Concerted nucleophilic substitution, known as SN2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon-carbon and carbon-heteroatom bonds1. SN2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp3)-X bond (X= halogen or other leaving group), resulting in complete inversion of a stereocenter 2. In contrast, the corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp2 vinyl electrophiles, namely concerted SNV(σ) reaction, is much rarer and so far, limited to carefully designed substrates mostly in ring-forming processes3,4. Here we show that concerted SNV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates. This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise. Further application to the synthesis of bioactive compounds containing multi-substituted alkenes is also demonstrated. Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction.
Since the discovery of the palladium/norbornene (Pd/NBE)-catalyzed ortho amination in 2013, escaping the limitation of only yielding tertiary anilines has been a long-standing challenge. Here, we describe that, by carefully choosing the phosphine ligand and NBE mediator, the installation of a N-mono-alkylamino group becomes feasible. The reaction tolerates a wide range of aryl iodide substrates and various N-mono-tertiary alkylamine-derived electrophiles. Both ipso alkenylation and alkynylation can be realized. The synthetic utility of this method is exemplified by the formation of primary amino group via selective deprotection and streamlined access to N-heterocycles. Preliminary success of installing a bulky N-secondary alkylamino group and a mechanistic understanding of the decomposition pathways of mono N-alkylamine electrophiles have been obtained.
1,2-Azaborines, a unique class of BN-isosteres of benzene, have attracted great interest across several fields. While significant advancements have been made in the postfunctionalization of 1,2-azaborines, challenges still exist for the selective functionalization of the C4 position and access to 1,2-azaborines with five or six independently installed substituents. Here we report a rapid and modular method for C3 and C4 difunctionalization of 1,2-azaborines using the palladium/norbornene (Pd/NBE) cooperative catalysis. Enabled by the C2 amide-substituted NBE, diverse 3-iodo-1,2-azaborines can be used as substrates, showing broad functional group tolerance. Besides ortho arylation, preliminary success of ortho alkylation has also been realized. In addition, a range of alkenes and nucleophiles can be employed for ipso C3 functionalization. The reaction is scalable, and various postfunctionalizations, including forming hexa-substituted 1,2-azaborines, have been achieved.
Boron Compounds , Palladium , Catalysis , Norbornanes
Scalable fabrication of graphene nanoribbons with narrow band gaps has been a nontrivial challenge. Here, we have developed a simple approach to access narrow band gaps using hybrid edge structures. Bottom-up liquid-phase synthesis of bent N = 6/8 armchair graphene nanoribbons (AGNRs) has been achieved in high efficiency through copolymerization between an o-terphenyl monomer and a naphthalene-based monomer, followed by Scholl oxidation. An unexpected 1,2-aryl migration has been discovered, which is responsible for introducing kinked structures into the GNR backbones. The N = 6/8 AGNRs have been fully characterized to support the proposed structure and show a narrow band gap and a relatively high electrical conductivity. In addition, their application in efficient gas sensing has also been demonstrated.
As an important class of multicomponent reactions, the palladium/norbornene (Pd/NBE) cooperative catalysis has been mainly restricted to the coupling of an aryl halide, an electrophile and a nucleophile. Here, we report the development of a Pd/NBE-catalyzed four-component reaction, which involves ortho C-H amination/ipso conjunctive coupling using an alkene and an external nucleophile. The use of alkene-tethered nitrogen electrophiles provides a rapid and modular synthesis of 3,3-disubstituted indolines from readily available aryl iodides. The reaction exhibits broad functional group tolerance, and its utility is exemplified in a streamlined formal synthesis of a rhodamine dye. Preliminary results of the asymmetric version of this reaction have also been obtained.
1,2-Azaborines represent a unique class of benzene isosteres that have attracted interest for developing pharmaceuticals with better potency and bioavailability. However, it remains a long-standing challenge to prepare monocyclic 1,2-azaborines, particularly multi-substituted ones, in an efficient and modular manner. Here we report a straightforward method to directly access diverse multi-substituted 1,2-azaborines from readily available cyclopropyl imines/ketones and dibromoboranes under relatively mild conditions. The reaction is scalable, shows a broad substrate scope, and tolerates a range of functional groups. The utility of this method is demonstrated in the concise syntheses of BN isosteres of a PD-1/PD-L1 inhibitor and pyrethroid insecticide, bifenthrin. Combined experimental and computational mechanistic studies suggest that the reaction pathway involves boron-mediated cyclopropane ring-opening and base-mediated elimination, followed by an unusual low-barrier 6π-electrocyclization accelerated by the BN/CC isomerism. This method is anticipated to find applications for the synthesis of BN-isostere analogues in medicinal chemistry, and the mechanistic insights gained here may guide developing other boron-mediated electrocyclizations.
Preparation of diverse homologs from lead compounds has been a common and important practice in medicinal chemistry. However, homologation of carboxylic acid derivatives, particularly amides, remains challenging. Here we report a hook-and-slide strategy for homologation of tertiary amides with tunable lengths of the inserted carbon chain. Alkylation at the α-position of the amide (hook) is followed by highly selective branched-to-linear isomerization (slide) to effect amide migration to the end of the newly introduced alkyl chain; thus, the choice of alkylation reagent sets the homologation length. The key step involves a carbon-carbon bond activation process by a carbene-coordinated rhodium complex with assistance from a removable directing group. The approach is demonstrated for introduction of chains as long as 16 carbons and is applicable to derivatized carboxylic acids in complex bioactive molecules.
Methods that can simultaneously install multiple different functional groups to heteroarenes via C-H functionalizations are valuable for complex molecule synthesis, which, however, remain challenging to realize. Here we report the development of vicinal di-carbo-functionalization of indoles in a site- and regioselective manner, enabled by the palladium/norbornene (Pd/NBE) cooperative catalysis. The reaction is initiated by the Pd(II)-mediated C3-metalation and specifically promoted by the C1-substituted NBEs. The mild, scalable, and robust reaction conditions allow for a good substrate scope and excellent functional group tolerance. The resulting C2-arylated C3-alkenylated indoles can be converted to diverse synthetically useful scaffolds. The combined experimental and computational mechanistic study reveals the unique role of the C1-substituted NBE in accelerating the turnover-limiting oxidative addition step.
Alkyl halides are versatile precursors to access diverse functional groups (FGs). Due to their lability, the development of surrogates for alkyl halides is strategically important for complex molecule synthesis. Given the stability and ease of derivatization inherent in common alkyl ketones, here we report a deacylative halogenation approach to convert various methyl ketones to the corresponding alkyl chlorides, bromides, and iodides. The reaction is driven by forming an aromatic byproduct, i.e., 1,2,4-triazole, in which N'-methylpicolinohydrazonamide (MPHA) is employed to form a prearomatic intermediate and halogen atom-transfer (XAT) reagents are used to quench the alkyl radical intermediate. The reaction is efficient in yielding primary and secondary alkyl halides from a wide range of methyl ketones with broad FG tolerance. It also works for complex natural-product-derived and fluoro-containing substrates. In addition, one-pot conversions of methyl ketones to various other FGs and annulations with alkenes and alkynes through deacylative halogenation are realized. Moreover, an unusual iterative homologation of alkyl iodides is also demonstrated. Finally, mechanistic studies reveal an intriguing double XAT process for the deacylative iodination reaction, which could have implications beyond this work.
Oxygen-substituted arenes widely exist in biologically important molecules and can serve as versatile handles to install other functional groups. However, direct and site-selective installation of oxygen groups to common aromatic compounds remains challenging, especially when additional arene functionalization is simultaneously required. Current arene C-H oxidation strategies generally require directing groups or precisely prefunctionalized substrates to control site-selectivity. While palladium/norbornene cooperative catalysis is promising for site-specific arene vicinal difunctionalization through simultaneous reactions with an electrophile and a nucleophile, the electrophile scope has been limited to species based on relatively 'soft' elements, such as carbon, nitrogen and sulfur. Here we report the development of an ortho oxygenation reaction with common aryl halides to rapidly deliver diverse aryl ethers. The coupling of the 'hard' oxygen electrophile is enabled by a stable, polarity-reversed, conformationally predistorted N-O reagent and facilitated by a C7-bromo-substituted norbornene mediator. Mechanistic studies reveal a unique SN2-type pathway between the N-O reagent as the oxygen electrophile and an electron-rich Pd(II) nucleophile.
Synthesis of sequence-defined monodisperse π-conjugated polymers with versatile backbones remains a substantial challenge. Here we report the development of an integrated iterative binomial synthesis (IIBS) strategy to enable backbone engineering of conjugated polymers with precisely controlled lengths and sequences as well as high molecular weights. The IIBS strategy capitalizes on the use of phenol as a surrogate for aryl bromide and represents the merge between protecting-group-aided iterative synthesis (PAIS) and iterative binomial synthesis (IBS). Long and monodisperse conjugated polymers with diverse irregular backbones, which are inaccessible by conventional polymerizations, can be efficiently prepared by IIBS. In addition, topology-dependent and chain-length-dependent properties have been investigated.
The value of Matteson-type reactions has been increasingly recognized for developing automated organic synthesis. However, the typical Matteson reactions almost exclusively focus on homologation of carbon units. Here, we report the detailed development of sequential insertion of nitrogen and carbon atoms into boronate C-B bonds, which provides a modular and iterative approach to access functionalized tertiary amines. A new class of nitrenoid reagents is uncovered to allow direct formation of aminoboranes from aryl or alkyl boronates via N-insertion. The one-pot N-insertion followed by controlled mono- or double-carbenoid insertion has been realized with widely available aryl boronates. The resulting aminoalkyl boronate products can undergo further homologation and various other transformations. Preliminary success on homologation of N,N-dialkylaminoboranes and sequential N- and C-insertions with alkyl boronates have also been achieved. To broaden the synthetic utility, selective removal of a benzyl or aryl substituent permits access to secondary or primary amine products. The application of this method has been demonstrated in the modular synthesis of bioactive compounds and the programmable construction of diamines and aminoethers. A plausible reaction mechanism, supported by preliminary NMR (nuclear magnetic resonance) and computational studies, is also proposed.
While Catellani reactions have become increasingly important for arene functionalizations, they have been solely catalyzed by palladium. Here we report the first nickel-catalyzed Catellani-type annulation of aryl triflates and chlorides to form various benzocyclobutene-fused norbornanes in high efficiency. Mechanistic studies reveal a surprising outer-sphere concerted metalation/deprotonation pathway during the formation of the nickelacycle, as well as the essential roles of the base and the triflate anion. The reaction shows a broad functional group tolerance and enhanced regioselectivity compared to the corresponding palladium catalysis.
Herein we report the development of deacylative thiolation of diverse methyl ketones. The reaction is redox-neutral, and heavy-metal-free, which provides a new way to introduce thioether groups site-specifically to unactivated aliphatic positions. It also features excellent functional group tolerance and broad substrate scope, thus allowing late-stage derivatization. The process benefits from efficient condensation between the activation reagent and ketone substrates, which triggers aromatization-driven C-C fragmentation and rapid radical coupling with thiosulfonates. Experimental and computational mechanistic studies suggest the involvement of a radical chain pathway.
Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure-activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.
Biological Products , Biological Products/chemistry , Stereoisomerism , Structure-Activity Relationship , Immunosuppressive Agents/pharmacology , Cell Survival
Direct functionalization of carbonyl ß C-H bonds without using directing groups has not been a trivial task, and it is even more challenging to realize the corresponding atom-economical transformations with common alkenes or alkynes as the coupling partner. Here, we describe the development of an iridium-catalyzed intramolecular direct ß-alkenylation of ketones with regular alkynes. The reaction is redox neutral, avoids strong acids or bases, and tolerates various functional groups. The combined experimental and computational mechanistic studies reveal a hydride-transfer pathway, involving ketone α,ß-desaturation, iridium-hydride-mediated alkyne insertion, conjugate addition, and α-protonation.
Alkynes , Iridium , Alkynes/chemistry , Ketones/chemistry , Catalysis , Alkenes/chemistry
Given the emerging demand to "escape from flatland" for drug discovery, synthetic methods that can efficiently construct complex three-dimensional structures with multi-stereocenters become increasingly valuable. Here, we describe the development of Rh(I)-catalyzed intramolecular annulations between cyclobutanones and 1,5-enyne groups to construct complex C(sp3)-rich scaffolds. Divergent reactivities are realized with different catalysts, and excellent diastereo- and enantioselectivity have been achieved. The use of (R)-H8-binap as the ligand favors forming the bis-bicyclic scaffolds with multiple quaternary stereocenters, while the (R)-segphos ligand prefers to generate the tetrahydro-azapinone products. Owing to the versatile reactivity of ketone moieties, these C(sp3)-rich scaffolds can be further functionalized. Experimental and computational mechanistic studies support a reaction pathway involving enyne-cyclometallation, 1,2-carbonyl addition, and then ß-carbon elimination; the divergent reactivities are dictated by a product-determining Rh-alkyl migratory insertion step.
Rhodium , Ligands
While enormous progress has been achieved in synthesizing atomically precise graphene nanoribbons (GNRs), the preparation of GNRs with a fully predetermined length and monomer sequence remains an unmet challenge. Here, we report a fabrication method that provides access to structurally diverse and monodisperse "designer" GNRs through utilization of an iterative synthesis strategy, in which a single monomer is incorporated into an oligomer chain during each chemical cycle. Surface-assisted cyclodehydrogenation is subsequently employed to generate the final nanoribbons, and bond-resolved scanning tunneling microscopy is utilized to characterize them.
Graphite , Nanotubes, Carbon , Graphite/chemistry , Nanotubes, Carbon/chemistry
A photoinduced palladium-catalyzed desaturation method that is suitable for converting the linear amides to their α,ß-unsaturated counterparts is reported. The reaction does not require strong base/acid or sulfur/selenium and oxidant reagents and can be carried out at room temperature through a simple one-step operation. The protocol exhibits great scalability and functional group tolerance. The reaction mechanism has been investigated through deuterium labeling experiments, radical clock, radical capture, and kinetic studies. Mechanistic studies suggested a radical pathway involving aryl/alkyl Pd-radical intermediates.
