A safe and reliable procedure for the iododeamination of aromatic and heteroaromatic amines in a continuous flow reactor

Malet-Sanz, Laia; Madrzak, Julia; Holvey, Rhian S.; Underwood, Toby J.

doi:10.1016/j.tetlet.2009.10.007

Cited by 39 publications

(18 citation statements)

References 34 publications

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“…[89] Alternatively, it is possible to generate aryl iodides under copper-free conditions and a continuous procedure for this reaction has been presented by Pfizer scientists (Scheme 13). [95] It should be noted that this transformation is believed to proceed via a triazene intermedi-ate rather than a diazonium ion, but regardless, the reaction still presents an explosion hazard on large scale. Using molecular iodine (55) as the iodide source enabled the authors to process a collection of 12 aromatic and heteroaromatic amines in moderate to good yields (43-91 % yield).…”

Section: Diazonium Ionsmentioning

confidence: 99%

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Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

Deadman

Collins

Maguire

2014

Chemistry A European J

178

104

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Type of publicationArticle ( 1 This is the pre-peer reviewed version of the following article: Deadman, B. J., Benjamin J. Deadman, [a] Stuart G. Collins [a] and Anita R. Maguire* [b] 2 This is the pre-peer reviewed version of the following article: Deadman, B. J., , Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds. Chem. Eur. J. which has been published in final form at http://dx.doi.org/10.1002/chem.201404348 DOI: 10.1002/chem.201404348 IntroductionDiazo and diazonium compounds are extremely versatile intermediates and reagents in organic synthesis. Diazoalkanes are important alkylating reagents, [1,2] while α-diazocarbonyls are important for their role in generating carbenes and metal carbenoids, [1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and also for providing access to reactive ketene and heteroanalogous intermediates via the Wolff rearrangement. [21][22][23][24][25][26] Diazo compounds are also important 1,3-dipoles for heterocycle-forming cycloaddition reactions. [27][28][29][30][31][32] The diazonium ion moiety is an important leaving group in Sandmeyer, [33][34][35] Meerwein, [36,37] Balz-Schiemann [38,39] and palladium catalysed cross coupling [40][41][42] chemistry; and is an essential reagent for the preparation of azo compounds, the backbone of the synthetic dye industry. [42,43] The versatility of the diazo and diazonium moieties is matched only by their fearsome reputation. Diazoalkanes are highly toxic due to their potent alkylation of DNA. [44] Furthermore, diazo and diazonium compounds are highly energetic by nature and explosions can be triggered by shock, heat or exposure to concentrated acids. [44,45] α-Diazocarbonyls are considerably more stable than diazoalkanes and diazoniums due to the resonance stabilisation of adjacent carbonyls but detonation is still possible under more forcing conditions. [44,46] These safety concerns necessitate caution when using diazo and diazonium intermediates in the laboratory, and have limited their use on scale in industry. The synthetic utility of these hazardous compounds has led to a recent interest in developing safer alternative methods for their preparation and use. [1,44] Continuous processing is rapidly growing in the academic, pharmaceutical and fine chemical sectors due to its favourable safety profile among other benefits such as efficient mixing, enhanced heat and mass transfer, access to extreme reaction conditions, reproducibility and scale up, in-line workups and automated operation. [47][48][49][50][51][52][53][54] The safety profile offered by continuous processing is perhaps the most compelling reason for its popularity in recent years. Sensitive and toxic reaction intermediates can be generated and consumed during a single flow process without the need for stockpiling hazardous quantities of material. Furthermore, the high surface area-tovolume ratio of tubular flow reactors also ensures rapid dissipation of heat and reduces the risk of reaction runaway.Continuou...

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Section: Diazonium Ionsmentioning

confidence: 99%

“…Continuous metal-free coupling reaction to generate aryl iodides (56) from in situ generated triazene intermediates. [95] P = pump, R = reactor coil. prone to leaching and the resulting precipitates of copper salts caused blockage of the system.…”

Section: Diazonium Ionsmentioning

confidence: 99%

Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

Deadman

Collins

Maguire

2014

Chemistry A European J

178

104

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“…[147] On-line Raman spectroscopy allowed the disappearance of the aniline to be monitored and dynamic optimization of the reaction conditions. [147] Similar basic reactor designs were used by other research groups for reactions involving aryldiazonium salts as intermediates, including Sandmeyer-type reactions, [148] Meerwein arylation, [149] and Heck reactions. [150] Ap articularly interesting example is the continuous-flow synthesis of arylsulfides by ap hotocatalytic Stadler-Ziegler reaction.…”

Section: Diazonium Compoundsmentioning

confidence: 99%

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

Gutmann¹,

Cantillo²,

Kappe³

2015

Angew Chem Int Ed

1,313

676

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In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

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“…4-Iodobenzonitrile (6c). 24 The reaction was carried out according to the general procedure for 4-iodonitrobenzene (6a) using 4-aminobenzonitrile (5c) (0.050 g, 0.38 mmol), p-toluenesulfonic acid monohydrate (0.24 g, 1.1 mmol), polymersupported nitrite (0.32 g, containing 1.1 mmol of NO 2 ) and sodium iodide (0.11 g, 0.74 mmol). Purication by ash column chromatography eluting with 20% ethyl acetate in petroleum ether (40-60) gave 4-iodobenzonitrile (6c) as a white solid (0.080 g, 68%).…”

Section: General Procedures For Preparation Of Polymer-supported Nitrimentioning

confidence: 99%

Late stage iodination of biologically active agents using a one-pot process from aryl amines

Sloan

Luthra²,

McRobbie³

et al. 2017

RSC Adv.

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A safe and reliable procedure for the iododeamination of aromatic and heteroaromatic amines in a continuous flow reactor

Cited by 39 publications

References 34 publications

Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

Late stage iodination of biologically active agents using a one-pot process from aryl amines

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