrical internal alkyne 1a as a model substrate to optimize the reaction conditions (13a Even if the reaction temperature was increased to 100 °C, only a trace amount of allylic alcohol product 2a was observed (entry 2), which indicates that the use of methanol in the catalytic C–C coupling reactions is indeed a big challenge. Various N-heterocyclic carbene ligands (L2–L6) were investigated (entries 3–9). We found that the selectivity of allylic alcohol 2a is challenged by a number of side reactions, such as the hydrogenation (3a), dimerization (4a) and trimerization (5a) of alkyne 1a. L4 is the most effective, providing 2a with the highest yield (40%) and excellent regioselectivity (14/1), but an appreciable quantity of dimerization and trimerization by-products 4a and 5a was still obtained (entry 5). Krische¹⁴ reported that PCy₃ could promote the reductive coupling of alkynes and paraformaldehyde, but we found that it is not effective for alkyne–methanol coupling (entry 8).Optimization of reaction conditions^a

Polycyclic heteroaromatics via hydrazine-catalyzed ring-closing carbonyl–olefin metathesis

The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.

Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.

Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).¹ For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine² and eupolauramine³ to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.⁴ Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.⁵ Meanwhile, chalcogenoarenes⁶ such as dinaphthofuran⁷ and benzodithiophene⁸ have attracted high interest for both their medicinal properties⁹ and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).¹⁰ These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.^1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis¹⁵ (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.¹⁶ In this case, 5 mol% FeCl₃ catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.^17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studies^a

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

β-Difluoroalkylborons, featuring functionally important CF₂ moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.^1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.^2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,^3a,b photoredox difluorination,⁴ radical difluorination,⁵ and cross-coupling reactions with suitable CF₂ carriers^6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.^7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).^7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.^7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.^7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.⁷ⁱOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates^8a–c as starting materials.^9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.^9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).¹⁰ While extending the scope of our previous work,^9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.^11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,¹⁰ could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.^12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et₃N·HF in association with PhI(OAc)₂ (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions

Ruthenium pincer complex-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides: substrate keeps the catalyst active

The electron pair of the heteroatom in heterocycles will coordinate with metal catalysts and decrease or even inhibit their catalytic activity consequently. In this work, a pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed. Benefitting from the pincer ligand, a variety of heterocycles, such as thiophenes, morpholine, unprotected indoles, pyrrole, pyridine, pyrimidine, furan, thiazole, pyrazole, benzothiadiazole, and triazole, are compatible here.

A pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed.

Since the pioneering work on the catalytic alkoxycarbonylation of unactivated alkyl halides reported by Heck and Breslow in 1963,¹ this transformation has attracted a great deal of interest due to its modularity and the direct employment of CO as a cheap and abundant C1 feedstock.² However, compared with aryl halides, the development of alkoxycarbonylation of alkyl halides has been much more gradual.^2,3 This situation is due to both the slow oxidative addition of C(sp³)–X bonds to the metal center and the easy β-hydride elimination of the alkyl-metal intermediate, particularly in the presence of carbon monoxide.⁴ Several catalytic systems for this process have been successfully developed in recent years (Scheme 1A), such as pure radical-based systems,⁵ palladium-based systems,⁶hν/palladium-based systems,⁷ rhodium-based systems,⁸ copper-based systems,⁹ and other metal carbonyl complex-based systems.¹⁰ Very recently, Neumann, Skrydstrup, and co-workers reported a nickel pincer-mediated alkoxycarbonylation for complete carbon isotope replacement, and this approach provided a procedure for generating carbon-labeled versions of potential simple carboxylate prodrug derivatives (Scheme 1B).¹¹ Besides their advantages, in these cases the heterocycles, particularly those containing multiple N atoms or NH groups, are hardly compatible, which is considered as a remaining challenge. We attribute this to the Lewis-basic atoms in heterocyclic motifs being particularly detrimental to catalyst activity and potentially quenching the radical intermediates.¹² Indeed, the development of heterocycle compatible catalytic systems remains an exciting task in the field of alkoxycarbonylation.Open in a separate windowScheme 1Approaches to alkoxycarbonylation of alkyl halides.On the other hand, heterocycles constitute important structural components of biologically active compounds and are ubiquitous in agrochemical and pharmaceutical industries.¹³ In a recent survey, 88% of small molecule drugs approved by the FDA between 2015 and June 2020 were found to contain at least one N-heterocycle.¹⁴ Specifically, heterocyclic subunits can modify the solubility, lipophilicity, polarity and hydrogen bonding ability of biologically active agents, thereby optimizing the corresponding ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) properties of drugs or drug candidates.¹⁵ Under this premise, the pursuit of new synthetic methods with good heterocycle compatibility is a worthwhile endeavor.Herein we report a heterocycle compatible catalytic system for alkoxycarbonylation of alkyl iodides. With a ruthenium pincer complex as the catalyst, the tight coordination of the pincer ligand can effectively prevent the ruthenium from deactivation by heterocycle coordination (Scheme 1C). To the best of our knowledge, this is the first example of a ruthenium pincer complex-catalyzed carbonylation reaction.¹⁶ This new catalytic system might lead to novel synthetic routes toward heterocyclic carbonyl-containing compounds.Pincer complexes of ruthenium are among the most effective catalysts for hydrogen transfer reactions between alcohols and unsaturated compounds.¹⁷ We initially used it to attempt the carbonylative coupling of acetophenone with iodobutane, as shown in eqn (1). Although we did not get the desired product I, the ester II could be obtained in 22% yield. By literature survey, we found there was no example showing that alkyl halides could be activated by ruthenium in previous reports on carbonylation reactions.^3,16,18 We thus envisioned that the ruthenium pincer complex played a key role in this transformation.^11,191With this discovery in mind, we started the investigation of this ruthenium-catalyzed alkoxycarbonylation of alkyl halides by examining the reaction of (3-iodopropyl)benzene (1) with isopropanol (2) at 100 °C under a CO atmosphere (10 bar) in the presence of a catalytic amount of various readily available ruthenium pincer complexes (†). The improved yield of the desired product 3 was obtained when utilizing Milstein''s catalyst Ru-2²⁰ (21 were applied in the reaction; however, the selectivity obtained was unsatisfactory (eqn (2), when we removed isopropanol from the reaction, byproduct 2 which was produced by carbonylative homocoupling of the alkyl halide could be obtained in 71% yield.²² However, the reduced conversion and the absence of byproduct 3 implied that the alcohol plays more than a nucleophile role in this reaction. It is important to mention that the addition of water had no effect on the yield of byproduct 2. Concerning the effects from bases, organic bases, such as NEt₃ and DBU, were tested, but no desired ester could be detected. Inorganic bases, including K₂CO₃ and K₃PO₄, were also tested, but very low yield of the ester was obtained. Notably, comparable yield of ester 3 can be obtained when LiO^tBu was used as the base.2Optimization of the alkoxycarbonylation of 1^a

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented.

Alkenes are important and versatile building blocks in organic synthesis. 1,2-Difunctionalization of alkenes offers a highly valuable synthetic strategy to access 1,2-difunctionalized alkanes by sequentially forming two vicinal σ-bonds.^1a–h Among these vicinal difunctionalizations, the 1,2-carboamination of alkenes, in which a C–N and a C–C bond are formed, provides an attractive route for the straightforward preparation of structurally diverse amine derivatives (Scheme 1a).^2a–c Along these lines, transition-metal-catalyzed or radical 1,2-carboaminations of activated and unactivated alkenes have been reported.^3a–p However, the 1,2-carboamination of vinylboron reagents, a privileged class of olefins,^4a–h to form valuable 1,2-aminoboron compounds which can be readily used in diverse downstream functionalizations,^{5a–c,6a–d} has been rarely investigated. To the best of our knowledge, there are only two reported examples, as shown in Schemes 1b and c. In 2013, Molander disclosed a Rh-catalyzed 1,2-aminoarylation of potassium vinyltrifluoroborate with benzhydroxamates via C–H activation (Scheme 1b).⁷ Thus, the 1,2-carboamination of vinylboron reagents is still underexplored but highly desirable.Open in a separate windowScheme 1Intermolecular 1,2-carboamination of alkenes.1,2-Alkyl/aryl migrations induced by β-addition to vinylboron ate complexes have been shown to be highly reliable for 1,2-difunctionalization of vinylboron reagents (Scheme 1c).^4d–h In 1967, Zweifel''s group developed 1,2-alkyl/aryl migrations of vinylboron ate complexes induced by an electrophilic halogenation.⁸ In 2016, the Morken group reported the electrophilic palladation-induced 1,2-alkyl/aryl migration of vinylboron ate complexes.^9a–k Shortly thereafter, we,^10a–c Aggarwal,^11a–c and Renaud¹² developed alkyl radical induced 1,2-alkyl/aryl migrations of vinylboron ate complexes. In these recent examples, the migration is induced by a C-based radical/electrophile, halogen and chalcogen electrophiles.^13a,bIn contrast, N-reagent-induced migration of vinylboron ate complexes proceeding via β-amination is not well investigated. To our knowledge, as the only example the Aggarwal laboratory described the reaction of a vinylboron ate complex with an aryldiazonium salt as the electrophile, but the desired β-aminated rearrangement product was formed in only 9% NMR yield (Scheme 1c).^13a No doubt, β-amino alkylboronic esters would be valuable intermediates in organic synthesis. Encouraged by our continuous work on amidyl radicals^14a–i and 1,2-migrations of boron ate complexes,^{10a–c,15a–f} we therefore decided to study the amidyl radical-induced carboamination of vinyl boronic esters for the preparation of 1,2-aminoboronic esters. N-chloroamides were chosen as N-radical precursors,^16a–c as these N-chloro compounds can be easily prepared from the corresponding N–H analogues.¹⁷ Herein, we present a catalyst-free three-component 1,2-carboamination of vinyl boronic esters with N-chloroamides and readily available alkyl/aryl lithium reagents (Scheme 1d).We commenced our study by exploring the reaction of the vinylboron ate complex 2a with tert-butyl chloro(methyl)carbamate 3a applying photoredox catalysis. Complex 2a was generated in situ by addition of n-butyllithium to the boronic ester 1a in diethyl ether at 0 °C. After solvent removal, the photocatalyst fac-Ir(ppy)₃ (1 mol%) and THF were added followed by the addition of 3a. Upon blue LED light irradiation, the mixture was stirred at room temperature for 16 hours. To our delight, the desired 1,2-aminoboronic ester 4a was obtained, albeit with low yield (26%, EntryPhotocatalystSolventT (°C)Yield^b (%)1 fac-Ir(ppy)₃THFrt262 fac-Ir(ppy)₃DMSOrt23 fac-Ir(ppy)₃MeCNrt564Ru(bpy)₃Cl₂·6H₂OMeCNrt695Na₂Eosin YMeCNrt696^cNa₂Eosin YMeCNrt707^cNoneMeCNrt458^cNoneMeCN0789^cNoneMeCN−2088 (85)10^c,dNoneMeCN−202Open in a separate window^aReaction conditions: 1a (0.20 mmol), ⁿBuLi (0.22 mmol), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar. After vinylboron ate complex formation, solvent exchange to the selected solvent (2 mL) was performed.^bGC yield using n-C₁₄H₃₀ as an internal standard; yield of isolated product is given in parentheses.^c4 mL MeCN was used.^dReaction carried out in the dark.With optimal conditions in hand, we then investigated the scope of this new 1,2-carboamination protocol keeping 2a as the N-radical acceptor (Scheme 2). This transformation turned out to be compatible with various primary amine reaction partners bearing carbamate (4a, 4b and 4d–4g) or acyl protecting groups (4c) (20–85%). Notably, N-chlorolactams can be used as N-radical precursors, as shown by the successful preparation of 4h (71%). Moreover, Boc-protected ammonia was also tolerated, delivering 4i in an acceptable yield (55%).Open in a separate windowScheme 21,2-Carboamination of 1a with various amidyl radical precursors. Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), ⁿBuLi (0.22 mmol, 1.1 equiv.), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar; then [N]-Cl (0.24 mmol, 1.2 equiv.), −20 °C, 16 h, in MeCN (4 mL). Yields given correspond to yields of isolated products. ^aA solution of [N]-Cl (0.30 mmol, 1.5 equiv.) in MeCN (1 mL) was used. See the ESI^† for experimental details.We continued the studies by testing a range of vinylboron ate complexes (Scheme 3). To this end, various vinylboron ate complexes were generated by reacting the vinyl boronic ester 1a with methyllithium, n-hexyllithium, isopropyllithium and tert-butyllithium. For the n-alkyl-substituted vinylboron ate complexes, the 1,2-carboamination worked smoothly to afford 4j and 4k in good yields. However, the vinylboron ate complex derived from isopropyllithium addition provided the desired products in much lower yield (4l, 18% yield). When tert-butyllithium was employed, only a trace of the targeted product was detected (see ESI^†). As expected, cascades comprising a 1,2-aryl migration from boron to carbon worked well. Thus, by using PhLi for vinylboron ate complex formation, the 1,2-aminoboronic esters 4m–4o were obtained in 69–73% yields with the Boc (t-BuOCONClMe), ethoxycarbonyl-(EtOCONClMe) and methoxycarbonyl (Moc)-(MeOCONClMe) protected N-chloromethylamines (for the structures of 3, see ESI^†) as radical amination reagents. Keeping 3b as the N-donor, other aryllithiums bearing various functional groups at the para position of the aryl moiety, such as methoxy (4p), trimethylsilyl (4q), methyl (4r), phenyl (4s), trifluoromethoxy (4t), trifluoromethyl (4u), and halides (4v–4x) all reacted well in this transformation. Aryl groups bearing meta substituents are also tolerated, as documented by the preparation of 4y (81%). To our delight, a boron ate complex generated with a 3-pyridyl lithium reagent engaged in the cascade and the carboamination product 4z was isolated in high yield (82%).Open in a separate windowScheme 3Scope of vinylboron ate complexes. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), R_MLi (0.22 mmol, 1.1 or 1.3 equiv.), Et₂O or THF, under Ar; then [N]-Cl (0.30 mmol, 1.5 equiv.), −20 °C, 16 h, in MeCN. Yields given correspond to yields for isolated products. See the ESI^† for experimental details.The reason for the dramatic reduction in yield when α-branched alkyllithium or electron-rich aryllithium reagents were used might be that the corresponding vinylboron ate complexes could be oxidized by N-chloroamides via a single-electron oxidation process.^18a–e Furthermore, the α-unsubstituted vinyl boronic ester and vinyl boronic ester bearing various α-substituents are suitable N-radical acceptors and the corresponding products 4aa–4ac were obtained in 48–70% yield.To gain insights into the mechanism of this 1,2-carboamination, a control experiment was conducted. The reaction could be nearly fully suppressed when the reaction was carried out in the presence of a typical radical scavenger (2,2-6,6-tetramethyl piperidine-N-oxyl, TEMPO), indicating a radical mechanism (Scheme 4a). Further, considering an ionic process, the N-chloroamides would react as Cl⁺-donors that would lead to Zweifel-type products, which were not observed under the applied conditions. The proposed mechanism is shown in Scheme 4b. As chloroamides have been recently proposed to undergo homolysis under visible light irradiation,^19a,b we propose that initiation proceeds via homolytic N–Cl cleavage generating the electrophilic amidyl radical A, which then adds to the electron-rich vinylboron ate complex 2a to give the adduct boronate radical B. The radical anion B then undergoes single electron transfer (SET) oxidation with 3a in an electron-catalyzed process^20a,b or chloride atom transfer with 3a to provide C or D along with the amidyl radical A, thereby sustaining the radical chain. Intermediates C or D can then react via a boronate 1,2-migration^10c,11c,21 to eventually give the isolated product 4a.Open in a separate windowScheme 4Control experiment and proposed mechanism.To document the synthetic utility of the method, a larger-scale reaction and various follow-up transformations were conducted. Gram-scale reaction of 2a with 3a afforded the desired product 4a in good yield, demonstrating the practicality of this transformation (Scheme 5a). Oxidation of 4a with NaBO₃ provided the β-amino alcohol 5 in 89% yield (Scheme 5b). The N-Boc homoallylic amine 6 was obtained by Zweifel-olefination with a commercially available vinyl Grignard reagent and elemental iodine in good yield (79%).²² Heteroarylation of the C–B bond in 4a was realized by oxidative coupling of 4a with 2-thienyl lithium to provide 7.²³Open in a separate windowScheme 5Gram-scale reaction and follow-up chemistry.In summary, we have described an efficient method for the preparation of 1,2-aminoboronic esters from vinyl boronic esters via catalyst-free three-component radical 1,2-carboamination. Readily available N-chloro-carbamates/carboxamides, which are used as the N-radical precursors, react efficiently with in situ generated vinylboron ate complexes to afford the corresponding valuable 1,2-aminoboronic esters in good yields. The reaction features broad substrate scope and high functional group tolerance. The value of the introduced method was documented by Gram-scale reaction and successful follow-up transformations.     

Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions

CF₂H groups are unique due to the combination of their lipophilic and hydrogen bonding properties. The strength of H-bonding is determined by the group to which it is appended. Several functional groups have been explored in this context including O, S, SO and SO₂ to tune the intermolecular interaction. Difluoromethyl ketones are under-studied in this context, without a broadly accessible method for their preparation. Herein, we describe the development of an electrochemical hydrodefluorination of readily accessible trifluoromethylketones. The single-step reaction at deeply reductive potentials is uniquely amenable to challenging electron-rich substrates and reductively sensitive functionality. Key to this success is the use of non-protic conditions enabled by an ammonium salt that serves as a reductively stable, masked proton source. Analysis of their H-bonding has revealed difluoromethyl ketones to be potentially highly useful dual H-bond donor/acceptor moieties.

The electrochemical hydrodefluorination of trifluoromethylketones under non-protic conditions make this single-step reaction at deeply reductive potentials uniquely amenable to challenging electron-rich substrates and reductively sensitive functionalities.

The difluoromethyl group (CF₂H) has attracted significant recent attention in medicinal chemistry,^1,2 which complements the well-documented importance and growing use of fluorine in small molecule pharmaceuticals.^3–6 The CF₂H group is an H-bond donor^7,8 that is also lipophilic,^9,10 a unique combination that positions it as an increasingly valuable tool within drug-discovery.¹¹ CF₂H has been used as a bioisostere of OH and SH in serine and cystine moieties, respectively, as well as NH₂ groups, where greater lipophilicity and rigidity provide advantages to pharmacokinetics and potency.^12–14The hydrogen-bond acidity of CF₂H groups is exceptionally dependent on the atom or group to which it is appended (Fig. 1A).^1,2 The H-bond acidity of alkyl-CF₂H groups is half that of O–CF₂H and even a quarter of SO₂–CF₂H groups.¹ This mode of control allows the H-bonding strength and, therefore its function, to be finely tuned. While much research has focused on the synthesis, behaviour and use of XCF₂H groups, where X = O, S, SO, SO₂, Ar, it is surprising that the corresponding carbonyl containing moiety (X = CO) has remained relatively elusive in these contexts. Not only would difluoromethyl ketones (DFMK) be expected to provide a relatively strong H-bond, but the carbonyl unit provides a complementary, yet proximal mode of intermolecular interaction (Fig. 1B). Indeed, the dual action of neighbouring H-bond donor and acceptor functionalities provides the fundamental basis for many biological systems, including in the secondary structure assembly mechanisms for proteins and DNA/RNA nucleobase pairing, as well as in enzyme/substrate complexes. Indeed, the DFMK functionality has demonstrated important utility in biological applications, including anti-malarial and -coronaviral properties.¹⁵ Finally, the carbonyl provides a useful synthetic handle for further derivatization.Open in a separate windowFig. 1H-Bonding in DFMKs and their synthesis via hydrodefluorination.While some progress has been made on the synthesis of DFMKs,¹⁶ there still remains a need for a general and more broadly accessible route to their preparation. Current strategies for DFMK preparation require multi-step processes, expensive reagents, installation of activating groups, or are inherently low yielding.^15a,16–25 The hydrodefluorination of trifluoromethyl ketones (1) potentially represents the most accessible strategy, as the starting materials are most readily prepared through a high-yielding trifluoroacetylation of C–H or C–X bonds.^26–29 In 2001, Prakash demonstrated the viability of this approach using 2 equivalents of magnesium metal as stoichiometric reductant to drive the defluorination, with a second hydrolysis step (HCl (3–5 M) or fluoride, overnight stirring) to reveal the product.³⁰ The scope in this 2-step process (6 substrates) reflects the limitations of using a reductant, such as Mg, that has a fixed reduction potential, as well as incompatibilities arising from Mg/halide exchange with aryl halides. Similar limitations with the use of electron-rich substrates were revealed in related contributions from Uneyama.³¹In order to access more electron-rich and reductively challenging substrates, such as those containing medicinally relevant heterocycles, we postulated that electrochemical reduction could be employed (Fig. 1C). Electrosynthesis is becoming an increasingly valuable enabling technology and has seen a recent resurgence due to the precise control, unique selectivity, and the potential scalability and sustainability benefits that it offers.^32–36 This strategy would avoid the undesirable use of stoichiometric metals and the ‘deep-reduction’ potentials required are readily accessed by simply selecting the applied potential. Pioneering early work from Uneyama on the cathodic formation of silylenol ether intermediate 2, suggested this approach could be viable.^37,38 The fundamental challenge in designing a practical, single-step process under highly reducing potentials (<−2.0 V vs. Fc/Fc⁺), is to avoid the reduction of the proton source, which would otherwise compete to generate H₂ gas and leave the starting material untouched. Uneyama does not demonstrate hydrodefluorination, presumably due to this problem. Additional challenges posed by ‘deep-reduction’ include a lack of tolerance for reduction-sensitive functionality (alkene, C–X bonds etc.), low mass balance due to substrate decomposition and the undesirable use of sacrificial metal anodes.³⁹ Solving these problems should provide generally applicable, safe and scalable conditions for the hydrodefluorination of readily accessible trifluoromethyl ketones (1).Given the electron-rich nature of indoles, their ubiquity in bioactive compounds, and their ease of functionalisation, we chose indole 1a as the model substrate for optimisation. The highly reductive potentials required will render it a challenging substrate, which should lead to more general conditions suitable for other important substrate classes. Indeed, when we applied the Mg conditions of Prakash to this substrate, no silyl enol ether intermediate (2a) was observed, nor product 3a, and the starting material remained completely untouched ( EntryConditions different from aboveReductantProton source 1a ^a/%(2a) 3a^a/%1 Mg ⁰, THF, no electricity (Prakash conditions for3)Mg⁰—100(0) n/a2^bUndivided cell, TBAPF₆Sacrificial Mg anode—100(0) n/a3^bPb:C (cath:an), 0 ^oC, 30 mA (Uneyama conditions for2)TBABr (4 eq.)—33(32) 04^b—TBABr (2 eq.)(a) Acetic acid; (b) oxalic acid.51; 1000; 05^b—TBABr (2 eq.)Dimethylurea8206^b—TBABr (2 eq.)TEAPF₆ (4 eq.)49457TMSCl (0 eq.)TBABr (2 eq.)TEAPF₆ (4 eq.)8308^bTMSCl (6 eq.)TBABr (2 eq.)TEAPF₆ (4 eq.)49499^c TMSCl (3 + 3 eq.) TBABr (2 eq.) TEAPF ₆ (4 eq.) 0 97 10^cEntry 9, but Pt:Gr (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)09411^cEntry 9, but Ni:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)08312^cEntry 9, but Stainless Steel:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)08513^cEntry 9, but Gr:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)018Open in a separate window^{a 19}F NMR yields.^bTMSCl only added to cathodic chamber.^cTMSCl added to both cathodic and anodic chambers.The electrochemical conditions of Uneyama for preparing silylenol ethers (2) were applied to our indole 1a (entry 3). Unsurprisingly, no hydrodefluorinated product was observed, however intermediate 2a was formed in a 32% yield. In an effort to improve this yield we explored several solvents, reductants, additives and electrode materials, all of which were conducted in a divided cell at constant current and ambient temperature.⁴⁰ In addition, as we were keen to develop a single-step protocol, by avoiding the second hydrolysis step that can readily form homo-coupled aldol side products,³⁸ we surveyed a range of added proton sources for in situ delivery of 3a. The addition of carboxylic acids, such as acetic or oxalic acid (entry 4), gave no desired product, as the competing reduction of protons to H₂ gas dominated. Dimethylurea was recently used as a proton source in an electrochemical ‘deep-reduction’,⁴¹ but it returned no trace of intermediate 2a or product 3a (entry 5). We hypothesized that increasing the conductivity of the system, with additional tetraalkylammonium salts (from 2 to 4 eq.), the formation of intermediate 2a may be facilitated by avoiding large cell potentials. While this change did facilitate a lower cell potential, we discovered these salts behaved as reductively stable yet competent masked proton donors: 4 eq. NEt₄PF₆ gave 45% yield of product 3a, with no sign of intermediate 2a (entry 6). The detection of triethylamine in solution suggests donation through a Hoffmann elimination.⁴² With the exception of NMe₄⁺, other tetraalkylammonium salts were also competent proton donors (NEt₄⁺ > NBu₄⁺ > NPr₄⁺).A critical improvement to the yield was observed when the use of the radical anion trapping agent, TMSCl, was optimised. With no TMSCl, 3a was not observed (entry 7), and a loading of 6 equivalents saw little improvement over 3 equivalents (entry 8 vs. 6). Experiments hitherto described were conducted with TMSCl added only to the cathodic chamber (entries 2–8). Only when the 6 equivalents was split between both chambers was a drastic improvement observed (entry 9), giving an optimised yield of 97%. Notably, the increase in conversion still occurred with only 2 F, implying that a lower steady-state concentration may be important in the cathode chamber. To test this hypothesis, TMSCl was slowly added to the catholyte by syringe-pump addition over the course of the reaction, which gave a similar yield of 94%.⁴⁰ Although intermediate 2a is transient and was never observed, the importance of TMSCl to trap and stabilise reduced 1a was revealed by DFT (B3LYP/6-311+g(d)) calculations,⁴⁰ which suggested a thermodynamically highly challenging reaction in its absence.The oxidation of bromide to tribromide occurs on the anode, which is an ideal counter-electrode process: not only is bromide an inexpensive and metal-free sacrificial reductant, but as the produced Br₃⁻ is anionic, it does not rapidly migrate to the cathodic chamber, preventing unwanted side reactions.⁴³ The generated Br₃⁻ can even be used in follow-up bromination reactions.⁴⁴ An increase in the applied cell potential during the reaction signifies the consumption of Br⁻, and the oxidation of Br₃⁻ to Br₂ (Fig. 2).⁴⁵ Despite needing 3 equivalents of Br⁻ to form 2 equivalents of Br₃⁻ after 2 F, the loading of Br⁻ could be reduced to 2 equivalents without affecting yield. No over-reduction of 3a to the monofluoromethyl ketone was observed, which is significant considering the small difference in reduction potentials.⁴⁰ This emphasises the importance of a flat chronopotentiometry trace that is achieved with Br⁻ oxidation. Other reductants were found to be sub-optimal, including diisopropylamine and oxalic acid.⁴⁰Open in a separate windowFig. 2Reaction of 1a to 3a with 3 different Br⁻ concentrations.A graphite anode performed equally well as platinum for the counter electrode reaction (entry 10). Only marginally reduced yields were observed with nickel and stainless-steel cathodes (entries 11 and 12), however, a drastic decrease in the yield was observed with a graphite cathode (entry 13), possibly due to substrate grafting.³⁹We proceeded to explore the substrate scope with our optimized conditions, Fig. 3. As expected, our electrochemical conditions were suitable for the hydrodefluorination of electron-poor acetophenone derivatives (1b, 1c). However, unlike with the use of Mg,³⁰ substrates containing electron donating substituents are now well tolerated (1d–k). In addition, no hydrodebromination was observed for 1b, highlighting the selectivity and orthogonality granted by the use of our Mg-free, non-protic conditions. A selection of extended π-systems was tolerated, producing pyridyl 3l, biphenyl 3m, benzothiophene 3n, primary amine 3o, and pyrimidines 3p and 3q and in moderate to excellent yields. Chromoionophore dye 1r and stilbene 1s and were transformed in excellent yield, demonstrating tolerance to reductively sensitive alkenes, which would otherwise hydrogenate under protic electrochemical conditions.⁴⁶ Anthracenyl 1t and naphthyl substrates 1u and 1v all transformed efficiently in good to excellent yields, the latter of which underwent direct double hydrodefluorination. 4.5% over-reduction was observed in the double defluorination product, 3v, which was the only instance where this side-product was observed in greater than 1% quantities.⁴⁰ The good mass-balance and faradaic efficiency is notable considering the delocalization of charge around extended π-systems increases the likelihood of grafting.⁴⁷Open in a separate windowFig. 3Isolated yields of DFMKs tested under the reaction conditions at 0.5 mmol scale. NMR yields in parentheses. ^aReaction run at 10 mA; ^breaction run in IKA Divided ProSyn: quantitative yield based on RSM; ^c5 mmol scale, Ni foil:Gr (cath:an); ^disolated as the corresponding ketone following purification on silica.⁴⁹The model indole substrate 1a gave an excellent yield of DFMK at 0.5 mmol scale, which gave equally high yields when scaled up 10-fold (5 mmol), thereby demonstrating the robustness and practicality of the technique. We were also able to successfully prepare 3a in a commercially available divided cell set-up.⁴⁰ Alternative groups on nitrogen, including Boc, perfluoropyridyl and benzyl (3w–y), as well as the free indole 3z, were well tolerated and gave moderate to good yields of 3. Tosyl and acetyl groups on nitrogen were less well tolerated.⁴⁰ As with the acetophenones, indoles with electron donating (1aa) and withdrawing (1ab) groups proceeded to product. Methoxy demethylation of 3aa should lead to the corresponding phenol,⁴⁸ which is difficult to prepare using other methodologies due to competing side-reactions. Halide substitution also successfully yielded DFMKs (3ac–ag). The inclusion of the aryl-iodide functionality is especially notable due to its facile reduction; when a silver cathode was used to convert 1ag, hydrodeiodination was observed, but which was absent under our non-protic conditions with a Pt cathode. Increased steric bulk around the reacting center in thiophenyl and phenyl-substituted substrates 1ah and 1ai had no negative influence and gave good yields of product.Heterocyclic trifluoromethylketones were successfully hydrodefluorinated under the standard conditions, including indole 3aj, carbazole 3ak, pyrrole 3al, pyridine 3am, and pyrazoles 3an and 3ao, the latter of which leads to a compound with anti-malarial activity.^15a Alkyl trifluoromethylketones are more difficult to reduce compared to aromatic trifluoromethylketones, and are therefore challenging substrates to hydrodefluorinate, and impossible to convert using other methods. Nevertheless, oleyl 1ap, cyclohexyl 1aq and ethyl 1ar substrates were all amenable to the conditions, although the smaller alkyl products were cumbersome to isolate due to their volatility. The non-protic optimized conditions ensured no loss of mass-balance at these enhanced reduction potentials (|E_cell| = ca. 3.4–3.7 V for alkyl substrates vs. ca. 2.3–2.7 V for acetophenones and indoles). Finally, we tested the conditions on trifluoroacetamide 1as, thioester 1at and imines 1au and 1av. For each of these, the corresponding product was returned in moderate to good yields. Despite some complications in their isolation, these results are notable considering their difference in structure and lack of precedent. Unsuccessful substrates included a nitro-substituted indole, which was insoluble in the reaction medium, and hydrated TFMKs.⁴⁰We tested a variety of substrates with the Mg-mediated conditions reported by Prakash to gauge the level of complementary between the methods.³⁰ While acetophenone derivatives 1k and 1am were amenable to reduction with Mg, bromide substitution in 1b was unsurprisingly not tolerated with Grignard formation dominating. Indoles – 1a, 1ai, pyrazole – 1an, alkyl – 1aq, 1ar and anilide – 1as based trifluoromethylketones were untouched by Mg in all cases, with starting materials recovered only.To explore the value of the DFMK moiety in synthesis, we derivatized it in a variety of ways, Fig. 4. Resubjecting the product 3a to our non-protic hydrodefluorination conditions led to monofluorinated product 4, providing an alternative to the use of electrophilic fluorine sources.⁵⁰ Reduction of the ketone in 3ae to the methyl ether and alcohol successfully gave products, 5 and 6, respectively. The dithiane of 3a, which is a useful synthetic intermediate, was formed in excellent yield (7). A Corey–Chaykovsky methenylation gave epoxide 8 in good yield. A Horner–Wadsworth–Emmons reaction transformed the carbonyl to give alkene 9. Nucleophilic attack of the ketone was demonstrated with a trifluoromethylation reaction to give highly fluorinated alcohol 10. Orthogonal reactivity was also demonstrated with a Suzuki–Miyaura cross-coupling that gave biaryl 11. Interestingly, deuterium was not exchanged into 3a when stirred in a mixture of D₂O and MeCN, providing evidence for a less favourable enolization.Open in a separate windowFig. 4[A] Derivatization of DFMKs. X = H (3a) for 4, 7, and 8, X = Br (3ae) for others; [B] H-bond strength (A-value) correlated to σ_m Hammett parameter; [C] intermolecular H-bond revealed in X-ray crystal structure of 3ae; [D] DFT calculated (B3LYP/6-311+g(d)) relative energies of conformers with rotation around HC–CO bond. Brown arrows indicate direction of dipole.The H-bond strength (A-value) was measured for a series of phenyl substituted X–CF₂H derivatives using the NMR method from Abraham, Fig. 4B.^51–53 These experiments confirmed the sensitivity of the H-bonding ability to the identity of X. DFMK 3g and sulfoxide–CF₂H were found to be comparable H-bond donors, which were only marginally less than the sulfone–CF₂H. The H-bond strength correlated best with the σ_m parameter, reflecting the strong influence of inductive effects. Multiple regression analysis showed that any contribution of σ_p was statistically insignificant (P value = 0.33).Analysis of the X-ray crystal structure of 3ae, showed an inter-molecular H-bond between the CF₂H and a carbonyl from a neighbouring molecule (Fig. 4C). DFT was used to calculate the relative conformer energy with rotation about the (O)C–CF₂H dihedral bond (Fig. 4D). The lowest energy conformer eclipsed the H with the carbonyl, implying the possibility of an energy lowering intra-molecular H-bond. However, analysis of the other derivatives in the set (C(O)CH₃, C(O)CFH₂ and C(O)CF₃) revealed that the alignment of dipoles was the dominant effect (brown arrows, Fig. 4D).⁴⁰ The absence of an unusually low or even negative A-value also provides evidence against an intramolecular H-bond.⁵¹ Interestingly, in the solid-state structure (Fig. 4C), the highest energy conformer (with dipoles aligned) is adopted, highlighting the stronger propensity of this moiety to engage in H-bonding interactions.In conclusion, we have developed a mono-selective hydrodefluorination to access a broad scope of DFMKs, enabled by non-protic electrochemical conditions at deeply reducing potentials. These moieties have been studied and diversified and reveal themselves to be potentially useful dual H-bond donor/acceptor moieties. This is especially interesting considering the structurally related trifluoromethylketones are known reversible protease inhibitors;^54,55 thus, the additional H-bonding moiety could enhance interaction within enzymatic active sites.¹⁵     

HydroFlipper membrane tension probes: imaging membrane hydration and mechanical compression simultaneously in living cells

HydroFlippers are introduced as the first fluorescent membrane tension probes that report simultaneously on membrane compression and hydration. The probe design is centered around a sensing cycle that couples the mechanical planarization of twisted push–pull fluorophores with the dynamic covalent hydration of their exocyclic acceptor. In FLIM images of living cells, tension-induced deplanarization is reported as a decrease in fluorescence lifetime of the dehydrated mechanophore. Membrane hydration is reported as the ratio of the photon counts associated to the hydrated and dehydrated mechanophores in reconvoluted lifetime frequency histograms. Trends for tension-induced decompression and hydration of cellular membranes of interest (MOIs) covering plasma membrane, lysosomes, mitochondria, ER, and Golgi are found not to be the same. Tension-induced changes in mechanical compression are rather independent of the nature of the MOI, while the responsiveness to changes in hydration are highly dependent on the intrinsic order of the MOI. These results confirm the mechanical planarization of push–pull probes in the ground state as most robust mechanism to routinely image membrane tension in living cells, while the availability of simultaneous information on membrane hydration will open new perspectives in mechanobiology.

HydroFlippers respond to membrane compression and hydration in the same fluorescence lifetime imaging microscopy histogram: the responses do not correlate.

The detection and study of membrane mechanics in living cells is a topic of current concern.^1–14 To enable this research, appropriate chemistry tools, that is small-molecule fluorescent probes that allow imaging of membrane tension, are needed.¹⁵ With the direct imaging of physical forces being intrinsically impossible, design strategies toward such probes have to focus on the suprastructural changes caused by changes in membrane tension.¹⁵ These suprastructural changes are divers, often interconnected, and vary with the composition of the membrane.^15–25 Beyond the fundamental lipid compression and decompression, they include changes in membrane curvature, from rippling, buckling and budding to tubules extending from the membrane and excess lipid being ejected. Of similar importance are changes in membrane organization, particularly tension-induced phase separation and mixing, i.e. assembly and disassembly of microdomains. Consequences of these suprastructural changes include microdomain strengthening and softening and changes in membrane hydration and viscosity.^16–25The currently most developed fluorescent flipper probes have been introduced^26,27 to image membrane tension by responding to a combination of mechanical compression and microdomain assembly in equilibrium in the ground state.¹⁵ Extensive studies, including computational simulations,²⁸ have shown that flipper probes align non-invasively along the lipid tails of one leaflet and report changes in membrane order and tension as changes in fluorescent lifetimes and shifts of excitation maxima.¹⁵ Among other candidates, solvatochromic probes respond off-equilibrium in the excited state to changes in membrane hydration and have very recently been considered for the imaging of membrane tension in living cells.^29–36 So far not considered to image tension, ESIPT probes also report off equilibrium in the excited state on membrane hydration, but for different reasons.^37,38 Mechanosensitive molecular rotors respond off equilibrium in the excited state to changes in microviscosity.^{17,30,32,39–53} The same principle holds for the planarization of bent, papillon or flapping fluorophores.^54–57 The response of all possible probes to tension can further include less desired changes in positioning and partitioning between different domains, not to speak of more catastrophic probe aggregation, precipitation, disturbance of the surrounding membrane structure, and so on. Although the imaging of membrane tension is conceivable in principle with most of above approaches, the complex combination of parameters that has to be in place can thus far only be identified empirically, followed by much optimization.¹⁵The force-induced suprastructural changes are accompanied by the alteration in several unrelated physical properties of membranes. It is, for instance, well documented that membrane hydration increases with membrane disorder, from solid-ordered (S_o) to liquid-disordered (L_d) phases.^29,58 Increasing cholesterol content decreases membrane hydration in solid- and liquid-ordered membranes.⁵⁹ However, studies in model membranes also indicate that membrane hydration and membrane fluidity do not necessarily correlate.⁵⁹ The dissection of the individual parameters contributing to the response of fluorescent membrane tension probes would be important for probe design and understanding of their responses, but it remains a daunting challenge. In this study, we introduce fluorescent flipper probes that simultaneously report on mechanical membrane compression and membrane hydration at equilibrium in the ground state. Changes of both in response to changes in membrane tension and membrane composition are determined in various organelles in living cells.The dual hydration and membrane tension probes are referred to as HydroFlippers to highlight the newly added responsiveness to membrane hydration. The mechanosensing of lipid compression in bilayer membranes by flipper probes has been explored extensively.¹⁵ Fluorescent flippers²⁷ like 1 are designed as bioinspired⁶⁰ planarizable push–pull probes²⁶ (Fig. 1). They are constructed from two dithienothiophene fluorophores that are twisted out of co-planarity by repulsion of methyls and σ holes on sulfurs^61,62 next to the twistable bond. The push–pull system is constructed first from formal sulfide and sulfone redox bridges in the two twisted dithienothiophenes. These endocyclic donors and acceptors are supported by exocyclic ones, here a trifluoroketone acceptor and a triazole donor.⁶³ To assure stability, these endo- and exocyclic donors are turned off in the twisted ground state because of chalcogen bonding and repulsion, respectively.⁶²Open in a separate windowFig. 1The dual sensing cycle of HydroFlippers 1–5, made to target the indicated MOIs in living cells and responding to membrane compression by planarization and to membrane hydration by dynamic covalent ketone hydration. With indication of excitation maxima (ref. 63) and fluorescence lifetimes (this study).Mechanical planarization of the flipper probe establishes conjugation along the push–pull systems, electrons flow from endocyclic donors to acceptors, which turns on the exocyclic donors and acceptors to finalize the push–pull system.⁶² This elaborate, chalcogen-bonding cascade switch has been described elsewhere in detail, including high-level computational simulations.⁶² The planar high-energy conformer 1dp excels with red shifted excitation and increased quantum yield and lifetime compared to the twisted conformer 1dt because the less twisted Franck-Condon state favors emission through planar intramolecular charge transfer (PICT) over non-radiative decay through twisted ICT, or conical intersections.¹⁵Flipper probe 1 was considered for dual responsiveness to membrane tension and hydration because of the trifluoroketone acceptor.⁶³ Dynamic covalent hydration of 1dt yields hydrate 1ht.^64–76 Blue-shifted excitation and short lifetime of 1ht are not expected to improve much upon planarization because the hydrate is a poor acceptor and thus, the push–pull system in 1hp is weak. The dynamic covalent chemistry of the trifluoroketone acceptor has been characterized in detail in solution and in lipid bilayer membranes.⁶³To explore dual responsiveness to membrane tension in any membrane of interest (MOI) in living cells, HydroFlippers 2–5 were synthesized. While HydroFlipper 1 targets the plasma membrane (PM), HydroFlippers 2–4 were equipped with empirical targeting motifs.⁷⁷ HydroFlipper 5 terminates with a chloroalkane to react with the self-labeling HaloTag protein, which can be expressed in essentially any MOI.⁷⁸ Their substantial multistep synthesis was realized by adapting reported procedures (Schemes S1–S4^†).The MOIs labeling selectivity of HydroFlippers was determined in HeLa Kyoto (HK) cells by confocal laser scanning microscopy. Co-localization experiments of flippers 1–4 with the corresponding trackers gave Pearson correlation coefficients (PCCs) >0.80 for the targeting of mitochondria, lysosomes and the endoplasmic reticulum (ER, Fig. S4–S6^†). HydroFlipper 5 was first tested with stable HGM cells, which express both HaloTag and GFP on mitochondria (referred to as 5_M).^78,79 The well-established chloroalkane penetration assay demonstrated the efficient labeling of HaloTag protein by 5 as previously reported HaloFlippers (Fig. S3^†).⁷⁸ By transient transfection, HydroFlippers 5 were also directed to lysosomes (5_L), Golgi apparatus (GA, 5_G)⁸⁰ and peroxisomes (5_P) with HaloTag and GFP expressed on their surface.⁷⁸ PCCs >0.80 for co-localization of flipper and GFP emission confirmed that MOI labeling with genetically engineered cells was as efficient as with empirical trackers (Fig. S7–S11^†).Dual imaging of membrane compression and hydration was envisioned by analysis of fluorescence lifetime imaging microscopy (FLIM) images using a triexponential model (Fig. 2).⁸¹ FLIM images of ER HydroFlipper 4 in iso-osmotic HK cells were selected to illustrate the concept (Fig. 3a). Contrary to classical flipper probes, the fluorescence decay curve of the total FLIM image (Fig. 2a, grey) showed a poor fit to a biexponential model (Fig. 2a, cyan, b). Consistent with their expected dual sensing mode, a triexponential fit was excellent (Fig. 2a, dark blue, c). Lifetimes τ_1i = 4.3 ns (†) were obtained besides background. This three-component model was then applied to every pixel of FLIM images (Fig. 3c). The resulting reconvoluted FLIM histogram revealed three clearly separated populations for τ₁ (red), τ₂ (green), and background (τ₃, blue, Fig. 2d). Maxima of these three clear peaks were at the lifetimes estimated by triexponential fit of the global decay curve, thus demonstrating the validity of the methodology at necessarily small photon counts. Irreproducible fitting would give randomly scattered data without separated peaks.Open in a separate windowFig. 2(a) Fluorescence decay curve (grey, corresponding to the total image, not to a single pixel) with biexponential (cyan) and triexponential fit (dark blue). (b, c) Residual plots for bi- (b) and triexponential fit (c). (d) Histogram with the intensities associated with the τ₁ (red), τ₂ (green), and τ₃ (blue, background) components obtained by triexponential fit of the fluorescence decay curve of each pixel of the FLIM image, fit to Gaussian function (black solid curves).Open in a separate windowFig. 3FLIM images of HK cells labelled with ER flipper 4 before (a, c) and after (b, d) hyper-osmotic shock, showing average lifetimes τ_av (a, b) and τ₁ (c, d) from triexponential reconvolution; scale bars = 10 μm. (e) Distribution of the photon counts associated with the τ₁ component of 4 in HK cells after triexponential reconvolution of FLIM images before (c, τ_1i) and after (d, τ_1h) hyper-osmotic shock, showing decreasing lifetimes for τ₁ (4d). (f) The dehydration factor dh_i defined as total integrated photon counts for τ₁ (Στ₁) divided by Στ₂ (i.e., dh_i = area Στ_1i/area Στ_2i) for 4 in strongly hydrated ER (dh_i < 2, turquoise) and 1 in weakly hydrated plasma membrane (dh_i > 6, purple) of HK Kyoto cells under iso-osmotic conditions.Dual response of HydroFlippers to changes in membrane tension^a

Manganese(i)-catalyzed access to 1,2-bisphosphine ligands

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. However, the transition metals typically used are scarce and expensive noble metals, while the synthetic routes to access chiral phosphine ligands are cumbersome and lengthy. To make homogeneous catalysis more sustainable, progress must be made on both fronts. Herein, we present the first catalytic asymmetric hydrophosphination of α,β-unsaturated phosphine oxides in the presence of a chiral complex of earth-abundant manganese(i). This catalytic system offers a short two-step, one-pot synthetic sequence to easily accessible and structurally tunable chiral 1,2-bisphosphines in high yields and enantiomeric excess. The resulting bidentate phosphine ligands were successfully used in asymmetric catalysis as part of earth-abundant metal based organometallic catalysts.

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. Mn(i)-catalyzed hydrophosphination offers a two-step, one-pot synthetic sequence to access chiral 1,2-bisphosphines.

The vast majority of important catalytic transformations make use of very effective catalysts based on scarce, expensive and toxic noble transition metals and phosphine containing ligands that, especially when chiral, are often as expensive as the noble metals themselves due to their cumbersome synthetic accessibility.¹ The past decade has witnessed significant progress towards the development of competitive catalysts that contain earth-abundant transition metals instead. These catalysts, however, still frequently rely on the use of chiral phosphine ligands. Bisphosphine ligands (Scheme 1A) for instance Pyrphos,^2a Chiraphos,^2b as well as Josiphos^2c are among the most successful chiral ligands used in homogeneous catalysis. In recent years, bis(phosphine) monoxide compounds such as Bozphos,^2d and Binap(o)^2e have been shown to be powerful ligands in asymmetric catalysis as well. Unfortunately, the synthesis of these frequently and successfully used chiral phosphine-based ligands often requires stoichiometric amounts of chiral auxiliaries, enantiopure substrates, or separation by resolution to obtain them enantiomerically pure.^1b–fOpen in a separate windowScheme 1(A) Examples of phosphine ligands commonly used in homogeneous catalysis. (B) Catalytic asymmetric hydrophosphination of various Michael acceptors. (C) This work: Mn (i)-catalyzed access to chiral 1,2-bisphosphines.Catalytic asymmetric hydrophosphination is one of the most straightforward approaches for generating optically active P-chiral or C-chiral phosphines, from which chiral ligands can be derived.³ The potential of hydrophosphination reactions to access enantioenriched chiral phosphines catalytically was demonstrated for the first time by Glueck and coworkers in 2001 using a catalytic system based on Pt and the chiral bisphosphine ligand Me-DuPhos.⁴ Following the publication of this initial work, precious noble metal complexes such as chiral Pd or Pt catalysts have been widely used in the field of asymmetric hydrophosphination (Scheme 1B).⁵ Only few examples utilizing earth-abundant metals such as Ni,⁶ Cu⁷ and very recently Mn⁸ have been reported to date for catalytic asymmetric hydrophosphination. Apart from metal based catalytic systems, examples of asymmetric organocatalytic hydrophosphination reactions were also presented in the literature.⁹ So far, all successful methods that rely on the addition of phosphines to α,β-unsaturated conjugated systems provide chiral monophosphines.³ Interestingly, the only reported example of catalytic hydrophosphination that allows access to chiral 1,2-bisphosphine ligands utilizes a Michael acceptor with a P-containing electron-withdrawing group.^7bWhile α,β-unsaturated phosphine oxides are bench stable and readily available Michael acceptors, their application is less common when compared to conventional carbonyl based Michael acceptors, which is in part due to their lower reactivity.¹⁰ Yin and co-workers found an elegant solution to this problem by transforming α,β-unsaturated phosphine oxides into phosphine sulphides. This allows a ‘soft–soft’ interaction to be established between the Cu(i) atom of the chiral Cu(i)-catalyst and the S atom of the phosphine sulphide, enabling catalytic hydrophosphination towards the synthesis of chiral bisphosphines.^7b While successful in applying this strategy for catalytic synthesis of variety of chiral bisphosphines, nevertheless it requires 6-steps synthetic sequence starting from α,β-unsaturated phosphine oxides (Scheme 1C).^7bHerein, we present a highly efficient, short and scalable catalytic protocol for the synthesis of chiral 1,2-bisphosphines from readily available, bench stable α,β-unsaturated phosphine oxides employing Mn(i)-catalyzed hydrophosphination as its core transformation (Scheme 1D).The last five years witnessed remarkable success of Mn(i)-complexes as catalysts for reductive transformations of carbonyl compounds including asymmetric variants.^11–13 Next to these reports, we have recently demonstrated that such complexes are capable of catalytic H–P bond activation of diarylphosphines.⁸ Based on these findings we hypothesised that Mn(i)-complexes should be able to bring the phosphine oxide and the phosphine reagents into closer proximity thus allowing the hydrophosphination reaction to take place directly with α,β-unsaturated phosphine oxides. This approach would avoid the additional synthetic steps and purifications procedures necessitated by the installation and removal of the sulphur atom that are intrinsic to the method utilising phosphine sulphides.At the outset of this work, bench-stable α-substituted α,β-unsaturated phosphine oxide 1a was chosen as the model substrate in the reaction with HPPh₂ (i)-complex, Mn(i)-L, developed by Clark and co-workers13a,d for hydrogenation and transfer hydrogenation of carbonyl compounds, was selected as the chiral catalyst. After extensive optimization, the reaction with 5 mol% t-PentOK, 2.5 mol% Mn(i)-L, 1.05 equiv. of HPPh₂ in toluene at room temperature for 16 hours was found to be optimal. Under these conditions, the product 3aa was obtained with 96% isolated yield and over 99% ee (entry 1).Optimization of the reaction conditions^a

Dirhodium(ii)-catalysed cycloisomerization of azaenyne: rapid assembly of centrally and axially chiral isoindazole frameworks

Described herein is a dirhodium(ii)-catalyzed asymmetric cycloisomerization reaction of azaenyne through a cap-tether synergistic modulation strategy, which represents the first catalytic asymmetric cycloisomerization of azaenyne. This reaction is highly challenging because of its inherent strong background reaction leading to racemate formation and the high capability of coordination of the nitrogen atom resulting in catalyst deactivation. Varieties of centrally chiral isoindazole derivatives could be prepared in up to 99 : 1 d.r., 99 : 1 er and 99% yield and diverse enantiomerically enriched atropisomers bearing two five-membered heteroaryls have been accessed by using an oxidative central-to-axial chirality transfer strategy. The tethered nitrogen atom incorporated into the starting materials enabled easy late-modifications of the centrally and axially chiral products via C–H functionalizations, which further demonstrated the appealing synthetic utilities of this powerful asymmetric cyclization.

Rh(ii)-catalyzed asymmetric cycloisomerization of azaenyne through a cap-tether synergistic modulation strategy was described. Diverse centrally and axially chiral isoindazoles were prepared and directed C–H late-stage modifications were developed.

Known as one of the most significant and reliable access methods to chiral heterocycles, asymmetric cycloisomerization of conjugated enyne has caught extensive attention and interest for its wide applications in synthetic route design and mechanistic investigation.¹ Specifically, asymmetric cyclization of conjugated enynone (X = C, Z = O) has been successfully developed and applied to the rapid construction of various chiral furan-containing skeletons with high efficiency in an extremely operationally simple manner (Scheme 1a).² However, compared to the fruitful research with enynone, it is surprising that the analogous asymmetric version of azaenyne (Z = N–R) still remains underdeveloped.³ In fact, no successful example of catalytic asymmetric cyclization of azaenyne has been reported in the literature despite the apparent significance of nitrogen-containing five-membered heterocycles in the synthetic and pharmaceutical community.⁴ In 2004, Haley and Herges reported a detailed experimental and theoretical study of the cyclization reaction of (2-ethynylphenyl)-phenyldiazene, which is a unique azaenyne.⁵ According to the DFT calculations, very close and low activation barriers for 5-exo-dig and 6-endo-dig cyclization pathways under catalyst-free conditions were found, which shed light on the inherent challenges of the asymmetric reaction of azaenyne (Scheme 1b). For instance, there was usually a regioselectivity issue (5-exo and 6-endo) in the cyclization reaction of azaenyne because of their close reaction barriers where the competitive 6-endo-dig cyclization^3a,6 may lead to troublesome side-product formation. In addition, the low activation barrier deriving from the strong N-nucleophilicity of azaenyne may easily lead to self-cyclization which will cause severe background reactions to interfere with the asymmetric process. More troublingly, this transformation might suffer from catalyst deactivation arising from the high coordinating capability of the nitrogen atom in both starting materials and products, which might give more opportunities to the propagation of detrimental background reactions. In some cases, even a super-stoichiometric amount of transition metal has to be used to ensure effective conversion.^3a,7 Therefore, although many nonchiral approaches have been reported,^3,5 catalytic asymmetric cyclization of azaenyne still remains elusive due to the inherent obstacles aforementioned. With our continuous interest in alkyne chemistry,^2a,8 herein we designed a cap-tether synergistic modulation strategy to tackle these challenges, envisioning that modulation of the tethered atom and protecting cap of nitrogen in the azaenyne would intrinsically perturb and alter the reactivity of the starting material, and therefore the azaenyne motif could be effectively harnessed as a promising synthon for asymmetric transformations (Scheme 1c). It should be noted that the obtained centrally chiral product produced from intramolecular C–H insertion of donor-type metal carbene⁹ might be potentially converted into the axially chiral molecule via a central-to-axial chirality conversion strategy.Open in a separate windowScheme 1Development of the asymmetric cyclization reaction of conjugated azaenyne.With this design in mind, different types of azaenynes bearing typical tethering atoms and capping groups were chosen to test our hypothesis and representative results are shown in Scheme 2. First, tBu-capping imine (X = C, R = tBu) was selected as a substrate to test our hypothesis.^6a It was found that the imine exhibited low reactivity and the reaction temperature has to be elevated to 100 °C to initiate the transformation with or without catalyst. Unfortunately, the desired 5-exo-dig cyclization product was not detected, but isoquinoline from 6-endo-dig cyclization was obtained instead (Scheme 2a). To further regulate and control the regioselectivity and reactivity, triazene (X = N, R = N-piperidyl) was then investigated. Similarly, this substrate also showed low reactivity and it is still required to be heated at 100 °C for conversion. In the absence of a metal catalyst, an unexpected alkyne, deriving from the fragmentation of the triazene moiety, was produced in 41% yield. When 2 mol% Rh₂(OPiv)₄ was added as a catalyst, the side reaction could be efficiently suppressed and the reaction selectivity was apparently reversed. In this case, the target C–H insertion dihydrofuran was furnished as the major product in 30% yield but still accompanied by concomitant formation of 12% yield of undesired alkyne (Scheme 2b). The above investigations showed neither the imine nor triazene was an ideal substrate for the asymmetric reaction. Thus, we moved our attention to the diazene substrate (X = N, R = aryl). As demonstrated by Haley''s and Herges'' pioneering work, ortho-alkynyl diazene, compared with imine and triazene, was more unstable and tended to self-cyclization even at room temperature.^5a As shown in Scheme 2c, the ortho-alkynyl diazene degrades and 5-exo-dig cyclization products could be observed even in DCE solvent without any catalyst at room temperature. When the phenyl capping group was installed in the substrate, the reaction furnished 10% yield of isoindazole derivative. The uncatalyzed self-cyclization reaction was obviously accelerated when an electron-rich capping group (4-MeO–C₆H₄–) was introduced, affording the corresponding product in 20% yield. Inspired by these findings, we assumed that installation of an electron deficient group on the capping phenyl would reduce the nucleophilicity of the nitrogen atom and thus the troublesome self-cyclization reaction might be effectively inhibited. To our delight, when a bromo-substituent was introduced onto the phenyl cap, the undesired self-cyclization was almost suppressed. When Rh₂(OPiv)₄ was added as a catalyst, the desired carbene-involved C–H insertion product was furnished in 90% yield at room temperature. Worthy of note was the total absence of any cinnoline formation from 6-endo-dig cyclization.^3a,6b In short, the synthetic challenges associated with regioselectivity (5-exo-dig and 6-endo-dig), strong background reaction and catalyst deactivation could be successfully regulated and controlled via a tether-cap synergistic modulation strategy.Open in a separate windowScheme 2Typical substrate investigation.Encouraged by the above findings, ortho-alkynyl bromodiazene 1a was chosen as a model substrate and different types of chiral dirhodium catalysts¹⁰ were screened in DCE at room temperature for 48 h. As shown in EntryRh(ii)*SolventYield^b [%]er^c1Rh₂(R-DOSP)₄DCE5629 : 712Rh₂(5S-MEPY)₄DCE1750 : 503Rh₂(S-BTPCP)₄DCE618 : 924Rh₂(S-PTPA)₄DCE9191 : 95Rh₂(S-PTTL)₄DCE8697 : 36Rh₂(S-PTAD)₄DCE9394 : 67Rh₂(S-NTTL)₄DCE9296 : 48Rh₂(S-TCPTTL)₄DCE9598 : 2 9 Rh ₂ (S-TFPTTL) ₄ DCE 98 ^d 98 : 210Rh₂(S-TFPTTL)₄DCM8898 : 211Rh₂(S-TFPTTL)₄Toluene9298 : 212Rh₂(S-TFPTTL)₄MeCN1692 : 813Rh₂(S-TFPTTL)₄ n-Hexane9698 : 214^eRh₂(S-TFPTTL)₄DCE65^f96 : 4 Open in a separate window^aUnless otherwise noted, reactions were performed at 0.1 M in DCE using 0.20 mmol substrate and catalyst (2 mol%) under a N₂ atmosphere.^bDetermined by ¹H NMR spectroscopy.^cThe er value of 2a was determined by HPLC using a chiral stationary phase.^dIsolated yields.^e1 mol% catalyst was used.^f25% starting material was recovered.With the optimized reaction conditions in hand (Scheme 3, the catalytic process could be successfully applied to azaenynes 1 bearing different ether side chains. For example, in addition to 1a, various azaenyne derivatives containing benzylic ethers could be efficiently converted into the desired products 2b–i with excellent diastereoselectivities and enantioselectivities (>99 : 1 d.r., 97:3–99 : 1 er). The yields were typically higher than 90% for most substrates. Satisfyingly, the substrates with bulkier aryl groups were well-tolerated to afford the isoindazole products 2j–m in good yields with excellent diastereo- and enantiocontrol (>97 : 3 d.r., > 95 : 5 er). In addition to azaenynes with arylmethyl ether, this protocol was also successfully applied to substrates with allylic ether, propargyl ether and even aliphatic ether to furnish the cyclization products 2n–u in good yields with decent diastereo- and enantioselectivities (>93 : 7 d.r., > 90 : 10 er). In the cases of allylic and propargyl ether, only C–H insertion products (2n–p) were observed though cyclopropanation or cyclopropenation often took place competitively when using the allylic or propargyl substrate to trap the carbene intermediate.¹¹ It was noted that the azaenynes with aliphatic ether, which represent challenging substrates^2a in the asymmetric carbene transfer reactions, also showed good reactivities to afford the corresponding chiral dihydrobenzofurans (2q–u) with excellent diastereoselectivities (>93 : 7 d.r.) and enantioselectivities (>98 : 2 er). Interestingly, when phenyl and methoxyphenyl capping azaenynes, which potentially suffered from the undesired background reactions, were subjected to the standard conditions, chiral products (2v–w) could be obtained with high optical purity (>99 : 1 d.r., > 96 : 4 er) as well. These results might be attributed to the high catalytic activity of Rh₂(S-TFPTTL)₄ in the asymmetric cyclization process, which eventually led to complete suppression of the uncatalyzed self-cyclization. The scopes with respect to the group R¹ on the fused phenyl ring were further investigated. Both electron-rich and -deficient substituents R¹ were well accommodated, with the product yields ranging from 80% to 99%, enantiomeric ratios ranging from 95 : 5 to 97 : 3 and diastereomeric ratios higher than 99 : 1 (2x–z). In addition, azaenyne substituted with an alkyl side chain at the alkynyl carbon atom was also tested, giving tetrahydrofuran (2aa) with excellent diastereoselectivity (>99 : 1 d.r.), good enantioselectivity (90 : 10 er) and moderate yield (43%). In addition to the side chain of ether, this asymmetric protocol could even be extended to the more challenging nitrogen- and thio-tethered analogues, albeit with somewhat lower reactivities (46–65% yields) but good stereoselectivities (93 : 7 er and 84 : 16 d.r. for 2ab; 81 : 19 er and >99 : 1 d.r. for 2ac). Structures of the resulting products were confirmed by X-ray crystallographic analysis of their analogue 2h.Open in a separate windowScheme 3 ^aUnless otherwise noted, the reactions were performed under standard conditions for 48 h or monitored by TLC until the starting material disappeared. ^b5 mol% catalyst was used. ^cReactions were performed in n-hexane, using 2 mol% Rh₂(S-TCPTTL)₄ as the catalyst.The successful preparation of centrally chiral isoindazole through the asymmetric cyclization reaction prompted us to explore the further applications of this protocol. Axially chiral biaryl skeletons are undoubtedly regarded as one of the most prominent structural motifs for their ubiquity in natural products, pharmaceuticals and useful chiral ligands in asymmetric catalysis.¹² Due to the lower rotational barrier, there are only limited examples of the enantioselective synthesis of axially chiral atropisomers featuring a five-membered ring, especially those bearing two pentatomic aromatics.¹³ Compared with the furan analogue, the extending cap in the isoindazole scaffold provides additional ortho steric hindrance making these molecules possible candidates for the preparation of five-five-membered biaryl atropisomers. Considering the unique chiral skeleton of dihydrofuranyl isoindazole 2, we began to explore their potential application in chiral atropisomer synthesis via a central-to-axial chirality transfer strategy. As shown in Scheme 4, oxidative aromatization of representative dihydrofuran candidate 2m furnished two configurationally unstable atropisomers, which might be attributed to their relatively low rotational barriers as five-membered atropisomers especially when the furan ring was incorporated (see ESI^† for details). Therefore, it was hypothesized that extending the fused phenyl to naphthyl might afford stable atropisomers by enhancing the ortho steric hindrance (Scheme 4b).Open in a separate windowScheme 4Investigation of central-to-axial chirality transfer.To our delight, as shown in Scheme 5, naphthyl-fused dihydrofurans 4 could be easily accessed through the above established dirhodium-catalyzed cyclization process and configurationally stable atropisomers 5 could be generated via further oxidative dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidant (see ESI^† for the proposed mechanism). For example, asymmetric cyclization reactions proceeded smoothly to give the centrally chiral compounds 4 in good yields (54–99%) with excellent diastereoselectivities (92 : 8–99 : 1 d.r.) and enantioselectivities (95 : 5–99 : 1 er) under slightly modified reaction conditions. This reaction was compatible with a variety of arylmethyl side chains in azaenynes and well-accommodated with various functional groups (F, Cl, Br, OMe, and –CO₂Me). Additionally, oxidative dehydrogenation of chiral candidates 4 with DDQ smoothly resulted in the formation of axially chiral atropisomers 5 in 90–99% yields with only slight loss of chiral integrity (90 : 10–97 : 3 er). An enantiomerically pure atropisomer could be obtained through a simple recrystallization procedure as exemplified by compound 5g. The structure and absolute configuration of isoindazole 4g and atropisomer 5g were confirmed by their single-crystal X-ray diffraction analysis.Open in a separate windowScheme 5 ^aConditions for cyclization of azaenyne: Rh₂(S-TCPTTL)₄ (2 mol%), n-hexane, rt for 48 h or monitored by TLC until the starting material disappeared; conditions for oxidative chirality transfer: DDQ (2 equiv.), DCE, −20 °C for 48 h or monitored by TLC until the starting material disappeared. ^b45 °C. ^cDDQ (5 equiv.). ^dRoom temperature. ^eAfter one recrystallization.With centrally and axial chiral molecules in hand, further transformations of these compounds were also explored. The tethered nitrogen atom in azaenynes not only showed a synergetic effect with the capping group on promoting asymmetric cyclization but also served as an innate directing group for late-stage modifications via C–H functionalization. As shown in Scheme 6, a variety of functional groups could be directly introduced onto the capping aromatic rings, allowing for rapid build-up of molecular complexity. For example, synthetically valuable alkenyl,¹⁴ allyl¹⁵ and alkynyl¹⁶ groups could be easily incorporated into the final structures, which had wide potential applications in organic synthesis (6a–c). Furthermore, C–H alkylation,¹⁷ amidation¹⁸ and selenylation¹⁹ were performed smoothly to afford the desired products 6d–g. It is noteworthy that unique chiral chelation backbones were constructed by amidation and selenylation of the isoindazole moiety (6e–g). In addition to centrally chiral compounds, axial chiral atropisomers 5 themselves could be efficiently converted to their functionalized scaffolds as well (6h–i) through a similar directed C–H functionalization process.Open in a separate windowScheme 6Late-stage modification of chiral isoindazoles. Reaction conditions: ^a4-octyne, [Rh(Cp*Cl₂)]₂, AgSbF₆, Cu(OAc)₂, DCE, 80 °C. ^bAllyl carbonate, [Rh(Cp*Cl₂)]₂, AgSbF₆, PivOH, PhCl, 40 °C. ^cHypervalent iodine-alkyne, [Rh(Cp*Cl₂)]₂, Zn(OTf)₂, DCE, 80 °C. ^dAlkene, [Rh(Cp*Cl₂)]₂, AgSbF₆, AcOH, 1,4-dioxane, 50 °C. ^e3-Phenyl-1,4,2-dioxazol-5-one, [Cp*Co(MeCN)₃](SbF₆)₂, DCE, 80 °C. ^fPhSeCl, [Rh(Cp*Cl₂)]₂, AgSbF₆, THF, 60 °C.     

Ligand design for Rh(iii)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones

We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cp^t affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.C–H activation mediated processes have provided a unique retrosynthetic approach to access a variety of substituted heterocycles.¹ One tactic that has received increased attention is the coupling of π-components with heteroatom containing molecules.² A variety of transition metals are capable of catalyzing this type of transformation, providing access to dozens of heterocyclic motifs.^1–3 A challenge for these methods is controlling the regioselectivity of migratory insertion across alkenes and alkynes after the metallacycle forming C–H activation (eqn 1).Steric and electronic effects are understood to control migratory insertion of unsymmetrical alkynes in Rh(iii) catalyzed isoquinolone syntheses (eqn 1). When the substituents are electronically similar, the larger group resides β- to Rh in the metallacycle to avoid unfavorable steric interactions (selectivity is generally >10 : 1).⁴ When the substituents are electronically different, the more electron-donating group prefers being α- to rhodium in the metallacycle, presumably to stabilize the electron poor metal.^5,6 The type of C–H bond being activated also plays an important role in the regioselectivity of migratory insertion; aromatic substrates typically provide synthetically useful regioselectivities when electronically different alkynes are used (>10 : 1) but alkenyl C–H activation leads to products with lower regioselectivities, presumably due to minimal steric interactions during migratory insertion.^7,8 We found that sterically bulky di-tert-butylcyclopentadienyl ligand (Cp^t) enhances the regioselectivity of the alkyne migratory insertion event in these cases, delivering regioselectivities (>10 : 1) modestly above those achievable by Cp* ligated Rh complexes (<6 : 1). However, when the alkyne migratory insertion was poorly selective with RhCp* (<3 : 1), RhCp^t complex was ineffective at providing synthetically useful levels of selectivity. Furthermore, the Cp^t ligand was only effective with aryl substituted alkynes, presumably because of strong steric interactions between the ligand and alkyne in the insertion event. Migratory insertion of alkenes to access heterocycles using C–H activation chemistry is still relatively rare, with seminal studies by Glorius and Fagnou reporting the synthesis of dihydroisoquinolones.^9–11 Similar to alkynes, alkenyl electron-donating groups favor the position adjacent to the metal in the metallacycle delivering high regioselectivity. In contrast to alkynes, aliphatic alkenes afford product with poor regioselectivity (2 : 1) (eqn 2).^5h,12 We hypothesized competing steric and electronic effects cause the low regioselectivity, with steric effects favoring the formation of a 4-substituted product and electronics favoring the formation of a 3-substituted product.¹³ As a temporary solution to this problem, our group and others have employed tethering strategies to increase the regioselectivity of the migratory insertion event (eqn 3).^14,15 Of course, regioselectivity controlled by the ligand on Rh would be the optimal solution to the selectivity problem (eqn 4).¹⁶ Consequently, we focused our attention toward developing an intermolecular variant of this reaction that would provide product with improved regioselectivity.As a model system, we explored the impact ligands have on the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1-decene 2a to provide dihydroisoquinolones 3a and 3a′. When Cp* is used as a ligand, the desired products are isolated in excellent yield but poor selectivity (2.4 : 1 3a : 3a′) ( a

Redox-neutral manganese-catalyzed synthesis of 1-pyrrolines

This report describes a manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functional 1-pyrrolines. In this redox-neutral process, the oxime ethers function as internal oxidants and H-donors. The reaction involves sequential rupture of C–C, C–H and N–O bonds and proceeds under mild conditions. This intermolecular protocol provides an efficient approach for the synthesis of structurally diverse 1-pyrrolines.

Described herein is a novel manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functionalized 1-pyrrolines.

Pyrroline and its derivatives appear frequently as the core of the structure of natural products and biologically active molecules (Fig. 1A).¹ Such compounds also serve as versatile feedstocks in various transformations, such as 1,3-dipolar cyclization, ring opening, reduction and oxidation, leading to diverse and valuable compounds.^2–4 Over the past few decades, great effort has been devoted to the preparation of pyrrolines. This has resulted in several elegant approaches that rely on photoredox catalysis (Fig. 1B).⁵ The groups of Studer,^5a,b Leonori,^5c and Loh^5d–f disclosed intramolecular addition of the intermediate iminyl radical to alkenes to construct pyrrolines. Generally, the synthetic value of a method can be further improved by using an intermolecular reaction pattern. For example, Alemán et al. recently reported a radical-polar cascade reaction involving the addition to ketimines of alkyl radicals formed in hydrogen atom transfer (HAT) reactions.^5g That the existence of benzylic C–H bonds in the substrates is requisite for the HAT, compromises the substrate scope. Despite the appealing photochemical processes, development of new redox approaches to enrich the product diversity of pyrrolines, especially with inexpensive transition-metal catalysts, is still in demand.Open in a separate windowFig. 1(A) Importance of pyrrolines, and (B and C) synthetic approaches to pyrrolines.Prompted by extensive applications of cyclopropanols in synthesis⁶ and our achievements in manganese-catalyzed ring-opening reactions,⁷ we conceived a radical [3 + 2] cyclization using cyclopropanol as a C3 synthon and oxime ethers as a nitrogen source (Fig. 1C). Hypothetically, single-electron oxidation of cyclopropanol by Mnⁿ generates the β-keto radical (I), which undergoes a radical [3 + 2] cascade reaction with an oxime ether to give the alkoxy radical species (II). Conversion of II to the intermediate (III), the pyrroline precursor, requires an extra H-donor to support a HAT process and an oxidant for recovery of Mnⁿ to perpetuate the catalytic cycle. In this scenario, the strategic inclusion of oxime ether is crucial to the overall transformation. The oxime ether is not only an internal oxidant and H-donor, but should also be subject to in situ deprotection by cleaving the N–O bond during the reaction. The choice of a proper Mnⁿ/Mnⁿ⁻¹ pair with suitable redox potentials is also vital to the catalytic cycle.Herein, we provide proof-of-principle studies for this hypothesis. The desired radical [3 + 2] cyclization of cyclopropanols and O-benzyl oxime ethers is accomplished with manganese catalysis. This redox-neutral process involves sequential rupture of C–C, C–H, and N–O bonds under mild conditions. The intermolecular protocol provides an ingenious approach to the synthesis of multi-functionalized 1-pyrrolines.With these considerations in mind, phenylcyclopropanol (1a) and oxime ether (2a) were initially chosen as model substrates to evaluate reaction parameters in the presence of manganese salt ( N bond of 2a (entry 2). The optimization of organic solvents was then conducted (entries 3–8), and it was found that the use of fluorinated alcohols, such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents provided excellent yields (entries 7 and 8). Decreasing the amount of Mn(acac)₃ to 1.2 equiv. gave a comparable yield (entry 9), but further reducing the amount compromised the yield (entry 10). Replacing Mn(acac)₃ with Mn(OAc)₃ or MnCl₂ significantly decreased the reaction yield (entries 11 and 12). However, the use of Mn(acac)₂ gave a similar yield to Mn(acac)₃ (entries 13 vs. 9). The above results prompted us to think over the counteranion effect that the acetylacetone (acac) anion may be requisite to the reaction. Indeed, the synergistic use of stoichiometric MnCl₂ and acetylacetone led to a good yield of the desired product (entry 14). More importantly, a comparable yield was obtained with only 0.2 equiv. of MnCl₂ and added acetylacetone, realizing this reaction under a catalytic amount of Mn salts (entry 15). Given that the low solubility of the Mn salt may lead to poor efficiency, a reaction with 0.067 M concentration was carried out and gave a 89% yield (entry 16). Further reducing the amount of acetylacetone to 1.0 equiv. had no influence on the outcome of the reaction (entry 17), but the reaction efficiency slightly decreased when 0.6 equiv. of acetylacetone was used as the additive (entry 18). Use of a decreased amount (1.0 equiv.) of acetic acid led to the best yield (91%, entry 19), whereas the reaction in the presence of 0.5 equiv. acetic acid (entry 20) or without acetic acid (entry 21) also gave high yields. It is noted that acetic acid is not crucial to the reaction using MnCl₂ as catalyst, as the reaction could generate cat. HCl in situ. The reaction with substoichiometric amount (0.6 equiv.) of acac gave a decreased but also good yield (entry 22). Reducing the catalytic loading of MnCl₂ to 10 mol% slightly compromised the yield (entry 23).Optimization of the synthesis of 1-pyrrolines

Entrya	Mn salt (equiv.)	Additive (equiv.)	Solvent	Yield (%)
1	Mn(acac)3 (1.7)	None	CH3CN	33
2b	Mn(acac)3 (1.7)	None	CH3CN	Trace
3	Mn(acac)3 (1.7)	None	DCM	31
4	Mn(acac)3 (1.7)	None	Acetone	25
5	Mn(acac)3 (1.7)	None	DMSO	Trace
6	Mn(acac)3 (1.7)	None	DMF	Trace
7	Mn(acac)3 (1.7)	None	TFE	80
8	Mn(acac)3 (1.7)	None	HFIP	82
9	Mn(acac)3 (1.2)	None	HFIP	83
10	Mn(acac)3 (0.9)	None	HFIP	55
11	Mn(OAc)3·2H2O (1.2)	None	HFIP	36
12	MnCl2 (1.2)	None	HFIP	Trace
13	Mn(acac)2 (1.2)	None	HFIP	88
14	MnCl2 (1.2)	acac (3.6)	HFIP	80
15	MnCl2 (0.2)	acac (3.6)	HFIP	81
16c	MnCl2 (0.2)	acac (3.6)	HFIP	89
17c	MnCl2 (0.2)	acac (1.0)	HFIP	89
18c	MnCl2 (0.2)	acac (0.6)	HFIP	83
19c,d	MnCl2 (0.2)	acac (1.0)	HFIP	91
20c,e	MnCl2 (0.2)	acac (1.0)	HFIP	83
21c,b	MnCl2 (0.2)	acac (1.0)	HFIP	80
22c,d	MnCl2 (0.2)	acac (0.6)	HFIP	82
23c,d	MnCl2 (0.1)	acac (1.0)	HFIP	81

Open in a separate window^aReaction conditions: 1a (0.45 mmol), 2a (0.3 mmol), AcOH (2.0 equiv.), and Mn salt (as shown) in solvent (2.0 mL), at room temperature (rt) under N₂, for 16 h.^bWithout AcOH.^c0.067 M reaction.^d1.0 equiv. AcOH.^e0.5 equiv. AcOH. acac = acetylacetone.With the optimized conditions in hand for the synthesis of 1-pyrrolines, the compatibility of various cyclopropanols was inspected (Scheme 1). Common functional groups on the phenyl ring, including halides (3b–3d), ester (3f), ether (3j), were compatible under the reaction conditions. Regardless of the presence of electron-withdrawing or -donating substituents at the para-position of this phenyl ring, the reactions readily proceeded with generally high yields (3b–3j). The cyclopropanol (1k) with an ortho-methyl substituent underwent a cyclization reaction with excellent yield, demonstrating that steric effects had little effect on product of the reaction (3k). By replacing the phenyl group with a naphthyl or thienyl group, the corresponding products (3l and 3m) were produced with slightly lower yields. When 2-substituted cyclopropanols were utilized, these reactions gave rise to a portfolio of trisubstituted 1-pyrrolines (3n–3u).The relative configuration of 3u was determined by comparison with a reported structure.⁸ Remarkably, this protocol provided a convenient method for the construction of an N-containing spiro skeleton (3t). The reaction with alkyl cyclopropanols could also furnish the desired products (3v–3x) smoothly and with good yields.Open in a separate windowScheme 1Scope of cyclopropanols. Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations. ^aThe reaction is scaled up for 10 times.Next, we studied the scope of oxime ethers (Scheme 2). Steric hindrance from the ester moiety in the oxime ethers appeared not to influence the reaction outcome. Oxime ethers bearing various esters, such as phenyl (3y), biphenyl (3z and 3ab), 2-naphthyl (3aa), 2,4-di-tert-butylphenyl (3ac and 3ad), and 2,6-dimethylphenyl (3ae) esters all reacted smoothly. In addition, the substrate with tert-butyl ester also readily underwent cyclization to afford the desired product 3af with excellent yield. Remarkably, the trifluoromethyl-substituted pyrroline (3ag) was afforded almost quantitatively from the corresponding ketoxime ether. However, if the trifluoromethyl group was replaced by a methyl or phenyl group, the reaction failed to give rise to the desired product (3ah or 3ai), and this might be attributed to poorer electrophilic nature of the methyl or phenyl substituted substrate.Open in a separate windowScheme 2Scope of oxime ethers. Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations.To illustrate the utility of this protocol, we carried out a set of synthetic applications using 1-pyrroline (3a) (Scheme 3). Upon treatment with acetyl chloride and pyridine at 42 °C, 1-pyrroline (3a) could be readily converted into the acyclic amino acid derivative (4). The reaction between 3a and LiAlH₄ gave rise smoothly to the corresponding alcohol (5). In the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquin-4-one (DDQ) and triethylamine, the 2,5-disubstituted pyrrole (6) was obtained. Moreover, treatment of 3a with MeOTf and NaBH₄ delivered the N-methyl proline derivative (7).⁹Open in a separate windowScheme 3Synthetic applications. Reaction conditions: (a) AcCl, pyridine, dry DCE, 42 °C, 63% yield; (b) LiAlH₄, THF, reflux, 90% yield; (c) DDQ, Et₃N, DCM, rt, 53% yield; (d) MeOTf, DCM, and then NaBH₄, THF, 40% yield, cis : trans = 6.6 : 1.To probe the mechanistic pathways, we performed a radical trapping experiment in the presence of 2.0 equiv. of radical scavenger TEMPO. The radical trapping product (8) was detected by high-resolution mass spectrometry (HRMS) (Scheme 4A, top). In addition, the reaction was obviously suppressed when 1,1-diphenylethylene was added under standard condition (Scheme 4A, bottom). These results suggested that this process engaged in a radical pathway. Kinetic studies illustrated that the reaction immediately started with 20 mol% Mn(acac)₂ but an approximate 15 min of induction period was appeared by using Mn(acac)₃, which probably indicated that the reaction was initiated with Mn(ii) rather than Mn(iii), and the Mn(ii)/Mn(i) cycle might be involved in the transformation (Scheme 4B, for details see ESI^†).Open in a separate windowScheme 4(A and B) Mechanistic studies, and (C) proposed mechanism.On the basis of these results, a plausible mechanism for this radical process was proposed in Scheme 4C. Initially, the interaction between cyclopropanol (1a) and Mn(ii) salt gives rise to the alkoxy manganese species (I), which undergoes a ligand-to-metal charge transfer (LMCT) process, leading to the alkoxy radical (II).^5f Subsequent ring-opening of the alkoxyl radical (II) provides the alkyl radical (III). The addition of intermediate (III) to the oxime ether, possibly activated by HFIP or HOAc, furnishes the N-centered radical (IV), which intramolecularly attacks the ketone to afford a new alkoxy radical (V).¹⁰ The subsequent 1,5-hydrogen atom transfer (HAT) process delivers the alkyl radical (VI) at the α-position adjacent to the O atom, thus driving N–O bond cleavage to generate the N-centered radical (VII),^5b,11 and benzaldehyde which was detected by TLC. This radical intermediate (VII) undergoes a single electron transfer (SET) mediated by the reduced-state Mn(i) species, and protonation to yield the cyclic pyrrolidine (VIII). Finally, dehydration of this intermediate produces 1-pyrroline (3a).     

Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.

Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.¹ Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).² Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).³ However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,⁴ substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.^5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.⁶ In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)^9,10 as well as the synthesis of chiral tetraarylmethanes,⁸ we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag₂O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)₃ (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO₂ gave only 60% conversion (entry 10).Evaluation of oxidants

Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp³)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.

Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.

Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.¹ Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).² Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.³ Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.^4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.⁶ Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.⁷ Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.⁸ Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.⁹ Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.¹⁰ The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.¹¹ Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.^12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.¹²Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,^15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.¹⁷ This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.¹⁸We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)₂ and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)₂ to be the optimal catalyst, while Pd(TFA)₂, PdCl₂ and PdBr₂ provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)₂ was instead used (entry 15).Optimization of reaction conditions^a

Entry	Pd source	L (mol%)	TDG1 (mol%)	Solvent (v/v, mL)	Yield (%)
1	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP	30
2	Pd(OAc)2	L1 (30)	TDG1 (40)	AcOH	<5
3	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 1)	28
4	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (9 : 1)	47
5	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 9)	<5
6	Pd(OAc)2	L1 (30)	TDG1 (60)	HFIP/AcOH (9 : 1)	50
7	Pd(OAc)2	L1 (30)	TDG1 (80)	HFIP/AcOH (9 : 1)	25
8	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	70(68)b
9	Pd(OAc)2	L1 (75)	TDG1 (60)	HFIP/AcOH (9 : 1)	51
10	Pd(TFA)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	60
11	PdCl2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	52
12	PdBr2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	54
13	Pd(OAc)2	—	TDG1 (60)	HFIP/AcOH (9 : 1)	9
14	Pd(OAc)2	L1 (60)	—	HFIP/AcOH (9 : 1)	0
15c	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	55

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by ¹H-NMR using dibromomethane as an internal standard.^bIsolated yield.^cPd(OAc)₂ (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp³)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. ^aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol⁻¹). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)₂]₃, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol⁻¹. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp³)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG^‡ = 37.4 kcal mol⁻¹). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol⁻¹. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp³)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol⁻¹, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp³)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol⁻¹. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG^‡ = 27.4 kcal mol⁻¹) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol⁻¹ (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol⁻¹) and thermodynamically favorable (30.7 kcal mol⁻¹). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol⁻¹). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced.     

Oxindole synthesis via polar–radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates.

Oxindoles, in particular the 3,3-disubstituted congeners, are highly valuable substructures in medicinal chemistry. The oxindole core can be found in various biologically active compounds, that are for example used in the treatment of cancer or as antibacterial agents.¹ In addition, the oxindole moiety also occurs in several complex natural products.² The first oxindole synthesis was reported by Baeyer and Knop in 1866.³ That time, isatin was converted by sodium amalgam reduction to the corresponding oxindole. Since then, many methods for the preparation of 3,3-disubstituted oxindoles have been developed that proceed via functionalization of a pre-existing oxindole core.⁴ In addition, methods for the construction of 3,3-disubstituted oxindoles starting from acyclic precursors have also been introduced.^5,6 Along these lines, transition metal-mediated reactions^5,7 or homolytic aromatic substitutions (HAS)^8–14 have found to be highly efficient for the construction of the oxindole core. Focusing on the latter approach, the intramolecular HAS proceeds via α-carbonyl radicals derived from radical addition to N-arylacrylamides,⁸ reduction of α-haloarylamides⁹ or oxidation of the corresponding enolates^10–14 (Scheme 1a).Open in a separate windowScheme 1Selected strategies for the synthesis of oxindoles.In 2017, the group of Taylor developed a transition metal-free enolate oxidation-HAS-approach towards oxindoles at low temperature using elemental iodine as the oxidant and malonic acid derived N-aryl amides as substrates which are readily deprotonated.¹⁴The unique reactivity of ketenes¹⁵ has been explored extensively,¹⁶ especially in [2 + 2]-cycloadditions.¹⁷ Moreover, Staudinger,¹⁸ Lippman¹⁹ and Taylor²⁰ showed that ketenes react with aryl nitrones in a tandem [3 + 2]-cycloaddition-[3,3]-sigmatropic-rearrangement cascade²¹ followed by hydrolysis to provide oxindoles (Scheme 1b). The use of chiral nitrones leads to chirality transfer and enantiomerically enriched oxindoles can be obtained via this approach.^21,22 In contrast to the examples discussed in Scheme 1a, two σ-bonds are formed and the overall sequence can be regarded as a formal [3 + 2] cycloaddition. Despite good yields and high enantiomeric excess, nitrones have to be used as precursors and an aldehyde is formed as the byproduct diminishing reaction economy of these elegant cascades.To address these drawbacks, we decided to use the nucleophilic addition^23–26 of deprotonated anilines to ketenes for the generation of the corresponding amide enolates that should then be oxidized in a single electron transfer process to α-amide radicals which can undergo a homolytic aromatic substitution providing direct access to sterically challenging 3,3-disubstituted oxindoles in a straightforward one-pot sequence (Scheme 1c). This polar–radical crossover reaction shows high atom economy and as the reaction with the nitrones can also be regarded as a formal [3 + 2] cycloaddition.We initiated the optimization study with N-methylaniline 1a and ethyl phenyl ketene 2a, which was prepared in an easy and scalable one-pot protocol starting from the corresponding carboxylic acid, as model substrates. Deprotonation of 1a with n-BuLi in THF and subsequent addition to the ketene 2a led to desired Li-enolate which was confirmed by protonation with water and isolation of the amide 4aa (56%). Pleasingly, addition of ferrocenium hexafluorophosphate (FcPF₆, 2.2 equiv.) at room temperature to the Li-enolate afforded the desired oxindole 3aa in 29% yield (14 Light does not appear to play a crucial role in this transformation, as performing the reaction in the dark does not have a significant effect on the reaction outcome ( EntryBaseConc. (M)Oxidant (equiv.)Yield 3aa (%)^b1 n-BuLi0.1FcPF₆ (2.2)29 (18)^c2^d n-BuLi0.1CuCl₂ (2.2)34^c3 n-BuLi0.1I₂ (2.2)41^c4EtMgBr0.1I₂ (2.2)44^c5EtMgBr0.02I₂ (2.2)78 6 EtMgBr 0.01 I ₂ (2.2) 90 (82) ^c 7EtMgBr0.01I₂ (1.2)258EtMgBr0.01NIS^e (2.2)399EtMgBr0.01I₂ (1.2)^f8010EtMgBr0.01I₂ (2.2)^g8211EtMgBr0.01I₂ (2.2)^h7412EtMgBr0.01I₂ (2.2)ⁱ93Open in a separate window^aReactions (0.20 mmol) were conducted under argon atmosphere.^{b 1}H NMR yield using 1,3,5-trimethoxybenzene as internal standard.^cIsolated yield.^dStep 1 and 2 were conducted at 0 °C.^e N-Iodosuccinimide.^fIodine addition at −78 °C, then slowly allowed to warm to room temperature.^14gIn the dark.^hIrradiation with blue LED (40 W, 467 nm, rt, 8 h).ⁱRefluxing THF for step 3, reaction completed within 2 h.With the optimized reaction conditions in hand, we investigated the scope by first varying the R¹-substituent at the N-atom using the ketene 2a as the reaction partner (Scheme 2). In general, increasing the steric bulk at the nitrogen leads to diminished yields of the targeted oxindoles. The lower yields go along with the formation of a larger amount of the corresponding α,β-unsaturated amide side product 5. Thus, as compared to the parent N-methyl derivative, all other N-alkyl derivatives were formed in lower yields (49%, 3ab; 35%, 3ac; 49%, 3ad). The N-benzyl protected oxindole 3af and the N-phenyl oxindole 3ae were isolated in 54% and 56% yield, respectively. Next, a diastereoselective oxindole synthesis was attempted using chiral anilines 1g and 1h. Surprisingly, despite the bulkiness of these nucleophiles containing styryl-type N-substituents, good yields were obtained for the oxindoles 3ag and 3ah (73–79%). Unfortunately, diastereocontrol was low in both cases (1.9 : 1 d.r. and 1.5 : 1 d.r.). Of note, addition of Mg-1g and Mg-1h to ketene 2a was rather slow under the standard reaction condition and a significant amount of unreacted aniline was recovered. That problem could be solved by prolonging the reaction time of both step 1 (deprotonation) and also step 2 (Mg-enolate formation).Open in a separate windowScheme 2Substrate scope – variation of substituents at the nitrogen. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a For step 1 and 2 reaction time was 1 h.Next, the substrate scope was investigated by using different anilines in combination with the ketene 2a (Scheme 3). N-Methyl-p-toluidine 1i and N-methyl-p-haloanilines 1j–m could be successfully transformed to the corresponding oxindoles 3al–am in moderate to good yields (53–87%). Electron-withdrawing and also electron-donating substituents are tolerated and oxindoles derived from p-cyano- (3an, 92%), p-acetyl- (3ao, 30%), p-methoxycarbonyl- (3ap, 82%) and p-methoxy- (3aq, 71%) anilines were isolated in moderate to excellent yields documenting a high functional group tolerance of this reaction. The meta-methyl aniline afforded oxindole 3ar in 76% yield as a 1.8 : 1 mixture of the two regioisomers (only the major isomer drawn). For the pyridyl derivative 3as, a lower yield was obtained (39%), but reaction occurred with complete regiocontrol. Of note, ortho-methyl N-methylaniline provided the corresponding oxindole only in trace amounts (not shown).Open in a separate windowScheme 3Substrate Scope – variation of anilines and ketenes. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a Isolated as an inseparable mixture (1 : 1.4) with the protonated enolate 4fa (56% combined yield).The ketene component was also varied using N-methylaniline 1a as the reaction partner. The transformation of methyl phenyl ketene 2b provided the oxindole 3ba in 58% yield. p-Bromophenyl ethyl ketene 2c and p-iodophenyl ethyl ketene 2d afforded the oxindoles 3ca and 3da in good yields (70% and 76%). For the ibuprofene-derived ketene 2e a lower yield was obtained (3ea, 40%) and the bulkier phenyl isopropyl congener 3fa was isolated in 27% yield as an inseparable mixture with the protonated enolate 4fa (56% combined yield). In the latter case, increasing the reaction time did neither lead to a higher yield of 3fa nor to a suppression of the formation of 4fa. The lower yield is likely caused by steric effects. Surprisingly, diphenyl ketene 2g delivered the targeted oxindole 3ga in acceptable 55% yield despite the steric demand of the two phenyl groups and the high stability of the corresponding α-amide radical. Spirocyclic oxindoles are of great interest due to their high pharmaceutical potential.²⁷ We were pleased to find that our method also works for the preparation of such spiro compounds as documented by the successful synthesis of 3ha (26%).Mechanistically, we propose initial formation of the enolate A by nucleophilic attack of the deprotonated aniline to the ketene 2, which is then oxidized by elemental iodine to the α-amide radical B (pathway b). The radical nature of the transformation is supported by the fact that electronic effects on the arene show no influence on the efficiency of the cyclization, as would be shown by a conceivable polar aromatic substitution. Radical B readily cyclizes onto the aniline ring to generate the cyclohexadienyl radical D which is oxidatively rearomatized via cationic intermediate E to finally give the oxindole 3 (Scheme 4).^10–14 Alternatively, enolate A can be iodinated with I₂ to give the unstable iodide C which then undergoes C–I bond homolysis to generate the radical B (pathway a). Indeed, Taylor and coworkers¹⁴ observed under similar reaction conditions the decay of α-iodinated compounds of type Cvia C–I homolysis^14,28 to give radicals of type B. Usually, we observed α,β-unsaturated amides analogous to 5aa as by-products. However, the corresponding protonated enolates were detected only in tiny amounts in most of these cases. This strongly suggests that those amides are not formed via disproportionation of radical B. HI-elimination seems more likely, pointing towards the presence of the iodinated species C and thus the contribution of pathway b to product formation. In addition, dimerization of radical B was also not observed.Open in a separate windowScheme 4Suggested mechanism.To further support pathway b, isolation of the iodinated intermediate C was attempted at low temperature. Upon addition of iodine (1.2 equiv.) to the preformed Mg-enolate A derived from aniline 1a and ketene 2a at −78 °C,¹⁴ TLC analysis showed a clean conversion to a single new compound, which was analyzed by rapid ESI-MS analysis and provided evidence for the formation of the iodinated intermediate C (Scheme 5). However, isolation of this highly unstable compound was not possible due to rapid HI-elimination to the amide 5aa. Note that oxindole formation worked well upon I₂-addition at −78 °C and subsequent warming to room temperature (see Scheme 5). This is consistent with the observation from our optimization studies that irradiation with blue light does not contribute to the yield of oxindole 3aa (Open in a separate windowScheme 5Mechanistic experiments. (a) (1) EtMgBr (1.1 equiv.), rt, 30 min, (2) 2a (1.5 equiv.), −78 °C, 30 min, (3) I₂ (1.2 equiv.), −78 °C, 15 min in THF (0.01 M). (b) Warm to room temperature in THF (0.01 M), 18 h. (c) NaI (1.2 equiv.) in acetone (0.77 M), rt, 18 h. (d) Irradiation with blue LED (40 W, 467 nm) in THF (0.01 M), rt, 8 h.     

Pd/Cu-Catalyzed amide-enabled selectivity-reversed borocarbonylation of unactivated alkenes

The addition reaction between CuBpin and alkenes to give a terminal boron substituted intermediate is usually fast and facile. In this communication, a selectivity-reversed procedure has been designed and established. This selectivity-reversed borocarbonylation reaction is enabled by a cooperative action between palladium and copper catalysts and proceeds with complete regioselectivity. The key to the success of this transformation is the coordination of the amide group and slower CuBpin formation by using KHCO₃ as the base. A wide range of β-boryl ketones were produced from terminal unactivated aliphatic alkenes and aryl iodides. Further synthetic transformations of the obtained β-boryl ketones have been developed as well.

A selectivity-reversed borocarbonylation reaction has been developed with complete regioselectivity.

The catalytic borocarbonylation of alkenes represents a novel synthetic tool for the simultaneous installation of boron and carbonyl groups across alkenes, enabling rapid construction of molecules with high complexity from abundant alkenes. In particular, the obtained organoboron compounds are versatile synthetic intermediates that can be readily converted into a wide range of functional groups with complete stereospecificity.¹ Consequently, several catalytic systems have been developed to diversify the molecular frameworks through carbonylative borofunctionalization.² In general, carbonylative borofunctionalization of alkenes proceeds via an alkyl-copper intermediate, which was produced by the addition of CuBpin to the terminal position of the alkene starting material,³ followed by CO insertion and other related steps. A new C–B bond is formed at the terminal position of the alkene and a carbonyl group has been installed at the β-position simultaneously (Scheme 1a). However, in contrast to the progress in the borocarbonylation, a selectivity-reversed procedure (the boryl group is installed at the internal position) to give β-boryl ketone products is still unprecedented.Open in a separate windowScheme 1Strategies for borocarbonylation of activated alkenes.Recently, several attractive strategies have emerged for the borofunctionalization of unactivated alkenes to give β-boryl products.^4–7 In 2015, Fu, Xiao and their co-workers established a copper-catalyzed regiodivergent alkylboration of alkenes.^4a In the same year, Miura and Hirano''s group reported a copper-catalyzed aminoboration of terminal alkenes.^4b In these two attractive procedures, the regioselectivity was controlled by the ligand applied. More recently, an intermolecular 1,2-alkylborylation of alkenes was described by Ito''s research group.⁵ A radical-relay strategy was used to achieve the targeted regioselective addition. Furthermore, Engle and co-workers explored a palladium-catalyzed 1,2-carboboration and -silylation reaction of alkenes.⁶ Stereocontrol can be achieved in this new procedure with the assistance of a chiral auxiliary which is a coordinating group in this case.Inspired by these pioneering studies, we assumed that if the reaction could be initiated by the insertion of an acylpalladium complex into alkenes, followed by transmetalation with CuBpin before reductive elimination, β-boryl ketones can finally be produced (Scheme 1b). However, due to the inherent reactivity of the palladium species toward alkenes, olefin substrates were usually restricted to styrenes and a large excess of them is typically required (>6 equivalents).^8,9 Therefore, the critical part of the reaction design is to promote the reaction of the acylpalladium intermediate with alkenes faster than the insertion of CuBpin into olefins. One of the ideas is taking advantage of the coordinating group to transform the reaction from intermolecular to intramolecular. Among the developed directing groups,¹⁰ 8-aminoquinoline (AQ) is interesting and has been relatively well studied by various groups in a number of novel transformations.^11–13 Although the AQ directing group contains a NH group which can participate in intramolecular C–N bond formation,¹⁴ we believe that the selectivity-reversed borocarbonylation of alkenes can potentially be achieved through cooperative Pd/Cu catalysis. Then, valuable β-boryl ketones can be produced from readily available substrates directly and effectively.To test the viability of our design on selectivity-reversed borocarbonylation of alkenes, N-(quinolin-8-yl)pent-4-enamide (1a), iodobenzene (2a), and bis(pinacolato)diboron (B₂pin₂) were chosen as model substrates for systematic studies. As shown in 15 In the testing of palladium precursors, allylpalladium chloride dimer proved to be the best palladium catalyst for this reaction, affording 3a in 41% yield (†) and tend to generate the by-product β-aminoketone. Xantphos was found to be superior to the other tested bidentate ligands ( Entry[Pd]LigandCuBaseYield of 3a (%)1Pd(TFA)₂ L1 IMesCuClK₂CO₃292Pd(OAc)₂ L1 IMesCuClK₂CO₃343[Pd(η³-C₃H₅)Cl]₂ L1 IMesCuClK₂CO₃414[Pd(cinnamyl)Cl]₂ L1 IMesCuClK₂CO₃365[Pd(η³-C₃H₅)Cl]₂ L1 IPrCuClK₂CO₃06[Pd(η³-C₃H₅)Cl]₂ L1 CuClK₂CO₃337[Pd(η³-C₃H₅)Cl]₂ L1 CuBrK₂CO₃418[Pd(η³-C₃H₅)Cl]₂ L1 CuIK₂CO₃509[Pd(η³-C₃H₅)Cl]₂ L2 CuIK₂CO₃3810[Pd(η³-C₃H₅)Cl]₂ L3 CuIK₂CO₃4711[Pd(η³-C₃H₅)Cl]₂ L4 CuIK₂CO₃012[Pd(η³-C₃H₅)Cl]₂ L5 CuIK₂CO₃013[Pd(η³-C₃H₅)Cl]₂ L6 CuIK₂CO₃<214[Pd(η³-C₃H₅)Cl]₂ L7 CuIK₂CO₃1015[Pd(η³-C₃H₅)Cl]₂ L8 CuIK₂CO₃1216[Pd(η³-C₃H₅)Cl]₂ L1 CuIKHCO₃58 (51)^b17[Pd(η³-C₃H₅)Cl]₂ L1 CuIK₂HPO₄2618[Pd(η³-C₃H₅)Cl]₂ L1 CuINaHCO₃019[Pd(η³-C₃H₅)Cl]₂ L1 CuINaO^tBu1120^c[Pd(η³-C₃H₅)Cl]₂ L1 CuIKHCO₃<521[Pd(η³-C₃H₅)Cl]₂ L7 CuIKHCO₃40 Open in a separate window^aAll reactions were carried out on a 0.1 mmol scale with alkene (0.1 mmol) and aryl iodide (2.0 equiv.). Yields were determined by ¹H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard.^bIsolated yield.^cXantphos (10 mol%).With the optimized reaction conditions in hand, we examined the scope of this selectivity-reversed borocarbonylation with various unactivated alkenes and aryl iodides toward the synthesis of β-boryl ketones ( C bond even when there are two C C bonds in the amide substrates (4i and 4j). In addition, sterically hindered 4-pentenoic amide was subjected to the optimized reaction conditions, and the corresponding product was formed in 42% yield (4k). Furthermore, mono-substitution at the β-position of 4-pentenoic amides could also be employed, affording the corresponding products in moderate yields (4l and 4m). Iodoarenes containing more complex substrates such as L-menthol, L-borneol, vitamin E, diacetonfructose and nerol were also competent substrates and gave moderate to good yields of the corresponding products. Finally, no desired product could be detected when 3-butenoic amide, 2-vinylbenzamide or internal alkene was tested under our standard conditions.Substrate scope for the synthesis of β-boryl ketones^aOpen in a separate window^aAll reactions were carried out on a 0.1 mmol scale. Alkenes (0.1 mmol), aryl iodides (2.0 equiv.), B₂pin₂ (1.5 equiv.), CuI (10 mol%), [Pd(η³-C₃H₅)Cl]₂ (2.5 mol%), xantphos (5 mol%), KHCO₃ (2.0 equiv.), CO (10 bar), and DMSO (0.2 M) were stirred at 70 °C for 18 h. The dr value given was determined by ¹H NMR.To demonstrate the synthetic utilities of the obtained borocarbonylation products, a series of further synthetic transformations of the β-boryl ketones were performed (Scheme 2). From a practical point of view, the reaction can be easily performed on the gram-scale and gave the target product 3m in 67% yield. β-Hydroxyl ketone 6a (CCDC: 2079475;^† determined by X-ray crystallography and the ORTEP drawing with 50% thermal ellipsoids) was produced in 95% yield by oxidation of the parent β-boryl ketone 3a. Furthermore, the C–B bond can be easily converted into a C–N bond, affording β-aminoketone 6b in 60% yield. Upon the reduction reaction of 3m with NaBH₄, the corresponding reduced oxaborole amide 6c could be isolated in 70% yield. Finally, a two-step transamination process was performed to remove the AQ group.¹⁶Open in a separate windowScheme 2Diversification of β-boryl ketones.To gain some insight into the mechanism of this selectivity-reversed borocarbonylation of alkenes, several control experiments were performed. The target product 3a was not formed, instead byproduct 6b was obtained in 40% yield, in the case without xantphos. Possible explanations for this result are: (i) the bidentate directing group AQ increases the stability of Pd(ii) species and promotes the carbonylation step; (ii) the role of xantphos is to coordinate to C(sp³)–Pd(ii) species after its formation and inhibit the formation of the C–N bond to give byproduct 6b (Scheme 3a). In addition, copper and B₂pin₂ were proven to be important, and KHCO₃ was essential for the carbonylation step (Scheme 3b). Analysis of the copper system in the absence of palladium and iodobenzene revealed that alkenes failed to undergo CuBpin insertion under this condition and no hydroboration products could be detected after work-up (Scheme 3c). Additionally, alkenes without the directing group were also tested under our standard conditions, and no reaction occurred.Open in a separate windowScheme 3Control experiments.Although we did not observe compound 7a during our optimization and substrate scope processes, even after stopping the reaction after 8 hours, we tested the possibility that 7a might act as an intermediate. When 7a was subjected to this transformation, the product 3a was delivered in 24% yield and 6b was generated in 37% (Scheme 3d). No significant difference in the yield outcome was observed when xantphos was added. Additionally, in our deuterated substrate testing, the amount of the deuterated product obtained is lower than the theoretical value (Scheme 3e). Thus, a pathway of β-H elimination followed by hydroboration could be involved as well. However, we believe the direct reaction between palladium and copper intermediates is the main one for this procedure due to the proven importance of the AQ group and the known achievements of copper-catalyzed hydroboration of enones, even with enantioselective versions.¹⁷On the basis of the above results and related literature studies,^7,11–14 a possible reaction pathway is proposed (Scheme 4). Initially, the AQ directing group coordinates with Pd⁰, which produces the active AQ-Pd⁰ catalyst I. This is followed by oxidative addition to aryl iodides to generate Pd^II species II, and then by base promoted iodine dissociation to form complex III. After the CO insertion step, the acyl-Pd^II species IV coordinates with the alkene and undergoes migratory insertion to generate C(sp³)–Pd^II intermediate V, which is stabilized by the xantphos ligand and AQ directing group. Subsequently, C(sp³)–Pd^II complex V reacts especially with CuBpin to give the desired product β-boryl ketone and regenerate the Pd(0) complex. Finally, ligand exchange of Pd⁰Ln regenerates AQ-Pd⁰I for the next catalytic cycle. Additionally, another minor pathway that involves the carbonylative Heck reaction to give an enone derivative, followed by its hydroboration to give the final product could be included as well.Open in a separate windowScheme 4Proposed catalytic cycle.In summary, a novel Pd/Cu catalyzed amide-directed selectivity-reversed borocarbonylation for the selective synthesis of β-boryl ketones from terminal alkenes has been developed. Various aryl iodides and aliphatic alkenes were transformed into the desired β-boryl ketones in moderate to excellent yields. In this catalyst system, the assistance from the AQ directing group is essential for successful reaction design.     

Organocatalytic discrimination of non-directing aryl and heteroaryl groups: enantioselective synthesis of bioactive indole-containing triarylmethanes

Despite the enormous developments in asymmetric catalysis, the basis for asymmetric induction is largely limited to the spatial interaction between the substrate and catalyst. Consequently, asymmetric discrimination between two sterically similar groups remains a challenge. This is particularly formidable for enantiodifferentiation between two aryl groups without a directing group or electronic manipulation. Here we address this challenge by using a robust organocatalytic system leading to excellent enantioselection between aryl and heteroaryl groups. With versatile 2-indole imine methide as the platform, an excellent combination of a superb chiral phosphoric acid and the optimal hydride source provided efficient access to a range of highly enantioenriched indole-containing triarylmethanes. Control experiments and kinetic studies provided important insights into the mechanism. DFT calculations also indicated that while hydrogen bonding is important for activation, the key interaction for discrimination of the two aryl groups is mainly π–π stacking. Preliminary biological studies also demonstrated the great potential of these triarylmethanes for anticancer and antiviral drug development.

Excellent enantiodiscrimination between aryl and heteroaryl groups without a directing group has been achieved with organocatalysis. The highly enantioenriched triarylmethane products exhibit anticancer and antiviral activities.

Asymmetric catalysis has evolved arguably into the most powerful method for the synthesis of enantioenriched molecules.¹ It features high efficiency and atom-economy in principle as compared to other approaches such as chiral resolution and auxiliary-based asymmetric synthesis, thereby enabling increasing applications in industrial synthesis.² In the past few decades, a wide range of chiral catalytic systems with diverse activation modes have been developed. However, the fundamental basis for enantiocontrol remains essentially unchanged, i.e., spatial interaction between the substrate and catalyst.^1,2 For example, in the construction of a tetrahedral C(sp³)-chiral center from a prochiral C(sp²)-based planar substrate (e.g., carbocation, radical, carbonyl, and olefin), a chiral catalyst typically provides enantiodifferentiation by blocking one face of the plane and directing the reaction partner (Y) to approach towards the other face (Scheme 1a). To achieve this, the catalyst must be able to effectively discriminate between the two substituents (R¹ and R²) on the prochiral carbon. Obviously, the larger the difference of these two substituents is, the better enantioselectivity will be expected. Consequently, it has been well-established to achieve high enantioselectivity for cases bearing two sterically different groups (e.g., alkyl/aryl vs. H and large alkyl vs. small alkyl). In contrast, for cases bearing two substituents of a similar size, it remains challenging.¹Open in a separate windowScheme 1Introduction to asymmetric differentiation in C(sp²)-prochiral centers.1,1-Diarylmethinyl stereocenters are a widely prevalent structural motif in various natural products and biologically important molecules.³ Asymmetric addition to the 1,1-diaryl C C and C = X (X = heteroatom) bonds represents one of the most direct approaches for the construction of this unit.^4–8 However, this requires effective discrimination between two (often) sterically similar aryl groups, which represents a notable challenge in asymmetric catalysis (Scheme 1b).⁴ So far, success has mainly relied on the use of a directing group in one aryl group to allow catalyst recognition (e.g., by coordination) or electronic difference by incorporating electron-donating/withdrawing groups.^6,7 Notably, the effective enantiodifferentiation between aryl and heteroaryl groups still remains challenging, particularly in the absence of a directing group.⁸ Moreover, despite the above-mentioned important progress, it is worth noting that almost all these examples relied on metal catalysis, and little success has been achieved by organocatalysis.^4–8 In this context, here we describe organocatalytic discrimination of non-directing aryl and heteroaryl groups, providing access to highly enantioenriched triarylmethanes, and in view of the general diverse biological activities of triarylmethanes,⁹ we have also investigated the anticancer and antiviral activities of these products.Indole imine methides (IIMs) have recently emerged as versatile intermediates for the asymmetric synthesis of enantioenriched indole derivatives, a family of useful units in medicinal chemistry.^10–12 In particular, those with the methide motif adorned in the 2-position of indole are particularly useful to construct indole-fused polyheterocycles via asymmetric annulation processes, as pioneered by Shi and co-workers.^10,11 In continuation of our interest in IIMs,¹² we envisioned that these types of intermediates would be a good platform to study the power of organocatalysis for the challenging discrimination between aryl and heteroaryl groups lacking a directing group (Scheme 1c). However, additional challenges should be expected since this intermediate II is likely generated as a Z/E mixture, typically in equilibrium with carbocation I. Therefore, the equilibrium should be made in synergy with the nucleophilic addition step to allow dynamic asymmetric control in order to achieve high enantioselectivity.To test our hypothesis, we employed racemic tertiary alcohol 1a as the model precursor to the 2-indole imine methide intermediate. Notably, no directing group is incorporated in the two aryl groups (phenyl and thienyl) to be discriminated by the catalyst. Despite the above-mentioned substantial challenges in this asymmetric control, considerable efforts were devoted to condition optimization and ultimately led to excellent reaction efficiency and enantiocontrol (13 With benzothiazoline 2a as the hydride source,¹⁴ the asymmetric reduction proceeded smoothly to form indole-containing triarylmethane 3a under mild conditions in essentially quantitative yield and 95% ee (entry 1, 15 gave drastically low enantiocontrol (entry 8). Other solvents did not provide a better result either (entries 9–11). The reaction was very sensitive to coordinating solvents, such as ether and ethyl acetate, which completely shut down the reaction, presumably due to competing binding with the acid catalyst. Decreasing the reaction temperature to 0 °C maintained high enantioselectivity, but moderately affected the reaction rate (entry 12). Finally, at a higher concentration, slightly lower enantioselectivity was observed (entry 13).Evaluation of the reaction conditions^a

Illuminating anti-hydrozirconation: controlled geometric isomerization of an organometallic species

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm. Mechanistic delineation of the contra-thermodynamic isomerization step indicates that a minor reaction product functions as an efficient in situ generated photocatalyst. Coupling of the E-vinyl zirconium species with an alkyne unit generates a conjugated diene: this has been leveraged as a selective energy transfer catalyst to enable E → Z isomerization of an organometallic species. Through an Umpolung metal–halogen exchange process (Cl, Br, I), synthetically useful vinyl halides can be generated (up to Z : E = 90 : 10). This enabling platform provides a strategy to access nucleophilic and electrophilic alkene fragments in both geometric forms from simple arylacetylenes.

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm.

The venerable Schwartz reagent (Cp₂ZrHCl) is totemic in the field of hydrometallation,¹ where reactivity is dominated by syn-selective M–H addition across the π-bond.^2,3 This mechanistic foundation can be leveraged to generate well-defined organometallic coupling partners that are amenable to stereospecific functionalization. Utilizing terminal alkynes as readily available precursors,⁴ hydrozirconation constitutes a powerful strategy to generate E-configured vinyl nucleophiles that, through metal–halogen exchange, can be converted to vinyl electrophiles in a formal Umpolung process.⁵ Whilst this provides a versatile platform to access the electronic antipodes of the E-isomer, the mechanistic course of addition renders access to the corresponding Z-isomer conspicuously challenging. To reconcile the synthetic importance of this transformation with the intrinsic challenges associated with anti-hydrometallation and metallometallation,⁶ it was envisaged that a platform to facilitate geometric isomerization⁷ would be of value. Moreover, coupling this to a metal–halogen exchange would provide a simple Umpolung matrix to access both stereo-isomers from a common alkyne precursor (Fig. 1).Open in a separate windowFig. 1The stereochemical course of alkyne hydrometallation using the Schwartz reagent and an Umpolung platform to generate both stereo-isomers from a common alkyne precursor.Confidence in this conceptual blueprint stemmed from a report by Erker and co-workers, in which irradiating the vinyl zirconium species derived from phenyl acetylene (0.5 M in benzene) with a mercury lamp (Philips HPK 125 and Pyrex filter) induced geometric isomerization.⁸ Whilst Hg lamps present challenges in terms of safety, temperature regulation, cost and wavelength specificity, advances in LED technology mitigate all of these points. Therefore, a process of reaction development was initiated to generalize the anti-hydrozirconation of arylacetylenes. Crucial to the success of this venture was identifying the light-based activation mode that facilitates alkene isomerization. Specifically, it was necessary to determine whether this process was enabled by direct irradiation of the vinyl zirconium species, or if the E → Z directionality results from a subsequent selective energy transfer process involving a facilitator. Several accounts of the incipient vinyl zirconium species reacting with a second alkyne unit to generate a conjugated diene have been disclosed.^9,10 It was therefore posited that the minor by-product diene may be a crucial determinant in driving this isomerization (Fig. 2).Open in a separate windowFig. 2A working hypothesis for the light-mediated anti-hydrozirconation via selective energy transfer catalysis.To advance this working hypothesis and generalize the formal anti-hydrozirconation process, the reaction of Cp₂ZrHCl with 1-bromo-4-ethynylbenzene (A-1) in CH₂Cl₂ was investigated (‡ for full details). This generates a versatile electrophile for downstream synthetic applications. Gratifyingly, after only 15 minutes, a Z : E-composition of 50 : 50 was reached (entry 1) and, following treatment with NBS, the desired vinyl bromide (Z)-1 was obtained in 76% yield (isomeric mixture) over the two steps. Further increasing the irradiation by 15 minute increments (entries 2–4) revealed that the optimum reaction time for the isomerization is 45 minutes (74%, Z : E = 73 : 27, entry 3). Extending the reaction time to 60 minutes (entry 4, 54%) did not lead to an improvement in selectivity and this was further confirmed by irradiating the reaction mixture for 90 minutes (entry 5). In both cases, a notable drop in yield was observed and therefore the remainder of the study was performed using the conditions described in entry 3. Next, the influence of the irradiation wavelength on the isomerization process was examined (entries 6–11). From a starting wavelength of λ = 369 nm, which gave a Z : E-ratio of 27 : 73 (entry 6), a steady improvement was observed by increasing the wavelength to λ = 374 nm (Z : E = 44 : 56, entry 7) and λ = 383 nm (Z : E = 53 : 47, entry 8). The selectivity reached a plateau at λ = 400 nm, with higher wavelengths proving to be detrimental (Z : E = 60 : 40 at λ = 414 nm, entry 9; Z : E = 26 : 74 at λ = 435 nm, entry 10). It is interesting to note that at λ = 520 nm, Z-1 was not detected by ¹H NMR (entry 11).Reaction optimization^a

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a