Electron-poor Substrates Research Articles

Tandem Condensation-Cycloaddition of Propargylic Amines with α-Azido Ketones and β-Alkoxy-γ-Azido Enones.

α-Azido ketones and their vinylogous relatives β-alkoxy-γ-azido enones are versatile building blocks for constructing diverse heterocyclic products, but are prone to azide decomposition. Here, we report their condensation with propargylic amines and investigate the fate of the intermediate azido-enamine condensation products, both experimentally and theoretically. Efficient intramolecular cycloaddition was observed for electron-poor azide substrates, and a range of diversely substituted [1,2,3]triazolo[1,5-a]pyrazine products is reported. For electron-rich substrates, azide decomposition predominated. Computational modeling of possible pathways from the azido-enamine intermediates revealed two alternative mechanisms for azide decomposition, which were consistent with observed side products.

Rapid Electrophilic 211At-Astatination of Trimethylgermyl Arenes.

A set of 211At-astatoarenes were synthesized from corresponding trimethylgermyl arenes with an average radiochemical conversion (RCC) of ca. 50 % for electron-rich and approx. 70 % in case of electron-deficient arenes. Both electron rich and electron poor substrates were successfully radiolabeled at room temperature (RT) using relatively low precursor amounts (0.15 μmol/0.02 mL solvent (7.5 mM)). Ready access to ortho-, para- and meta- astatinated arenes was achievable. Optimized reaction conditions were successfully applied to label a poly (ADP-ribose) polymerase (PARP) inhibitor with a RCC of approx. 50 %. We believe that trimethylgermyl derivatives are a viable addition to the astatination precursor toolbox and facilitate astatination of arenes. The developed labeling method should easily be applicable for productions under good manufacturing practice (GMP).

Organocatalytic Decarboxylative Borylation of Cyclopropane N-Hydroxyphthalimide Esters.

A convenient protocol for the two-step organocatalytic decarboxylative borylation of 1,1-disubstituted, 1,2-disubstituted, and bicyclic cyclopropane carboxylic acids via the corresponding N-hydroxyphthalimide esters is described, using tert-butyl or ethyl isonicotinate as an inexpensive and readily available catalyst. The scope of the method was demonstrated, being limited mainly by electron-poor substrates. The reaction sequence showed good scalability (up to 51.5 g) and excellent trans diastereoselectivity (for the case of 1,2-disubstituted substrates). Therefore, the proposed approach is a very promising alternative to other existing (i.e., metal-catalyzed) methods for borodecarboxylation.

Synchronous and basic asynchronous hydrogen-atom abstraction of benzylic substrates by high-valent iron–oxo porphyrin species

The unsubstituted iron–oxo porphyrin reacts with unsubstituted benzylic C–H bond substrates via a synchronous HAT mechanism. In contrast, when an electron-rich iron–oxo porphyrin reacts with electron-poor substrates, it follows a basic asynchronous HAT mechanism.

Synthesis and Palladium-Catalyzed Cross-Coupling of an Alkyl-Substituted Alkenylboronic Acid Pinacol Ester with Aryl Bromides

The palladium-catalyzed cross-coupling reaction of alkyl-substituted alkenylboron reagents with aryl halides is a versatile method to introduce a hydrophobic hydrocarbon chain onto organic compounds of interest. The application of the cross-coupling reaction is enabled by synthetic methods for the preparation of alkenylboron reagents. The geometrically pure, alkyl-substituted alkenylboron reagent, (E)-octenylboronic acid pinacol ester, was prepared by 9-BBN-catalyzed hydroboration reaction of 1-octene with pinacolborane in refluxing 1 M THF solution. This reagent was then evaluated in palladium-catalyzed cross-coupling reactions with aryl bromides. The highest yield of the (E)-1-phenyloctene was obtained when SPhos was used as the ligand, K2CO3 was used as the base, and DMF was used as the reaction solvent. Other electron-rich, electron-poor, sterically hindered, and heteroaromatic substrates produced the corresponding (E)-1-phenyloctene derivatives in moderate to good yield. KEYWORDS: Organic synthesis; Aryl alkene synthesis; Palladium-catalyzed cross-coupling; Suzuki-Miyaura reaction; Stereocontrolled alkene preparation; Hydroboration; 9-Borobicyclo[3.3.1]nonane; Reaction optimization

Exploring Synthetic Strategies for 1H-Indazoles and Their N-Oxides: Electrochemical Synthesis of 1H-Indazole N-Oxides and Their Divergent C-H Functionalizations.

The selective electrochemical synthesis of 1H-indazoles and their N-oxides and the subsequent C-H functionalization of the 1H-indazole N-oxides are described. The electrochemical outcomes were determined by the nature of the cathode material. When a reticulated vitreous carbon cathode was used, a wide range of 1H-indazole N-oxides were selectively synthesized, and the electrosynthesis products were deoxygenated to N-heteroaromatics, owing to cathodic cleavage of the N-O bond via paired electrolysis, while Zn cathode was used. The scope of this electrochemical protocol is broad, as both electron-rich and electron-poor substrates were tolerated. The potency of our electrochemical strategy was demonstrated through the late-stage functionalization of various bioactive molecules, making this reaction attractive for the synthesis of 1H-indazole derivatives for pharmaceutical research and development. Detailed mechanistic investigations involving electron paramagnetic resonance spectroscopy and cyclic voltammetry suggested a radical pathway featuring iminoxyl radicals. Owing to the rich reactivity of 1H-indazole N-oxides, diverse C-H functionalization reactions were performed. We demonstrated the synthetic utility of 1H-indazole N-oxides by synthesizing the pharmaceutical molecules lificiguat and YD (3); key intermediates for bendazac, benzydamine, norepinephrine/serotonin reuptake inhibitors, SAM-531, and gamendazole analogues; and a precursor for organic light-emitting diodes.

Oxidative Trifluoroacetoxylation of 1°, 2°, and 3° Benzylic C(sp3)-H Bond Donors Using N-Trifluoroacetoxyquinuclidinium Salts under Photoredox Catalysis.

N-Trifluoroacetoxyquinuclidinium trifluoroacetate was prepared in situ from quinuclidine N-oxide and (CF3CO)2O. Except for some electron-poor substrates, this reagent allows for the high-yielding oxidative trifluoroacetoxylation of 1°, 2°, and 3° benzylic C-H bonds under photocatalytic conditions. The trifluoroacetoxylation of an ibuprofen methyl ester allowed the selective functionalization of a 2° benzylic C-H bond. For alkylbenzenes, hydrogen-atom transfer from a benzylic C-H bond to a quinuclidine cation radical was proposed to be the reaction-product-determining step.

Chemodivergent Organolanthanide-Catalyzed C-H α-Mono-Borylation of Pyridines.

Chemodivergent synthetic methodologies enable the efficient introduction of structural diversity into high-value organic products via simple chemical alterations. In this regard, C-H activation and functionalization of pyridinoid azines are important transformations in the synthesis of many natural products, pharmaceuticals, and functional materials. Reflecting on azinyl nitrogen lone-pair steric repulsion, its tendency to irreversibly coordinate metal ion catalysts, and the electron deficiency of pyridine, C-H functionalization at the important α-position remains challenging. Thus, developing earth-abundant catalysts for α-selective azine mono-functionalization is an attractive target for chemical synthesis. Here, the selective organolanthanide-catalyzed α-mono-borylation of a diverse series of 18 pyridines is reported using Cp*2LuCH(TMS)2 (Cp* = η5-C5Me5) (TMS = SiMe3) and affording valuable precursors for subsequent functionalization. Experimental and theoretical mechanistic data reported here support the intermediacy of a C-H-activated η2-lanthanide-azine complex, followed by intermolecular α-mono-borylation via σ-bond metathesis. Notably, varying the lanthanide identity and substrate substituent electronic character promotes marked chemodivergence of the catalytic selectivity: smaller/more electrophilic lanthanide3+ ions and electron-rich substrates favor selective α-C-H functionalization, whereas larger/less electrophilic lanthanide3+ ions and electron-poor substrates favor selective B-N bond-forming 1,2-dearomatization. Such lanthanide series catalytic chemodivergence is, to our knowledge, unprecedented.

Synthesis of Ester-Substituted Indolizines from 2-Propargyloxypyridines and 1,3-Dicarbonyls.

Two new complementary Au(I)-catalyzed methods for the preparation of ester-substituted indolizines from easily accessible 2-propargyloxypyridines and either acetoacetates or dimethyl malonate are reported. These reactions tolerate a wide range of functionality, allowing for diversification at three distinct positions of the product (R, R1, R2). For electron-poor substrates, the highest yields are observed upon reaction with acetoacetates, while neutral and electron-rich substrates give higher yields upon treatment with dimethyl malonate.

Intramolecular Alkene Fluoroarylation of Phenolic Ethers Enabled by Electrochemically Generated Iodane.

The 3-substituted chromane core is found in several bioactive natural products. Herein, we describe a route to 3-fluorinated chromanes from allylic phenol ethers. Our external oxidant-free approach takes advantage of an electrochemical generation of a hypervalent iodine species, difluoro-λ3-tolyl iodane, which mediates the alkene fluoroarylation. High yields and selectivity for this transformation are achieved for electron poor substrates. The redox chemistry has been characterized for the electrochemical generation of the iodane in the presence of fluoride, and insights into the mechanism are given. The transformation has been demonstrated on gram scales, which indicates the potential broader utility of the process.

1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates.

Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O2 and FeCl3·6H2O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N'-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe3+. The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.

Iridium-Catalyzed Synthesis of Substituted Indanones from Aromatic Carboxylates and Unsaturated Ketones

A catalytic annulation is presented that provides straightforward, modular synthetic access to 3-substituted indanones from benzoic acids and α,β-unsaturated ketones. It is catalyzed by a bimetallic Ir/In system and proceeds via hydroarylation followed by Claisen condensation and optional retro-Claisen deacylation. The annulation may be combined into a one-pot procedure with the synthesis of the unsaturated ketone substrates from aldehydes and acetone. Two complementary reaction protocols are provided that are applicable to diversely functionalized electron-rich and electron-poor substrates.

Copper(I) selenophene-2-carboxylate (CuSC) promoted C–S cross-coupling reaction of thiols with aryl iodides

ABSTRACTWe reported the synthesis of copper (I)-selenophene-2-carboxylate (CuSC) and application as new catalyst in the cross-coupling reactions of thiols with aryl iodide to afford the corresponding unsymmetrical thioethers. The optimized reaction conditions were applied to thiols and aryl iodides having a wide range of functional groups, including electron rich and electron poor substrates. The chemoselectivity of the reaction with 4-iodobromobenzene and 2-aminothiophenol derivatives was briefly examined through the competitive iodine versus bromine and thiol versus nitrogen cross-coupling.

Oxidative Addition, Transmetalation, and Reductive Elimination at a 2,2'-Bipyridyl-Ligated Gold Center.

Three-coordinate bipyridyl complexes of gold, [(κ2-bipy)Au(η2-C2H4)][NTf2], are readily accessed by direct reaction of 2,2'-bipyridine (bipy), or its derivatives, with the homoleptic gold ethylene complex [Au(C2H4)3][NTf2]. The cheap and readily available bipyridyl ligands facilitate oxidative addition of aryl iodides to the Au(I) center to give [(κ2-bipy)Au(Ar)I][NTf2], which undergo first aryl-zinc transmetalation and second C-C reductive elimination to produce biaryl products. The products of each distinct step have been characterized. Computational techniques are used to probe the mechanism of the oxidative addition step, offering insight into both the origin of the reversibility of this process and the observation that electron-rich aryl iodides add faster than electron-poor substrates. Thus, for the first time, all steps that are characteristic of a conventional intermolecular Pd(0)-catalyzed biaryl synthesis are demonstrated from a common monometallic Au complex and in the absence of directing groups.

Synthesis of Polyflourinated Biphenyls; Pushing the Boundaries of Suzuki-Miyaura Cross Coupling with Electron-Poor Substrates.

Polyfluorinated biphenyls are interesting and promising substrates for many different applications. Unfortunately, all current methods for the syntheses of these compounds only work for a hand full of molecules or only in very special cases. Thus, many of these compounds are still inaccessible to date. Here we report a general strategy for the synthesis of a wide range of highly fluorinated biphenyls. In our studies we investigated crucial parameters, such as different phosphine ligands and the influence of various nucleophiles and electrophiles with different degrees of fluorination. These results extend the scope of the already very versatile Suzuki–Miyaura reaction toward the synthesis of very electron-poor products, making these more readily accessible. The presented methodology is scalable and versatile without the need for elaborate phosphine ligands or Pd-precatalysts.

Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation.

We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.

Different Performance of Two Isomeric Phosphinobiphenyl Amidosulfonates in Pd-Catalyzed Cyanation of Aryl Bromides

A hydrophilic phosphinobiphenyl amidosulfonate, 2′-(dicyclohexylphosphino)-2- {[(sulfonatomethyl)amino]carbonyl}[1,1′-biphenyl], triethylammonium salt (L2), was prepared and, together with its isomer bearing the polar amido-sulfonate tag in the position 4 of the biphenyl scaffold (compound L1), evaluated as a supporting ligand in Pd-catalyzed cyanation of aryl bromides using K4[Fe(CN)6] as the non-toxic cyanide source. The less sterically demanding ligand L1 was found to form more active catalysts than the newly prepared compound L2. A catalyst formed in situ from palladium(II) acetate and L1 efficiently mediated cyanation of aryl bromides bearing electron-donating substituents but failed in the analogous reactions with electron-poor substrates.

Xenon Difluoride Mediated Fluorodecarboxylations for the Syntheses of Di- and Trifluoromethoxyarenes

XeF2 is demonstrated to be a more proficient fluorine-transfer reagent than either NFSI or Selectfluor in fluorodecarboxylations of both mono- and difluoroaryloxy acetic acid derivatives. This method efficiently converts a wide range of neutral and electron-poor substrates to afford the desired di- and trifluoromethyl aryl ethers in good to excellent yields. The purifications are facile, and the reaction times are less than 5 min, which makes these fluorodecarboxylations promising for future PET-imaging applications.

Synthesis of Indole-2-carboxylate Derivatives via Palladium-Catalyzed Aerobic Amination of Aryl C-H Bonds.

A direct oxidative C-H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C-H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.

ChemInform Abstract: Heterogeneous Cu‐MnO Catalyzed Monoselective ortho‐Halogenation of Aromatic C—H Bonds under Visible Light.

Heterogeneous Cu-MnO-catalyzed selective monohalogenation of aromatic compounds with cheap N-halosuccinimide (NXS) as a halogenating agent in the presence of molecular oxygen as an oxidant, under irradiation with visible light is reported. Monochlorination, bromination, and iodinations were achieved in a highly selective fashion. Our developed heterogeneous Cu-MnO catalyst without any additive and ligands works well for halogenation with electron-rich substrates and also works selectively with electron poor substrates. Moreover, chlorination occurs efficiently with the more challenging substrates benzoic esters. The heterogeneous nature of the reaction was proven by hot filtration test.