- Copper-catalyzed hydroformylation and hydroxymethylation of styrenes
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Hydroformylation catalyzed by transition metals is one of the most important homogeneously catalyzed reactions in industrial organic chemistry. Millions of tons of aldehydes and related chemicals are produced by this transformation annually. However, most of the applied procedures use rhodium catalysts. In the procedure described here, a copper-catalyzed hydroformylation of alkenes has been realized. Remarkably, by using a different copper precursor, the aldehydes obtained can be further hydrogenated to give the corresponding alcohols under the same conditions, formally named as hydroxymethylation of alkenes. Under pressure of syngas, various aldehydes and alcohols can be produced from alkenes with copper as the only catalyst, in excellent regioselectivity. Additionally, an all-carbon quaternary center containing ethers and formates can be synthesized as well with the addition of unactivated alkyl halides. A possible reaction pathway is proposed based on our results. This journal is
- Franke, Robert,Geng, Hui-Qing,Meyer, Tim,Wu, Xiao-Feng
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p. 14937 - 14943
(2021/12/02)
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- An Asymmetric SN2 Dynamic Kinetic Resolution
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The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.
- Rezayee, Nomaan M.,Enem?rke, Valdemar J.,Linde, Sif T.,Lamhauge, Johannes N.,Reyes-Rodríguez, Gabriel J.,J?rgensen, Karl Anker,Lu, Chenxi,Houk
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supporting information
p. 7509 - 7520
(2021/05/26)
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- Enantioselective α-Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy
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Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position. In the presence of a benzoquinone oxidant, the polarity of the α-position of racemic α-branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen-based nucleophiles and an amino acid-derived primary amine catalyst. A survey of benzoquinone oxidants identified p-fluoranil and DDQ as suitable reaction partners. p-Fluoranil enables the preparation of α-aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one-step or a two-step, one-pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an SN2 dynamic-kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α-position of aldehydes.
- Corti, Vasco,J?rgensen, Karl Anker,Lamhauge, Johannes N.,Liu, Yidong
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p. 18728 - 18733
(2021/07/12)
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- Synthesis of rac-ɑ-aryl propionaldehydes via branched-selective hydroformylation of terminal arylalkenes using water-soluble Rh-PNP catalyst
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This work detailed the preparation of a class of water-soluble PNP ligands that differed by the nature of the substitute on phenyl ring of ligands. These ligands were incorporated into water-soluble rhodium-PNP complex catalysts that were used to regioselective hydroformylation of a series of terminal arylalkenes, providing efficient access to rac-α-aryl propionaldehydes in good to excellent yield (up to 97%) and branched-regioselectivity (up to 40:1 b/l ratio). Furthermore, gram-scale and diverse synthetic transformation demonstrated synthetic application of this methodology for non-steroidal antiinflammatory drugs.
- Chen, Fen-Er,Gao, Peng,Ke, Miaolin,Liang, Guanfeng,Ru, Tong
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- New process for synthesizing racemic naproxen based on Heck coupling
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The invention discloses a novel process for synthesizing racemic naproxen based on Heck coupling, which comprises the following steps: (1) carrying out Heck coupling reaction on 2-X substituted-6-methoxynaphthalene and crotonamide in an aprotic organic solvent under the action of a palladium catalyst and alkali to generate 3-(6-methoxynaphthyl-2-)-crotonamide; and (2) carrying out Hofmann degradation reaction on the 3-(6-methoxynaphthyl-2-)-crotonamide in an alkaline solution of hypochlorite to generate 2-(6-methoxynaphthyl-2-)-propionaldehyde, directly adding the 2-(6-methoxynaphthyl-2-)-propionaldehyde into chlorite without separation, and conducting oxidizing at room temperature to obtain racemic naproxen. The process provided by the invention does not need to prepare a highly active Grignard reagent, does not need a harsh anhydrous condition, and is relatively high in conversion rate and easy in product purification.
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-
Paragraph 0031; 0037-0040
(2021/08/06)
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- Method for preparing naproxen intermediate
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A technical scheme of the invention provides a method for preparing a naproxen intermediate represented by a chemical structural formula I. Preparation reactions are as follows: 6-methoxy-2-acetonaphthone and trimethyl sulfonium hydrogen sulfate are subjected to an epoxidation reaction in the presence of alkali so as to prepare 2-(6-methoxynaphthyl)-1,2-epoxypropane, the 2-(6-methoxynaphthyl)-1,2-epoxypropane is subjected to catalyzed rearrangement through silica gel or FeCl3 and then reacts with hydroxylamine hydrochloride, thereby preparing an intermediate, i.e., 2-(6-methoxy-2-naphthyl)propyl oxime (I) in one step. Naproxen is prepared by employing a one-pot method through a key intermediate, i.e., 2-(6-methoxy-2-naphthyl)propyl oxime.
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Paragraph 0074-0077; 0082-0084; 0086-0097; 0103-0104
(2020/12/08)
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- Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction
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A simple methodology for the asymmetric synthesis of chiral α,β-unsaturated δ-lactones was achieved by copper(I)-catalyzed direct vinylogous aldol reaction (DVAR) of β,γ-unsaturated esters and various aldehydes, including aromatic aldehydes, heteroaromatic aldehydes, α,β-unsaturated aldehydes, and aliphatic aldehydes. For aromatic and heteroaromatic aldehydes, a one-pot reaction consisting of DVAR, isomerization of the unsaturated carbon-carbon double bond from (E)-form to (Z)-form, and subsequent intramolecular transesterification was required to get the lactones in moderate to high yields with high enantioselectivity. For α,β-unsaturated and aliphatic aldehydes, the DVAR proceeded directly to afford the lactones in moderate yields with high enantioselectivity. In the DVAR, various functional groups were well tolerated. Moreover, the methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product, and derivatives of drug molecules (atomoxetine and naproxen). The mechanism studies revealed that α-addition was reversible and not favored, which accounted for the excellent regioselectivity in the DVAR. The copper(I)-dienolate species generated through deprotonation was proposed to form an equilibrium with an allylcopper(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes. Finally, the robustness of the present reaction was demonstrated by a gram-scale reaction, and the utility of the present methodology was showcased by the formal asymmetric synthesis of ezetimibe and fostriecin.
- Zhang, Hai-Jun,Yin, Liang
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supporting information
p. 12270 - 12279
(2018/09/25)
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- Continuous Liquid Vapor Reactions Part 1: Design and Characterization of a Reactor for Asymmetric Hydroformylation
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A research scale continuous reactor system was designed and developed for high pressure asymmetric hydroformylation (AHF) reactions with an 8 h reaction time. The continuous reactor achieved high kLa, low axial dispersion, and an 8 mL liquid holdup volume. The reactor consisted of 20 vertical bubble flow pipes-in-series, connected by small diameter tubing jumpers. This type of continuous reactor is proven to be scalable up to 360 L in our GMP pharmaceutical manufacturing plant for high pressure hydrogenation. The continuous reactor was used for the AHF of styrene and 2-vinyl-6-methoxynaphthalene catalyzed by rhodium(bisdiazaphospholane) (BDP) complexes. The CSTRs-in-series numerical model fit the experimental data better than the plug flow with dispersion model. Samples were taken along the length of the continuous reactor and used for kinetic data modeling. Vapor liquid mass transfer rate constants were about 3 orders of magnitude higher than reaction rate constants.
- Johnson, Martin D.,May, Scott A.,Calvin, Joel R.,Lambertus, Gordon R.,Kokitkar, Prashant B.,Landis, Clark R.,Jones, Bradley R.,Abrams, M. Leigh,Stout, James R.
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p. 888 - 900
(2016/06/13)
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- MICROWAVE INDUCED SINGLE STEP GREEN SYNTHESIS OF SOME NOVEL 2-ARYL ALDEHYDES AND THEIR ANALOGUES
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The present invention provides a process for the preparation of some novel 2-aryl and 2,2-diaryl aldehydes and analogues which are privileged intermediates for commercially important nonsteroidal anti-inflammatory drugs including naproxen, flurbiprofen and potent anticancer drug candidates, including phenstatin through a unique single step synthetic methodology utilizing easily available substrates in the form of aryl alkenes as well as environmentally benign aqueous reaction conditions in the form of solvents such as mixtures of water and DMSO or Dioxane and reagents N-bromosuccinimide, N-iodosuccinimide, N-cholorosuccinimide and phase transfer catalyst such as cetyltrimethyl ammonium bromide, N-hexyl ammonium chloride for a reaction time varying from 1 min-30 min, depending upon microwave or conventional heating, without using expensive transition metal catalysts or lewis acids/bases with yield varying from 35-55%, depending upon the solvent and substrate used. The developed method provides a clean and convenient alternative to access a diverse range of medicinally important 2-aryl and 2,2-diaryl aldehyde based scaffolds in lieu of the conventional multistep protocols employing expensive and hazardous transition metal catalysts and lewis acids/bases.
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Page/Page column 5
(2012/03/08)
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- Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases
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We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.
- Galletti, Paola,Emer, Enrico,Gucciardo, Gabriele,Quintavalla, Arianna,Pori, Matteo,Giacomini, Daria
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scheme or table
p. 4117 - 4123
(2010/10/03)
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- Rhodium phosphino-enolate complexes as chemo- and regioselective catalysts for the hydroformylation of styrenes
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The catalytic utility of [κ2-{3-iPr 2P-2-O-indene}Rh(COD)] (COD = η4-1,5-cyclooctadiene) 1a in the hydroformylation of styrenes was examined. Complex 1a was shown to be an effective pre-catalyst in benzene and tetrahydrofuran, exhibiting good conversions to aldehyde and high branched o-linear selectivity for styrene, 4-chlorostyrene, and 4-methylstyrene under reasonably mild conditions (1000 psi syngas; 1.8 mol% Rh, 45 °C, 2-5 h). Under analogous conditions, the iridium congener of 1a proved inactive for hydroformylation. The synthesis and crystallographic characterization of the new complex [κ2-{2- iPr2PC6H4O}Rh(COD)] 2 is also reported; the catalytic performance of 2 in the hydroformylation of styrene was found to be comparable to that of 1a under similar catalytic conditions. We report herein on the use of rhodium phosphino-enolate complexes as effective pre-catalysts for the hydroformylation of styrene substrates, exhibiting high branched o-linear selectivity under relatively mild conditions.
- Uh, Yoon-Seo,Boyd, Alaina,Little, Vanessa R.,Jessop, Philip G.,Hesp, Kevin D.,Cipot-Wechsler, Judy,Stradiotto, Mark,McDonald, Robert
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scheme or table
p. 1869 - 1872
(2010/09/09)
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- Use of a robust dehydrogenase from an archael hyperthermophile in asymmetric catalysis-dynamic reductive kinetic resolution entry into (s)-profens
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Described is an efficient heterologous expression system for Sulfolobus solfataricus ADH-10 (Alcohol Dehydrogenase isozyme 10) and its use in the dynamic reductive kinetic resolution (DYRKR) of 2-arylpropanal (Profen-type) substrates. Importantly, among the 12 aldehydes tested, a general preference for the (S)-antipode was observed, with high ee's for substrates corresponding to the NSAIDs (nonsteroidal anti-inflammatory drugs) naproxen, ibuprofen, flurbiprofen, ketoprofen, and fenoprofen. To our knowledge, this is the first application of a dehydrogenase from this Sulfolobus hyperthermophile to asymmetric synthesis and the first example of a DYRKR with such an enzyme. The requisite aldehydes are generated by Buchwald-Hartwig-type Pd(0)-mediated α-arylation of tert-butyl propionate. This is followed by reduction to the aldehyde in one [lithium diisobutyl tert-butoxyaluminum hydride (LDBBA)] or two steps [LAH/Dess-Martin periodinane]. Treatment of the profenal substrates with SsADH in 5% EtOH/phosphate buffer, pH 9, with catalytic NADH at 80 °C leads to efficient DYRKR, with ee's exceeding 90% for 9 aryl side chains, including those of the aforementioned NSAIDs. An in silico model, consistent with the observed broad side chain tolerance, is presented. Importantly, the SsADH-10 enzyme could be conveniently recycled by exploiting the differential solubility of the organic substrate/product at 80 °C and at rt. Pleasingly, SsADH-10 could be taken through several thermal cycles, without erosion of ee, suggesting this as a generalizable approach to enzyme recycling for hyperthermophilic enzymes. Moreover, the robustness of this hyperthermophilic DH, in terms of both catalytic activity and stereochemical fidelity, speaks for greater examination of such archaeal enzymes in asymmetric synthesis.
- Friest, Jacob A.,Maezato, Yukari,Broussy, Sylvain,Blum, Paul,Berkowitz, David B.
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supporting information; experimental part
p. 5930 - 5931
(2010/07/05)
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- MICROWAVE INDUCED SINGLE STEP GREEN SYNTHESIS OF SOME NOVEL 2-ARYL ALDEHYDES AND THEIR ANALOGUES
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The present invention provides a process for the preparation of some novel 2-aryl and 2,2-diaryl aldehydes and analogues which are privileged intermediates for commercially important nonsteroidal anti-inflammatory drugs including naproxen, flurbiprofen and potent anticancer drug candidates, including phenstatin through a unique single step synthetic methodology utilizing easily available substrates in the form of aryl alkenes as well as environmentally benign aqueous reaction conditions in the form of solvents such as mixtures of water and DMSO or Dioxane and reagents N-bromosuccinimide, N- iodosuccinimide, N-cholorosuccinimide and phase transfer catalyst such as cetyltrimethyl ammonium bromide, N-hexyl ammonium chloride for a reaction time varying from 1min- 30min, depending upon microwave or conventional heating, without using expensive transition metal catalysts or lewis acids/bases with yield varying from 35-55 %, depending upon the solvent and substrate used. The developed method provides a clean and convenient alternative to access a diverse range of medicinally important 2-aryl and 2,2- diaryl aldehyde based scaffolds in lieu of the conventional multistep protocols employing expensive and hazardous transition metal catalysts and lewis acids/bases.
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Page/Page column 16
(2010/09/17)
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- Water-promoted cascade synthesis of α-arylaldehydes from arylalkenes using N-halosuccinimides: An avenue for asymmetric oxidation using Cinchona organocatalysis
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The direct oxidation of arylalkenes into α-arylaldehydes is achieved for the first time in water without relying on transition metal catalysts, and a novel organocatalytic enantioselective approach is also explored to provide up to 30% ee in initial investigations.
- Sharma, Abhishek,Sharma, Naina,Kumar, Rakesh,Sharma, Upendra K.,Sinha, Arun K.
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supporting information; scheme or table
p. 5299 - 5301
(2010/01/31)
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- NAPROXCINOD PROCESS AND SOLID DISPERSION
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Processes for the preparation of naproxcinod and its purification, solid dispersions of naproxcinod with a pharmaceutically acceptable carrier, and processes for making dispersions. Also provided is crystalline 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate and methods for its preparation.
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Page/Page column 26-28
(2009/12/28)
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- Ruthenium porphyrin-catalyzed aerobic oxidation of terminal aryl alkenes to aldehydes by a tandem epoxidation-isomerization pathway
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(Figure Presented) Catalytic oxidation of 1-alkenes to aldehydes by an epoxidation-isomerization pathway with air or dioxygen as terminal oxidant has been realized for bulky ruthenium(VI) porphyrin catalysts. For the new, recyclable catalyst [RuVI(tmttp)O2], product yields of up to 99% and total turnover numbers of up to 1144 were obtained.
- Jiang, Gaoxi,Chen, Jian,Thu, Hung-Yat,Huang, Jie-Sheng,Zhu, Nianyong,Che, Chi-Ming
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supporting information; experimental part
p. 6638 - 6642
(2009/03/12)
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- Ionic diamine rhodium(I) complexes - Highly active catalysts for the hydroformylation of olefins
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Rhodium(I) complexes composed of an anionic rhodium centre containing chloride ligands, and a cationic rhodium centre coordinated by a diamine ligand, were synthesized and characterized. These complexes are able to catalyze the hydroformylation reaction under mild reaction conditions in excellent activity and regioselectivity, and in the absence of a phosphorus ligand. The Royal Society of Chemistry 2005.
- Kim, Jai Jun,Alper, Howard
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p. 3059 - 3061
(2007/10/03)
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- Hydroformylation Reactions with Recyclable Rhodium-Complexed Dendrimers on a Resin
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Rhodium-complexed dendrimers supported on a resin were evaluated as catalysts for the hydroformylation of aryl olefins and vinyl esters. The results showed the reactions proceeded very efficiently at room temperature with excellent yields. Outstanding selectivity for the branched aldehydes was also observed in all cases. The dendritic catalysts can be recycled by simple filtration and reused even up to the tenth cycle without loss of activity and selectivity. These results represent a dramatic improvement over those previously described for rhodium-catalyzed (dendrimer and nondendrimer based) hydroformylation reactions.
- Lu, Shui-Ming,Alper, Howard
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p. 13126 - 13131
(2007/10/03)
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- Application of P-stereogenic aminophosphine phosphinite ligands in asymmetric hydroformylation
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New chiral aminophosphine phosphinite ligands with a stereogenic center at the aminophosphine phosphorus atom were prepared based on (R,S)-ephedrine as the chiral auxiliary and backbone. Substituents at the chiral aminophosphine as well as at the phosphinite phosphorus atom were varied. These new ligands were applied to the rhodium-catalyzed asymmetric hydroformylation of vinyl arenes. The enantiomeric excess reached up to 77%. 1H and 31P NMR studies of the Rh complexes under syngas pressure reveal that [HRh(CO)2(P/P)] complexes with the NP* moiety in an axial position are responsible for enantioselectivity.
- Ewalds, Regine,Eggeling, Eva B.,Hewat, Alison C.,Kamer, Paul C. J.,Van Leeuwen, Piet W. N. M.,Vogt, Dieter
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p. 1496 - 1504
(2007/10/03)
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- Process for preparation of 2-(6-methoxy-2-naphthyl)propionic acid and intermediates therefor utilizing 2,6-diisopropylnaphthalene
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A process is disclosed for the synthesis of 2-(6-methoxy-2-naphthyl)propionic acid that utilizes 2,6-diisopropylnaphthalene.
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- Synthesis of 2,6-Disubstituted Dihydronaphthalenes and Naphthalenes by Electrocyclic Reaction of o-Quinodimethane. A Synthesis of (+/-)-Naproxen
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A survey of the electrocyclic reactions of o-quinodimethanes generated in situ by the thermolysis of dihydrobenzocyclobutenes with a variety of olefinic substituents at C-1 is reported.These reactions provide convenient access to the 2,6-disubstituted dihydronaphthalenes (11) and the naphthalenes (12).Thermolysis of the benzocyclobutenes (10) at 180 deg C in the presence of manganese dioxide affords in good yields the 2,6-di- and 2,3,6-tri-substituted naphthalenes (12) and (16).The naphthalenes (12b,f,h) thus obtained were easily converted into (+/-)-naproxen (5).
- Shishido, Kozo,Yamashita, Akitake,Hiroya, Kou,Fukumoto, Keiichiro
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p. 469 - 475
(2007/10/02)
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- STEREOSELECTIVE SYNTHESIS OF (E)-2-ALKENE-1,4-DIOLS VIA METALLATED ALLYLIC SULPHOXIDES
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Reaction of allyl sulphinyl anion with chiral α-methylaldehydes affords α- or γ-adducts in highly regiocontrolled fashion, depending on reaction conditions.From the α-adducts syn (E)-2-alkene-1,4-diols are obtained as major (d.r. 2:1 28:1) products by thiophile promoted desulphurization.
- Annunziata, Rita,Cinquino, Mauro,Cozzi, Franco,Raimondi, Laura,Stefanelli, Stefania
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p. 5443 - 5450
(2007/10/02)
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- HYDROFORMYLATION CATALYSED BY RHODIUM COMPLEXES OF TREHALOSE-DERIVED LIGANDS αα and ββ-TREDIP; A HIGHLY REGIOSELECTIVE ROUTE TO α-METHYLARYLPROPIONALDEHYDES
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Rhodium complexes of the ligand αα-TREDIP give 62:1 iso-regioselectivity in the hydroformylation of styrene under ambient conditions without excess posphine, higher than any previously reported value.The results are compared with those obtained with other ligands, and extended to preparation of 2-(6-methoxy-2-naphthyl)-propanal, a precursor of the anti-inflammatory drug naproxen.
- Brown, John M.,Cook, Stephen J.,Khan, Riaz
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p. 5105 - 5110
(2007/10/02)
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- A FACILE PREPARATION OF 2-ARYLPROPIONALDEHYDE FROM 1-ARYL-1-PROPENE
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1-Aryl-1-propenes were converted into the corresponding 2-arylpropionaldehydes in high yields by treatment with iodine and silver(I)oxide in aqeous dioxane at room temperature.
- Kikuchi, Haruhiko,Kogure, Katsura,Toyoda, Masashi
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p. 341 - 344
(2007/10/02)
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