Rapid and Highly Selective Copper‐Free Sonogashira Coupling in High‐Pressure, High‐Temperature Water in a Microfluidic System

Kawanami, Hajime; Matsushima, Keiichiro; Sato, Masahiro; Ikushima, Yutaka

doi:10.1002/anie.200700611

Cited by 91 publications

(27 citation statements)

References 52 publications

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“…Micro-processing of the catalyzed Sonogashira C-C coupling reaction was aimed at establishing a process flow for large product volumes in very short reaction times with simple separation [100]. As a green process, a water-mediated approach based on "step-by-step rapid mixing and heating" was developed in a microfluidic system.…”

Section: Copper-free Sonogashira Couplingmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

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Driven by the economics of scale, the size of reaction vessels as the major processing apparatus of the chemical industry has became bigger and bigger [1,2]. Consequently, the efforts for ensuring mixing and heat transfer have also increased, as these are scale dependent. This has brought vessel operation to (partly severe) technical limits, especially when controlling harsh conditions, e.g., due to large heat releases. Accordingly, processing at a very large scale has resulted in taming of the chemistry involved in order to slow it down to a technically controllable level. Therefore, reaction paths that already turned out too aggressive at the laboratory scale are automatically excluded for later scale-up, which constitutes a common everyday confinement in exploiting chemical transformations. Organic chemists are barely conscious that even the small-scale laboratory protocols in their textbooks contain many slow, disciplined chemical reactions. Operations such as adding a reactant drop by drop in a large diluted solvent volume have become second nature, but are not intrinsic to the good engineering of chemical reactions. These are intrinsic to the chemical apparatus used in the past. In contrast, today's process intensification [3][4][5][6][7][8][9][10][11][12] and the new flow-chemistry reactors on the micro-and milli-scale allow such limitations to be overcome, and thus, enable a complete, ab-initio type rethinking of the processes themselves. In this way, space-time yields and the productivity of the reactor can be increased by orders of magnitude and other dramatic performance step changes can be achieved. A hand-in-hand design of the reactors and process re-thinking is required to enable chemistry rather than subduing chemistry around the reactor [40]. This often leads to making use of process conditions far from conventional practice, under harsh environments, a procedure named here as Novel Process Windows. Starting Point: Novel Process WindowsIntensify Rather than OptimizeThe aim of the following introductory remarks, and the paper as whole, is to make sensible -while everyone in the field would agree that microstructured reactors and micro-process technology [3-12] form a major direction within process intensification -that the exploitation of such innovation can still profit considerably by joining both concepts. It is frequently thought that the use of a microstructured reactor automatically and implicitly results in process intensification; simply because this is a major direction within process intensification and since the latter is also concerned with apparatus developments. This is only partly true and actually ignores significant chances for process breakthrough. In many investigations, the use of a microstructured reactor is still more concerned with process optimization, which is involves a slight to moderate improvement of processes using classical paths, in particular with the same or similar chemical and processing protocol. Often, the most radical and innovative step is the

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Section: Copper-free Sonogashira Couplingmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

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“…Traditionally, most synthetic transformations performed in microreactors have involved ambient or even low-temperature conditions in order to safely conduct highly exothermic reactions [7][8][9][10][11][12][13][14][15][16][17][18][19]. More recently, following the concepts of "Process Intensification" and "Novel Process Windows", flow chemistry at elevated temperature conditions in sealed/pressurized microreaction devices [20][21][22][23][24][25][26] and related continuous flow reactors [27][28][29][30][31][32][33][34][35][36][37][38], have been reported, although the number of publications describing synthetically valuable transformations in a genuine combined high-temperature and high-pressure flow regime, i.e., > 200°C and > 50 bar, is rather limited, with most applications focusing on the generation of high-temperature or supercritical water (scH 2 O) [39][40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Accessing Novel Process Windows in a High‐Temperature/Pressure Capillary Flow Reactor

2009

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High-temperature/pressure organic synthesis can be performed under continuous flow conditions in a stainless steel microtubular flow reactor capable of achieving temperatures of 350°C and 200 bar (X-Cube Flash™). Using these extreme experimental environments, the Claisen rearrangement of allyl phenyl ether together with the ensuing rearrangement chemistry of the resulting 2-allylphenol product was investigated. Reaction optimization was performed by changing the temperatures, pressures and flow rates "on-the-fly". In addition, the high-temperature/pressure flow system allowed the study of these transformations in low boiling point solvents in or near their supercritical state. In general, the chemistry optimized under high-temperature microwave batch conditions could be successfully translated to a scalable flow regime.

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“…A number of palladium-catalyzed Sonogashira reactions are performed in aqueous media with the help of solubilizing additives [10] or organic co-solvents. [11] In some cases, the aqueous protocols required more forcing reaction conditions, such as microwave heating, [12] sub-supercritical water, [13] or photo-activation. [14] However, the cross-coupling of aryl bromides with terminal alkynes using water as sole medium is rarely reported.…”

Section: Introductionmentioning

confidence: 99%

Thermoregulated Copper‐Free Sonogashira Coupling in Water

Liu

et al. 2011

Eur J Org Chem

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The Sonogashira cross‐coupling reaction between aryl halides and terminal alkynes was carried out smoothly in water over a thermoregulated ligand–palladium catalyst under copper‐free conditions, resulting in good to excellent yields. The Sonogashira reaction was sensitive to the electronic nature of the substituents on the aryl halides. Aryl halides with an electron‐withdrawing group showed higher reactivity than those with an electron‐donating group. Particularly, this protocol could be applied to the synthesis of liquid crystals involving trans‐cyclohexyltolans. The products could be separated from the reaction system easily by decanting, and the catalyst was recovered in water and used directly for the next run.

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Rapid and Highly Selective Copper‐Free Sonogashira Coupling in High‐Pressure, High‐Temperature Water in a Microfluidic System

Cited by 91 publications

References 52 publications

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Accessing Novel Process Windows in a High‐Temperature/Pressure Capillary Flow Reactor

Thermoregulated Copper‐Free Sonogashira Coupling in Water

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