Mechanisms of C–H bond activation: rich synergy between computation and experiment

Boutadla, Youcef; Davies, David; Macgregor, Stuart A.; Poblador‐Bahamonde, Amalia I.

doi:10.1039/b904967c

Cited by 430 publications

(318 citation statements)

References 108 publications

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“…1). A base-assisted deprotonation step (here, the base is 2pb) is modelled for the cyclometallation (rhodacycle formation), in which a second substrate (basic) molecule acts as a base to abstract the proton; this step is similar to the CMD mechanism reported by Fagnou [18][19][20] (or the AMLA mechanism reported by Macgregor 16,17 ) in which deprotonation occurs from a coordinated ligand (e.g., CH3COO…”

Section: Resultsmentioning

confidence: 85%

A potential role of a substrate as a base for the deprotonation pathway in Rh-catalysed C–H amination of heteroarenes: DFT insights

et al. 2016

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Section: Resultsmentioning

confidence: 85%

A potential role of a substrate as a base for the deprotonation pathway in Rh-catalysed C–H amination of heteroarenes: DFT insights

et al. 2016

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“…[21] In base-assisted deprotonation, the C À H bond cleavage is slow with respect to the coordination of the aryl function to the metal center, however,the rate-determining step in the catalytic manifold may not be the CÀHb ond cleavage.I ndeed, ac ompetition experiment between 1 and [7-D]-1 (Scheme 5) shows only amodest kinetic isotope effect (KIE), inconsistent with CÀHb ond cleavage being the ratedetermining step in the cycle. [22] With regard to the type of palladium species responsible for the C7 arylation, the requirement for SPhos makes it likely that the active component is ahomogeneous complex.…”

Section: Methodsmentioning

confidence: 99%

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

2015

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The regiodivergent palladium-catalyzed C À Ha rylation of pyrazolo [1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. Ap hosphinecontaining palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas ap hosphine-free catalyst targets the most electron-rich position (C3).The direct CÀHa rylation of heterocyclics ubstrates (Scheme 1) is ap owerful synthetic tool for the construction of functionalized heterocycles.I tm aintains the expediency associated with simple cross-coupling reactions,b ut with greater step economy and lower waste production.[1] In heterocycles with multiple C À Hg roups,i tw ould be highly advantageous to be able to choose which CÀHg roup is functionalized, ideally with complete selectivity and with the ability to "switch" regioselectivity at will.[2] Seminal examples of this approach include the vinylation or arylation of pyrroles and indoles at either C2 or C3, where the outcome is driven by achange in substrate derivatization, [3,4] solvent, [5] or oxidant.[6]In these cases,the site selectivity is typically controlled by prohibiting or encouraging migration between positions C3 and C2. By contrast, we were interested to find out whether site selectivity could be engendered in the arylation of remote CÀHg roups,a nd whether catalyst "tuning" could be employed to drive this selectivity. [7] We report herein the catalyst-controlled switching in regioselectivity between the remote positions C3 and C7 of pyrazolo[1,5-a]pyrimidine (1; Figure 1). We chose this motif [8] because it forms the core of ar ange of biologically active compounds.S pecifically,a ryl-substituted pyrazolo[1,5-a]pyrimidines show antitumor [9] and anti-inflammatory properties, [10] have been examined as hepatitis Cvirus inhibitors and estrogen receptor ligands, [11,12] and are found in the approved sedative agents zaleplon and indiplon as well as in the anxiolytic agent ocinaplon.We began our study with the optimization of the coupling of compound 1 with bromobenzene in the presence of av ariety of palladium sources,w ith and without phosphines, changing solvents,bases,additives,and conditions.The results from this survey are summarized in the Supporting Information, and Scheme 2highlights the optimized conditions. Theu se of the monodentate phosphine ligand SPhos proved crucial to achieving site selectivity at C7, giving the desired product 2a in good yield.[13] NMR and UHPLC/ES-MS analyses of the crude reaction mixture showed at race amount (4 %) of the 3,7-diphenylated product (4a)b ut none of the 3-arylated species 3a,t hus indicating that arylation at C3 can only occur (to avery limited extent) after arylation at C7. [14] Conveniently,the reaction works just as well under air as under an inert atmosphere.The relatively high air stability of SPhos is obviously apivotal factor here.

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“…34,35 Indeed, the key role of acetate as an internal or external base has been proposed for several catalytic systems with Pd. 36,37 Davies and Macgregor have published a computational study evaluating proposed aromatic C−H bond activation mechanisms involving palladium acetate. 27 On the basis of this, we have formulated five different C−H activation mechanisms involving a proton abstraction in Scheme 4.…”

Section: ■ Computational Studymentioning

confidence: 99%

Mechanistic Investigation of Palladium-Catalyzed Allylic C–H Activation

et al. 2013

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The mechanism for the palladium-catalyzed allylic C–H activation was investigated using a combination of experimental and theoretical methods. A Hammett study revealed a buildup of a partial negative charge in the rate-determining step, and determination of the kinetic isotope effect (KIE) indicated that the C–H bond is broken in the turnover-limiting transition state. These experimental findings were further substantiated by carrying out a detailed density functional theory (DFT)-based investigation of the entire catalytic cycle. The DFT modeling supports a mechanism in which a coordinated acetate acts as a base in an intramolecular fashion during the C–H activation step. The reoxidation of palladium was found to reach an energy level similar to that of the C–H activation. Calculations of turnover frequencies for the entire catalytic cycle for the C–H alkylation were used to acquire a better understanding of the experimental KIE value. The good correspondence between the experimental KIE and the computed KIE values allows discrimination between scenarios where the acetate is acting in an intramolecular fashion (C–H alkylation) and an intermolecular fashion (C–H acetoxylation and C–H amination).

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Mechanisms of C–H bond activation: rich synergy between computation and experiment

Cited by 430 publications

References 108 publications

A potential role of a substrate as a base for the deprotonation pathway in Rh-catalysed C–H amination of heteroarenes: DFT insights

A potential role of a substrate as a base for the deprotonation pathway in Rh-catalysed C–H amination of heteroarenes: DFT insights

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

Mechanistic Investigation of Palladium-Catalyzed Allylic C–H Activation

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