Arylboronic Acid Pinacol Esters Research Articles

Copper-Catalyzed Trifluoromethylation of (Hetero)aryl Boronic Acid Pinacol Esters with YlideFluor.

A copper-catalyzed trifluoromethylation of (hetero)arylboronic acid pinacol esters with YlideFluor for the preparation of trifluoromethylated (hetero)arenes was described. The reaction conditions are mild and compatible with a broad range of functional groups. Heteroaryl boronic acid pinacol esters could also be trifluoromethylated in high yields. Application of this protocol for trifluoromethylation of drug and OLED molecules was demonstrated.

Visible‐Light‐Induced Decarboxylative and Deboronative Radical Addition to Alkenes in Two‐Molecule Photoredox System Using Dibenzo[g,p]chrysene

AbstractVisible‐light‐induced decarboxylative and deboronative radical addition of aliphatic carboxylic acids and arylboronic acid pinacol esters to electron‐deficient alkenes using two‐molecule organic photoredox catalysts, such as dibenzo[g,p]chrysene as an electron donor and 1,4‐dicyanobenzene as an electron acceptor, proceeded efficiently to furnish radical adducts via the generation of alkyl and aryl radicals. The base and substrate play important roles in this photochemical system, and the sequential photoinduced decarboxylation of glutamic acid having two different carboxy groups was successful.

Copper-mediated aerobic trifluoromethyltelluration of boronic acids with [Me4N][TeCF3

A copper-mediated trifluoromethyltelluration of arylboronic acids with [Me4N][TeCF3] using air as an environmental friendly oxidant is presented. The reaction proceeded smoothly under mild conditions in the presence of Cu(OTf)2 and bipyridine to provide the corresponding trifluoromethyltellurated products in good yields. Vinylboronic acid and arylboronic acid pinacol ester were also suitable substrates in the conversion but the yields are low. This transformation featured simplicity, good functional group tolerance, and a wide range of substrates, allowing for a convenient access to various TeCF3-containing molecules, and represented the first Chan-Lam type trifluoromethyltelluration with the highly reactive [Me4N][TeCF3] salt.

Ph4P]+[Cu(CF2H)2]−: A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation

AbstractThe quest of the active species in copper‐mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4P]+[Cu(CF2H)2]−2. Complex2was able to difluoromethylate a variety of electrophiles including electron‐deficient and electron‐rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex2reacted with various lithiumnbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex2could transmetalate the difluoromethyl reagent to other metals such as [Ph4P]+[CuCl2]−and [(DPPF)PdCl2].

Ph4 P]+ [Cu(CF2 H)2 ]- : A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation.

The quest of the active species in copper-mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4 P]+ [Cu(CF2 H)2 ]- 2. Complex 2 was able to difluoromethylate a variety of electrophiles including electron-deficient and electron-rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex 2 reacted with various lithium nbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex 2 could transmetalate the difluoromethyl reagent to other metals such as [Ph4 P]+ [CuCl2 ]- and [(DPPF)PdCl2 ].

Nickel-catalyzed carbonylative domino cyclization of arylboronic acid pinacol esters with 2-alkynyl nitroarenes towardN-aroyl indoles

A nickel-catalyzed carbonylative domino cyclization of arylboronic acid pinacol esters with 2-alkynyl nitroarenes has been developed.

Cu‐Mediated Radiofluorination of Aryl Pinacolboronate Esters: Alcohols as Solvents with Application to 6‐L‐[18F]FDOPA Synthesis

Cu‐mediated radiofluorination of arylboronic acid pinacol esters (ArylBPin) using Cu(OTf)2(Py)4 complex is a useful approach for the introduction of [18F]fluorine into non‐activated arenes and heteroarenes. Owing to the complexity of the mechanism and wide variation in substrate reactivity the choice of reaction conditions must be made individually for every precursor. Careful selection of phase‐transfer catalysts also plays a role, as Cu‐catalyst and ArylBPin precursors are known to be unstable in basic conditions. Using tetrabutylammonium triflate alcohol solution for elution of [18F]fluoride from ion‐exchange cartridge and employing same alcohol as a co‐solvent in the following labelling step, we have developed a general protocol resulting in >80 % fluorination efficiency of ArylBPin precursors for 4‐[18F]fluoro‐D,L‐phenylalanine and 6‐L‐[18F]FDOPA. Radiofluorination in neat alcohol was particularly effective for the synthesis of 6‐L‐[18F]FDOPA, allowing for substantial increase of yield and decrease of synthesis time compared to current methods (activity yield 14.5 ± 0.5 %, 70 min synthesis time).

A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography.

The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR’s role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (18F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Ki ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18F-YJH08 was prepared via Cu(OTf)2(py)4-mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18F-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that 18F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.

Reaction of Cycloalkene‐1‐carboxamides with Aryl Boronates via Rhodium(III)‐Catalyzed C−H Activation: A Versatile Route to 3,4‐Cycloalkaquinolin‐2(1H)‐ones

AbstractUnder rhodium(III) catalysis, substituted N‐methoxycycloalkene‐1‐carboxamides successfully reacted with aryl boronic acid pinacol esters to provide 3,4‐cycloalkaquinolin‐2(1H)‐ones via direct functionalization of the β‐alkenyl C−H bond and form C−C/C−N bond in one pot. The gram‐scale synthesis of the title compound demonstrated the great synthetic utility of this methodology.magnified image

Hydrogen Atom Transfer Induced Boron Retaining Coupling of Organoboronic Esters and Organolithium Reagents.

α-Functionalization of alkyl boronic esters and homologation of aryl boronic esters by regioselective radical C(sp3)–H activation in boron-ate complexes is reported. Reaction of commercial or readily accessed aryl boronic acid pinacol esters with alkyl lithium reagents provides boron-ate complexes. Selective α-C–H abstraction by in situ generated trifluoromethyl radicals leads to radical anions that undergo electron transfer oxidation followed by 1,2-aryl/alkyl migration from boron to carbon to give the α-arylated/alkylated alkyl boronic esters. The valuable boronic ester functionality remains in the products and the cheap trifluoromethyl iodide acts as the oxidant in these C–C couplings. The 1,2-alkyl migration from boron to carbon is highly stereospecific allowing access to stereoisomerically pure boronic esters.

LiHMDS-Promoted Palladium or Iron-Catalyzed ipso-Defluoroborylation of Aryl Fluorides.

A novel and efficient method for the synthesis of arylboronic acid pinacol esters via a palladium- or iron-catalyzed cross-coupling reaction of aryl fluorides with bis(pinacolato)diboron (B2pin2) in the presence of LiHMDS was developed. The Pd-catalyzed defluoroborylation of fluoroarenes is compatible with a variety of functional groups such as primary and secondary amine, ketone, trifluoromethyl, alkoxy, and boryl. Remarkably, no external ligand is required for enhanced conversion efficiency.

Copper‐Catalyzed N‐Arylation with Boronic Acid Pinacol Esters

AbstractA copper‐catalyzed facile N‐arylation of 2‐acyl substituted anilines has been disclosed. Through chelation assistance of the weakly coordinating carbonyl groups, the Chan−Evans−Lam (CEL) C−N cross‐coupling reactions proceeded at room temperature in open flasks. Furthermore, such chelation effects also enabled the direct utilization of aryl boronic acid pinacol esters in Cu‐catalyzed CEL reactions under mild conditions.

Suzuki–Miyaura Coupling Reactions Using Low Loading of Ligand-activated Palladium Catalyst by Cooperative Copper Catalysis

A highly active Pd/Cu cooperative catalytic system based on biphenylene-substituted di-tert-butylruthenocenylphosphine (R-Phos) was developed for performing Suzuki–Miyaura coupling reactions of (hetero)aryl, alkenyl, and benzyl bromides with (hetero)arylboronic acid pinacol esters. A variety of sterically and/or electronically diverse bromides and boronate esters were successfully coupled in good to excellent yields at room temperature using 0.1 mol % Pd and 5 mol % Cu.

A Zinc Catalyzed C(sp3 )-C(sp2 ) Suzuki-Miyaura Cross-Coupling Reaction Mediated by Aryl-Zincates.

The Suzuki–Miyaura (SM) reaction is one of the most important methods for C−C bond formation in chemical synthesis. In this communication, we show for the first time that the low toxicity, inexpensive element zinc is able to catalyze SM reactions. The cross‐coupling of benzyl bromides with aryl borates is catalyzed by ZnBr2, in a process that is free from added ligand, and is compatible with a range of functionalized benzyl bromides and arylboronic acid pinacol esters. Initial mechanistic investigations indicate that the selective in situ formation of triaryl zincates is crucial to promote selective cross‐coupling reactivity, which is facilitated by employing an arylborate of optimal nucleophilicity.

Ni-Catalyzed Alkene Carboacylation via Amide C-N Bond Activation.

We report Ni-catalyzed formal carboacylation of o-allylbenzamides with arylboronic acid pinacol esters. The reaction is triggered by oxidative addition of an activated amide C-N bond to a Ni(0) catalyst and proceeds via alkene insertion into a Ni(II)-acyl bond. The exo-selective carboacylation reaction generates 2-benzyl-2,3-dihydro-1H-inden-1-ones in moderate to high yields (46-99%) from a variety of arylboronic acid pinacol esters and substituted o-allylbenzamides. These results show that amides are practical substrates for alkene carboacylation via amide C-N bond activation, and this approach bypasses challenges associated with alkene carboacylation triggered by C-C bond activation.

Synthesis and evaluation of 18F-labeled CJ-042794 for imaging prostanoid EP4 receptor expression in cancer with positron emission tomography

The potent and selective prostanoid EP4 receptor antagonist CJ-042794 was radiolabeled with 18F, and evaluated for imaging EP4 receptor expression in cancer with positron emission tomography (PET). The fluorination precursor, arylboronic acid pinacol ester 4, was prepared in 4 steps with 42% overall yield. 18F-CJ-042794 was synthesized via a copper-mediated 18F-fluorination reaction followed by base hydrolysis, and was obtained in 1.5±1.1% (n=2) decay-corrected radiochemical yield. PET/CT imaging and biodistribution studies in mice showed that 18F-CJ-042794 was excreted through both renal and hepatobiliary pathways with significant retention in blood. The EP4-receptor-expressing LNCaP prostate cancer xenografts were clearly visualized in PET images with 1.12±0.08%ID/g (n=5) uptake value and moderate tumour-to-muscle contrast ratio (2.73±0.22) at 1h post-injection. However, the tumour uptake was nonspecific as it could not be blocked by co-injection of cold standard, precluding the application of 18F-CJ-042794 for PET imaging of EP4 receptor expression in cancer.

ChemInform Abstract: Chan—Evans—Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem.

AbstractThe reaction conditions for Chan—Evans—Lam amination of alkyl and aryl amines with aryl boronic acid pinacol esters are revised.

ChemInform Abstract: Rhodium‐Catalyzed ipso‐Borylation of Alkylthioarenes via C—S Bond Cleavage.

Rhodium-catalyzed transformation of alkyl aryl sulfides into arylboronic acid pinacol esters via C–S bond cleavage is reported. In combination with transition-metal-catalyzed sulfanyl group-guided regioselective C–H borylation reactions of alkylthioarenes, this method allows the synthesis of a diverse range of multisubstituted arenes.

ChemInform Abstract: Ligand‐Promoted Rh(III)‐Catalyzed Coupling of Aryl C—H Bonds with Arylboron Reagents.

AbstractA regioselective Rh(III)‐catalyzed C—H arylation of arenes with arylboronic acid pinacol esters is developed using N‐pentafluorophenylbenzamide as directing group.

Rhodium-Catalyzed ipso-Borylation of Alkylthioarenes via C-S Bond Cleavage.

Rhodium-catalyzed transformation of alkyl aryl sulfides into arylboronic acid pinacol esters via C-S bond cleavage is reported. In combination with transition-metal-catalyzed sulfanyl group-guided regioselective C-H borylation reactions of alkylthioarenes, this method allows the synthesis of a diverse range of multisubstituted arenes.