The use of phase-transfer catalysis for the synthesis of phenol ethers

McKillop, Alexander; Fiaud, J.-C.; Hug, R.

doi:10.1016/s0040-4020(01)97250-3

Cited by 207 publications

(84 citation statements)

References 15 publications

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“…N,N-Dimethylanilines were obtained commercially when available and purified by preparative TLC when necessary, using the above system for TLC and adjusting the ratio of hexane to (C 2 H 5 ) 2 O. The N-CD 3 (d 3 ) and N-CD 2 H (d 2 ) derivatives were generally prepared by treatment of the N-methylaniline with CD 3 I or CD 2 HI (Cambridge Isotopes, Cambridge, MA, Ն98% atomic excess abundance) in refluxing acetone/K 2 CO 3 (14,32) or, occasionally, tetran-butylamine chloride/benzene/H 2 O (33,34). The d 6 (N-(CD 3 ) 2 ) derivatives were prepared by similar methods.…”

Section: Chemicals-mnmentioning

confidence: 99%

Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1

Guengerich

Yun

Macdonald

1996

Journal of Biological Chemistry

158

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Many enzymes catalyze N-dealkylations of alkylamines, including cytochrome P450 (P450) and peroxidase enzymes. Peroxidases, exemplified by horseradish peroxidase (HRP), are generally accepted to catalyze N-dealkylations via 1-electron transfer processes. Several lines of evidence also support a 1-electron mechanism for many P450 reactions, although this view has been questioned in light of reported trends for kinetic hydrogen isotope effects for N-demethylation with a series of 4-substituted N,N-dimethylanilines. No continuous trend for an increase of isotope effects with the electronic parameters of para-substitution was seen for the P450 2B1-catalyzed reactions in this study. The larger value seen with the 4-nitro derivative is consistent with a shift in mechanism due to either a reversible electron transfer step preceding deprotonation or to a hydrogen atom abstraction mechanism. With HRP, the trend is to lower isotope effects with para electronwithdrawing substituents, due to an apparent shift in rate-limiting steps. Biomimetic model high-valent porphyrins showed reduction rates with variously 4-substituted N,N-dialkylanilines that were consistent with a positively charged intermediate; such relationships were not seen for anisole O-demethylation with P450 2B1. In contrast to the case with the NADPH-supported P450 reactions, high deuterium isotope effects (ϳ7) were seen in the N-dealkylations supported by the oxygen surrogate iodosylbenzene. With iodosylbenzene, colored aminium radicals were observed in the oxidations of aminopyrine, N,N-dimethyl-4-aminothioanisole, and 4-methoxy-N,N-dimethylaniline. With the latter compound, a substantial intermolecular deuterium isotope effect was observed for N-demethylation. In the N-dealkylation of N-ethyl,N-methylaniline by P450 2B1 (NADPH-supported), the ratio of N-demethylation to Ndeethylation was 16. Although it is probably possible for P450s to catalyze amine N-dealkylations via hydrogen atom abstraction when such a course is electronically or sterically favored, we interpret the evidence to favor a 1-electron pathway with N,N-dialkylamines with P450 2B1 as well as HRP and several biomimetic models.

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Section: Chemicals-mnmentioning

confidence: 99%

Evidence for a 1-Electron Oxidation Mechanism in N-Dealkylation of N,N-Dialkylanilines by Cytochrome P450 2B1

Guengerich

Yun

Macdonald

1996

Journal of Biological Chemistry

158

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“…The reaction of 2-naphthalenol with benzyl bromide (entry 10) yielded a mixture of two products: the desired benzyl ether as the major compound (88% yield) and a double alkylation by-product (simultaneous O-and C-alkylation, 8% yield). The presence of this side product was described in the literature [10] and its structure was confirmed by NMR analysis as 1-benzyl-2-(benzyloxy) naphthalene.…”

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confidence: 54%

“…A 10-mL-volume PTFE-tubing reactor with 1-mm internal diameter was used. )As test reactants, 4-tert-butyl phenol and benzyl bromide (BnBr) were dissolved in dichloromethane (DCM) (organic phase, solution A), while NaOH and tetrabutylammonium bromide (TBAB) were dissolved in water (aqueous phase, solution B) [10]. The two immiscible solutions, pumped separately as depicted in Scheme 1, were mixed together at a T-junction inlet before the reactor, to form the segmented flow (dimensions of each single segment: 1-2 mm).…”

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confidence: 99%

Phase-Transfer Catalysis under Continuous Flow Conditions: An Alternative Approach to the Biphasic Liquid/Liquid O-Alkylation of Phenols

Zani¹,

Colombo²

2012

J Flow Chem

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O-Alkylation of phenol compounds was performed in a continuous flow apparatus under biphasic liquid/liquid conditions and promoted by tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst. The segmented flow that is generated within the flow system is able to afford the desired ethers in high yield and in very short times.Keywords: alkylation, ether, flow chemistry, phase-transfer catalysis, phenolIn the last few years, continuous flow organic synthesis has received wider attention both in academia and in industry. Laboratory-scale flow reactors are characterized by the small dimensions of the channel in which the reaction takes place (diameter from 10 to 500 mm for microreactors and up to 1 mm for meso-flow reactors). The main benefits of these reduced dimensions are the resulting high surface to volume ratio that leads to a fast and efficient heat and mass transfer and the possibility of working under superheating conditions. In these ways, reaction times, selectivity, yields, and safety of the reaction are generally improved and the precise control of the process variables, such as temperature, pressure, and residence time, can lead to a faster setup of the reaction conditions [1][2][3].A phase-transfer-catalyzed biphasic liquid/liquid system is one of the most widely used synthetic methods for the alkylation of phenols, due to the undoubted advantage of using cheap inorganic bases and water as the main solvent.Continuous flow reactors can be useful devices not only for homogeneous reactions but also for bi-(solid/liquid, immiscible liquid/liquid, and liquid/gas) and tri-phasic (solid/liquid/ gas) heterogeneous systems. In the case of biphasic liquid/liquid mixtures, when two immiscible solvents with high interfacial tension are introduced in the small-diameter channels of flow system through two different inlets connected by a T-junction, a "segmented flow" is formed. This flow is characterized by a series of regular liquid segments of one phase separated by segments of the other phase (Figure 1). Within each segment, a fluid vortex is generated by interaction of the liquid with the channel wall that allows rapid internal mixing and a continuous refreshing of the interface. By utilizing the large interfacial area provided by segmented flow, efficient phase-transfer processes can be performed with high yields and short reaction time. On the basis of this concept, in the last few years, an increasing interest has emerged in the utilization of segmented flow to perform organic reactions in heterogeneous liquid/liquid systems [4][5][6][7][8][9].Herein we report an efficient application of the continuous flow conditions for the O-alkylation of substituted phenols with alkyl halides. The results obtained in the flow mode will be compared with those obtained by classical batch mode and by microwave (MW) irradiation. (All the reactions were performed in a flow reactor configured as a combination of R-2 Pump Module and R-4 Reactor Module (Vapourtec Ltd). A 10-mL-volume PTFE-tubing reactor with 1-mm internal ...

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“…Methylation with iodomethane and NaH in THF gave 8-methoxy-2-methylquinoline (2) 9 in 96% yield. (Attempts to methylate 1 by phase transfer catalysis 10,11 did not produce the desired product 2. )…”

Section: Resultsmentioning

confidence: 99%