- Hindered dialkyl ether synthesis with electrogenerated carbocations
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Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.
- Xiang, Jinbao,Shang, Ming,Kawamata, Yu,Lundberg, Helena,Reisberg, Solomon H.,Chen, Miao,Mykhailiuk, Pavel,Beutner, Gregory,Collins, Michael R.,Davies, Alyn,Del Bel, Matthew,Gallego, Gary M.,Spangler, Jillian E.,Starr, Jeremy,Yang, Shouliang,Blackmond, Donna G.,Baran, Phil S.
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p. 398 - 402
(2019/11/05)
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- Facile preparation of α-aryl nitriles by direct cyanation of alcohols with TMSCN under the catalysis of InX3
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(Chemical Equation Presented) A convenient and efficient synthesis of α-aryl nitrites was developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis acid. Using 5-10 mol % of InBr3 as the catalyst, a variety of benzylic alcohols can be converted to the corresponding nitriles in 5-30 min with yields of 46-99%.
- Chen, Gang,Wang, Zheng,Wu, Jiang,Ding, Kuiling
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supporting information; experimental part
p. 4573 - 4576
(2009/05/07)
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- Photochemical and Photophysical Properties of Indoprofen
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The photophysical properties and photochemistry of indoprofen (INP) have been investigated. Absorption and emission spectroscopies in phosphate buffer, ethanol and ether show that INP photophysics is dominated by a singlet-singlet transition of ππ* character. INP fluoresces at room temperature, with a quantum yield ~0.04. Flash photolysis experiments together with the lack of phosphorescence at room temperature point to a very weak intersystem crossing. The photoreactivity of INP is centered on the propionic acid chain and gives rise to photoproducts similar to those obtained with other arylpropionic acids (ethyl, hydroxyethyl and acetyl derivatives). Thus, irradiation of INP in aqueous buffer results in photodecarboxylation and leads mainly to oxidative compounds whose proportions increase with increasing oxygen concentration. These data suggest a photoreactivity occurring from the excited singlet state.
- Lhiaubet-Vallet,Trzcionka,Encinas,Miranda,Chouini-Lalanne
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p. 487 - 491
(2007/10/03)
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- A facile preparation of phthalimides and a new approach to the synthesis of indoprofen via carbonylation
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This report describes an improved synthesis of a heterocyclic propionic acid, 2-4(1-oxo-2-isoindolinyl) phenyl propionic acid, Indoprofen (I) via carbonylation, a potent anti-inflammatory agent1 and an analgesic. The synthesis highlights the preparation of Indoprofen starting from readily available o-toluic acid and p-amino acetophenone by a sequence of reactions that included oxidative addition of carbonylation.
- Prasad, Chalasani S.N.,Varala, Ravi,Adapa, Srinivas R.
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p. 281 - 286
(2007/10/03)
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