Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins

Houpis, Ioannis N.; Schils, Didier; Nettekoven, Ulrike; Schnyder, Anita; Bappert, Erhart; Weerts, Koen; Canters, Martine; Vermeulen, Wim A. A.

doi:10.1021/op9001609

Cited by 2 publications

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“…The literature shows it and its substituted analogs being used in the synthesis of allenes, 1 Nheterocyclic carbenes, 2 and substituted furans 3 and as a reactant in Sonogashira cross-couplings. 4 Its polymerization is well known and has been studied with various catalysts. 5 However, under certain conditions, propargyl alcohol can also decompose explosively, resulting in destructive force; its detonation has been previously studied.…”

Section: ■ Introductionmentioning

confidence: 99%

Thermal Hazards of Using Propargyl Alcohol with Strong Bases

Brown

Allian

Chen

2021

Org. Process Res. Dev.

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Thermal hazard screening of a reaction mixture that involves the use of propargyl alcohol as the reactant/solvent along with potassium hydroxide as catalyst resulted in catastrophic thermal decomposition that ruptured an accelerating rate calorimeter (ARC) test cell. Due to this critical hazard, scale-up of the chemistry was not advisible. In order to enable scale-up, further investigations into solvent and base combinations were carried out. New optimum conditions enabled the synthesis of the desired product in a safe manner. The main purpose of this manuscript is to alert the scientific community to the thermal hazards of this compound.

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Section: ■ Introductionmentioning

confidence: 99%

Thermal Hazards of Using Propargyl Alcohol with Strong Bases

Brown

Allian

Chen

2021

Org. Process Res. Dev.

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“…Houpis et al reported an unexpected exotherm during the synthesis of the active pharmaceutical ingredient 64 via the Sonogashira cross-coupling of bromide 61 with propargyl alcohol (62) (Scheme 17). 59 More specifically, during a reaction involving ca. 100 g of bromide 61 in which all of the reaction components were mixed at room temperature in a 2 L reactor and heated to 70 °C, an abrupt temperature rise to 145 °C was observed along with visible formation of dark polymeric material.…”

Section: Introductionmentioning

confidence: 99%

Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions

Yang

Babij

Good

2019

Org. Process Res. Dev.

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The potential safety hazards associated with Pd-catalyzed cross-coupling reactions have been underappreciated and inadequately discussed. These hazards have not been universally recognized in the past decades, perhaps overshadowed by the ubiquity of this class of chemistry and the desire to pursue new scientific advancements. The awareness of these hazards is further limited by the fact that synthetic chemists who develop these types of reactions on small scales are not typically trained in reactive chemistry hazard evaluation, and existing studies from industrial chemists and chemical engineers are often not published in journals that are commonly read by academic groups and synthetic chemists that typically work on small scales. This review summarizes observations of the exothermic behavior associated with the Pd-catalyzed α-arylation, Buchwald–Hartwig amination, Kumada–Corriu, Mizoroki–Heck, Negishi, Sonogashira, and Suzuki–Miyaura cross-coupling reactions. This exothermic behavior is consistently observed across each subset of cross-coupling reactions and appears to be relatively independent of the nucleophile, electrophile, base, solvent, and catalyst system employed. The magnitude of the exotherms poses potential safety hazards that could result in runaway scenarios in cases where the maximum temperature of a synthesis reaction (MTSR) exceeds the solvent boiling point and/or the onset temperature for reaction mixture decomposition. This contribution will serve as an educational resource to encourage researchers to conduct reaction safety evaluations and to develop control strategies accordingly to mitigate such potential safety risks prior to practicing Pd-catalyzed cross-coupling as well as other transition-metal-catalyzed cross-coupling reactions.

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Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins

Abstract: In the article they were spelled incorrectly as Didier Shilds and Wim Vermuelen.

Cited by 2 publications

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Thermal Hazards of Using Propargyl Alcohol with Strong Bases

Thermal Hazards of Using Propargyl Alcohol with Strong Bases

Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions

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