Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

C(sp3)–H oxygenation via alkoxypalladium(ii) species: an update for the mechanism

Pd-catalyzed C(sp³)–H oxygenation has emerged as an attractive strategy for organic synthesis. The most commonly proposed mechanism involves C(sp³)–H activation followed by oxidative addition of an oxygen electrophile to give an alkylpalladium(iv) species and further C(sp³)–O reductive elimination. In the present study of γ-C(sp³)–H acyloxylation of amine derivatives, we show a different mechanism when tert-butyl hydroperoxide (TBHP) is used as an oxidant—namely, a bimetallic oxidative addition-oxo-insertion process. This catalytic model results in an alkoxypalladium(ii) intermediate from which acyloxylation and alkoxylation products are formed. Experimental and computational studies, including isolation of the putative post-oxo-insertion alkoxypalladium(ii) intermediates, support this mechanistic model. Density functional theory reveals that the classical alkylpalladium(iv) oxidative addition pathway is higher in energy than the bimetallic oxo-insertion pathway. Further kinetic studies revealed second-order dependence on [Pd] and first-order on [TBHP], which is consistent with DFT analysis. This procedure is compatible with a wide range of acids and alcohols for γ-C(sp³)–H oxygenation. Preliminary functional group transformations of the products underscore the great potential of this protocol for structural manipulation.

Alkoxypalladium(ii) species lead to γ-C(sp³)–H acyloxylation and alkoxylation products using tert-butyl hydroperoxide as the oxidant.     

Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Electrochemically selective double C(sp2)–X (X = S/Se,N) bond formation of isocyanides

The construction of C(sp²)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn growing attention since heteroatomic compounds play a prominent role from biological to pharmaceutical sciences. The current study demonstrates the C(sp²)–S/Se and C(sp²)–N bond formation of one carbon of isocyanides with thiophenols or disulfides or diselenides and azazoles simultaneously. The reported findings could provide access to novel multiple isothioureas, especially hitherto rarely reported selenoureas. The protocol showed good atom-economy and step-economy with only hydrogen evolution and theoretical calculations accounted for the stereoselectivity of the products. Importantly, the electrochemical reaction could exclusively occur at the isocyano part regardless of the presence of susceptible radical acceptors, such as a broad range of arenes and alkynyl moieties, even alkenyl moieties.

We have developed an efficient and sustainable electrochemical strategy for the double C(sp²)–X (S/Se, N) bond formation of isocyanides simultaneously. A series of novel isothio/selenoureas were obtained via a three-component cross-coupling.

The construction of C(sp²)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn increased attention from researchers since heteroatomic compounds play a prominent role in various fields.¹ Traditionally, the transition-metal-catalyzed cross-coupling of a nucleophile and an electrophile is an important method for the formation of C(sp²)–X bonds.² Obviously, the direct cross-coupling of C(sp²)–H/X–H is a time-, effort-, and resource-economical process to construct C(sp²)–X bonds as it avoids the pre-functionalization of substrates.³ Alternatively, radical chemistry provides greener and more mild strategies for the formation of C(sp²)–X bonds, and a variety of high added-value compounds can be afforded successfully.⁴ Despite the numerous advances, these reported reactions are limited as they involve only single C(sp²)–X bond formation. Access to double C(sp²)–X bonds formation of one carbon remains still a room for improvement stimultaneously.As an ideal connector, isocyanides could be inserted into metal–carbon and metal–heteroatom bonds to construct double C(sp²)–X bonds.⁵ On the other hand, isocyanides could transform into heteroatomic molecules with electrophiles, nucleophiles and radicals.⁶ Although many elegant studies have been reported, the above methods are largely limited by the pre-functionalization of the substrate, the toxicity of metals or tedious synthesis steps. From the point of synthetic efficiency and economy, exploiting a novel, efficient, and diverse radical strategy to access double C(sp²)–X bonds under mild conditions and with broad functional group tolerance is of paramount importance and in urgent demand.Radical transformation processes are ubiquitous throughout synthesis chemistry and provide new ideas for forging new bonds and novel molecules, especially valuable product motifs.⁷ As a complementary strategy to conventional radical-based reactions, electrochemistry, effectively transferring electrons from the electrode surface to the substance, has been developed into a powerful synthetic technique toward radical chemistry.⁸ This electrochemical strategy further stimulated a resurgence of interest in radical chemistry with good atom-economy and step-economy.⁹ Myriad electrochemical-induced radical reactions have been reported via single-electron oxidation/reduction with a plethora of radicals and radical acceptors. As reported, alkenes, alkynes, and cyano and aromatic compounds could be considered to be favorable radical acceptors in diverse transformations, such as cross-coupling, cyclization and difunctionalization reactions.¹⁰ However, the application of isocyanides as radical acceptors is limited in utility due to electrochemical tandem cyclization.¹¹ Therefore, on the basis of our research on electrochemical oxidative functionalization of isocyanides,¹² we continued to explore the properties of isocyanides as radical acceptors under electrochemical conditions.Initially, we commenced our investigations by using abundant and inexpensive phenyl disulfide (1), ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as model substrates in a single operation via a three-component cross-coupling. After systematic optimization, the isothiourea 21 could been obtained in 90% isolated yield. To gain insights into the reaction process, we continued to carry out a series of control experiments as shown in Scheme 1. The control experiment demonstrated that electricity is indispensable. Under standard conditions, addition of 2.0 equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) showed no traces of product. Similarly, the reaction was suppressed in the presence of butylated hydroxytoluene (BHT). The P(OEt)₃-trapping product could be detected by gas chromatography mass spectrometry (GCMS). Simultaneously, a S-centred radical signal (g = 2.0070, AN = 13.40 G, AH = 14.88 G) was quickly trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) via electron paramagnetic resonance (EPR) experiments. The reported results revealed that this reaction might proceed via S-radical pathways.Open in a separate windowScheme 1Control experiments.For deeper research of the priority of interaction for isocyanides vs. other radical acceptors with radicals, we sought to conduct robustness screening of a wide range of radical acceptors as shown in Scheme 2.¹³ The addition of an aryl olefin led to the complete shutdown of product formation (21) and the products of difunctionalization of alkenes were also not detected. To our delight, the alkenyl moiety did not affect the reaction efficiency under the electrochemical conditions. Unlike the aryl olefin, the addition of phenylacetylene did not inhibit product formation (21), delivering a yield of 93%. Similarly, ethyl 2-isocyanoacetate could be transformed into product (21) smoothly with 1-heptyne. The addition of mesitylene preserved the yield, while the yield decreased slightly with anisole. With the addition of furan and thiophene, an excellent yield of product (21) could still be obtained. Beside electron-donating arenes, we continued to add electron-withdrawing arenes to the reaction system. As expected, a satisfactory yield was obtained with 4-cyanopyridine. The results revealed that the electrochemical reaction exclusively occurred at the isocyano part regardless of the presence of electron-withdrawing arenes, electron-donating arenes and the alkynyl moiety, even the alkenyl moiety, which are also susceptible to radical conditions.Open in a separate windowScheme 2Competitive experiments of isocyanides vs. other radical acceptors with radicals. Conditions: 1 (0.15 mmol), 2 (0.6 mmol), 3 (0.5 mmol), R. A. = radical acceptors (0.6 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. ¹HNMR yield, dibromomethane as an internal standard.In order to further investigate the compatibility, we firstly examined the substrate scope of alkyl disulfides for the synthesis of isothioureas with ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as shown in Scheme 3. To our delight, the yields did not decrease significantly with the increase of the carbon chain from methyl to decyl in this transformation (4–7). Isopropyl, isobutyl, cyclopentyl and cyclohexyl were well tolerated with good to excellent yields (8–11). Substances, containing sensitive benzylic C–H bonds, were tolerated to access novel isothioureas in this electrochemical induced-radical process (12–14, 34). Afterwards, we continued to explore the applicability from alkyl disulfides to thiophenol and a series of molecule isothioureas were obtained successfully with satisfactory yield. Thiophenol, containing electron-neutral (F, Cl, Br, H), electron-withdrawing (OCF₃, CF₃, and CO₂Me) and electron-donating (Me, Et, ^tBu, OMe, and SMe) groups, could smoothly transform to realize this process with high stereoselectivity under mild conditions (15–26). The structure of Z-conformer (16) was confirmed by X-ray crystallographic analysis. In addition, this protocol was successfully applied to thiophenols bearing diverse groups at different positions with good yields, indicating that steric hindrance has no obvious effect (20, 27–31). With curiosity, we tried to evaluate the tolerance of diselenides to construct novel Se–C–N bonds simultaneously. Unexpectedly, regardless of alkyl diselenides (32–33), benzyl diselenide (34) or aryl diselenide (35), all were well tolerated under electrochemical conditions, providing a series of unprecedented isoselenoureas, which were inaccessible by conventional methods. The compatibility of sensitive functional groups provides an opportunity for further molecular modification. The sensitive functional architectures including but not limited to ester (36), benzyloxy (37), allyl and allyloxy as well as endene (38, 41–44), labile alkyl chloride (39) and alkyl bromide (40), propargyl (44), and thiophene (45), all remained intact, enriching the diversity of heteroatom compounds. The merit of this methodology was further demonstrated by elaboration of a wide gamut of functional molecules and drug molecules to diverse isothioureas. Natural products including l-menthol and geraniol (46–47), food additives including isopulegol and furfuryl alcohol (48–49), and pharmaceuticals including ibuprofen (50) were apt to give rise to the corresponding isothioureas in 50–78% yields.Open in a separate windowScheme 3Scope of thiophenols/disulfides/diselenides. Conditions: ^a disulfides/diselenides (0.15 mmol) or ^b thiophenols (0.3 mmol), isocyanides (0.6 mmol), 1H-benzotriazole (0.5 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. Isolated yield.After defining the scope of thiophenols and disulfides, we turned our attention to explore the substrate scope with respect to nucleophiles in Scheme 4. Benzotriazole, with mono-substitution or multi-substitution, could be efficiently converted to the corresponding skeletons in 55–75% yields (51–54). Under standard conditions, pyrazole also showed great reactivity with phenyl disulfide or ethyl disulfide (55–56). The introduction of a halogen group in pyrazolylcycle, especially a subtle C–I bond, was compatible with satisfactory results (57–59, 64–65). 4-Methyl-1H-pyrazole as a coupling partner also realized the aminosulfenylation of isocyanide, albeit less efficiently (62). Of note is that the yield was increased to 70% from 40% by replacing methyl with phenyl (63). In addition to benzotriazole and pyrazole derivatives, other triazoles and tetrazole were proved to be viable coupling partners as well, enabling access to the target products in synthetically useful yields (66–70). Subsequently, with this established-optimized condition, we set out to investigate substrates for isocyanide coupling partners. With methyl isocyanoacetate (71), a similar effect was observed in an electrochemical difunctionalization reaction. As expected, both tosylmethyl isocyanide and benzyl isocyanide were demonstrated to be competent substrates (72–73). Cyclohexyl isocyanide, as a representative of secondary isocyanides, converted into the corresponding product (74). Gratifyingly, isocyanides, regardless of the steric effect, could engage with thiophenols to give the corresponding adducts in good yields (75–76). Aryl isocyanides however afforded the desired products in low yields under standard reaction conditions (77–78).Open in a separate windowScheme 4Scope of azazoles. Conditions: ^a disulfides/diselenides (0.15 mmol) or ^b thiophenols (0.3 mmol), isocyanides (0.6 mmol), azazoles (0.5 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. Isolated yield.To evaluate the feasibility of this electrochemical protocol, we monitored the reaction on a 4.5 mmol scale as shown in Scheme 5. Under similar conditions, by prolonging the reaction time to 34 h, a good isolated yield of 72% was obtained, which provided an opportunity for further synthetic manipulations.Open in a separate windowScheme 5Gram-scale synthesis.In order to account for the stereoselectivity of products, theoretical calculations were performed. The result demonstrated that the free energy of the Z-conformer of the product 16 is 2.3 kcal mol⁻¹ smaller than that of the E-conformer.Based on a previously reported mechanistic study¹⁴ and these above observations, a synthetically possible mechanism for the electrochemical intermolecular difunctionalization reaction is depicted in Scheme 6. A sulfur radical was formed via single-electron-transfer (SET) reduction of the disulfide or SET oxidation of the thiophenol. Subsequently, the exclusive capture of the S-radical by the isocyano part yields the imine C-radical I. Further SET oxidation of this radical intermediate to the corresponding imine carbocation II, followed by nucleophilic trapping intermolecularly, affords the final isothioureas.Open in a separate windowScheme 6Proposed reaction mechanism.     

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

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

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

Allylic C(sp3)–H alkylation via synergistic organo- and photoredox catalyzed radical addition to imines

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described. The transformation achieves an efficient, redox-neutral synthesis of homoallylamines with broad functional group tolerance, under very mild reaction conditions. Mechanistic investigations indicate that the reaction proceeds through the N-centered radical intermediate which is generated by the allylic radical addition to the imine.

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Deaminative meta-C–H alkylation by ruthenium(ii) catalysis

Precise structural modifications of amino acids are of importance to tune biological properties or modify therapeutical capabilities relevant to drug discovery. Herein, we report a ruthenium-catalyzed meta-C–H deaminative alkylation with easily accessible amino acid-derived Katritzky pyridinium salts. Likewise, remote C–H benzylations were accomplished with high levels of chemoselectivity and remarkable functional group tolerance. The meta-C–H activation approach combined with our deaminative strategy represents a rare example of selectively converting C(sp³)–N bonds into C(sp³)–C(sp²) bonds.

Precise structural modifications of amino acids are of importance to tune biological properties or modify therapeutical capabilities relevant to drug discovery.     

Triarylamine-based porous coordination polymers performing both hydrogen atom transfer and photoredox catalysis for regioselective α-amino C(sp3)–H arylation

Direct functionalization of C(sp³)–H bonds in a predictable, selective and recyclable manner has become a central challenge in modern organic chemistry. Through incorporating different triarylamine-containing ligands into one coordination polymer, we present herein a heterogeneous approach to the combination of hydrogen atom transfer (HAT) and photoredox catalysis for regioselective C–H arylation of benzylamines. The different molecular sizes and coordination modes of the ligands, tricarboxytriphenylamine (H₃TCA) and tris(4-(pyridinyl)phenyl)amine (NPy3), in one coordination polymer consolidate the triarylamine (Ar₃N) moiety into a special structural intermediate, which enhances the chemical and thermal stability of the polymers and diminishes structural relaxation during the catalytic process. The inherent redox potentials of Ar₃N moieties prohibit the in situ formed Ar₃N˙⁺ to earn an electron from C(sp³)–H nucleophiles, but allow the abstraction of a hydrogen atom from C(sp³)–H nucleophiles, enabling the formation of the C(sp³)˙ radical and the cross-coupling reaction to proceed at the most electron-rich sites with excellent regioselectivity. The new heterogeneous photoredox HAT approach skips several interactions between transient species during the typical synergistic SET/HAT cycles, demonstrating a promising redox-economical and reagent-economical heterogeneous platform that has not been reported for α-amino C–H arylation to form benzylamine derivatives. Control experiments based on monoligand coordination polymers suggested that the mixed-ligand approach improved the photochemical and photophysical properties, providing important insight into rational design and optimization of recyclable photocatalysts for rapid access to complex bioactive molecules and late-stage functionalized pharmaceuticals.

The efficiency of photosensitization and hydrogen atom transfer (HAT) catalysis is balanced in a recyclable heterogeneous manner by the modification of the N-central conformation in Cd-MIX.     

Peptide late-stage C(sp3)–H arylation by native asparagine assistance without exogenous directing groups

There is a strong demand for novel native peptide motifs for post-synthetic modifications of peptides without pre-installation and subsequent removal of directing groups. Herein, we report an efficient method for peptide late-stage C(sp³)–H arylations assisted by the unmodified side chain of asparagine (Asn) without any exogenous directing group. Thereby, site-selective arylations of C(sp³)–H bonds at the N-terminus of di-, tri-, and tetrapeptides have been achieved. Likewise, we have constructed a key building block for accessing agouti-related protein (AGRP) active loop analogues in a concise manner.

An efficient method for peptide late-stage C(sp³)-H arylations assisted by unmodified side chain of asparagine (Asn) without any exogenous directing group has been reported.     

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Suzuki-type cross-coupling of alkyl trifluoroborates with acid fluoride enabled by NHC/photoredox dual catalysis

The Suzuki–Miyaura cross-coupling of C(sp³)-hybridised boronic compounds still remains a challenging task, thereby hindering the broad application of alkyl boron substrates in carbon–carbon bond-forming reactions. Herein, we developed an NHC/photoredox dual catalytic cross-coupling of alkyl trifluoroborates with acid fluorides, providing an alternative solution to the classical acylative Suzuki coupling chemistry. With this protocol, various ketones could be rapidly synthesised from readily available materials under mild conditions. Preliminary mechanistic studies shed light on the unique radical reaction mechanism.

An acylative Suzuki-type cross-coupling of alkyl trifluoroborates and acid fluorides was developed by merging NHC organocatalysis with photoredox catalysis. A broad spectrum of ketones could be facilely synthesised under mild reaction conditions.     

Benzylic C(sp3)–C(sp2) cross-coupling of indoles enabled by oxidative radical generation and nickel catalysis

A mechanistically unique functionalization strategy for a benzylic C(sp³)–H bond has been developed based on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical generation at the benzylic position of the substrate, with subsequent transition metal catalysis to complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp²)-based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer (HAT) processes, which are frequently encountered in conventional methods, are not involved in the product formation process of the developed strategy.

A mechanistically distinct Ni-catalysed benzylic functionalization of indoles is developed by the facile oxidation of arenes. The method exhibits a wide substrate scope and pronounced chemoselectivity that cannot be accessed via known protocols.     

Diverse strategies for transition metal catalyzed distal C(sp3)–H functionalizations

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field. Despite severe challenges, distal C–H functionalizations of aliphatic molecules by overriding proximal positions have witnessed tremendous progress. While usage of stoichiometric directing groups played a crucial role, reactions with catalytic transient directing groups or methods without any directing groups are gaining more attention due to their practicality. Various innovative strategies, slowly but steadily, circumvented issues related to remote functionalizations of aliphatic molecules. A systematic compilation has been presented here to provide insights into the recent developments and future challenges in the field. The Present perspective is expected to open up a new dimension and provide an avenue for deep insights into the distal C(sp³)–H functionalizations that could be applied routinely in various pharmaceutical and agrochemical industries.

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field.     

Iron-catalyzed remote functionalization of inert C(sp3)–H bonds of alkenes via 1,n-hydrogen-atom-transfer by C-centered radical relay

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp³ C-centered radical to promote selective cleavage of inert C(sp³)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF₃-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Remote functionalization of inert C(sp³)–H bonds is described via iron-catalyzed sp³ C-centered radical relay.     

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters

Herein we describe the first construction of fluorinated tertiary stereocenters based on an alkene C(sp²)–C(sp²) bond cleavage. The new process, that takes advantage of a Rh-catalyzed carbyne transfer, relies on a branched-selective fluorination of tertiary allyl cations and is distinguished by a wide scope including natural products and drug molecule derivatives as well as adaptability to radiofluorination.

We report a previously unknown disconnection approach to valuable fluorinated tertiary stereocenters based on the skeletal modification of 1,1-disubstituted alkenes by a Rh-catalyzed carbyne transfer.     

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)–C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal–organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Using a high-temperature ball-milling technique, a practical mechanochemical protocol for the Sonogashira cross-coupling of polyaromatic halides was achieved, which provides efficient access to materials-oriented aromatic alkynes.     

Modular synthesis of unsymmetrical [1]benzothieno[3,2-b][1]benzothiophene molecular semiconductors for organic transistors

A modular approach to underexplored, unsymmetrical [1]benzothieno[3,2-b][1]benzothiophene (BTBT) scaffolds delivers a library of BTBT materials from readily available coupling partners by combining a transition-metal free Pummerer CH–CH-type cross-coupling and a Newman–Kwart reaction. This effective approach to unsymmetrical BTBT materials has allowed their properties to be studied. In particular, tuning the functional groups on the BTBT scaffold allows the solid-state assembly and molecular orbital energy levels to be modulated. Investigation of the charge transport properties of BTBT-containing small-molecule:polymer blends revealed the importance of molecular ordering during phase segregation and matching the highest occupied molecular orbital energy level with that of the semiconducting polymer binder, polyindacenodithiophene-benzothiadiazole (PIDTBT). The hole mobilities extracted from transistors fabricated using blends of PIDTBT with phenyl or methoxy functionalized unsymmetrical BTBTs were double those measured for devices fabricated using pristine PIDTBT. This study underscores the value of the synthetic methodology in providing a platform from which to study structure–property relationships in an underrepresented family of unsymmetrical BTBT molecular semiconductors.

A modular approach to underexplored, unsymmetrical [1]benzothieno[3,2-b][1]benzothiophene (BTBT) scaffolds, combining a transition-metal free Pummerer CH–CH-type cross-coupling and a Newman–Kwart reaction, delivers a library of BTBT materials.     

Inhibition of (dppf)nickel-catalysed Suzuki–Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki–Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki–Miyaura cross-coupling reactions. However, the corresponding Kumada–Tamao–Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Nickel complexes with a dppf ligand can form inactive dinickel(ii) complexes during Suzuki–Miyaura cross-coupling reactions. However, these complexes can react with Grignard reagents in Kumada–Tamao–Corriu cross-coupling reactions.     

Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp³)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp³)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp³)–H functionalization.

The photoinduced C–H sulfination of abundant aliphatic C–H bonds provides direct access to all major classes of organosulfur compounds via the intermediacy of synthetically versatile sulfinate salts.