Synergistic Steric Effects in the Development of a Palladium‐Catalyzed Alkyne Carbohalogenation: Stereodivergent Synthesis of Vinyl Halides

Abstract

We report our finding that by exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd-catalyzed alkyne carbohalogenation can be achieved. This operationally simple method uses the bulky Pd/ Q-Phos combination and allows access to tetrasubstituted vinyl halides from the corresponding aryl chlorides, bromides, and iodides. Steric effects in the substrate play a key role by promoting C sp 2-halogen reductive elimination and enabling catalytic turnover. Through a reversible oxidative addition mechanism, a thermodynamically driven isomerization reaction is observed at elevated temperatures. Thus by changing the reaction temperature, both stereoisomers of the reaction become readily accessible.Aryl and vinyl halides are versatile building blocks in organic synthesis due to their applicability toward a vast range of transition-metal-catalyzed cross-coupling reactions. Oxidative addition into an aryl or vinyl halide bond constitutes the first step in many traditional Pd-catalyzed cross-coupling reactions and is generally considered to be an irreversible and thermodynamically favorable step. [1] Consequently, carbonhalogen reductive elimination from Pd II complexes (i.e., the microscopic reverse reaction) is rarely encountered when using conventional ligand sets. [2][3][4] This long-standing paradigm was shifted when Hartwig reported the stoichiometric reductive elimination of aryl halides from monomeric ArPd II X species in 2003. [3b] Interestingly, this reductive elimination was promoted by the addition of excess PtBu 3 , an electron-rich and sterically encumbering ligand (Scheme 1 a). Typically, electron-poor Pd II complexes are better suited to undergo reductive elimination compared to electron-rich complexes with similar steric properties. [5] However, these studies reveal that unfavorable electronic effects can be overridden in the reductive elimination of C sp 2 À X bonds from electron-rich Pd II centers, provided that bulky phosphine ligands are employed. In this study, both K eq and yield are increased upon the use of ortho-substituted aryl halide complexes, thus suggesting that substrate sterics may also play an intimate role in promoting this elementary process.Our group has demonstrated that the use of bulky monodentate phosphine ligands, such as PtBu 3 and Q-Phos, can effectively promote C sp 3 À I reductive elimination in the Pd 0 -catalyzed carboiodination of alkenes (Scheme 1 b). [4a-f] To date, the successful realization of an alkyne carbohalogenation reaction has been impeded by a limited library of ligands fitting the criteria for promoting a difficult carbon-halogen reductive elimination step. Furthermore, the reactive nature of the final vinyl halide product presents additional complications, which stem from reinsertion of the Pd 0 catalyst, followed by potential catalyst deactivation, attenuation in turnover numbers and/or the initiation of unwanted coupling or oligomerization processes. Scheme 1. a) Hartwig's stoichiometric studies on aryl halide reductive el...

ChemInform Abstract: Formal anti‐Carbopalladation Reactions of Non‐Activated Alkynes: Requirements, Mechanistic Insights, and Applications.

“…In contrast to recent suggestions [21] we were not able to find am etallocarbene species as local minimum, neither with nor without the help of an external nucleophile.A ttempts to localize and isomerize such ac omplex led to huge energy barriers.H owever,a fter removing one PMe 3 from the metal complex generating the 14 VE Pd species syn-19,atransition state for the cis-trans isomerization 21.5 kcal mol À1 higher in energy than the starting complex could easily be localized (Figure 1). However,i ts structure did not resemble ac ommon carbene complex.…”

Palladium‐katalysierte decarbonylierende Iodierung von Carbonsäuren, ermöglicht durch Ligand‐unterstützten Halogenaustausch

“…[15] Nachfolgende Berichte der Gruppen von Buchwald, Sanford und weiteren haben das Spektrum Pd 0 /Pd II -katalysierter Methoden zur Installation von Kohlenstoff-Halogen-Bindungen erweitert. [6,16] Unter den aromatischen Halogeniden nehmen Aryliodide eine privilegierte Rolle ein, da sie einzigartige Eigenschaften aufweisen, wie eine überlegene Reaktivitätb ei Kreuzkupplungsreaktionen [17] oder ihre Anwendung in der hypervalenten Iodchemie. [18] Tr otz der jüngsten Fortschritte bei der übergangsmetallkatalysiertenI nstallation von Kohlenstoff-Halogen-Bindungen [6,11a,b,f, 12c,d] sind allgemeine und milde Methoden zur Installation von C(sp 2 )-Iod-Bindungen nach wie vor sehr gefragt.…”

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

“…[6,7] With olefins, alkynylation to give 1,3-enynes has been limited to electronically activated substrates, in particular enones and acrylamides (Scheme 2 A). [7c, 8] By contrast, the selective C À H alkynylation reaction of unactivated alkenes has enjoyed considerably less attention, presumably because of the significant chemical challenges imposed by the additional reactivity pathways accessible to olefins, such as olefin E/Z isomerization, [3,[9][10][11][12][13] allylic functionalization, [14] and intramolecular nucleopalladation. [15,16] As part of a study focused on arenes, the groups of Zhao and Sarpong independently reported the reaction of three derivatives of two simple ethanamines, namely but-3-en-1-amine and cyclohexenylethanamine (Scheme 2 A).…”