Ortho Functionalization Research Articles

Pd-Catalyzed Remote δ-C(sp2)–H Functionalization in Phenylalaninol: Expanding the Library of Phenylalaninols

AbstractWe report the Pd(II)-catalyzed, picolinamide-directed δ-C(sp2)–H (ortho) functionalization of phenylalaninol scaffolds. Assembling of (ortho) δ-C–H arylated, alkylated, benzylated, alkenylated, brominated, and iodinated phenylalaninol scaffolds was accomplished. The δ-C(sp2)–H arylation reaction of phenylalaninol occurred under neat conditions. Hydrolysis of the picolinamide moiety and synthetic utility of the δ-C(sp2)–H arylated substrates were explored. We have also shown the preparation of some modified Matijin–Su (aurantiamide) derivatives using the bis δ-C–H (ortho) arylated phenylalaninol compounds obtained from the δ-C(sp2)–H arylation reaction (Matijin–Su is an anti-HBV agent possessing the phenylalaninol unit). Considering the importance of phenylalaninols, this work contributes to expanding the phenylalaninol library and demonstrates the substrate scope development in remote δ-C(sp2)–H functionalization reactions.

Palladium-Catalyzed Direct Selanylation of Chalcogenophenes and Arenes Assisted by 2-(Methylthio)amide.

The direct and selective conversion of a C-H bond into a C-Se bond remains a significant challenge, which is even more intricate with substrates having an innate regioselectivity under several reaction conditions, such as chalcogenophenes. We overrode their selectivity toward selanylation using palladium, copper, and the 2-(methylthio)amide directing group. This chelation-assisted direct selanylation was also suitable for mono and double ortho functionalization of arenes. The mechanistic studies indicate high-valent Pd(IV) species in the catalytic cycle, a reversible C-H activation step, and Cu(II) as a sequestering agent for organoselenide byproducts.

Construction of β‐Phenylalanine Derivatives through Pd‐Catalyzed, C(sp2)−H (ortho) Functionalization

AbstractThis paper describes the Pd(II)‐catalyzed, picolinamide‐directing‐group‐aided C(sp2)−H (ortho) functionalization of racemic and enantiopure β‐phenylalanines and 3‐amino‐3‐phenylpropanols (1,3‐amino alcohols). The C(sp2)−H (ortho) functionalizations including arylation, bromination, iodination, and alkoxylation were attempted. The C(sp2)−H (ortho) arylation reactions gave biaryl or terphenyl‐type β‐phenylalanine scaffolds, halogenation and methoxylation reactions gave ortho C−H halogenated or methoxylated β‐phenylalanines. Additionally, the C−H arylation of an ortho‐methyl substituted β‐phenylalanine containing both C(sp2)−H and remote C(sp3)−H bonds was investigated. β‐Phenylalanine is an arylated β‐amino acid motif present in various natural products, bioactive molecules, and β‐peptides and it is a precursor to medicinally active compounds. Accordingly, this work contributes to the expansion of the library of unnatural β‐phenylalanine (β‐amino acid) derivatives through site‐selective C−H functionalization.

Pd(II) and Rh(I) Catalytic Precursors for Arene Alkenylation: Comparative Evaluation of Reactivity and Mechanism Based on Experimental and Computational Studies.

We combine experimental and computational investigations to compare and understand catalytic arene alkenylation using the Pd(II) and Rh(I) precursors Pd(OAc)2 and [(η2-C2H4)2Rh(μ-OAc)]2 with arene, olefin, and Cu(II) carboxylate at elevated temperatures (>120 °C). Under specific conditions, previous computational and experimental efforts have identified heterotrimetallic cyclic PdCu2(η2-C2H4)3(μ-OPiv)6 and [(η2-C2H4)2Rh(μ-OPiv)2]2(μ-Cu) (OPiv = pivalate) species as likely active catalysts for these processes. Further studies of catalyst speciation suggest a complicated equilibrium between Cu(II)-containing complexes containing one Rh or Pd atom with complexes containing two Rh or Pd atoms. At 120 °C, Rh catalysis produces styrene >20-fold more rapidly than Pd. Also, at 120 °C, Rh is ∼98% selective for styrene formation, while Pd is ∼82% selective. Our studies indicate that Pd catalysis has a higher predilection toward olefin functionalization to form undesired vinyl ester, while Rh catalysis is more selective for arene/olefin coupling. However, at elevated temperatures, Pd converts vinyl ester and arene to vinyl arene, which is proposed to occur through low-valent Pd(0) clusters that are formed in situ. Regardless of arene functionality, the regioselectivity for alkenylation of mono-substituted arenes with the Rh catalyst gives an approximate 2:1 meta/para ratio with minimal ortho C-H activation. In contrast, Pd selectivity is significantly influenced by arene electronics, with electron-rich arenes giving an approximate 1:2:2 ortho/meta/para ratio, while the electron-deficient (α,α,α)-trifluorotoluene gives a 3:1 meta/para ratio with minimal ortho functionalization. Kinetic intermolecular arene ethenylation competition experiments find that Rh reacts most rapidly with benzene, and the rate of mono-substituted arene alkenylation does not correlate with arene electronics. In contrast, with Pd catalysis, electron-rich arenes react more rapidly than benzene, while electron-deficient arenes react less rapidly than benzene. These experimental findings, in combination with computational results, are consistent with the arene C-H activation step for Pd catalysis involving significant η1-arenium character due to Pd-mediated electrophilic aromatic substitution character. In contrast, the mechanism for Rh catalysis is not sensitive to arene-substituent electronics, which we propose indicates less electrophilic aromatic substitution character for the Rh-mediated arene C-H activation.

Molecular characterization of polyOAPS-imide isomer hyper-cross-linked membranes: Free-volume morphologies and sorption isotherms for CH4 and CO2

PolyPOSS-imides are hybrid hyper-cross-linked networks based on inorganic octa(aminopropyl)silsesquioxane (POSS) cages covalently bonded via organic imide bridges. They were initially developed for separations under harsh conditions, but they cannot be used above 300 °C due to the decomposition of their –(CH2)3– propyl linkers. Replacing the aliphatic-arm POSS with its phenyl-arm derivative, octa(aminophenyl)silsesquioxane (OAPS), should thus increase their resistance. However, OAPS has three possible isomers depending on the meta, para or ortho position of the –NH2 group on the phenyl ring. To pre-screen the most interesting structures before attempting synthesis, molecular dynamics (MD) simulations were recently used to compare twenty-two model networks based on the OAPS isomers, the initial POSS and several imide precursors at high temperatures. Six phenyl-arm polyOAPS-PMDA and polyOAPS-6FDA and two aliphatic-arm polyPOSS-PMDA and polyPOSS-6FDA were selected for further analyses of their CH4 and CO2 sorption isotherms at 35 °C. All of them have an average number of ~5 links per cage and cross-linking densities of ~3.8. In terms of connectivities and free-volume morphologies, both the metaOAPS and paraOAPS networks are found to be open structures with many low-energy sites and high penetrant solubilities. On the other hand, the ortho functionalization leads to denser morphologies associated to lower solubilities, which makes it closer to the POSS networks. Differences are enhanced when the inorganic precursor is associated to a rigid organic linker such as PMDA.The iterative GCMC (Grand Canonical Monte Carlo)-MD sorption-relaxation technique was used to predict the single-gas uptakes of CH4 and CO2 in the networks over an extended 0–60 bar pressure range at 35 °C. The sorption capacities varied in the order paraOAPS > metaOAPS > orthoOAPS > POSS for the inorganic precursor, and PMDA > 6FDA for the organic precursor (except for the orthoOAPS). All correlate directly to the accessible free-volume, but the CO2/CH4 ideal sorption selectivities remained essentially the same over the whole pressure range. Compared to POSS, OAPS showed less swelling at equivalent penetrant concentrations in the matrix. It is also more resistant to other mechanical deformations such as isotropic dilation or uniaxial tension. This confirms that the polyOAPS-imides can indeed be used under harsher conditions than the current polyPOSS-imides, without loss of the CO2/CH4 sorption selectivities.

Ruthenium(II)‐Catalyzed Direct Ortho Functionalization of 1‐Arylpyrazoles with Maleimides: A Condition Controlled Installation of Succinimides and Maleimides on Arenes

AbstractRuthenium(II)‐catalyzed switchable ortho functionalization of 1‐arylpyrazoles with maleimides is developed in this study. This divergent reaction proceeds via five‐membered ruthenacycle formation and selectively installs diverse succinimides and maleimides substituents on the aromatic ring of 1‐arylpyrazoles through alkylation and alkenylation under acidic and basic conditions. This methodology features broad substrate scope, high functional group tolerance, selective functionalization, and superior reactivity.

C–H Functionalization of Aromatic Amides

AbstractSince the beginning of the 21stcentury, significant progress has been made in transition metal‐catalyzed C–H functionalization of aromatic amides. The achievements in this field have mainly focused onortho(proximal) functionalization, there have been far fewer reports on remote C–H functionalization, andpara‐andmeta‐selective functionalizations remain a major challenge. Interestingly, there are few related comments in this field. In a few published cases, the scope of the report is relatively narrow, either to comment on the functionalization of a specific directing group or to summarize the functionalization of a specific reaction site. Herein, for the first time, we have comprehensively summarized the C–H functionalization of aromatic amides. This review is divided into three parts:ortho‐,para‐andmeta‐C–H functionalization of aromatic amides, and is subdivided according to the type of catalyst. The directing groups, reaction types, conditions, mechanism and applications of the corresponding reactions are discussed in detail.magnified image

Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catalysis

Palladium/norbornene (Pd/NBE) cooperative catalysis, also known as the Catellani reaction, has become an increasingly useful method for site-selective arene functionalization; however, certain constraints still exist due to its intrinsic mechanistic pathway. Herein we report a redox-neutral ortho functionalization of aryl boroxines via Pd/NBE catalysis. An electrophile, such as carboxylic acid anhydrides or O-benzoyl hydroxylamines, is coupled at the boroxine ortho position, and a proton as the second electrophile is introduced at the ipso position. This reaction does not require extra oxidants or reductants, and avoids stoichiometric bases or acids, thereby tolerating a wide range of functional groups. In particular, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated, which could be used to control reaction sequences. Finally, a deuterium labelling study supports the ipso-protonation pathway. This unique mechanistic feature could inspire the development of a new class of Pd/NBE-catalyzed transformations.

Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis.

Achieving site-selectivity in arene functionalization that is complementary to the site-selectivity from electrophilic aromatic substitution reactions has been a long-standing quest in organic synthesis. Palladium/norbornene cooperative catalysis potentially offers a unique approach to this problem, but its use has been hampered by the ortho constraint, which is the requirement of an ortho substituent for mono ortho functionalization of haloarenes. Here, we show that such a challenge could be addressed using a new class of bridgehead-modified norbornenes, thereby enabling a broadly useful strategy for arene functionalization with complementary site-selectivity. A range of ortho-unsubstituted aryl iodides, previously problematic substrates, can now be employed to provide mono ortho-functionalized products effectively. This method is applicable for late-stage functionalization of complex bioactive molecules at positions that are difficult to reach by conventional approaches.

Modular ipso/ ortho Difunctionalization of Aryl Bromides via Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing poly substituted arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard substrates for Pd-catalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development of general approaches for aryl bromide-mediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Importantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility of these methods has been demonstrated in sequential cross coupling/ ortho functionalization reactions, consecutive Pd/NBE-catalyzed difunctionalization to construct penta-substituted aromatics and two-step meta functionalization reactions. Moreover, the origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic compounds.

Synthesis of Highly Substituted Arenes via Cyclohexadiene–Alkene C–H Cross Coupling and Aromatization

The development of a cross-coupling method for the regioselective β-alkenylation of 2,5-cyclohexadiene carboxylic acid derivatives to form ortho-alkenylarenes through in situ decarboxylation and aromatization is described. The carboxylic acid functionality is used as a traceless directing group for efficient and mild β-alkenylation. The modular sequence comprises a reductive Birch α-alkylation, ionic δ-alkylation followed by a Pd-catalyzed decarboxylative β-alkenylation with subsequent aromatization resulting in an overall three-fold ipso–para–ortho functionalization of readily accessed benzoic acid derivatives. Efficient synthesis of various alkyl-alkenylarenes under mild conditions in moderate to excellent yields is presented.

ChemInform Abstract: Iron‐Catalyzed Arylation of Heterocycles via Directed C—H Bond Activation.

AbstractEmploying an imine directing group allows for the ortho functionalization of N‐,O‐, and S‐containing heterocycles within a short time.

Iron-catalyzed arylation of heterocycles via directed C-H bond activation.

The iron-catalyzed arylation of aromatic heterocycles, such as pyridines, thiophenes, and furans, has been achieved. The use of an imine directing group allowed for the ortho functionalization of these heterocycles with complete conversion in 15 min at 0 °C. Yields up to 88% were observed in the synthesis of 15 heterocyclic biaryls.

Electrochemical Ortho Functionalization of 2-Phenylpyridine with Perfluorocarboxylic Acids Catalyzed by Palladium in Higher Oxidation States

The electochemical oxidation of palladium acetate or palladium perfluoroacetate in the presence of 2-phenylpyridine promotes catalytic ortho C–H substitution reactions. As possible intermediates, Pd(II) metallacycles with Pd-bound acetate, perfluoroacetate, and perfluoroheptanoate substituents have been isolated and characterized: binuclear [(PhPy)Pd(μ-OAc)]2 and [(PhPy)Pd(μ-TFA)]2 and mononuclear [(PhPy)Pd(TFA)](CH3CN), [(PhPy)Pd(TFA)](PhPy), and [(PhPy)Pd(PFH)](PhPy). The fluorinated derivatives were found to exist in solvent-dependent equilibria between mononuclear and binuclear forms. Cyclic voltammetry was used to elucidate redox properties of the palladacycles and the oxidation route to the final products.

Enantioselective Synthesis of Atropisomeric Benzamides through Peptide-Catalyzed Bromination

We report the enantioselective synthesis of atropisomeric benzamides employing catalytic electrophilic aromatic substitution reactions involving bromination. The catalyst is a simple tetrapeptide bearing a tertiary amine that may function as a Brønsted base. A series of tri- and dibrominations were accomplished for a range of compounds bearing differential substitution patterns. Tertiary benzamides represent appropriate substrates for the reaction since they exhibit sufficiently high barriers to racemization after ortho functionalization. Mechanism-driven experiments provided some insight into the basis for selectivity. Examination of the observed products at low conversion suggested that the initial catalytic bromination may be regioselective and stereochemistry-determining. A complex between the catalyst and substrate was observed by NMR spectroscopy, revealing a specific association. Finally, the products of these reactions may be subjected to regioselective metal-halogen exchange and trapping with I(2), setting the stage for utility.

ChemInform Abstract: Synthesis of 3‐Trifluoromethylbenzo[b]furans from Phenols via Direct ortho Functionalization by Extended Pummerer Reaction.

AbstractA variety of para‐, ortho‐ and meta‐substituted phenols is directly converted to the target 2‐methylthio‐3‐trifluoromethylbenzofurans in a Tf2O‐mediated reaction.

Functionalization of Methyl (R)-Phenylglycinate Through Orthopalladation: C−Hal, C−O, C−N, and C−C Bond Coupling

The ortho functionalization of methyl R-phenylglycinate has been easily achieved using the known orthopalladated complex [Pd(mu-Cl){R-C(6)H(4)(CH(CO(2)Me)NH(2))-2}](2) (1) as synthetic tool. Different functional groups have been introduced at the ortho position of the aryl ring. The reaction of (R)-1 with X(2) or PhI(OAc)(2) gives XC(6)H(4)(CH(CO(2)Me)NH(2))-2 (X = I, Br, OMe, OEt) through oxidative coupling, while the reaction with CO gives an isoindolone. (R)-1 also reacts with one, two, or three alkyne molecules to give different metal-containing or metal-free heterocycles. The resulting functionalized amino esters or heterocycles retain the chirality of (R)-1, according with the values of the optical rotation and the obtained ee values ranging from 22%-87%. The X-ray structures of six representative compounds have also been determined.

Highly Regio‐, Diastereo‐, and Enantioselective [2+2+2] Cycloaddition of 1,6‐Enynes with Electron‐Deficient Ketones Catalyzed by a Cationic RhI/H8‐binap Complex

Two quaternary carbon centers are created in the title reaction to form fused dihydropyrans (see scheme). The same catalyst promotes the ortho functionalization of aryl ketones with 1,6-enynes with excellent regio- and enantioselectivity. Z=amide, C(CO2Me)2, O; E=CO2Et, Ac; R1=Me, aryl, CO2Me; R2=Me; R3=Me, CO2Et. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z704758_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Indirect ortho Functionalization of Substituted Toluenes Through ortho Olefination of N,N‐Dimethylbenzylamines Tuned by the Acidity of Reaction Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Total Synthesis of the Cyclopeptide Alkaloid Abyssenine A. Application of Inter- and Intramolecular Copper-Mediated Coupling Reactions in Organic Synthesis

The first total synthesis of the 15-membered ring cyclopeptide alkaloid abyssenine A 1 has been achieved with a longest linear sequence of 15 steps. Central to the synthetic approach was an efficient copper-mediated Ullmann coupling/Claisen rearrangement sequence allowing for both ipso and ortho functionalization of aromatic iodide 4. This sequence was used for the synthesis of the aromatic core. The synthetic utility of copper-catalyzed coupling reactions was further demonstrated to install the enamide with a concomitant straightforward macrocyclization starting from acyclic alpha-amido-omega-vinyl iodide 13.