First Example of Alkyl–Aryl Negishi Cross-Coupling in Flow: Mild, Efficient and Clean Introduction of Functionalized Alkyl Groups

Egle, Brecht; Muñoz, Juan M. de; Alonso, Nerea; Borggraeve, Wim M. De; Hoz, Antonio de la; Díaz‐Ortiz, Ángel; Alcázar, Jesús

doi:10.1556/jfc-d-13-00009

Cited by 43 publications

(25 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the catalyst could be used for more than 8 h of continuous processing (0.125 M , 0.2 mL min −1 ) without a decrease in the catalytic activity and very low levels of metal leaching (10–20 ppb were detected in the reaction mixture). More recently the same group has reported alkyl‐aryl Negishi cross‐couplings in flow using similar conditions (toluene/THF 1:1, 60 °C) catalyzed by the packed SiliaCat DDP‐Pd catalyst 78. Also in this case low levels of palladium leaching and a good catalyst stability was encountered.…”

Section: Transition Metal‐catalyzed Cross Couplings In Continuous mentioning

confidence: 80%

Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching

2014

View full text Add to dashboard Cite

In the not too distant future many industrially important chemicals (including pharmaceuticals) will probably be manufactured using continuous flow technology. For a significant number of synthetic steps involved in these protocols transition metal (mostly palladium)‐catalyzed carbon–carbon or carbon–heteroatom bond forming reactions (“cross‐coupling chemistry”) will play an important role. Designing a process for continuous cross‐coupling chemistry involves either the use of a homogeneous or of a heterogeneous (immobilized) catalyst/ligand system. In the latter case, the catalyst/ligand system is typically in the form of a packed‐bed reactor, through which the reaction mixture is pumped, employing an appropriate temperature regime and residence time. Although this approach has been widely popular during the past 15 years, there is growing evidence that suggests that the use of immobilized transition metal catalysts for performing cross‐coupling chemistry in continuous flow is, in fact, not very practical. As demonstrated in this review, significant leaching of the transition metal out of the packed‐bed catalyst will almost inevitably occur, leading to decreased catalyst activity and contamination of the product with transition metal. This is a consequence of the well‐known fact that the reaction mechanism for these kinds of transformations is (quasi)homogeneous and involves the transformation of a Pd0 species into a (soluble) PdII species. Using an immobilized catalyst in a batch protocol the transient leaching of palladium will not be immediately obvious, as, after completion of the catalytic cycle, Pd0 will typically redeposit onto the support. In contrast, in continuous flow mode, the palladium metal will progressively be “chromatographed” through the packed‐bed catalyst until, ultimately, all palladium will be removed from the support. This effect typically will become only evident when long run experiments are performed. The preferred alternative, in particular for larger scale experiments, is to use a homogeneous (pre)catalyst in combination with an appropriate catalyst recycling technology.

show abstract

Section: Transition Metal‐catalyzed Cross Couplings In Continuous mentioning

confidence: 80%

Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching

2014

View full text Add to dashboard Cite

show abstract

“…Using these reaction conditions, an average conversion of 99% could be reached for more than 30 h. The time scale of the performed continuous reaction experiments was chosen based on other studies for continuous Pdcatalyzed C-C coupling reactions (Suzuki, Heck, and Negishi couplings) in single-pass packed-bed flow reactors (2 and 40 h) [41,[44][45][46][47]. To the best of our knowledge, Pandarus et al [41] set the benchmark for a stable single-pass packed-bed flow process with 30 for the synthesis of 4-methoxybiphenyl.…”

Section: Resultsmentioning

confidence: 99%

Continuous Suzuki-Miyaura Reactions with Novel Ce-Sn-Pd Oxides and Integrated Crystallization as Continuous Downstream Protocol

Lichtenegger¹,

Maier²,

Khinast³

et al. 2016

J Flow Chem

View full text Add to dashboard Cite

An integrated process including continuous-flow syntheses directly coupled to product isolation via continuous crystallization is presented. For the synthesis part, Ce 0.495 Sn 0.495 Pd 0.01 O 2-δ was used as heterogeneous catalyst in a custom-made packed-bed reactor (the so-called "Plug and Play" reactor) for continuous Suzuki-Miyaura crosscouplings of various para-and ortho-substituted bromoarenes with phenylboronic acid using environmentally friendly aqueous ethanolic mixtures as reaction solvents. The reactions were stable for up to 30 h without any detectable catalyst deactivation. The desired biaryl products were obtained in gram scale with good to excellent yields and high selectivity. For three methyl-, ketyl-, and nitrile-functionalized biphenyl products, isolation was done using water as antisolvent in an integrated crystallization process as continuous downstream protocol. The desired products could be isolated with high purity and with yields of up to 95% for the overall process.

show abstract

“…We found an alternative Pd source with appropriate particle size specifications in the form of SiliaCat® DPP-Pd which has been shown to be a useful catalyst for many kinds of Pd-catalyzed reactions (Heck, Sonogashira, Kumada, Suzuki, Stille reactions, and Buchwald aminations) in flow [52][53][54]. This catalyst was used in the optimization of temperature and residence time for the debenzylation in flow using the model system 1-benzyloxy-N,N-diethyl-5,6-dimethylpyrazin-2(1H)-one-3-carboxamide (3h) with ammonium formate in methanol (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of N-Hydroxypyrazin-2(1H)-ones via Selective O-Debenzylation of 1-Benzyloxypyrazin-2(1H)-ones Using Flow Methodology

Hung¹,

Borggraeve²

2015

J Flow Chem

Self Cite

View full text Add to dashboard Cite

show abstract

First Example of Alkyl–Aryl Negishi Cross-Coupling in Flow: Mild, Efficient and Clean Introduction of Functionalized Alkyl Groups

Cited by 43 publications

References 34 publications

Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching

Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching

Continuous Suzuki-Miyaura Reactions with Novel Ce-Sn-Pd Oxides and Integrated Crystallization as Continuous Downstream Protocol

Synthesis of N-Hydroxypyrazin-2(1H)-ones via Selective O-Debenzylation of 1-Benzyloxypyrazin-2(1H)-ones Using Flow Methodology

Contact Info

Product

Resources

About