Coupling Of Phenols Research Articles

Cost Efficient Synthesis of Diaryl Ethers Catalysed by CuI, Imidazolium Chloride and Cs2CO3

AbstractSynthetically versatile imidazolium chlorides, especially 1,3‐bis‐(2,6‐diisopropylphenyl)‐imidazolium chloride (IPrHCl) along with copper (I) iodide and cesium carbonate, were found to be useful to form C−O bonds via coupling of phenols and aryl/heteroaryl bromides. In this catalysis, the metal:ligand (Cu:IPr) loading was optimised to 1.0 mol%, making it an inexpensive and a simple one pot catalytic route for synthesising a variety of diaryl ethers. The catalytic cycle was probed by UV‐Vis, FT‐IR and HRMS techniques confirming involvement of a copper‐imidazolium‐carbonate complex.

Development of the radical C–O coupling reaction of phenols toward the synthesis of natural products comprising a diaryl ether skeleton

Compounds comprising a diaryl ether skeleton exist among natural phenols. The diaryl ether skeleton is thought to be biosynthesized through the coupling of two or more phenols. It is an important structural feature in medicines and agrochemicals, and it is imperative to develop methods for constructing such skeletons in organic synthesis. However, by the synthesis method through the coupling of phenols, coupling occurs preferentially at the ortho-substituted carbon atom of phenols. In this study, various radical-generating reagents and conditions were investigated with the aim of developing a short-step construction method of the diaryl ether skeleton by the radical homo-coupling of two phenol molecules. In addition, cross-coupling reactions between radicals of 2,4,6-tri-tert-butylphenol and p-substituted phenol were conducted to synthesize eight C (ortho)–O coupling products. Based on the results, a computational chemical approach was employed to verify the cause of C (ortho)–O bond formation.

Enantioselective Phenol Coupling by Laccases in the Biosynthesis of Fungal Dimeric Naphthopyrones.

Biaryl compounds are ubiquitous metabolites that are often formed by dimerization through oxidative phenol coupling. Hindered rotation around the biaryl bond can cause axial chirality. In nature, dimerizations are catalyzed by oxidative enzymes such as laccases. This class of enzymes is known for non-specific oxidase reactions while inherent enantioselectivity is hitherto unknown. Here, we describe four related fungal laccases that catalyze γ-naphthopyrone dimerization in a regio- and atropselective manner. In vitro assays revealed that three enzymes were highly P-selective (ee >95 %), while one enzyme showed remarkable flexibility. Its selectivity for M- or P-configured dimers varied depending on the reaction conditions. For example, a lower enzyme concentration yielded primarily (P)-ustilaginoidin A, whereas the M atropisomer was favored at higher concentration. These results demonstrate inherent enantioselectivity in an enzyme class that was previously thought to comprise only non-selective oxidases.

Enantioselective Phenol Coupling by Laccases in the Biosynthesis of Fungal Dimeric Naphthopyrones

AbstractBiaryl compounds are ubiquitous metabolites that are often formed by dimerization through oxidative phenol coupling. Hindered rotation around the biaryl bond can cause axial chirality. In nature, dimerizations are catalyzed by oxidative enzymes such as laccases. This class of enzymes is known for non‐specific oxidase reactions while inherent enantioselectivity is hitherto unknown. Here, we describe four related fungal laccases that catalyze γ‐naphthopyrone dimerization in a regio‐ and atropselective manner. In vitro assays revealed that three enzymes were highly P‐selective (ee >95 %), while one enzyme showed remarkable flexibility. Its selectivity for M‐ or P‐configured dimers varied depending on the reaction conditions. For example, a lower enzyme concentration yielded primarily (P)‐ustilaginoidin A, whereas the M atropisomer was favored at higher concentration. These results demonstrate inherent enantioselectivity in an enzyme class that was previously thought to comprise only non‐selective oxidases.

Cobalt(II)[salen]-Catalyzed Selective Aerobic Oxidative Cross-Coupling between Electron-Rich Phenols and 2-Naphthols.

A selectivity-driven catalyst design approach was adopted to address chemoselectivity issues in the oxidative coupling of phenols. This approach was utilized for developing a Co(II)[salen]-catalyzed aerobic oxidative cross-coupling of phenols in a recyclable 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvent. The waste-free conditions offer a sustainable entry to nonsymmetric biphenols via a mechanistic scheme that involves coupling of a liberated phenoxyl radical with a ligated 2-naphthoxyl radical.

Fungal Dirigent Protein Controls the Stereoselectivity of Multicopper Oxidase-Catalyzed Phenol Coupling in Viriditoxin Biosynthesis.

Paecilomyces variotii produces the antibacterial and cytotoxic ( M)-viriditoxin (1) together with a trace amount of its atropisomer ( P)-viriditoxin 1'. Elucidation of the biosynthesis by heterologous pathway reconstruction in Aspergillus nidulans identified the multicopper oxidase (MCO) VdtB responsible for the regioselective 6,6'-coupling of semiviriditoxin (10), which yielded 1 and 1' at a ratio of 1:2. We further uncovered that VdtD, an α/β hydrolase-like protein lacking the catalytic serine, directs the axial chirality of the products. Using recombinant VdtB and VdtD as cell-free extracts from A. nidulans, we demonstrated that VdtD acts like a dirigent protein to control the stereoselectivity of the coupling catalyzed by VdtB to yield 1 and 1' at a ratio of 20:1. Furthermore, we uncovered a unique Baeyer-Villiger monooxygenase (BVMO) VdtE that could transform the alkyl methylketone side chain to methyl ester against the migratory aptitude.

Access to Biphenyls by Palladium-Catalyzed Oxidative Coupling of Phenyl Carbamates and Phenols

The oxidative cross-coupling of phenols (3 equiv) to various substituted phenyl N,N-diethylcarbamates was explored with a variety of substrates. Pd(OAc)2 was employed as the catalyst (20 mol%) and K2S2O8 as the stoichiometric oxidant in trifluoroacetic acid as the solvent (50 °C, 2 h). Carbamates without or with a substituent on the phenyl ring (Me, Ph, Cl, OMe) underwent the reaction unless the phenyl substituent was too strongly electron withdrawing (CN). Cross-coupling occurred exclusively in the ortho position relative to the carbamate group. The regioselectivity at the phenol (ortho or para to hydroxy) was mainly determined by steric factors. Yields up to 60–70% were achieved for specific carbamate/phenol combinations.

Temperature-dependent growth and hypericin biosynthesis in Hypericum perforatum

Hypericum perforatum is a perennial herb that produces the anti-depression metabolite hypericin (Hyp). While several efforts to increase Hyp production have been made, the effects of temperatures on growth and Hyp biosynthesis are still limited. In this study, the growth morphophysiological traits, Hyp biosynthesis and their related genes expression, as well as major bioactive compounds accumulation and antioxidant capacity were assessed by exposing H. perforatum seedlings to three different temperatures (15, 22 and 30 °C). The results showed that aerial parts biomass was greater at 15 °C with 1.3 and 1.6-fold increase compared to at 22 and 30 °C, in large part because of greater increase in chlorophyll content, stem number and leaf area on a per plant basis. Hyp content in the aerial parts was greater 1.9 and 5.6-fold on a per plant basis compared to 22 and 30 °C treatments, and the contents of other bioactive compounds (flavonoids and phenolics) as well as antioxidant capacity in the aerial parts, on dry weight and per plant basis, also exhibited significant increases with the temperatures decrease. The mRNA expressions of eight genes (psbA, psbB, psbC, psbD, ycf3, ycf4, ycf5 and matK) related to photosynthesis and two genes (Polyketide synthase, PKS; Phenolic oxidative coupling protein, Hyp-1) involved in Hyp biosynthesis were also up-regulated at 15 °C. The findings are useful in guiding cultivation and regulating Hyp biosynthesis in H. perforatum.

Cover Feature: Direct Metal‐ and Reagent‐Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis (Chem. Eur. J. 28/2019)

Driven by electricity, a powerful and sustainable synthesis of sulfones is possible. This work reports on a direct reagent- and metal-free coupling of phenols with sulfinates using electrosynthesis. This conversion is characterized by its high atomic economy and its simple implementation. The use of sulfinates as a coupling substrate and supporting electrolyte is remarkable, making the usage of additional supporting electrolyte superfluous. More information can be found in the Communication by S. R. Waldvogel et al. on page 6891.

Eight-Step Total Synthesis of Phalarine by Bioinspired Oxidative Coupling of Indole and Phenol.

We report for the first time that the benzofuro[3,2-b]indoline framework could be obtained by PIDA-mediated direct oxidative coupling of 2,3-disubstituted-indoles with phenols. Application of this chemistry allows for an eight-step total synthesis of phalarine from commercially available tryptamine.

Eight‐Step Total Synthesis of Phalarine by Bioinspired Oxidative Coupling of Indole and Phenol

AbstractWe report for the first time that the benzofuro[3,2‐b]indoline framework could be obtained by PIDA‐mediated direct oxidative coupling of 2,3‐disubstituted‐indoles with phenols. Application of this chemistry allows for an eight‐step total synthesis of phalarine from commercially available tryptamine.

Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and Catechols

We describe a selective, catalytic aerobic cross-dehydrogenative coupling (CDC) reaction of phenols and catechols that creates aryl ethers. To avoid challenges of selectivity, we employ copper (Cu) coordination to confine substrate redox to the inner coordination sphere of the metal. This minimizes nonselective radical processes to provide high levels of selectivity for cross over homo coupling, by C–O instead of C–C bond formation. The method remains efficient on synthetically useful substrates and scales and enables a convergent synthesis of the tetrahydroisoquinoline alkaloid (S, S)-thalicarpine featuring diaryl ether formation in the late stages of the synthesis. Related molecules are difficult to prepare by traditional Ullman-type coupling and provide a benchmark for evaluating the potential utility of our methodology.

Interfacial Domain Formation Enhances Electrochemical Synthesis

The electroorganic C,C coupling of phenols to other aryl components is controlled by the fluoroalcohol-alcohol mixture solvents. Classical molecular dynamics and static density functional theory reveal that both kinds of solvents interact with the substrates, influencing the electronic structure of a phenoxyl radical intermediate in a cooperative manner to achieve maximal efficiency and selectivity. Simulations of the electrolyte-electrode interface showed that the substrates adsorb on the diamond surface in such a way that the repulsive fluorous-lipophilic interactions can be minimized and the attractive lipophilic-lipophilic interplay can be maximized, whereas the advantageous hydrogen bonding with the solvent can be retained. Accordingly, the solvent induces efficiency through the interaction of hydrogen bonding and the structure that controls the mesoscopic separation in these fluids. Since these findings are not specific to electrochemistry, by extending this principle to other heterogeneous processes, e.g., catalysis, their rate, yield, and selectivity can be potentially increased as well.

C-X (X = N, O) Cross-Coupling Reactions Catalyzed by Copper-Pincer Bis(N-Heterocyclic Carbene) Complexes.

Over the last two decades, N-heterocyclic carbene (NHC)–copper catalysts have received considerable attention in organic synthesis. Despite the popularity of copper complexes containing monodentate NHC ligands and recent development of poly(NHC) platforms, their application in C–C and C–heteroatom cross-coupling reactions has been limited. Recently, we reported an air-assisted Sonogashira-type cross-coupling catalyzed by well-defined cationic copper-pincer bis(NHC) complexes. Herein, we report the application of these complexes in Ullmann-type C–X (X = N, O) coupling of azoles and phenols with aryl halides in a relatively short reaction time. In contrast to other well-defined copper(I) catalysts that require an inert atmosphere for an efficient C–X coupling, the employed Cu(I)-pincer bis(NHC) complexes provide good to excellent yields in air. The air-assisted reactivity, unlike that in the Sonogashira reaction, is also affected by the base employed and the reaction time. With Cs2CO3 and K2CO3, the oxygen-generated catalyst is more reactive than the catalyst formed under argon in a short reaction time (12 h). However, the difference in reactivity is compromised after a 24 h reaction with K2CO3. The efficient pincer Cu-NHC/O2/Cs2CO3 system provides great to excellent cross-coupling yields for electronically diverse aryl iodides and imidazole derivatives. The catalyst scope is controlled by a balance between nucleophilicity, coordinating ability, and the steric hindrance of aryl halides and N-/O-nucleophiles.

Selective Oxidative Phenol Coupling by Iron Catalysis.

The iron-catalyzed oxidative coupling of phenols has emerged as a powerful method for preparing complex phenolic frameworks from simple and readily available compounds. This synopsis describes the selectivity challenges inherent in oxidative coupling reactions while at the same time presents our mechanistic-driven strategy employed to confront them.

Asymmetric Construction of Heterocycles via Dearomative Coupling and Addition Reactions of Phenol and Aniline Derivatives

Asymmetric Construction of Heterocycles via Dearomative Coupling and Addition Reactions of Phenol and Aniline Derivatives

Biobased phenol and furan derivative coupling for the synthesis of functional monomers

Generally, chemistry, and in particular polymer chemistry, faces the major challenge of finding solutions to ensure the sustainable and environmentally benign development of industry to meet consumer needs.

Copper‐Catalyzed Coupling Reactions of Aryl Halides and Phenols by 4,4’‐Dimethoxy‐2,2’‐bipyridine and 4,7‐Dimethoxy‐1,10‐phenanthroline

AbstractSeveral Cu(I) complexes of 2,2’‐bipyridines were studied for the catalytic coupling of aryl iodides and phenols and 4,4’‐dimethoxy‐2,2’‐bipyridine was shown to be an effective ligand of CuI in 1:2 (CuI:ligand) ratio for the synthesis of a wide range of diaryl ethers (up to 97% yield) using K3PO4 as base in DMF at 100 °C. The catalysis was highly dependent on the reaction temperature and was successfully applied in the coupling with more attractive and challenging substrates, aryl bromides, at 140 °C in good‐to‐excellent yields (78−95%). Moreover, the heteroaromatic effect for the reaction was studied and gave a comparable result with phenyl group (up to 95% yield). Significantly, a structurally related N,N‐bidentate ligand, 4,7‐dimethoxy‐1,10‐phenanthroline, exhibited better performance for less‐reactive combinations of aryl halides and phenols.

A convenient synthesis of phenols

Anilines are rapidly, often within 60 minutes, converted into the corresponding phenols in up to 87% isolated yield. The presented experimentally simple protocol display broad compatibility with a variety of functional groups, and in particular, well suited for the preparation of methyl-substituted phenols. Such phenols are not easily available by other synthetic approaches. The formation of phenolic radical coupling products was not observed even for activated anilines using this open flask method.

Enantioselective Vanadium-Catalyzed Oxidative Coupling: Development and Mechanistic Insights

The evolution of a more reactive chiral vanadium catalyst for enantioselective oxidative coupling of phenols is reported, ultimately resulting in a simple monomeric vanadium species combined with a Brønsted or Lewis acid additive. The resultant vanadium complex is found to effect the asymmetric oxidative ortho-ortho coupling of simple phenols and 2-hydroxycarbazoles with good to excellent levels of enantioselectivity. Experimental and quantum mechanical studies of the mechanism indicate that the additives aggregate the vanadium monomers. In addition, a singlet to triplet crossover is implicated prior to carbon-carbon bond formation. The two lowest energy diastereomeric transition states leading to the enantiomeric products differ substantially with the path to the minor enantiomer involving greater torsional strain between the two phenol moieties.