- Immobilization of ruthenium catalysts for allylations with allyl alcohol
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[RuCp(PP)]+ complexes active for allylation of alcohols with allyl alcohol as the allylating agent were immobilized on solid supports. Two different immobilization methods have been applied: (1) via electrostatic interactions of the cationic complex on ion-exchange resins, where the anion is present on the support and (2) via a coordination bond with a ligand covalently-bound on the support. Both methods give high yields of immobilized complex through relatively simple procedures. The catalysts immobilized via ionic interactions prove to be able to allylate both 1-octanol and 4-tert-butylphenol with very low leaching of the catalyst, thus forming allyl octyl ether and C-allylated phenol, respectively. The accumulation of water in the highly hydrophilic resin precludes the O-allylation of phenol and also retards the C-allylation reaction. The catalysts immobilized via a coordination bond are not hydrophilic; with these catalysts selective O-allylation of phenols is achieved, with recycling of the catalysts over multiple runs. Leaching of the catalyst from the support is somewhat higher than for the electrostatically-bound catalyst and quarternisation (allylation) of the excess of phosphine groups present on the support plays an important role in the activity of the immobilized catalysts for the allylation reaction.
- Van Rijn, Jimmy A.,Bouwman, Elisabeth,Drent, Eite
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- Ecofriendly Claisen rearrangement of allyl-4-tert-butylphenyl ether using heteropolyacid supported on hexagonal mesoporous silica
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The Claisen rearrangement of allyl phenyl ethers is a valuable reaction in organic synthesis having a variety of applications in perfumes, flavours, pharmaceuticals, and intermediate industries. The replacement of traditional environmentally threatening h
- Yadav, Ganapati D.,Lande, Sharad V.
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- Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands – Functional characterization and modeling studies on H3 and H4 receptors
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Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH3R affinity (pKi > 7), compound 1h being the most potent (pKi 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gαi activity indicated that the compounds are potent antagonists. Only one compound (2c, pKi 7.1) presented high affinity for hH4R. In contrast to what was observed for hH3R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH3R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH3R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH4R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH3R and hH4R.
- Corrêa, Michelle F.,Balico-Silva, André L.,Kiss, Dóra J.,Fernandes, Gustavo A.B.,Maraschin, Jhonatan C.,Parreiras-e-Silva, Lucas T.,Varela, Marina T.,Sim?es, Sarah C.,Bouvier, Michel,Keser?, Gy?rgy M.,Costa-Neto, Claudio M.,Fernandes, Jo?o Paulo S.
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- Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta
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Cardiovascular diseases (CVDs) present high prevalence rates in the current world. It is estimated that approximately one-third of the global deaths are related to CVDs, and thus there is still a need for novel drugs to treat these disorders. We serendipitously discovered that LINS01005 (5a) is a potent vasodilating agent in rat aorta, and therefore a set of analogues were evaluated for the vasodilating potency in Wistar and SHR rat thoracic aorta precontracted with norepinephrine, with endothelium intact (E+) or denuded (E–) aortic rings. Compounds 5a and 5b were the most potent, showing submicromolar potency for endothelium intact vessels (EC50 853 and 941 nM, respectively) and micromolar values for E– vessels (EC50 2.4 and 7.1 μM, respectively). These compounds were indeed significantly more potent vasodilating agents in SHR-derived aortic rings (p 50 2.4 nM (E+) 9.0 nM (E–)] and 5b [EC50 20 nM (E+) 2.1 μM (E–)]. SAR analysis though PCA and HCA were performed, suggesting that N-phenylpiperazine is essential to the activity, while increasing volume in the substituted aromatic moiety is detrimental to the potency. This is the first report of the vasodilating properties of such compounds, and studies regarding the mechanism of action are in progress in our group.
- Ginoza, Milton,Fernandes, Gustavo A.B.,Corrêa, Michelle F.,Fernandes, Jo?o Paulo S.
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- Profiling of LINS01 compounds at human dopamine D2 and D3 receptors
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Abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D2 receptor (D2R) and dopamine D3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [3H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (Ki 0.3–1.5 μM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (Ki 1.3–5.5 μM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. Graphic abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H3 receptor antagonists were evaluated as dopamine D2R and D3R ligands. The compounds showed micromolar affinities to both receptors[Figure not available: see fulltext.].
- Corrêa, Michelle F,Reiner, David,Fernandes, Gustavo A B,Varela, Marina T,Aranha, Cecília M S Q,Stark, Holger,Fernandes, Jo?o Paulo S
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- Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source
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Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cos
- Brodbeck, Daniel,álvarez-Barcia, Sonia,Meisner, Jan,Broghammer, Florian,Klepp, Julian,Garnier, Delphine,Frey, Wolfgang,K?stner, Johannes,Peters, René
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p. 1515 - 1524
(2019/01/09)
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- Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2, and H3 receptors
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Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds) have the selectivity for the H3R over the H4R. Here, we describe their pharmacological properties at the human H1R and H2R in parallel with the H3R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H3R-induced histamine responses, but no inhibition of H2R-induced responses was seen. Three compounds were weakly able to inhibit H1R-induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N-methyl group improves H3R affinity while the N-phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.
- Corrêa, Michelle Fidelis,Barbosa, álefe Jhonatas Ramos,Fernandes, Gustavo Ariel Borges,Baker, Jillian G.,Fernandes, Jo?o Paulo dos Santos
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- An Aluminum Fluoride Complex with an Appended Ammonium Salt as an Exceptionally Active Cooperative Catalyst for the Asymmetric Carboxycyanation of Aldehydes
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Al?F bonds are among the most stable σ bonds known, exhibiting an even higher bond energy than Si?F bonds. Despite a stability advantage and a potentially high Lewis acidity of Al?F complexes, they have not been described as structurally defined catalysts
- Brodbeck, Daniel,Broghammer, Florian,Meisner, Jan,Klepp, Julian,Garnier, Delphine,Frey, Wolfgang,K?stner, Johannes,Peters, René
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supporting information
p. 4056 - 4060
(2017/03/27)
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- Investigation on Claisen rearrangement of allyl phenyl ethers in near-critical water
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Catalyst-free Clasien rearrangement of allyl phenyl ethers were investigated in near-critical water. The effects on the reaction in near-critical water and conventional conditions were compared. The results demonstrate that near-critical water could greatly accelerate the Claisen rearrangement of allyl phenyl ethers. This process is simple, fast, efficient and environmentally benign.
- Xiao, Shangyou,He, Yi,Xu, Guang,Liu, Qi
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p. 3299 - 3305
(2015/06/08)
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- A diastereoselective route to trans-2-aryl-2,3-dihydrobenzofurans through sequential cross-metathesis/isomerization/allylboration reactions: Synthesis of bioactive neolignans
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A new highly diastereoselective synthetic route to trans-2,3-dihydrobenzofuran systems, in particular those bearing an aryl substituent at the C2 position, is described. The cornerstone of our strategy is the implementation of a cross-metathesis/isomerization/allylboration sequence starting from 2-allyl-substituted phenols and aldehydes. After an intramolecular Mitsunobu cyclization step, the anti-homoallylic alcohols allow the synthesis of the desired skeleton in a stereoselective fashion. As an illustration, we used this strategy for the preparation of the dihydrodehydrodiconiferyl alcohol (1a), a natural dihydrobenzofuran neolignan, as well as for a formal synthesis of its O-demethylated derivative 1b. An enantioselective version of this approach employing a chiral phosphoric acid in the allylboration step is also studied.
- Hemelaere, Rémy,Carreaux, Fran?ois,Carboni, Bertrand
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supporting information
p. 2470 - 2481
(2015/04/22)
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- PdI2-catalyzed regioselective cyclocarbonylation of 2-allyl phenols to dihydrocoumarins
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A simple, efficient, and regioselective synthesis of 3-methyl-3,4-dihydrocoumarins is reported. The reaction of 2-allyl phenols with synthesis gas was catalyzed by PdI2, and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (L1) and 1,3,5,7-tetramethyl-6-tetradecyl-2,4,8-trioxa-6-phosphaadamantane (L2) were effective as ligands, affording good product selectivity in all cases.
- Amzquita-Valencia, Manuel,Alper, Howard
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supporting information
p. 5827 - 5829
(2015/01/08)
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- Enantioselective synthesis of benzofurans and benzoxazines via an olefin cross-metathesis-intramolecular oxo-Michael reaction
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Chiral phosphoric acid and Hoveyda-Grubbs II were found to catalyze an olefin cross-metathesis-intramolecular oxo-Michael cascade reaction of the ortho-allylphenols and enones to provide a variety of benzofuran and benzoxazine derivatives in moderate to good yields and enantioselectivity.
- Zhang, Jun-Wei,Cai, Quan,Gu, Qing,Shi, Xiao-Xin,You, Shu-Li
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supporting information
p. 7750 - 7752
(2013/09/02)
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- Palladium-diphosphine complexes as catalysts for allylations with allyl alcohol
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Several palladium complexes with bidentate phosphine ligands were tested for their activity in the O-allylation of phenols with allyl alcohol. The use of C3-bridged bidentate phosphine ligands results in very high selectivity for O-allylation. The reactions do not require stoichiometric amounts of additives to control the chemoselectivity. Especially, catalysts with gem-dialkyl substituted C3-bridged bidentate phosphine ligands perform very well, resulting in a (equilibrium) conversion of ~50% of phenol with a selectivity of 99% for O-allylation. The use of diallyl ether as the allylating agent results in a significant increase in phenol conversion while maintaining high selectivity for O-allylation. Apart from Pd(OAc)2 as catalyst precursor, Pd(dba)2 was also employed, making it possible to use other types of phosphine or phosphite ligands. With the palladium catalytic system not only phenol, but also aliphatic alcohols can be allylated, as well as aromatic and aliphatic amines.
- Van Rijn, Jimmy A.,Dunnen, Angela Den,Bouwman, Elisabeth,Drent, Eite
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experimental part
p. 96 - 102
(2010/11/18)
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- PROCESS FOR THE PREPARATION OF AN ALLYL ARYL ETHER BY CATALYTIC O-ALLYLATON
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The invention provides a process for the preparation of an allyl aryl ether comprising the O-allylation of an aromatic hydroxyl containing compound with an allyl source in the presence of a catalyst, wherein the catalyst is a transition metal complex with a bidentate diphosphine ligand, and wherein the bidentate diphosphine ligand has 2 to 4 bridging atoms between the phosphorus atoms and wherein at least one of the bridging atoms is substituted. This invention further provides novel transition metal complexes that may be used in the above process. This invention further provides a process for the preparation of epoxy resins wherein as intermediate use is made of the allyl aryl ethers prepared by the process of the invention.
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Page/Page column 13; 14
(2010/08/09)
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- PROCESS FOR THE PREPARATION OF AN ALLYL ARYL ETHER BY CATALYTIC O-ALLYLATION
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The invention provides a process for the preparation of an allyl aryl ether comprising the O-allylation of an aromatic hydroxyl containing compound with an allyl source in the presence of a catalyst, wherein the catalyst is a transition metal complex with a phosphine ligand, and wherein the phosphine ligand is either a monodentate phosphine P(X)3, wherein each X independently is a an aliphatic substituent having from 1 to 9 carbon atoms, a cycloaliphatic substituent having from 5 to 9 carbon atoms or aromatic substituent having from 6 to 9 carbon atoms, or wherein two substituents X together form a divalent alkylene group, with from 3 up to 6 carbon atoms, or a bidentate diphosphine X2P-R-PX2 wherein each X has the same meaning as defined for the monodentate phosphine, wherein the divalent alkylene group is attached to the same or different phosphorus atom(s), and R is a bridging group having at least 4 bridging atoms between the phosphorus atoms, wherein the O-allylation is carried out in the presence of an acid in an amount of at least 0.1 mol% calculated on the aromatic hydroxyl containing compound. This invention further provides a process for the preparation of epoxy resins wherein as intermediate use is made of the allyl aryl ethers prepared by the process of the invention.
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Page/Page column 10; 12
(2010/08/09)
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- Remarkable activity of the isomerization catalyst [RuCp(PPh 3)2](OTs) in O-allylation of phenol with allyl alcohol
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It was surprisingly found that the highly active allyl alcohol redox isomerization catalyst [RuCp(PPh3)2](OTs) upon addition of a catalytic amount of a strong acid can change its catalytic action fully to the selective O-allylation of phenols with allyl alcohol. High turnover numbers (75,000 based on phenol; 200,000 based on allyl alcohol) are reached, and the catalyst is very stable in the presence of substrate. Addition of triphenylphosphine to the reaction mixture does not lead to further stabilization of the catalyst; instead, the free phosphine is rapidly allylated, thereby consuming the acid, which deactivates the catalytic system for allylation reactions. This catalyst with monodentate phosphine ligands is superior in both activity and selectivity to similar catalysts with bidentate phosphine ligands. Apart from phenols, also thiophenol can be efficiently allylated to form allyl phenyl sulfide.
- Van Rijn, Jimmy A.,Van Stapele, Esther,Bouwman, Elisabeth,Drent, Eite
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experimental part
p. 220 - 226
(2010/09/04)
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- Efficient Claisen rearrangement of allyl para-substituted phenyl ethers using microreactors
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A green way to synthesize allyl phenols has been developed. Quantitative yield of 2-allyl-4-methoxyphenol was obtained via a fast Claisen rearrangement in a microreactor system without solvent and work-up.
- Kong, Lingjie,Lin, Qi,Lv, Xiaoming,Yang, Yongtai,Jia, Yu,Zhou, Yaming
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supporting information; experimental part
p. 1108 - 1111
(2010/04/23)
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- Cationic ruthenium-cyclopentadienyl-diphosphine complexes as catalysts for the allylation of phenols with allyl alcohol; Relation between structure and catalytic performance in O-vs. C-allylation
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A new catalytic method has been investigated to obtain either O-or C-allylated phenolic products using allyl alcohol or diallyl ether as the allyl donor. With the use of new cationic ruthenium(II) complexes as catalyst, both reactions can be performed with good selectivity. Active cationic Ru(II) complexes, having cyclopentadienyl and bidentate phosphine ligands are generated from the corresponding Ru(II) chloride complexes with a silver salt. The structures of three novel (diphosphine)Ru(II)CpCl catalyst precursor complexes are reported. It appears that the structure of the bidentate ligand has a major influence on catalytic activity as well as chemoselectivity. In addition, a strong cocatalytic effect of small amounts of acid is revealed. Model experiments are described that have been used to build a reaction network that explains the origin and evolution in time of both O-allylated and C-allylated phenolic products. Some mechanistic implications of the observed structure vs. performance relation of the [(diphosphine)RuCp]+ complexes and the cocatalytic role of added protons are discussed.
- Van Rijn, Jimmy A.,Lutz, Martin,Von Chrzanowski, Lars S.,Spek, Anthony L.,Bouwman, Elisabeth,Drent, Eite
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experimental part
p. 1637 - 1647
(2011/02/25)
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- A new one-pot synthetic approach to the highly functionalized (Z)-2-(buta-1,3-dienyl)phenols and 2-methyl-2H-chromenes: Use of amine, ruthenium and base-catalysis
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A practical and simple one-pot multi-catalysis process for the synthesis of highly substituted benzo[b]oxepines 5, (Z)-2-(buta-1,3-dienyl)phenols 6 and 2-methyl-2H-chromenes 7 from simple starting materials was achieved for the first time through ring-closing metathesis/base-induced ring opening/[1,7]-sigmatropic hydrogen shift reactions. The synthesis of privileged (Z)-2-(buta-1,3-dienyl)phenols 6 via base-induced ring opening of highly functionalized benzo[b]oxepines 5 is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Ramachary, Dhevalapally B.,Narayana, Vidadala V.,Ramakumar, Kinthada
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supporting information; experimental part
p. 3907 - 3911
(2009/04/07)
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- Formal [2+3] cycloaddition between substituted phenols and allylsilane
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Treatment of various substituted phenols in the presence of allyltrimethylsilane, iodobenzene diacetate, and perfluorinated alcohol promotes oxidative formal [2+3] cycloaddition in moderate to useful yields. Georg Thieme Verlag Stuttgart.
- Bérard, Didier,Racicot, Léanne,Sabot, Cyrille,Canesi, Sylvain
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scheme or table
p. 1076 - 1080
(2009/04/06)
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- Intriguing formal [2+3] cycloaddition promoted by a hypervalent iodine reagent
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Treatment of various substituted phenols in the presence of iodobenzene diacetate, perfluorinated alcohols and furan, allylsilanes or cyclic enol ethers promotes an oxidative annulation process in moderate to useful yields. In only one step, this method p
- Bérard, Didier,Giroux, Marc-André,Racicot, Léanne,Sabot, Cyrille,Canesi, Sylvain
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p. 7537 - 7544
(2008/12/20)
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- UDCaT-5: A novel and efficient solid superacid catalyst for Claisen rearrangement of substituted allyl phenyl ethers
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The Claisen rearrangement of allyl phenyl ethers is a fundamental reaction in organic synthesis with a variety of applications in perfumes, flavors, pharmaceuticals, agrochemicals, polymers, fine chemicals, and intermediate industries. The development of environmentally benign processes using solid acid catalysts is becoming an area of growing interest. It was accomplished in an efficient, economical, environmentally friendly manner and is 100% selective toward alllyl phenols by employing UDCaT-5 as solid acid catalyst. Copyright Taylor & Francis Group, LLC.
- Yadav, Ganapati D.,Lande, Sharad V.
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p. 941 - 946
(2007/10/03)
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- An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans
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Twelve substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis.
- Van Otterlo, Willem A.L.,Morgans, Garreth L.,Madeley, Lee G.,Kuzvidza, Samuel,Moleele, Simon S.,Thornton, Natalie,De Koning, Charles B.
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p. 7746 - 7755
(2007/10/03)
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- A new synthesis of benzofurans from phenols via claisen rearrangement and ring-closing metathesis
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Based on Claisen rearrangement, the double bond isomerization of O-allyl function together with the formation of O-vinyl function in one pot, and ring-closing metathesis (RCM), various phenols were transformed into various benzofurans in good yields.
- Tsai, Tzu-Wei,Wang, Eng-Chi,Li, Sie-Rong,Chen, Yung-Hua,Lin, Yu-Li,Wang, You-Feng,Huang, Keng-Shiang
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p. 1307 - 1318
(2007/10/03)
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- Substituted phenols as fragrance, flavor and antimicrobial compounds
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A fragrance and/or flavor compound of the general formula (I): wherein R1 is one of propyl or a 2-propenyl group and R2 is a C1-C5 alkyl group, said compound having exactly one R1 and from one to four R2. The compounds possess antimicrobial activity as well as flavor or odor characteristics acceptable for use in flavors and fragrances, respectively. The compounds are useful in forming flavor and/or fragrance compositions having antimicrobial activity. Product formulations, such as detergents, are useful for imparting both acceptable fragrance and antimicrobial properties. Other product formulations, such as mouthwashes, are useful for imparting both acceptable flavor and antimicrobial properties.
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- Alternative Lewis acids to effect Claisen rearrangement
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Yb(OTf)3 and DIBAL-H are developed as alternative Lewis acids for effecting Claisen rearrangement of allyl, crotyl and prenyl aryl ethers.
- Sharma,Ilangovan,Sreenivas, Punna,Mahalingam
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p. 615 - 618
(2007/10/03)
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- 106. Synthetic Models of the Active Site of Cytochrome P-450. 1st Communication. The Synthesis of a Doubly-Briged Iron(II)-Porphyrin Carrying a Tightly Bound Thiolate Ligand
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The doubly-bridged iron(II)-tetraphenylporphyrin dervative 6, carrying a sterically fixed S- ligand in the 'proximal'position and the substrate at the 'distal' site, was synthesized as an enzyme model for cytochrome P-450.Compond 36, the CO com
- Staeubli, Beat,Fretz, Heinz,Piantini, Umberto,Woggon, Wolf-Dietrich
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p. 1173 - 1193
(2007/10/02)
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