Zur Interpretation des kinetischen Isotopeneffekts bei der Funktionalisierung von C‐H‐Bindungen durch Übergangsmetallkomplexe

Simmons, Eric M.; Hartwig, John F.

doi:10.1002/ange.201107334

Cited by 484 publications

(162 citation statements)

References 23 publications

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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. Indeed, a 31 P{ 1 H} NMR spectrum of ac atalytic reaction mixture of 1 reacting with PhBr (conditions A, Scheme 2) recorded after 1.5 h( corresponding to % 30 %c onversion to 2a)s howed the presence of two main species (in addition to free SPhos), [23] neither of which require the presence of either 1 or PhBr to form.…”

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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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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“…This pair of experiments suggested that the CÀHb ond activation is unlikely the rate limiting step. [24] Based on our preliminary mechanistic study (Supporting Information) we proposed ap lausible mechanism (Figure 4) using 1a as an example.First, five-membered silametallacycle I is formed via reversible oxidative insertion of Rh I complex into the SCB. [5,25] Subsequent b-H elimination of I,p ossibly enabled by the sterically hindered TMS-segphos ligand, would give the key hydrido-rhodium(III) II,i nw hich the terminal alkene probably still coordinates to the Rh.…”

Section: Angewandte Chemiementioning

confidence: 99%

Rhodium‐Catalyzed Intramolecular C−H Silylation by Silacyclobutanes

Zhang

Liu

et al. 2016

Angewandte Chemie

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Silacyclobutane was discovered to be an efficient CÀHbond silylation reagent. Under the catalysis of Rh I /TMSsegphos,s ilacyclobutane undergoes sequential CÀSi/CÀH bond activations,a ffording as eries of p-conjugated siloles in high yields and regioselectivities.T he catalytic cycle was proposed to involve ararely documented endocyclic b-hydride elimination of five-membered metallacycles,w hicha fter reductive elimination gave rise to aS i ÀRh I species that is capable of CÀHa ctivation.

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“…Al ow values of intermolecular kinetic isotope effect were observedi n both parallelr eactions (k H /k D = 1.1) and competitive reaction( k H /k D = 1.2), implying that the C À Hb ond cleavagem ay not be involvedi nt he rate-limiting step. [12] Ap lausible mechanism for the Rh-catalyzed phosphorylation process is showni nS cheme 4. Thea ctivated cationic Rh III species is generated in situ by the [RhCp*Cl 2 ] 2 /AgNTf 2 catalytic system.…”

Section: Resultsmentioning

confidence: 99%

Rhodium‐Catalyzed Direct C–H Phosphorylation of (Hetero)arenes Suitable for Late‐Stage Functionalization

et al. 2016

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Efficient rhodium-catalyzed direct C-H phosphorylation of (hetero)arenes was developed. Va riousd irecting groups andawide range of substrates,i ncluding heterocycles,c an be utilized in this C-H phosphorylation process,a llowing for the rapid installation of the phosphonate group into medicinally and biologicallyi mportantp rivileged scaffolds. Thee fficienta nd straightforward method could serve as an ew tool to streamlinel ate-stage C-H functionalization for preparing aryl phosphonates, which are important structural motif in synthetic and medicinalc hemistry.

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Zur Interpretation des kinetischen Isotopeneffekts bei der Funktionalisierung von C‐H‐Bindungen durch Übergangsmetallkomplexe

Cited by 484 publications

References 23 publications

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

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

Rhodium‐Catalyzed Intramolecular C−H Silylation by Silacyclobutanes

Rhodium‐Catalyzed Direct C–H Phosphorylation of (Hetero)arenes Suitable for Late‐Stage Functionalization

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