Mild and Rapid Pd‐Catalyzed Cross‐Coupling with Hydrazine in Continuous Flow: Application to the Synthesis of Functionalized Heterocycles

DeAngelis, Andrew; Wang, Donghui; Buchwald, Stephen L.

doi:10.1002/ange.201208544

Cited by 36 publications

(15 citation statements)

References 61 publications

(18 reference statements)

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“…[9c] Following our study, only one other report of palladium-catalyzed hydrazine cross-coupling has appeared, which employed as catalysts palladacycles derived from Buchwalds biaryl monophosphine lig-A C H T U N G T R E N N U N G ands. [26] Encouraged by the observation in our screening exercise that BippyPhos/[PdA C H T U N G T R E N N U N G (cinnamyl)Cl] 2 mixtures catalyze the selective monoarylation of ammonia using chlorobenzene, we turned our attention to exploring further this chemistry. As a starting point, we employed published conditions developed for the BHA of ammonia [9b] and hydrazine [9c] in combination with selected representative (hetero)-A C H T U N G T R E N N U N G aryl chlorides (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Crawford

Lavery

Stradiotto

2013

Chemistry A European J

135

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Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]2 catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.

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Section: Resultsmentioning

confidence: 99%

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Crawford

Lavery

Stradiotto

2013

Chemistry A European J

135

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“…[172] Ad irect palladium-catalyzed C À Nc ross-coupling with aryl chlorides and hydrazine was developed in the group of Buchwald (Scheme 48 b). [173] Thus,s olutions of precatalyst, aryl chloride,h ydrazine,a nd base were mixed consecutively, and introduced into af irst residence unit at room temperature.The residence unit was immersed in an ultrasound bath to prevent clogging as ar esult of NaCl precipitation during the coupling reaction. Upon exiting the residence unit, the mixture was combined with as tream of aqueous TFAt o dissolve the NaCl and to catalyze as ubsequent hydrazone formation.…”

Section: Hydrazinementioning

confidence: 99%

“…Similarly,b yi ntroducing bdiketones instead of aldehydes,acyclocondensation directly afforded 1-arylpyrazoles in good yields (> 69 %). [173] Thec ontinuous-flow synthesis of 1H-pyrazoles from hydrazine monohydrate and 1,3-diketones was described by Haswell and co-workers. [174] As elective iron-catalyzed reduction of nitroarenes to anilines with hydrazine hydrate as as toichiometric reducing agent was developed using amicrowave reactor as aconvenient device to screen and optimize small-scale reactions.…”

Section: Hydrazinementioning

confidence: 99%

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

Gutmann¹,

Cantillo²,

Kappe³

2015

Angew Chem Int Ed

1,283

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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“…[172] Eine direkte palladiumkatalysierte C-N-Kreuzkupplung von Arylchloriden mit Hydrazin wurde durch die Gruppe von Buchwald entwickelt (Schema 48 b). [173] So wurden Lçsungen von Präkatalysator,A rylchlorid, Hydrazin und Base nacheinander zugemischt und bei Raumtemperatur in eine erste Verweileinheit eingeleitet. Die Verweileinheit wurde in ein Ultraschallbad eingetaucht, um ein Zusetzen infolge der Abscheidung von Natriumchlorid während der Kupplungsreaktion zu verhindern.…”

Section: Durchflusschemieunclassified

“…In ähnlicher Weise lieferte eine Cyclokondensation mit b-Diketonen (anstatt Aldehyden) direkt 1-Arylpyrazole in guten Ausbeuten (> 69 %). [173] Die kontinuierliche Durchflusssynthese von 1H-Pyrazolen aus Hydrazinmonohydrat und 1,3-Diketonen wurde durch Haswell und Mitarbeitern beschrieben. [174] Unter Verwendung eines Mikrowellenreaktors als geeignetes Instrument für Screening und Optimierung von Reaktionen in kleinem Maßstab wurde eine selektive eisenkatalysierte Reduktion von Nitroarenen zu Anilinen mit Hydrazinhydrat als stçchiometrisches Reduktionsmittel entwickelt.…”

Section: Durchflusschemieunclassified

Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen

2015

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In den letzten Jahren haben Durchflussreaktoren mit Kanalabmessungen im Mikrometer‐ oder Millimeterbereich weitverbreitete Anwendung in der organischen Synthese gefunden. Diese Reaktoren sind durch ihre außergewöhnlich schnellen Wärme‐ und Stoffübertragung gekennzeichnet. Außer bei den schnellsten Reaktionen kann in mikrostrukturierten Bauelementen dieses Typs eine fast augenblickliche Vermischung der Reaktanten erreicht werden. Ebenso lassen sich Probleme wie Wärmestau, Überhitzungszonen (Hot‐Spots) und thermisches Durchgehen vermeiden. Aufgrund der kleinen Reaktorvolumina ist die Prozesssicherheit erheblich verbessert, selbst wenn harsche Reaktionsbedingungen angewendet werden. Somit bietet die Mikroreaktortechnologie eine einzigartige Möglichkeit, ultraschnelle exotherme Reaktionen durchzuführen, und erlaubt die Realisierung von Reaktionen, die über sehr instabile oder sogar explosive Zwischenprodukte ablaufen. Dieser Aufsatz behandelt aktuelle Literaturbeispiele für die organische Synthese unter kontinuierlichem Durchfluss, in denen eine gefährliche Chemie oder extreme Prozessfenster angewendet wurden, wobei der Schwerpunkt vor allem auf Anwendungen liegt, die für die Herstellung von Pharmazeutika von Bedeutung sind.

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Mild and Rapid Pd‐Catalyzed Cross‐Coupling with Hydrazine in Continuous Flow: Application to the Synthesis of Functionalized Heterocycles

Cited by 36 publications

References 61 publications

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

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

Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen

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