- Enantioselective Cleavage of Cyclobutanols Through Ir-Catalyzed C?C Bond Activation: Mechanistic and Synthetic Aspects
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The Ir-catalyzed conversion of prochiral tert-cyclobutanols to β-methyl-substituted ketones proceeds under comparably mild conditions in toluene (45–110 °C) and is particularly suited for the enantioselective desymmetrization of β-oxy-substituted substrates to give products with a quaternary chirality center with up to 95 % ee using DTBM-SegPhos as a chiral ligand. Deuteration experiments and kinetic isotope effect measurements revealed major mechanistic differences to related RhI-catalyzed transformations. Supported by DFT calculations we propose the initial formation of an IrIII hydride intermediate, which then undergoes a β-C elimination (C?C bond activation) prior to reductive C?H elimination. The computational model also allows the prediction of the stereochemical outcome. The Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for substrates bearing strongly coordinating groups. The method is of particular value for the stereo-controlled synthesis of substituted chromanes related to the tocopherols and other natural products.
- Ratsch, Friederike,Strache, Joss Pepe,Schlundt, Waldemar,Neud?rfl, J?rg-Martin,Adler, Andreas,Aziz, Sarwar,Goldfuss, Bernd,Schmalz, Hans-Günther
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supporting information
p. 4640 - 4652
(2021/02/11)
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- Synthetic method 4 - alkoxyphenol compounds
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The invention discloses a synthetic method of 4 - alkoxyphenol compounds, and belongs to the field of organic chemical synthesis. The method is as follows: An aryl alkyl ether compound is added to the sealing tube. The catalyst dimerization acetic acid rhodium and the oxidizing agent iodobenzene diethyl ester are added, a solvent trifluoroacetic anhydride is added, and the 4 -alkoxyphenol compound is prepared by heating reaction. To the invention, high regioselectivity direct hydroxylation of the aryl alkyl ether compound is realized, the application range of the substrate is wide, the yield is high, the activity after amplification reaction does not significantly decay, and higher yield is still obtained. The utility model has good practicability and industrial application prospect.
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Paragraph 0070-0072
(2021/09/29)
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- Para -Selective hydroxylation of alkyl aryl ethers
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para-Selective hydroxylation of alkyl aryl ethers is established, which proceeds with a ruthenium(ii) catalyst, hypervalent iodine(iii) and trifluoroacetic anhydride via a radical mechanism. This protocol tolerates a wide scope of substrates and provides a facile and efficient method for preparing clinical drugs monobenzone and pramocaine on a gram scale.
- Zhu, Runqing,Sun, Qianqian,Li, Jing,Li, Luohao,Gao, Qinghe,Wang, Yakun,Fang, Lizhen
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supporting information
p. 13190 - 13193
(2021/12/16)
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- From simple phenols to potent chain-breaking antioxidants by transposition of benzo[1,4]oxathiines to benzo[b]thiophenes
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Simple phenols, including food stock recycled derivatives, were used for the synthesis of 1,4-benzooxathiine intermediates, with limited or no antioxidant activity. Depending upon their substitution pattern, these compounds, through an acid promoted transposition, can be converted into o-hydroxydihydrobenzo[b]thiophenes or o-hydroxy-benzo[b]thiophenes as a new class of potent chain-breaking antioxidants, showing, in the reaction with alkyl peroxyl radicals, kinetic rate constants (kinh) comparable to that of α?tocopherol, the more potent natural lipophilic phenolic antioxidant.
- Viglianisi, Caterina,Pietro, Leonardo Di,Meoni, Valentina,Amorati, Riccardo,Menichetti, Stefano
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- Regioselective synthesis of gentisyl alcohol-type marine natural products
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Gentisyl alcohol-type natural products, possessing various important biological properties, have been synthesized from 4-methoxyphenol by using a selective phenol monohydroxymethylation/monochlorination, a CAN oxidation and a sodium dithionite reduction as the key steps. The natural product synthesis is efficient, atom- and step-economical, and requires no protecting groups.
- Wang, Hong-Shuang,Li, Hui-Jing,Wang, Long-Fei,Shen, Zhi-Lun,Wu, Yan-Chao
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supporting information
p. 1891 - 1896
(2018/05/29)
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- Tripodal O-N-O Bis-Phenolato Amine Titanium(IV) Complexes Show High in vitro Anti-Cancer Activity
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The octahedral titanium(IV) complexes trans,mer-[Ti{R3N(CH2C6H2-2-O-4-R2-6-R1)2}2] (R1 = Me, OMe, Cl; R2 = Me, OMe, F, Cl; R3 = Me, Et; not all combinations) are synthesised in two steps from simple phenols in 36–53 % overall yield. The highly crystalline (4 X-ray structures) complexes are active against MCF-7 (breast) and HCT-116 (colon) cancer cell lines showing widely varying GI50 values in the range 1–100 μM depending on R1–R3. Highest activities are realised when R1 = OMe and R2, R3 = Me (GI50 ca. 1 μM for MCF-7 and 2–3 μM for HCT-116). These are respectively 8× and 3× times greater than the activities of cisplatin in the same cell lines. These titanium complexes show some significant selectivity for cancer cell lines; up to 7× higher in MCF-7 compared to non-cancer (MRC-5) fibroblast cells. Details of cellular mode of action indicators (cell cycle perturbation, Annexin V, γ-H2AX, and caspase studies) that point to an apoptosis mode for the most active compound (R1 = OMe and R2, R3 = Me) are also reported.||||||.
- Abid, Mohammed,Nouch, Ryan,Bradshaw, Tracey D.,Lewis, William,Woodward, Simon
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supporting information
p. 2774 - 2780
(2019/06/13)
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- Metal-Free Electrocatalytic Aerobic Hydroxylation of Arylboronic Acids
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Hydroxylation of arylboronic acids to aryl alcohols was realized by a scalable electrocatalytic method. The present electrochemical hydroxylation employs low-cost methyl viologen as an organic cathodic electrocatalyst and involves O2 as a green and sustainable reactant. The electrochemical kinetic studies shown here can be a powerful tool to gain rich mechanistic and kinetic information and thus an in-depth understanding of the electrocatalytic mechanism.
- Luo, Jian,Hu, Bo,Sam, Alyssa,Liu, T. Leo
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supporting information
p. 361 - 364
(2018/01/28)
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- Examination of Selectivity in the Oxidation of ortho- and meta-Disubstituted Benzenes by CYP102A1 (P450 Bm3) Variants
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Cytochrome P450 CYP102A1 (P450 Bm3) variants were used to investigate the products arising from the P450 catalysed oxidation of a range of disubstituted benzenes. The variants used all generated increased levels of metabolites compared to the wild-type enzyme. With ortho-halotoluenes up to six different metabolites could be identified whereas the oxidation of 2-methoxytoluene generated only two aromatic oxidation products. Addition of an ethyl group markedly shifted the selectivity for oxidation to the more reactive benzylic position. Epoxidation of an alkene was also preferred to aromatic oxidation in 2-methylstyrene. Significant minor products arising from the migration of one substituent to a different position on the benzene ring were formed during certain P450-catalysed substrate turnovers. For example, 2-bromo-6-methylphenol was formed from the turnover of 2-bromotoluene and the dearomatisation product 6-ethyl-6-methylcyclohex-2,4-dienone was generated from the oxidation of 2-ethyltoluene. The RLYF/A330P variant altered the product distribution enabling the generation of certain metabolites in higher quantities. Using this variant produced 4-methyl-2-ethylphenol from 3-ethyltoluene with ≥90 % selectivity and with a biocatalytic activity suitable for scale-up of the reaction.
- Munday, Samuel D.,Dezvarei, Shaghayegh,Lau, Ian C.-K.,Bell, Stephen G.
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p. 2512 - 2522
(2017/07/12)
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- Copper-Catalyzed Hydroxylation of (Hetero)aryl Halides under Mild Conditions
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The combination of Cu(acac)2 and N,N′-bis(4-hydroxyl-2,6-dimethylphenyl)oxalamide (BHMPO) provides a powerful catalytic system for hydroxylation of (hetero)aryl halides. A wide range of (hetero)aryl chlorides bearing either electron-donating or -withdrawing groups proceeded well at 130 °C, delivering the corresponding phenols and hydroxylated heteroarenes in good to excellent yields. When more reactive (hetero)aryl bromides and iodides were employed, the hydroxylation reactions completed at relatively low temperatures (80 and 60 °C, respectively) at low catalytic loadings (0.5 mol % Cu).
- Xia, Shanghua,Gan, Lu,Wang, Kailiang,Li, Zheng,Ma, Dawei
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supporting information
p. 13493 - 13496
(2016/10/31)
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- Direct synthesis of anilines and nitrosobenzenes from phenols
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A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution (iSOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.
- St Amant,Frazier,Newmeyer,Fruehauf,Read De Alaniz
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supporting information
p. 5520 - 5524
(2016/07/06)
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- Photocatalytic synthesis of dihydrobenzofurans by oxidative [3+2] cycloaddition of phenols
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We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible-light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.
- Blum, Travis R.,Zhu, Ye,Nordeen, Sarah A.,Yoon, Tehshik P.
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supporting information
p. 11056 - 11059
(2015/03/30)
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- Facile conversion of para-benzoquinones to para-alkoxyphenols with primary/secondary alcohols and amberlyst-15: A process showing novel reducing property of such alcohols
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A new efficient methodology has been developed for the synthesis of para-alkoxyphenols, an important group of anti-melanoma compounds, by heating alcoholic solutions of para-benzoquinones in the presence of amberlyst-15. The most notable feature here is the behaviour of the used primary or secondary alcohol as an effective reducing agent.
- Mondal, Rina,Guha, Chayan,Mallik, Asok K.
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supporting information
p. 86 - 89
(2014/01/06)
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- Optimization of the antioxidant activity of hydroxy-substituted 4-thiaflavanes: A proof-of-concept study
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The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (kinh), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of kinh up to 4.0× 106 M-1 s -1 and BDE(OH) of 77.2 kcal mol-1. This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles. Sulfur makes the difference (again): The stereoelectronic features triggered by the sulfur atom in the benzo-fused six-membered ring of 4-thiaflavanes have been exploited to design a new family of phenolic antioxidants that show an ability to react with peroxyl radicals identical to that of α-tocopherol, the main component of vitamin E and the most potent natural lipophilic antioxidant (see scheme). Copyright
- Viglianisi, Caterina,Bartolozzi, Maria Grazia,Pedulli, Gian Franco,Amorati, Riccardo,Menichetti, Stefano
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supporting information; experimental part
p. 12396 - 12404
(2011/11/29)
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- NOVEL ESTROGEN RECEPTOR LIGANDS
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The invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt: wherein R3 is selected from the group consisting of ORA; -CHO; -C(O)C1-4alkyl; -C(O)phenyl; -O-C(O)RA; and N(RB)2; R6 is selected from certain cyclic groups defined in the specification; and the remaining groups are defined in the specification; together with a pharmaceutically acceptable carrier. Most of the compounds are novel. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition associated with a disease or disorder associated with estrogen receptor activity.
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Page/Page column 29
(2009/11/29)
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- Fluorinated bis(phenoxyketimine)titanium complexes for the living, isoselective polymerization of propylene: Multiblock isotactic polypropylene copolymers via sequential monomer addition
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A series of bis(phenoxyketimine)titanium dichloride complexes were synthesized and evaluated as catalysts for living, isoselective propylene polymerization upon activation with methylaluminoxane (MAO). Catalysts bearing phenoxyketimine ligands with different substituents at the ortho and para positions of the phenolate ring and substituents at the ketimine carbon were investigated. The identity of the ketimine substituent had the largest effect on the activity and isoselectivity of propylene polymerization. Complex 12/MAO promoted the living, isoselective polymerization of propylene ([m4] = 0.73, α = 0.94). This catalyst system was used for the synthesis of a number of block copolymers featuring isotactic polypropylene semicrystalline blocks and poly(ethylene-co-propylene) amorphous blocks. Several triblock samples with varying block lengths, a pentablock, and a heptablock copolymer were synthesized. Mechanical testing has revealed that each is elastomeric with elongations at break between ～790-1000%.
- Edson, Joseph B.,Wang, Zhigang,Kramer, Edward J.,Coates, Geoffrey W.
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p. 4968 - 4977
(2008/09/21)
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- A combined experimental and theoretical study on the conformation of multiarmed chiral aryl ethers
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(Graph Presented) Four series of multiarmed chiral aryl ethers carrying two, three, five, or eight side-chains on a variety of aromatic core molecules (2-5) were prepared. The structure and conformation of 2 and 3 (in the solid state) were determined by the X-ray crystallographic analyses. While a pair of alternated (anti) conformers (i.e, up-down and down-up) were found in the crystal of 2, three side-arms in 3 were aligned in the same direction to give a C3-symmetric syn-conformation. Examinations by dispersion-corrected density functional (DFT-D) calculations revealed that two out of six anti- and two out of four syn-conformers of 2 are energetically most important. Two calculated structures of anti-conformers are in good agreement with those found in the solid state by X-ray analysis. Similarly, relevant conformations of syn-3, fully alternated 4, and C5-symmetric 5 were optimized at the DFT-D-B-LYP/TZVP level. The structure and conformation of the side-arms in 2-5 in solution were further studied by temperature dependent 1H NMR and UV-vis spectroscopy. In addition, comparative experimental and theoretical CD spectral studies were carried out in order to elucidate the contribution of the thermodynamically less-stable minor isomers in solution. The CD spectral changes observed for 2 and 3 at varying temperatures were quite different, while the parent chiral arene 1, as well as 4 and 5, only showed an increased intensity of the negative Cotton effect for the 1Lb band. The latter behavior is readily accounted for in terms of the conformational freezing of the chiral groups at low temperatures. The unusual CD spectral behavior observed for 2 and 3 was rationalized by the conformational alteration of the side-arms. Because of attractive van der Waals interactions between the aromatic units of the arms in nonpolar solvents, the syn-conformations become gradually more important for 2 at low temperatures, which eventually results in a weak positive Cotton effect for the 1Lb band. This was also supported by the SCS-MP2/TZVPP single-point energy calculations for the relevant conformers of 2. For 3, the contribution of the C3-symmetrical conformer becomes more important than the less-symmetrical isomers at low temperatures. The conformations of 2 and 3 in their excited states as well as in the oxidized states were also examined.
- Mori, Tadashi,Grimme, Stefan,Inoue, Yoshihisa
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p. 6998 - 7010
(2008/02/11)
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- Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents
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A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme sele
- Clark, Richard F.,Zhang, Tianyuan,Wang, Xiaojun,Wang, Rongqi,Zhang, Xiaolin,Camp, Heidi S.,Beutel, Bruce A.,Sham, Hing L.,Gu, Yu Gui
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p. 1961 - 1965
(2008/02/02)
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- Selective oxidation of phenol and anisole derivatives to quinones with hydrogen peroxide and polymer-supported methylrhenium trioxide systems
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A convenient and efficient application of heterogeneous poly(4-vinylpyridine)/methyl rhenium trioxide (PVP/MTO) systems for the selective oxidation of substituted phenol and anisole derivatives to benzoquinones is described. Environment friendly, easily available, and low cost H2O2 was used as the oxygen atom donor. All catalysts were stable systems for at least five recycling experiments. In the oxidation of some natural phenols such as cardanol derivatives higher conversion and yields of benzoquinones were observed with respect to MTO in homogeneous phase suggesting a support-mediated molecular recognition process based on hydrogen-bonding interactions.
- Saladino, Raffaele,Neri, Veronica,Mincione, Enrico,Filippone, Paolino
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p. 8493 - 8500
(2007/10/03)
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- QSAR for the cytotoxicity of 2-alkyl or 2,6-dialkyl, 4-X-phenols: The nature of the radical reaction
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In a continuation of studies on the radical mediated toxicity of phenols to leukemia cells, a set of di- and tri-substituted phenols with mostly alkyl substituents in the ortho position were examined. These analogs are similar in structure to the commercial antioxidants BHA and BHT. A QSAR analysis of their growth inhibitory constants led to the formulation of this simple but unusual equation based on 18 congeners: log 1/C = -0.47Es-2 + 2.42RR + 2.43; r3 = 0.934 ES-2 is the Taft steric parameter for the larger of the two ortho substituents while ER is Otsu's radical parameter, which was originally defined to correlate radical reactions.
- Selassie, Cynthia D.,Verma, Rajeshwar P.,Kapur, Sanjay,Shusterman, Alan J.,Hansch, Corwin
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p. 1112 - 1117
(2007/10/03)
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- Reactivity in cleavage of dimethoxybenzenes by sodium in liquid ammonia
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The sodium/liquid ammonia cleavage of the dimethoxybenzenes and related substances, reported in large part by Birch in 1947, has been re-examined with use of improved techniques. Remarkable patterns of reactivity (e.g., ortho > meta ? para) that he described are confirmed and extended. They are agreeably rationalized by means of a simple, approximate adaptation from MO theory.
- Bunnett, Joseph F.,Jenvey, Judy
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p. 8069 - 8073
(2007/10/03)
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- COMPETITION BETWEEN NUCLEAR AND SIDE-CHAIN SUBSTITUTION IN THE OXIDATION OF SOME ALKYLAROMATIC COMPOUNDS BY CERIUM(IV) AMMONIUM NITRATE AND COBALT(III) ACETATE
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The distribution between nuclear and side-chain substitution (N:S ratio) in the oxidations of m-methoxytoluene, 2-methylnaphtalene, mesitylene, and fluorene by cerium(IV) ammonium nitrate (CAN) and cobalt(III) acetate in acetic acid has been determined.The two oxidants exhibit remarkably different behaviours, the propensity for nuclear substitution being much stronger with CAN than with Co(OAc)3.For example, with m-methoxytoluene, CAN affords only products of nuclear acetoxylation, whereas Co(OAc)3 gives side-chain acetoxylation exclusively.The N:S ratio and the isomeric distribution for the CAN-induced reactions are consistent with a mechanism involving a common radical cation intermediate for the side-chain and nuclear substitution.The same mechanism might hold in the reactions with Co(OAc)3; however, in this case, the simultaneous operation of two different mechanisms is an additional possibility: a radical cation mechanism for the nuclear substitution and a hydrogen atom transfer mechanism for the side-chain reaction.
- Baciocchi, Enrico,Rol, Cesare,Sebastiani, Giovanni V.
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p. 513 - 518
(2007/10/02)
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- Phenol transalkylation process
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Phenols having an unsubstituted ortho position are transalkylated in the ortho position by mixing them with an ortho-alpha-branched alkylphenol (e.g., 2,6-di-sec-butylphenol) and an aluminum phenoxide catalyst and heating the mixture to 100°-350°C., preferably in a closed system and in the presence of olefin corresponding in structure to the ortho-alpha-branched alkyl group.
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