- Oxygen-Free Regioselective Biocatalytic Demethylation of Methyl-phenyl Ethers via Methyltransfer Employing Veratrol- O-demethylase
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The cleavage of aryl methyl ethers is a common reaction in chemistry requiring rather harsh conditions; consequently, it is prone to undesired reactions and lacks regioselectivity. Nevertheless, O-demethylation of aryl methyl ethers is a tool to valorize natural and pharmaceutical compounds by deprotecting reactive hydroxyl moieties. Various oxidative enzymes are known to catalyze this reaction at the expense of molecular oxygen, which may lead in the case of phenols/catechols to undesired side reactions (e.g., oxidation, polymerization). Here an oxygen-independent demethylation via methyl transfer is presented employing a cobalamin-dependent veratrol-O-demethylase (vdmB). The biocatalytic demethylation transforms a variety of aryl methyl ethers with two functional methoxy moieties either in 1,2-position or in 1,3-position. Biocatalytic reactions enabled, for instance, the regioselective monodemethylation of substituted 3,4-dimethoxy phenol as well as the monodemethylation of 1,3,5-trimethoxybenzene. The methyltransferase vdmB was also successfully applied for the regioselective demethylation of natural compounds such as papaverine and rac-yatein. The approach presented here represents an alternative to chemical and enzymatic demethylation concepts and allows performing regioselective demethylation in the absence of oxygen under mild conditions, representing a valuable extension of the synthetic repertoire to modify pharmaceuticals and diversify natural products.
- Grimm, Christopher,Lazzarotto, Mattia,Pompei, Simona,Schichler, Johanna,Richter, Nina,Farnberger, Judith E.,Fuchs, Michael,Kroutil, Wolfgang
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p. 10375 - 10380
(2020/10/02)
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- A detour route for meta functionalization of phenols
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Cyclohexadienones participate in a two-step procedure, a Michael addition followed by aromatization, providing hitherto difficult-to-synthesize meta-functionalized phenol derivatives in good yield. Application of the developed approach is exemplified by synthesizing C-aryl acetophenones, C-aryl glycines, and elemicin - an allylphenol natural product. Georg Thieme Verlag Stuttgart · New York.
- Chittimalla, Santhosh Kumar,Kuppusamy, Rajesh,Bandi, Chennakesavulu
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p. 1991 - 1996
(2014/11/08)
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- Reductive cleavage of aryl O-carbamates to phenols by the Schwartz reagent. Expedient link to the directed ortho metalation strategy?
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A general, mild, and efficient method for the reductive cleavage of aryl O-carbamates to phenols, 1 → 2 using the Schwartz reagent is reported. The method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and, notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1) allowing new entries into difficult to prepare contiguously substituted aromatics and heteroaromatics.
- Morin, Justin,Zhao, Yigang,Snieckus, Victor
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supporting information
p. 4102 - 4105
(2013/09/12)
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- Schwartz Reagents: Methods of In Situ Generation and Use
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Embodiments of the invention provide a method of using Schwartz Reagent, Cp2Zr(H)Cl, without accumulating or isolating it. Methods provide mixtures of Cp2ZrCl2, reductants that selectively reduce Cp2ZrCl2, and substrates. After reaction of Cp2ZrCl2 and the reductant, an intermediate reduction product is formed, apparently Schwartz Reagent. The in situ Schwartz Reagent then selectively reduces certain functional groups on the substrate. Substrates include tertiary amides, tertiary benzamides, aryl O-carbamates, and heteroaryl N-carbamates, which are reduced to aldehydes, benzaldehydes, aromatic alcohols, and heteroaromatics, respectively. Compared to prior methods, reagents are inexpensive and stable, reaction times are short, and reaction temperature in certain cases is conveniently room temperature. It has been estimated that using the in situ method described herein instead of synthesized or commercially obtained Schwartz Reagent provides a 50% reduction in cost.
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Page/Page column 7; 15
(2010/06/19)
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- Facile and regioselective dealkylation of alkyl aryl ethers using niobium(V) pentachloride
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A simple and facile method for the cleavage of carbon-oxygen bonds promoted by niobium pentachloride(V) is described. Excellent yields and regioselectivities were observed with various alkyl aryl ethers to give the phenols. NMR studies revealed the formation of monoaryloxy niobium salt(V), and a neighboring-group effect may play a significant role in the regioselectivity. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Sudo, Yukinori,Arai, Shigeru,Nishida, Atsushi
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p. 752 - 758
(2007/10/03)
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- Synthesis of the CD-ring of the anticancer agent streptonigrin: studies of aryl-aryl coupling methodologies
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A series of functionalized 4-bromopyridines, representing the C-ring of the anticancer agent streptonigrin have been prepared and their abilities to undergo Pd-catalyzed cross-coupling with streptonigrin D-ring siloxanes were evaluated. The coupling reaction was generally tolerant to the preparation of hindered CD biaryls; however, the electronic effects of both partners play a pivotal role in the success of the coupling process. Analogs of the CD biaryl were prepared by coupling of aryl siloxane derivatives (D-ring component) with highly functionalized 4-bromopyridines (C-ring); however, the CD biaryl of the natural product could not be prepared in high yield by siloxane coupling due to the facile formation of reduced pyridine under the coupling conditions. Alternatively, the fully functionalized CD biaryl of streptonigrin was prepared using a Suzuki coupling of appropriately functionalized C-ring bromide and D-ring aryl boronic acid. The described approach is highly convergent and readily amenable to the synthesis of analogs.
- McElroy, William T.,DeShong, Philip
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p. 6945 - 6954
(2007/10/03)
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- Cross coupling strategies towards the synthesis of the streptonigrin CD moiety
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An efficient route to an appropriate model of the streptonigrin 4- phenylpyridine CD moiety is reported. 4-Chloro-3-nitropyridine was found to be the key precursor and its reactivity in cross coupling reactions was further investigated.
- Crous, Renier,Dwyer, Catherine,Holzapfel, Cedric W.
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p. 721 - 726
(2007/10/03)
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- Hydrogen peroxide/boric acid: An efficient system for oxidation of aromatic aldehydes and ketones to phenols
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Hydrogen peroxide activated by boric acid in the presence of sulfuric acid has been shown to be an efficient oxidizing system for direct conversion of aromatic aldehydes and ketones to phenols.
- Roy, Amrita,Reddy,Mohanta, Pramod K.,Ila,Junjappa
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p. 3781 - 3791
(2007/10/03)
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- Method for the production of alkoxy- and aryloxy-phenols
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Alkoxybenzaldehydes and aryloxybenzaldehydes are converted to the corresponding phenols by reacting the benzaldehydes in an organic solvent phase with formic acid and hydrogen peroxide in an aqueous solvent phase to produce the corresponding formate ester. The formate ester is then saponified to produce the corresponding phenol.
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- Baeyer-Villiger oxidation of β-aryl substituted unsaturated carbonyl compounds with hydrogen peroxide and catalytic selenium dioxide
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A simple and cheap oxidative procedure using 30% H2O2 and catalytic SeO2 allows to transform 2-aralkylidenecycloalkanones and hydroxy- or alkoxybenzaldehydes to give, in high yields, enollactones and arylformates, respectively.
- Guzman,Mendoza,Garcia,Garibay,Oliveras,Maldonado
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p. 2121 - 2133
(2007/10/02)
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- Photogeneration of HF from Fluoromethoxybenzenes in Aqueous Solution
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Photolysis of fluoromethoxybenzenes in aqueous solution results in a clean substitution of fluoride by water, resulting in the generation of HF, the mechanism of which is believed proceed via aryl cations from loss of fluoride ion in the primary photochemical step.
- Zhang, Guangzhong,Wan, Peter
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- Preparation of methoxyphenols by oxidation of methoxybenzaldehydes with hydrogen peroxide in presence of p-toluenesulphonic acid
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Methoxyphenols have been prepared efficiently from the corresponding methoxybenzaldehydes by oxidation with hydrogen peroxide at room temperature in the presence of p-toluenesulphonic acid in methanol.
- Baruah, Robindra N.
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p. 1103 - 1104
(2007/10/02)
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- PREPARATION OF 2-METHOXY-3,4-METHYLENEDIOXYBENZALDEHYDE (CROWEACIN ALDEHYDE) FROM PYROGALLOL
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2-Methoxy-3,4-methylenedioxybenzaldehyde (croweacin aldehyde) of high purity was prepared in 55percent overall yield from pyrogallol.
- Shirasaka, Tadashi,Takuma, Yuki,Imaki, Naoshi
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p. 1213 - 1221
(2007/10/02)
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- Direct Lithiation of Alkoxyphenols: Metalation vs Demethylation. An Experimental and Theoretical (MNDO) Study
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The direct lithiation of simple alkoxyphenols has been studied both from a theoretical and an experimental viewpoint.Efficient lithiations were achieved by using a 2:1 tBuLi-tBuOLi mixture (LICLIOR) in THF at room temperature.In most cases alkoxy groups are responsible for the regioselectivity observed, although for the case of 2-methoxyphenol both the OMe and OLi groups actually act as ortho-directing groups during lithiation.Demethylation has been shown to be a common side reaction of lithiation of phenolic or nonphenolic alkoxy aromatics.MNDO calculations provide good support for all the experimental observations.Thus, lithiation and demethylation are shown to be competing pathways, the former being kinetically favored whereas the latter leads to the thermodynamically more stable compounds.Calculations also show that the so-called geminal demethylations are more favored processes than the alternative vicinal demethylations.Moreover, MNDO allows the measurement of the extent of agostic activation of the ortho hydrogens with respect to the OMe and OLi groups involved in lithiation.Finally, MNDO nicely predicts the important role of reaction temperature in successful direct lithiation of simple alkoxyphenols.
- Morey, Jeroni,Costa, Antoni,Deya, Pere M.,Suner, Guillem,Saa, Jose M.
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p. 3902 - 3909
(2007/10/02)
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- The Baeyer-Villiger Oxidation of Aromatic Aldehydes and Ketones with Hydrogen Peroxide Catalyzed by Selenium Compounds
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A series of organoselenium compounds was investigated as activators of hydrogen peroxide in the Baeyer-Villiger oxidation.As a result, a convenient and cheap method for transformation of aromatic aldehydes, having polycondensed ring systems or electron-donating substituents, and polymethoxy derivatives of acetophenone, into phenols was elaborated.This method utilizes hydrogen peroxide activated by areneseleninic acids, as oxidizing agent.
- Syper, Ludwik
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p. 167 - 172
(2007/10/02)
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- Dealkylation of Activated Alkyl Aryl Ethers Using Lithium Chloride in Dimethylformamide
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Alkyl aryl ethers having electron-withdrawing substituents in the ortho or para positions are esily cleaved with lithium chloride in dimethylformamide.
- Bernard, Angela M.,Ghiani, M. Rossella,Piras, Pier Paolo,Rivoldini, Antonio
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p. 287 - 289
(2007/10/02)
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- The Structure and Synthesis of the Novel Orchid Pigments Dengibsin and Dengibsinin
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The structures of the orchid pigments dengibsin and dengibsinin have been revised to 2,5-dihydroxy-4-methoxy-9H-fluoren-9-one (4) and 3,5-dihydroxy-2,4-dimethoxy-9H-fluoren-9-one (5).The synthesis of these compounds is described.It has been found that 2'-methoxybiphenyl-2-carboxylic acids, on treatment with trifluoroacetic anhydride or oxalyl chloride, undergo cyclization giving 6H-dibenzopyran-6-ones.
- Sargent, Melvyn V.
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p. 2553 - 2564
(2007/10/02)
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- Regioselective 4-Demethoxylation of 1-n-Alkyl-3,4,5-trimethoxybenzenes: a Key Step in the Synthesis of Olivetol and its Homologues
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Selective removal of the 4-methoxy group in n-alkyl-3,4,5-trimethoxybenzenes was performed under electron-transfer conditions; a new synthesis of olivetol dimethyl ether is described.
- Azzena, Ugo,Denurra, Teresa,Melloni, Giovanni,Rassu, Gloria
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p. 1549 - 1550
(2007/10/02)
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- Chinone von Benzo- und Dibenzokronenethern
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The preparation of the 1,4-quinones of benzocrown-5 (1), benzocrown-6 (2), and dibenzocrown-6 (3) and their quinols is described.The quinones are obtained by Fremy salt oxidation of the corresponding 3-hydroxybenzo-crown ethers which are readily accessible by a double protective group synthesis from 1,2,3-trihydroxybenzene.The synthetic pathway also provides a general high yield preparation of 2,3-dialkoxy-1,4-benzoquinones.The new crown ethers are characterised by 1H- and 13C-N.M.R. as well as U.V. spectroscopy.Non-aqueous redox potentials aredetermined by cyclic voltammetry.Crystalline complexes of 1 and 2 with various ammonium, alkali, and alkaline earth cations are also described.
- Dietl, F.,Gierer, G.,Merz, A.
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p. 626 - 631
(2007/10/02)
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- Acid-Catalyzed Oxidation of Benzaldehydes to Phenols by Hydrogen Peroxide
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A wide variety of benzaldehydes were oxidized to phenols by hydrogen peroxide in acidic methanol.
- Matsumoto, Masakatsu,Kobayashi, Hisako,Hotta, Yasushi
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p. 4740 - 4741
(2007/10/02)
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- SELECTIVE DEALKYLATIONS OF ARYL ALKYL ETHERS AND THIOETHERS BY SODIUM IN HMPA
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The reaction of sodium with bis- and tris(alkoxy)benzenes in HMPA gives selectively the products of monodealkylation.The reaction proceeds through a dianion which fragments into an alkyl and an aryloxy anion.The positional selectivity of this fragmentation is governed by the structure of both the alkyl and aryloxy groups.With bis- and tris(alkoxy)benzenes which for symmetry reasons can afford aryloxy anions having the same basicity, the dealkylation involves exlusively the less substituted alkyl group.On the contrary, in the asymmetric terms, the positional selectivity of the dealkylation process is governed by the basicity of the aryloxy anion.On the basis of these concepts several efficient and synthetically useful reactions have been developed.In most cases the selectivity obtained in the present reactions in different from that observed with other previously developed methods which use sodium methoxide or sodium alkenethiolates in HMPA.It is shown that the appropriate choice of the reagent allows selective dealkylation of the desired alkoxy group of a poly(alkoxy)benzene.The reaction of sodium with bis(alkylthio)benzenes in HMPA gives the bis(mercapto)benzenes.If the reduction is carried out with a solution of sodium in HMPA, the reaction gives instead the products of monodealkylation.This however is not selective.It is suggested that in the case of thioethers the dealkylation products originate from the fragmentation of the radical anions.
- Testaferri, L.,Tiecco, M.,Tingoli, M.,Chianelli, D.,Montanucci, M.
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p. 3687 - 3692
(2007/10/02)
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