Photoinduced Triphenylphosphine and Iodide Salt Promoted Reductive Decarboxylative Coupling.

The transient electron donor-acceptor (EDA) complex has been an emerging area in the photoinduced organic synthesis field, generating radicals without exogenous transition-metal or organic dye-based photoredox catalysts. The catalytic platform to form suitable photoactive EDA complexes for photochemical reduction reactions remains underdeveloped. Herein, a general photoinduced reductive alkylation via the EDA complex strategy is described. A simple yet multifunctional system, triphenylphosphine and iodide salt, promotes the photoinduced decarboxylative hydroalkylation, and reductive defluorinative decarboxylative alkylation of trifluoromethyl alkenes, to access trifluoromethyl alkanes and gem-difluoroalkenes. Moreover, decarboxylative hydroalkylation can be applied to more kinds of electron-deficient alkenes as a general Giese addition reaction.

RAFT Polymerisation by the Radical Decarboxylation of Carboxylic Acids.

The controlled grafting of polymers from small- and macro-molecular substrates is an essential process for many advanced polymer applications. This usually requires the pre-functionalisation of substrates with an appropriate functional group, such as a RAFT agent or ATRP initiator, which requires additional synthetic steps. In this paper, we describe the direct grafting of RAFT polymers from carboxylate containing small molecules and polymers via photochemical radical decarboxylation. This method utilises the innate functional groups present in the substrates, and achieves efficient polymer initiation in a single step with excellent control of molecular weight and dispersity.

Mono and Dinuclear Palladium Pincer Complexes of NNSe Ligand as a Catalyst for Decarboxylative Direct C-H Heteroarylation of (Hetero)arenes.

This report describes the synthesis of a new NNSe pincer ligand and its mono- and dinuclear palladium(II) pincer complexes. In the absence of a base, a dinuclear palladium pincer complex (C1) was isolated, while in the presence of Et3 N base a mononuclear palladium pincer complex (C2) was obtained. The new ligand and complexes were characterized using techniques like 1 H, 13 C{1 H} nuclear magnetic resonance (NMR), fourier transform infrared (FTIR), high-resolution mass spectrometry (HRMS), ultraviolet-visible (UV-Visible), and cyclic voltammetry. Both the complexes showed pincer coordination mode with a distorted square planar geometry. The complex C1 has two pincer ligands attached through a Pd-Pd bond in a dinuclear pincer fashion. The air and moisture-insensitive, thermally robust palladium pincer complexes were used as the catalyst for decarboxylative direct C-H heteroarylation of (hetero)arenes. Among the complexes, dinuclear pincer complex C1 showed better catalytic activity. A variety of (hetero)arenes were successfully activated (43-87 % yield) using only 2.5 mol % of catalyst loading under mild reaction conditions. The PPh3 and Hg poisoning experiments suggested a homogeneous nature of catalysis. A plausible reaction pathway was proposed for the dinuclear palladium pincer complex catalyzed decarboxylative C-H bond activation reaction of (hetero)arenes.

Bulky Selenium Ligand Stabilized Trans-Palladium Dichloride Complexes as Catalyst for Silver-Free Decarboxylative Coupling of Coumarin-3-Carboxylic Acids.

This report describes the syntheses of three new trans-palladium dichloride complexes of bulky selenium ligands. These complexes possess a Cl-Pd-Cl rotor spoke attached to a Se-Pd-Se axle. The new ligands and palladium complexes (C1-C3) were characterized with the help of NMR, HRMS, UV-Vis., IR, and elemental analysis. The single-crystal structure of metal complex C2 confirmed a square planar geometry of complex with trans-orientation. The X-ray structure revealed intramolecular secondary interactions (SeCH-Cl) between chlorine of PdCl2 and CH2 proton of selenium ligand. Variable-temperature NMR data shows coalescence of diastereotopic protons, which indicates pyramidal inversion of selenium atom at elevated temperature. The relaxed potential energy scan of C2 suggests a rotational barrier of ∼12.5 kcal/mol for rotation of chlorine atom through Cl-Pd-Cl rotor. The complex C3 possesses dual intramolecular secondary interactions (OCH2 -Cl and SeCH2 -Cl) with stator ligand. Molecular rotor C2 was found to be a most efficient catalyst for the decarboxylative Heck-coupling under mild reaction conditions. The protocol is applicable to a broad range of substrates with large functional group tolerance and low catalyst loading (2.5 mol %). The mechanism of decarboxylative Heck-coupling reaction was investigated through experimental and computational studies. Importantly the reaction works under silver-free conditions which reduces the cost of overall protocol. Further, the catalyst also worked for decarboxylative arylation and decarboxylative Suzuki-Miyaura coupling reactions with good yields of the coupled products.

Synthesis of Unsymmetrical Biheteroarenes via Dehydrogenative and Decarboxylative Coupling: a Decade Update.

The design and development of robust and efficient methods for installing one heterocycle with another is endowed as a ubiquitous and powerful synthetic strategy to access complex organic biheterocycles in recent days due to their pervasive applications in medicinal as well as material chemistry. This perspective presents an overview on the recent findings and developments for the synthesis of unsymmetrical biheteroarenes via dehydrogenative and decarboxylative couplings with literature coverage mainly extending from 2011 to 2021. For simplification of the readers, the article has been subcategorized based on the catalysts used in the reactions.

Recent Developments in the Synthesis of ß-Diketones.

Apart from being one of the most important intermediates in chemical synthesis, broadly used in the formation of C-C bonds among other processes, the ß-dicarbonyl structure is present in a huge number of biologically and pharmaceutically active compounds. In fact, mainly derived from the well-known antioxidant capability associated with the corresponding enol tautomer, ß-diketones are valuable compounds in the treatment of many pathological disorders, such as cardiovascular and liver diseases, hypertension, obesity, diabetes, neurological disorders, inflammation, skin diseases, fibrosis, or arthritis; therefore, the synthesis of these structures is an area of overwhelming interest for organic chemists. This paper is devoted to the advances achieved in the last ten years for the preparation of 1,3-diketones, using different chemical (Claisen, hydration of alkynones, decarboxylative coupling) or catalytic (biocatalysis, organocatalytic, metal-based catalysis) methodologies: Additionally, the preparation of branched ß-dicarbonyl compounds by means of α-functionalization of non-substituted 1,3-diketones are also discussed.

Late-Stage Alkylation of Heterocycles Using N-(Acyloxy)phthalimides.

Synthetic methods enabling late-stage modification of heterocycles hold tremendous importance in the pharmaceutical and agrochemical industry and drug discovery. Accordingly, efficient, functional group tolerant and selective late-stage alkylation of valuable molecular entities is of enormous significance and well-acknowledged in medicinal chemistry. Radical alkylation of heteroarenes employing carboxylic acids as the alkyl radical precursor represents one of the most direct ways of C-H functionalizations of heterocycles. Recently, the field has undergone a revolutionary development especially with regard to the generation of alkyl radicals under much milder conditions. In this regard N-(acyloxy)phthalimides (NHPI esters) have emerged as a suitable precursor of a diverse set of alkyl radicals allowing formal C-H alkylation of not only N-heteroarenes but a diverse set of non-aromatic heterocycles under visible light photocatalysis or electrochemical conditions. This review delineates all these discoveries and provides readers a comprehensive overview of this rapidly expanding field.

A Practical and Efficient Synthesis of Uniform Conjugated Rod-Like Oligomers.

Herein, a more practical and efficient synthesis protocol for the preparation of uniform rod-like oligo(1,4-phenylene ethynylene)s (OPE)s is presented. Applying an iterative reaction cycle consisting of a decarboxylative coupling reaction and a saponification of an alkynyl carboxylic ester, a uniform pentamer is obtained in ten steps with 14% overall yield. The copper-free conditions prevent homocoupling until the trimer stage, resulting in a significantly easier work-up of the products. Homocoupling is observed from the tetramer stage on, but a simple variation of the work-up procedure also yields the uniform tetramer and pentamer. A thorough comparison with the commonly used and described Sonogashira approach reveals that with the new presented strategy, OPEs can be built in similar overall yield, but easier purification and in a quarter of the time. All oligomers are fully characterized by proton and carbon nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), size-exclusion chromatography (SEC), and infrared spectroscopy (IR).

An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis.

The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative cross-coupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.

On-DNA Decarboxylative Arylation: Merging Photoredox with Nickel Catalysis in Water.

A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, nickel precatalyst with a new electron-deficient pyridyl carboxamidine ligand was key to the development of a water-compatible nickel catalysis platform, which is a crucial requirement for the preparation of DNA-encoded libraries (DELs). Together with an iridium-based photocatalyst and a powerful light source, this dual catalysis approach enabled the efficient decarboxylative arylation of α-amino acids with DNA-tagged aryl halides. This C(sp2)-C(sp3) coupling tolerates a wide variety of functional groups on both the amino acid and the aryl halide substrates. Due to the mild and DNA-compatible reaction conditions, the presented transformation holds great potential for the construction of DELs. This was further evidenced by showing that well plate-compatible LED arrays can serve as competent light sources to facilitate parallel synthesis. Lastly, we demonstrate that this procedure can serve as a blueprint toward the adaptation of other established nickel metallaphotoredox transformations to the idiosyncratic requirements of a DEL.

Pd-Catalyzed Synthesis of Vinyl Arenes from Aryl Halides and Acrylic Acid.

Acrylic acid is presented as an inexpensive, non-volatile vinylating agent in a palladium-catalyzed decarboxylative vinylation of aryl halides. The reaction proceeds through a Heck reaction of acrylic acid, immediately followed by protodecarboxylation of the cinnamic acid intermediate. The use of the carboxylate group as a deciduous directing group ensures high selectivity for monoarylated products. The vinylation process is generally applicable to diversely substituted substrates. Its utility is shown by the synthesis of drug-like molecules and the gram-scale preparation of key intermediates in drug synthesis.

Transformation of Metal-Organic Frameworks into Stable Organic Frameworks with Inherited Skeletons and Catalytic Properties.

Metal-organic frameworks (MOFs) are an emerging class of porous materials with attractive properties, however, their practical applications are heavily hindered by their fragile nature. We report herein an effective strategy to transform fragile coordination bonds in MOFs into stable covalent organic bonds under mild annealing decarboxylative coupling reaction conditions, which results in highly stable organic framework materials. This strategy successfully endows intrinsic framework skeletons, porosity and properties of the parent MOFs in the daughter organic framework materials, which exhibit excellent chemical stability under harsh catalytic conditions. Therefore, this work opens a new avenue to synthesize stable organic framework materials derived from MOFs for applications in different fields.

Employing Photoredox Catalysis for DNA-Encoded Chemistry: Decarboxylative Alkylation of α-Amino Acids.

A new procedure for the photoredox-mediated conjugate addition of radicals that can be conveniently generated from α-amino acids to DNA-tagged Michael acceptors and styrenes is presented. This C(sp3 )-C(sp3 ) coupling tolerates a broad array of structurally diverse radical precursors, including all of the 20 proteinogenic amino acids. Importantly, this reaction proceeds under mild conditions and in DNA-compatible aqueous media. Furthermore, the presented reaction conditions are compatible with DNA, making this reaction platform well suited for the construction of DNA-encoded libraries. The scope and limitations of the chemistry are discussed herein along with proposals for how this methodology might be used to construct DNA-encoded libraries.

2-Phenylbenzo[b]furans: Synthesis and promoting activity on estrogen biosynthesis.

Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is closely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2-phenylbenzo[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to corresponding substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited promotive activity on estrogen biosynthesis. 2-(4-Chlorophenyl)-7-methoxybenzo[b]furan possessed the highest activity with EC50 value of 14.68µM. Furthermore, these compounds did not affect aromatase expression in HEK292A cells, indicating that these 2-phenylbenzo[b]furans might enhance estrogen biosynthesis via directly allosteric regulation of aromatase or indirectly via posttranslational modification.

Decarboxylative Alkyl-Alkyl Cross-Coupling Reactions.

Alkyl with alkyl: A significant development in alkyl-alkyl cross-coupling reactions, namely the nickel-catalyzed decarboxylative Negishi coupling of N-hydroxyphthalimide esters, was recently reported by Baran and co-workers. This method enables the synthesis of various highly functionalized compounds, including natural product derivatives.

Decarboxylative Coupling Reaction in ESI(-)-MS/MS of 4-Nitrobenzyl 4-Hydroxybenzoates: Triplet Ion-Neutral Complex-Mediated 4-Nitrobenzyl Transfer.

In negative electrospray ionization mass spectrometry of 4-nitrobenzyl 4-hydroxybenzoates, a decarboxylation reaction, which was significantly promoted by the presence of a nitro group on the benzyl group, competed with radical elimination reactions. Density functional theory calculations indicated that decarboxylation of deprotonated 4-nitrobenzyl vanillate occurred via a radical route involving homolytic cleavage of the Cbenzyl-O bond to give a triplet ion-neutral complex, followed by decarboxylative coupling.

Stereospecific Pd-Catalyzed Intermolecular C(sp(3))-C(sp) Cross-Coupling of Diarylmethyl Carbonates and Terminal Alkynes Under Base-Free Conditions.

A palladium-catalyzed intermolecular decarboxylative C(sp(3))-C(sp) coupling of diarylmethyl carbonates and terminal alkynes has been developed. The reaction proceeds smoothly under external base-free conditions to deliver the corresponding alkynylated diarylmethanes with the liberation of CO2 and MeOH as the sole byproducts. Moreover, enantioenriched diarylmethyl carbonates are stereospecifically converted to optically active cross-coupling products with inversion of configuration. Thus, the stereospecific palladium catalysis can provide new and unique access to the alkynylated chiral tertiary stereocenters, which are relatively difficult to construct by conventional methods.

Transition-metal-catalyzed C-H bond functionalizations: feasible access to a diversity-oriented ß-carboline library.

Diversification of the ß-carboline skeleton has been demonstrated to assemble a ß-carboline library starting from the tetrahydro-ß-carboline framework. This strategy affords feasible access to heteroaryl-, aryl-, alkenyl-, or alkynyl-substituted ß-carbolines at the C1, C3, or C8 position through three categorically different types of transition-metal-catalyzed CC bond-forming reactions, in the presence of multiple potentially reactive positions. These site-selective functionalizations include; 1) the Cu-catalyzed C1/C3-selective decarboxylative C sp 3C sp 2 and C sp 3Csp coupling of hexahydro-ß-carboline-3-carboxylic acid with a CH bond of a heteroarene or terminal alkyne; 2) the chelation-assisted Pd-catalyzed C1/C8-selective CH arylation of hexahydro-ß-carboline with aryl boron reagents; and 3) the chelation-assisted Pd-catalyzed C1/C3-selective oxidative CH/CH cross-coupling of ß-carboline-N-oxide with arenes, heteroarenes, or alkenes. The saturated structural feature of the hexahydro-ß-carboline framework can increase reactivity and control site selectivity. The robustness of these approaches has been demonstrated through the synthesis of hyrtioerectine analogues and perlolyrine. We believe that these strategies could provide inspiration for late-stage diversifications of bioactive core scaffolds.

Total synthesis of resveratrol-based natural products using a palladium-catalyzed decarboxylative arylation and an oxidative Heck reaction.

Controlled access to resveratrol-based natural products is offered by a novel, modular concept. A common building block readily available on a large scale serves as the starting material for the introduction of structurally important aryl groups by a Pd-catalyzed decarboxylative arylation and an oxidative Heck reaction with good yields and high stereoselectivity. The modular approach is convincingly documented by the successful synthesis of three racemic resveratrol-based natural products (quadrangularin A, ampelopsin D, and pallidol).