- Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols
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Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.
- Izzo, Joseph A.,Liu, Yidong,Mcleod, David,Poulsen, Thomas B.,Svenningsen, Esben B.,J?rgensen, Karl Anker,Ri?ko, Sebastijan
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supporting information
p. 8208 - 8220
(2021/06/27)
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- Palladium/Copper-catalyzed Oxidation of Aliphatic Terminal Alkenes to Aldehydes Assisted by p-Benzoquinone
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The development of an anti-Markovnikov Wacker-type oxidation for simple aliphatic alkenes is a significant challenge. Herein, a variety of aldehydes can be selectively obtained from various unbiased aliphatic terminal alkenes using PdCl2(MeCN)2/CuCl in the presence of p-benzoquinone (BQ) under mild reaction conditions. Isomerization of the terminal alkene to the internal alkene was suppressed via slow addition of the starting material to the reaction mixture. In addition to the Pd catalyst, CuCl and BQ were essential in order to obtain the anti-Markovnikov product with high selectivity. Terminal alkenes bearing a halogen substituent afforded their corresponding aldehydes with high anti-Markovnikov selectivity. The halogen acts as a directing group in the reaction. DFT calculations indicate that a μ-chloro Pd(II)?Cu(I) bimetallic species with BQ coordinated to Cu is the catalytically active species in the case of a terminal alkene without a directing group.
- Komori, Saki,Yamaguchi, Yoshiko,Murakami, Yuka,Kataoka, Yasutaka,Ura, Yasuyuki
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p. 3946 - 3955
(2020/07/06)
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- Repetition of chemistry from a recently retracted paper. A cautionary note
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The base-catalyzed condensation reaction between (E)-4-phenylbut-2-enal and phenylpropargyl aldehyde recently reported in the literature to provide formylcyclobutadiene was repeated under the published conditions. The product obtained was identified as (E)-5-phenyl-2-((E)-styryl)pent-2-en-4-ynal rather than the reported 2-phenyl-3-styrylcyclobutadiene-1-carboxaldehyde. The structure assignment is supported by NMR and IR data and a x-ray structure of the crystalline alcohol obtained by Luche reduction.
- Ryan, Wilson,Bedard, Korey,Baidilov, Daler,Tius, Marcus,Hudlicky, Tomas
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supporting information
p. 2467 - 2469
(2018/06/25)
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- Practical asymmetric synthesis of Sitagliptin phosphate monohydrate
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Optically pure sitagliptin phosphate monohydrate is efficiently and practically synthesized through a chiral hemiacetal as the key intermediate in 54% overall yield starting from (E)-4-(2,4,5-trifluorophenyl)but-2-enal and N-boc-protected hydroxylamine. The chiral hemiacetal fragment is constructed by a tandem aza-Michael/hemiacetal reaction catalyzed by an organocatalyst and the influence of acidity of Br?nsted acid on tandem aza-Michael/hemiacetal reaction is researched in detail.
- Gao, Haoling,Yu, Jiangang,Ge, Chengsheng,Jiang, Qun
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- Concise synthesis of valuable chiral N-Boc-β-benzyl-β-amino acid via construction of chiral N-Boc-3-benzyl-5-oxoisoxazolidine through cross-metathesis/conjugate addition/oxidation
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Valuable chiral N-Boc-β-benzyl-β-amino acid was concisely synthesized via construction of chiral N-Boc-3-benzyl-5-oxoisoxazolidine through cross-metathesis/conjugate addition/oxidation. All of the starting materials for the synthesis of chiral N-Boc-β-ben
- Jiang, Hong-Tao,Gao, Hao-Ling,Ge, Cheng-Sheng
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supporting information
p. 471 - 475
(2017/01/25)
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- Synthesis of α-pyrones by catalytic oxidative coupling of terminal alkynes and carbon dioxide
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The use of the complex [(dippe)Ni(μ-H)]2(1) as a catalyst precursor (10?mol%) in the presence of a variety of terminal alkynes and CO2allowed the production of substituted α–pyrones. This reaction occurs using relatively mild conditions (50?°C, 150 psi of CO2) with good to modest yields, depending on the nature of the substituents in the corresponding alkyne. The produced α–pyrones were characterized by different analytical methods and spectroscopic techniques.
- Oliveros-Cruz, Saray,Arévalo, Alma,García, Juventino J.
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- Stereoselective Organocatalytic Synthesis of α,α-Difluoro-γ,γ-Disubstituted Butenals
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A highly stereoselective reaction of α,α-difluoro-γ,γ-disubstituted butenals 2 bearing two different substituents at the γ position has been developed with an organocatalytic system of l-proline (30 mol %) and salicylic acid (60 mol %). This novel reactio
- Arimitsu, Satoru,Nakasone, Makoto
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p. 6707 - 6713
(2016/08/16)
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- Organoselenium-catalyzed, hydroxy-controlled regio- and stereoselective amination of terminal alkenes: Efficient synthesis of 3-amino allylic alcohols
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An efficient route to prepare 3-amino allylic alcohols in excellent regio- and stereoselectivity in the presence of bases by orangoselenium catalysis has been developed. In the absence of bases α,β-unsaturated aldehydes were formed in up to 97% yield. Control experiments reveal that the hydroxy group is crucial for the direct amination.
- Deng, Zhimin,Wei, Jialiang,Liao, Lihao,Huang, Haiyan,Zhao, Xiaodan
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supporting information
p. 1834 - 1837
(2015/04/27)
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- Palladium-catalyzed reactions of enol ethers: Access to enals, furans, and dihydrofurans
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The palladium-catalyzed oxidation of alkyl enol ethers to enals, which employs low loadings of a palladium catalyst, is described. The mild oxidation conditions tolerate a diverse array of functional groups, while allowing the formation of di-, tri-, and tetrasubtituted olefins. The application of this methodology to intramolecular reactions of alkyl enol ethers containing pendant alcohols provides furan and 2,5-dihydrofuran products.
- Lauer, Matthew G.,Henderson, William H.,Awad, Amneh,Stambuli, James P.
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supporting information
p. 6000 - 6003
(2013/02/25)
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- Asymmetric organocatalytic formal [2 + 2]-cycloadditions via bifunctional H-bond directing dienamine catalysis
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A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo-and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual ac
- Albrecht, Lukasz,Dickmeiss, Gustav,Acosta, Fabio Cruz,Rodriguez-Escrich, Carles,Davis, Rebecca L.,Jorgensen, Karl Anker
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supporting information; experimental part
p. 2543 - 2546
(2012/04/04)
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- Sequencing cross-metathesis and non-metathesis reactions to rapidly access building blocks for synthesis
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The olefin cross-metathesis reaction has been sequenced with four common organic transformations in a one- or two-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner-Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; (4) Brown allyl- and Roush crotyl-boration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols, and chiral non-racemic homoallylic alcohols, respectively. Many of these intermediates have been carried further to natural products, demonstrating the utility of the methodology.
- Sirasani, Gopal,Paul, Tapas,Andrade, Rodrigo B.
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experimental part
p. 2197 - 2205
(2011/04/22)
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- Simple one-pot conversion of aldehydes and ketones to enals
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A simple and efficient method to convert aldehydes into α,β-unsaturated aldehydes with a two-carbon homologation is presented. Hydroboration of ethoxy acetylene with BH3·SMe 2 generates tris(ethoxyvinyl) borane. Transmetalation with
- Valenta, Petr,Drucker, Natalie A.,Bode, Jeffrey W.,Walsh, Patrick J.
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supporting information; experimental part
p. 2117 - 2119
(2009/10/18)
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- Selective oxidation of aromatic primary alcohols to aldehydes using molybdenum acetylide oxo-peroxo complex as catalyst
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Selective oxidation of various aromatic alcohols to aldehydes has been carried out with very high conversion (90%) and selectivity (90%) for aldehydes using cyclopentadienyl molybdenum acetylide complex, CpMo(CO)3(C{triple bond, long}CPh) (1) as catalyst and hydrogen peroxide as environmentally benign oxidant. Water-soluble Mo acetylide oxo-peroxo species is formed in situ after reaction of 1 with aqueous hydrogen peroxide during the course of reaction as catalytically active species. Interestingly even though the catalyst is homogeneous it could be recycled very easily by separating the products in organic phase and catalyst in aqueous phase using separating funnel. Even after five recycles no appreciable loss in alcohol conversion and aldehyde selectivity was observed.
- Biradar, Ankush V.,Dongare, Mohan K.,Umbarkar, Shubhangi B.
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experimental part
p. 2885 - 2888
(2009/09/06)
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- [(NHC)AuCl]-catalyzed Meyer-Schuster rearrangement: scope and limitations
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An efficient catalytic system allowing for the synthesis of a variety of α,β-unsaturated ketones has been developed. [(NHC)AuCl] (NHC{double bond, long}N-heterocyclic carbene) in the presence of a silver(I) salt was found to catalyze the Meyer-Schuster rearrangement, leading to α,β-unsaturated ketones from easily accessible propargylic alcohols in high yields. Catalysis was performed in a 2:1 mixture of methanol and water at 60 °C and afforded good yields even for tertiary alcohols and sterically demanding substrates. Thorough evaluation of the present catalytic system uncovered that it was unsuitable for terminal alkynes and primary alcohols. In these cases low yields of the target molecules were obtained due to the formation of unexpected by-products.
- Ramón, Rubén S.,Marion, Nicolas,Nolan, Steven P.
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experimental part
p. 1767 - 1773
(2009/06/18)
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- [(NHC)AuI]-catalyzed formation of conjugated enones and enals: An experimental and computational study
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The [(NHC)AuI]-catalyzed (NHC = N-heterocyclic carbene) formation of α,β-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60°C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF6 and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/ AgSbF6 in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and SN2′ addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF6] and H 2O, instead of cationic [(NHC)AuSbF6] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the C≡C bond leading to the formation of a gold-allenolate is proposed.
- Marion, Nicolas,Carlqvist, Peter,Gealageas, Ronan,De Fremont, Pierre,Maseras, Feliu,Nolan, Steven P.
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p. 6437 - 6451
(2008/02/13)
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- γ-p-toluenesulfonyl-α,β-epoxysilane: A new and practical acrolein β-anion equivalent
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(Chemical Equation Presented) Reaction of γ-p-toluenesulfonyl- α,β-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF affords α,β-unsaturated aldehydes via a Brook rearrangement-mediated tandem process under extremely mild conditions.
- Sasaki, Michiko,Takeda, Kei
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p. 4849 - 4851
(2007/10/03)
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- A multicomponent coupling strategy suitable for the synthesis of the triene component of the oxazolomycin antibiotics.
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Concise and versatile routes suitable for the synthesis of three geometric isomers of an analogue of the left hand triene sub-unit of oxazolomycin are reported. A strategy based upon a key Heck reaction was unsuccessful, and this was traced to a combinati
- Bulger, Paul G,Moloney, Mark G,Trippier, Paul C
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p. 3726 - 3737
(2007/10/03)
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- PCC-mediated novel oxidation reactions of homobenzylic and homoallylic alcohols
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A new PCC-mediated carbon-carbon bond cleavage reaction during oxidation of homobenzylic alcohols leading to the formation of benzylic carbonyl compounds has been observed. Homobenzylic alcohols with no benzylic substitution (R1=H) gave benzylic aldehydes without further oxidation, while those with benzylic substitution (R1=Me, Et, Ar) gave benzylic ketones. In contrast, homoallylic alcohols gave products arising from double bond migration, cis- to trans-olefin isomerization and/or allylic oxidation.
- Fernandes, Rodney A.,Kumar, Pradeep
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p. 1275 - 1278
(2007/10/03)
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- Asymmetric synthesis of chiral organofluorine compounds: Use of nonracemic fluoroiodoacetic acid as a practical electrophile and its application to the synthesis of monofluoro hydroxyethylene dipeptide isosteres within a novel series of HIV protease inhibitors
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Two stereoselective routes to a series of diastereomeric inhibitors of HIV protease, monofluorinated analogues of the Merck HIV protease inhibitor indinavir, are described. The two routes feature stereoselective construction of the fluorinated core subunits by asymmetric alkylation reactions. The first-generation syntheses were based on the conjugate addition of the lithium enolate derived-from pseudoephedrine α-fluoroacetamide to nitroalkene 12, a modestly diastereoselective transformation. A more practical second-generation synthetic route was developed that is based on a novel method for the asymmetric synthesis of organofluorine compounds, by enolate alkylation using optically active fluoroiodoacetic acid as the electrophile in combination with a chiral amide enolate. Resolution of fluoroiodoacetic acid with ephedrine provides either enantiomeric form of the electrophile in ≥96% ee. Alkylation reactions with this stable and storable chiral fluorinated precursor are shown to proceed in a highly stereospecific manner. With the development of substrate-controlled syn- or anti-selective reductions of α-fluoro ketones 44 and 45 (diastereomeric ratios 12:1-84:1), efficient and stereoselective routes to each of the four targeted inhibitors were achieved. The optimized synthetic route to the most potent inhibitor (syn,syn-4, Ki = 2.0 nM) proceeded in seven steps (87% average yield per step) from aminoindanol hydrocinnamide 40 and (S)-fluoroiodoacetic acid, and allowed for the preparation of more than 1 g of this compound. The inhibition of HIV-1 protease by each of the fluorinated inhibitors was evaluated in vitro, and the variation of potency as a function of inhibitor stereochemistry is discussed.
- Myers,Barbay,Zhong
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p. 7207 - 7219
(2007/10/03)
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- New results on the functionalization of terminal alkenes by cross- metathesis reactions
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The ruthenium-catalyzed reaction of allylbenzene with several types of alkene provides good yields of the cross-metathesis products regardless of the structural characteristics of the alkene.
- Blanco, Olga M.,Castedo, Luis
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p. 557 - 558
(2007/10/03)
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- A New Oxidizing Reagent: Triethylsilyl Hydrotrioxide
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Triethylsilyl hydrotrioxide (Et3SiOOOH) is a new, short-lived oxidizing agent that can react at -78 deg C directly and rapidly with olefins to form 1,2-dioxetanes and oxidatively cleaved carbonyl products.
- Posner, Gary H.,Webb, Kevin S.,Nelson, William M.,Kishimoto, Takashi,Seliger, Howard H.
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p. 3252 - 3254
(2007/10/02)
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- THIOSTANNANE-MEDIATED PREPARATION OF γ-ALKOXYALLYL SULFIDES; EFFICIENT β-ALKYLATION OF α,β-UNSATURATED ALDEHYDES
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The title β-alkylation is achieved through a sequence of sulfenylation of α-enal acetals, t-BuLi-promoted alkylation, and oxidative hydrolysis.
- Sato, Tsuneo,Okazaki, Hiroshi,Otera, Junzo,Nozaki, Hitosi
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p. 2979 - 2982
(2007/10/02)
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- Oxopropenylation of Alkylmagnesium Halides by 3-(Trimethylsilyloxy)acroleins
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Oxopropenylation of alkylmagnesium halides 4 by 3-(trimethylsilyloxy)acroleins 3 selectively yields the (E)-isomers of α,β-unsaturated aldehydes such as 4-phenyl-2-butenals 9, 3-cyclopropylpropenals 10, 3-cyclohexylpropenals 11, 3-(3-menthyl)propenals 12, and 2,5-hexadienals 13. 3-Hydroxyenolsilylethers 6 are isolated when allylmagnesium chloride is used as carbon nucleophile; to conclude, the reaction primarily involves nucleophilic addition of the Grignard reagent at the aldehyde carbon of the acrolein 3.
- Ullrich, Friedrich-Wilhelm,Rotscheidt, Klaus,Breitmaier, Eberhard
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p. 1737 - 1744
(2007/10/02)
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- AN EFFICIENT REAGENT FOR SYNTHESIS OF α,β-UNSATURATED ALDEHYDES 3-METHYLTHIO-2-PROPENYL p-TOLYL SULFONE
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Alkylation of 3-methylthio-2-propenyl p-tolyl sulfone (1) with an alkyl halide and a base (NaH or KOH-TOMAC) took place at the position α to the sulfonyl group to give optionally a mono- or dialkylated product (2 or 3), which was converted to β-monosubstituted or β,β-disubstituted α,β-unsaturated aldehyde (6 or 7), respectively, by TiCl4-assisted hydrolysis followed by the removal of p-toluenesulfinic acid.
- Ogura, Katsuyuki,Iihama, Teruyuki,Takahashi, Kazumasa,Iida, Hirodata
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p. 2671 - 2674
(2007/10/02)
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- An Efficient Synthesis of α,β-Unsaturated Aldehydes by a Four-Carbon Unit Extension of Grignard Reagents
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Copper-catalyzed addition of organomagnesium halides to 2-(2,2-diethoxy-ethyl)oxirane (1) affords aldol acetals 2 which upon acid treatment undergo hydrolysis and dehydration to give α,β-unsaturated aldehydes 7 with high yields.
- Cloux, Roland,Schlosser, Manfred
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p. 1470 - 1474
(2007/10/02)
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- 3-Diethylphosphonoacrolein diethylthioacetal anion (6*), a reagent for the conversion of aldehydes to α,β-unsaturated ketene dithioacetals and three-carbon homologated α,β-unsaturated aldehydes
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A short synthesis of the title compound is reported.It can be used to transform aldehydes to the corresponding α,β-unsaturated ketene dithioacetals, the sulfoxides of which can be converted to α,β-unsaturated aldehydes.
- Just, George,Potvin, Pierre,Hakimelahi, Gholam Hosein
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p. 2780 - 2783
(2007/10/02)
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