Cross-coupling Methodology Research Articles

Total Synthesis of Exiguamines A and B Inspired by Catecholamine Chemistry

The evolution of a total synthesis of the exiguamines, two structurally unusual natural products that are highly active inhibitors of indolamine-2,3-dioxygenase (IDO), is described. The ultimately successful strategy involves advanced cross-coupling methodology and features a potentially biosynthetic tautomerization/electrocyclization cascade reaction that forms two heterocycles and installs a quaternary ammonium ion in a single synthetic operation.

Nickel Catalyzed Cross-Coupling of Aryl C–O Based Electrophiles with Aryl Neopentylglycolboronates

The efficiency of mesylates, sulfamates, esters, carbonates, carbamates, and methyl ethers as C-O-based electrophiles attached to the 1- or 2-position of naphthalene and to activated and nonactivated phenyl substrates was compared for the first time in Ni-catalyzed cross-coupling with phenyl neopentylglycolboronates containing electron-rich and electron-deficient substituents in their para-position. These experiments were performed in the presence of four different Ni(II)- and Ni(0)-based catalysts. Ni(II)-based catalysts mediate the cross-coupling of most 2-naphthyl C-O electrophiles with both arylboronic acids and with neopentylglycolboronates when K(3)PO(4) is used as base. The same catalysts are not efficient when CsF is used as base. However, Ni(0)-based catalysts exhibit selective efficiency, and when reactive, their efficiency is higher than that of Ni(II)-based catalysts in the presence of both K(3)PO(4) and CsF. These results provide both reaction conditions for the cross-coupling, and for the elaboration of orthogonal cross-coupling methodologies of various C-O based electrophiles with aryl neopentylglycolboronates. With the exception of mesylates and sulfamates the efficiency of all other 2-naphthyl C-O electrophiles was lower in cross-coupling with aryl neopentylglycolboronates than with arylboronic acids.

Synthesis of 6-aryl-2′-deoxyuridine nucleosides via a Liebeskind cross-coupling methodology

Hitherto, the synthesis of 6-substituted 2′-deoxyuridine nucleoside analogues via Pd-catalyzed Suzuki cross-coupling reaction was hampered by the instability of the TIPDS-protected precursor 6-iodo-2′-deoxyuridine 1 in alkaline media due to cleavage of the glycosidic bond. Herein, the successful application of the Liebeskind reaction under base-free conditions is reported. This method comprises of the stoichiometric use of copper thiophene carboxylate (CuTC) as co-reagent at slightly elevated temperatures. Fluoride-mediated desilylation and Yoshikawa-phosphorylation afforded the nucleotide analogues 4b–c, 4e, and 4i.

Nickel‐Catalyzed Cross‐Coupling of Aryl Bromides with Tertiary Grignard Reagents Utilizing Donor‐Functionalized N‐Heterocyclic Carbenes (NHCs)

One, two or three? The utilization of sterically hindered alkyl substrates represents a major challenge of the present cross-coupling methodology. The nickel-catalyzed Kumada cross- coupling of tertiary alkyl Grignard reagents with aryl bromides allows this difficult reaction with numerous different substrates. Optimal results were obtained using sterically demanding, bifunctional N-heterocyclic carbene ligands.

Synthetic Routes to 5,10,15-Triaryl-tetrabenzocorroles

Two different synthetic routes for the preparation of 5,10,15-triaryl-tetrabenzocorroles have been developed. The first approach is based on the condensation of a tetrahydroisoindole with aryl-aldehydes, and the second pathway involves a cross-coupling reaction between a bromo-substituted corrole and a suitable substrate to form the four β-fused aryl rings. These routes are successful to lead to the target tetrabenzocorroles, obtained in both cases as the corresponding Cu complex and with the highest yield obtained via the one-step cross-coupling methodology. Demetalation of the Cu-tetrabenzocorrole produces the corresponding free base; this macrocycle was further exploited to obtain the Sn and Co complexes in good yields.

Nickel‐Catalyzed Cross‐Coupling of Phenols and Arylboronic Acids Through an In Situ Phenol Activation Mediated by PyBroP

A new method for the Suzuki-Miyaura cross-coupling of phenols and arylboronic acids through in situ phenol activation mediated by PyBroP is presented. The reaction proceeds efficiently by using cost-effective, markedly stable [NiCl(2)(dppp)] (dppp=1,3-bis(diphenylphosphino)propane) as the catalyst in only 5 mol % loading, as well as in the absence of extra ligands. The method exhibits broad applicability and high efficiency towards a wide range of both phenols and boronic acids, including activated, nonactivated, deactivated, and heteroaromatic coupling partners. In addition, various functional groups, such as ether, amino, cyano, ester, and ketone groups, are compatible with this transformation. Notably, arylboronic acids containing an unprotected NH(2) group and 2-heterocyclic boronic acids, which are generally problematic for coupling under conventional conditions, are also viable substrates, although moderate yields were obtained for sterically hindered substrates. Consequently, the in situ cross-coupling methodology coupled with the use of an inexpensive and stable nickel catalyst provides a rapid and efficient pathway for the assembly of biaryls and heterobiaryls with structural diversity from readily available phenol compounds.

Synthetic Studies toward A-74528

A potentially biomimetic approach toward the complex polyketide A-74528 is described. It is based on highly substituted biaryl compounds, synthesized using advanced cross-coupling and condensation methodologies.

A tetrapyridine ligand with a rigid tetrahedral core forms metal–organic frameworks with PtS type architecture

A new tetradentate, pyridine ligand with a rigid tetrahedral core can be prepared in good yield by a cross-coupling methodology. Two metal organic framework structures of Cu(II) with PtS-type topology having a carbon atom as the tetrahedral node have been characterized utilising this ligand.

Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates.

Based on structural analysis of the human 2-oxoglutarate (2OG) dependent JMJD2 histone N(ε)-methyl lysyl demethylase family, 3-substituted pyridine 2,4-dicarboxylic acids were identified as potential inhibitors with possible selectivity over other human 2OG oxygenases. Microwave-assisted palladium-catalysed cross coupling methodology was developed to install a diverse set of substituents on the sterically demanding C-3 position of a pyridine 2,4-dicarboxylate scaffold. The subsequently prepared di-acids were tested for in vitro inhibition of the histone demethylase JMJD2E and another human 2OG oxygenase, prolyl-hydroxylase domain isoform 2 (PHD2, EGLN1). A subset of substitution patterns yielded inhibitors with selectivity for JMJD2E over PHD2, demonstrating that structure-based inhibitor design can enable selective inhibition of histone demethylases over related human 2OG oxygenases.

Exploring the selectivity of the Suzuki–Miyaura cross-coupling reaction in the synthesis of arylnaphthalenes

A series of 1-arylnaphthalenes and 1,8-diarylnaphthalenes were synthesized by the Suzuki–Miyaura cross-coupling methodology showing significant differentiation in the yields and selectivity between aryl rings with electron donating (higher yields), and electron withdrawing substituents (lower yields). These results strongly support the relation between the nucleophilicity of the boronate complex and its reactivity, and emphasize the importance of the transmetalation step in the overall efficiency of this cross-coupling reaction. The results obtained with non-symmetric 1,8-diarylnaphthalenes indicate preference for arylation of an already arylated species (the 1-aryl-8-bromonaphthalene intermediate) over mono-arylation of 1,8-dibromonaphthalene. Evidences for the existence of intramolecular Pd⋯π and aromatic interactions in some Pd(II) complexes were found.

A guideline for the arylation of positions 4 and 5 of thiazole via Pd-catalyzed cross-coupling reactions

The arylation of thiazoles in 4- and 5-position was investigated in detail. Suzuki–Miyaura and Stille cross-coupling reactions were tested using thiazoles either as halide or organometal species. The obtained results were critically compared to develop helpful guidelines for selection of the cross-coupling methodology with the best potential for good and reliable results for a given synthetic problem without the need for tedious optimization of reaction parameters.

Allyl Vinyl Ethers by Copper-Promoted Coupling of Vinyl Boronates to Alcohols

A cross-coupling methodology for the synthesis of allyl vinyl ethers from vinyl boronates and allylic alcohols mediated by Cu(OAc)2 is reported and a plausible reaction mechanism is presented. A variety of functional groups is tolerated, such as acetals, esters or sulfides.

Synthesis and electrochemical characterization of new optoelectronic materials based on conjugated donor–acceptor system containing oligo-tri(heteroaryl)-1,3,5-triazines

A series of novel oligoarylenes based on donor–acceptor system, containing triazine moiety as an electron-transporting central core, have been prepared by electrochemical polymerization. The redox behaviour of poly(2,4,6-tri[ p-(2-(3,4-ethylenedioxythienyl))-phenyl]-1,3,5-triazine) was studied by cyclic voltammetry and triple in situ ESR/UV–vis–NIR spectroelectrochemistry to get more details on the type of charge carriers within the film. To obtain desired oligoarylenes, triazine-core monomers possessing various electrochromic side groups have been synthesized by the Stille cross-coupling methodology. The structures have been confirmed by 1H NMR, 13C NMR, and elemental analysis. Monomers show good chemical stability in common organic solvents such as chloroform, dichloromethane or toluene and also exhibit excellent thermal stability over wide range of temperatures. Furthermore, their photophysical properties have been established with the use of fluorescence spectroscopy. Electrochemical results accompanied with fluorescence spectroscopy suggest that these derivatives of triazine can be successfully used in the fabrication of organic light-emitting diodes (OLEDs).

Synthesis and Properties of Functionalized Oligo(arylene) Molecular Wires with Thiolated Termini: Competing Thiol-Au and Nitro-Au Assembly

We report the synthesis by Suzuki cross-coupling methodology of oligo(arylene) molecular wires with protected thiolates at both termini and a central electron-acceptor unit (3,5-dinitrofluorenone, compounds 10-12) or an electron-donor unit [9-(1,3-dithiol-2-ylidene)fluorene, compounds 14-17] in the backbone. Core reagents are 2,7-dibromo-3,5-dinitrofluorenone 7 (obtained by nitration of 2,7-dibromofluorenone) and 2,7-dibromo-9-(4,5-dimethyl-1,3-dithiol-2-ylidene)fluorene 13. The solution electrochemical redox properties of these oligo(arylene) derivatives have been studied. The reduction CVs of the dinitrofluorenone-containing molecules display three reversible/quasireversible couples yielding, sequentially, radical anion, dianion, and radical trianion species, e.g., for 11 E(1red) -1.02 V (vs. Ag/Ag(+) in THF). The 1,3-dithiol-2-ylidene unit imparts good electron donor properties to molecules 14, 15, and 16 with radical cation formation observed at E(ox) ca. 0.65 V (vs. Ag/Ag(+) in DCM). We also report studies on the assembly of 11 and 15 on gold substrates. Current-voltage (I-V) characteristics and X-ray photoelectron spectra of the monolayers reveal that 11 assembles via competing S-Au and NO(2)-Au interactions. This unusual phenomenon is ascribed to the very electron deficient dinitrofluorenone core of 11 weakening the S-Au interaction. An important conclusion is that thiolated molecules which possess strongly electron-withdrawing core units, especially those containing nitro groups, may not be suitable for controlled assembly in junctions. In contrast, 15 assembles via conventional S-Au interactions.

Synthesis and redox properties of racemic electroactive polymers containing axially chiral adamantyl segments

A method of introducing chirality directly into a polymer backbone has been developed that employs the dissymmetry of an adamantane derivative with axial chirality. This new chiral adamantane building block was readily functionalized with electroactive thiophene rings using palladium-catalyzed cross-coupling methodology. The two resulting electroactive monomers were electropolymerized to create racemic electroactive polymers containing phenyl-capped oligothiophene segments alternating with chiral adamantyl segments. Synthesis, electrochemistry, and spectroelectrochemistry studies are reported.

Synthesis and Properties of Functionalized 4 nm Scale Molecular Wires with Thiolated Termini for Self-Assembly onto Metal Surfaces

We report the synthesis of new oligo(aryleneethynylene) molecular wires of ca. 4 nm length scale by palladium-catalyzed Sonogashira cross-coupling methodology. Key structural features are the presence of electron donor 9-(1,3-dithiol-2-ylidene)fluorene (compounds 13 and 14) and electron acceptor 9-[di(4-pyridyl)methylene]fluorene units (compound 16) at the core of the molecules. Terminal thiolate substituents are protected as cyanoethylsulfanyl (13 and 16) or thioacetate derivatives (14). The molecules display well-defined redox processes in solution electrochemical studies. The optical properties in solution are similar to those of the fluorenone analog 6: the strongest absorptions for 6, 13 and 16 are in the region lambda(max) = 387-393 nm, with 13 showing an additional shoulder at 415 nm which is not present for 6 and 16; this shoulder is assigned to a HOMO-LUMO transition from the dithiole to the fluorene unit. Molecules 6, 13, 14 and 16 form self-assembled monolayers on gold substrates which exhibit essentially symmetrical current-voltage (I-V) characteristics when contacted by a gold scanning tunelling microscope (STM) tip. The effects of the chemical modifications at the central unit of 6, 14 and 16 on the HOMO-LUMO levels and electron transport through the molecules in vacuum have been computed by an ab initio approach.

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC(50) value of 0.12 nM, although seven of its congeners are also highly potent (IC(50)<or=0.5 nM). They all bear the (5-triazolylmethyl-2-cyano)biphenyl structural motif. Docking of representative compounds into a homology model of human aromatase assists in the rationalisation of the SAR derived from the in vitro biological results and supports a crucial role for a cyano group on the "A" phenyl ring, which is accessible to hydrogen bond interactions with Ser 478. Further development of these compounds as potential therapeutic agents for the treatment of hormone-dependent breast cancer is warranted given the high level of potency observed for this class of aromatase inhibitor in vitro.

Functionalized Heteroarylpyridazines and Pyridazin-3(2H)-one Derivatives via Palladium-Catalyzed Cross-Coupling Methodology

A general method for the synthesis of functionalized pyridazinylboronic acids/esters is described involving a directed ortho metalation (DoM)--boronation protocol (Schemes 1 and 2). A comprehensive study of the reactivity of the C-B bond in palladium-catalyzed cross-couplings with aryl/heteroaryl halides is presented. Aryl-/heteroarylpyridazines are thereby obtained in synthetically viable yields (typically 40-75%) although in some cases competing protodeboronation has been observed. A series of pyridazin-3(2H)-one derivatives, including 4,6-diaryl/heteroaryl derivatives, have been obtained from the corresponding 3-methoxypyridazines in straightforward procedures (Schemes 3 and 4). Several X-ray crystal structures of aryl-/heteroarylpyridazines and derived pyridazin-3(2H)-one derivatives are reported. These multi-ring systems are of considerable interest in contemporary N-heterocyclic chemistry.

The palladium-catalysed copper-free Sonogashira coupling of isoindoline nitroxides: a convenient route to robust profluorescent carbon–carbon frameworks

A series of novel acetylene-substituted isoindoline nitroxides were synthesised via palladium-catalysed copper-free Sonogashira coupling. These results demonstrate that the Sonogashira reaction is suitable for the generation of a wide range of aryl nitroxides of expanded structural variety. The novel aryl-iodide containing nitroxide, 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl, 3, was a key intermediate for this coupling, giving acetylene-substituted isoindoline nitroxides in high yield. Subsequent reaction of the deprotected ethynyl nitroxide 12 with iodinated polyaromatics furnished novel aromatic nitroxides with extended-conjugation. Such nitroxides have been described as profluorescent, as their quantum yields are significantly lower than those of the corresponding diamagnetic derivatives. The quantum yields of the naphthyl- and phenanthryl-acetylene isoindoline nitroxides (13 and 14) were found to be 200-fold and 65-fold less than the non-radical methoxyamine derivatives (23 and 24). Ethyne- and butadiyne-linked nitroxide dimers could also be synthesised by this cross coupling methodology.

Microwave-Assisted Double Suzuki-Miyaura Cross-Coupling in the 6,8-Dibromoimidazo[1,2-a]pyridine Series

New, potentially bioactive, imidazopyridine derivatives were synthesized in a highly efficient synthesis in four steps from 2-amino-3,5-dibromopyridine using microwave-assisted double Suzuki-Miyaura cross-coupling methodology.