Competitive Metalation Research Articles

Theoretical Mechanistic Studies of Rh‐Catalyzed C(sp3)—H Amination: A Comparison with Co Analogue and Metal Effects

Summary of main observation and conclusionThe mechanism of Rh‐catalyzed C(sp3)—H amination has been computationally investigated. The reaction mechanism mainly involves sequential C(sp3)—H activation, decarboxylation, nitrene migration insertion, and protonation steps. Competitive concerted metalation deprotonation (CMD) and external base assisted deprotonation (EBAD) pathways are found for the involved C(sp3)—H activation in both Rh and Co analogous systems. This is different from the previously reported C(sp2)—H activation, where the CMD is dominant. The key mechanistic difference between the two systems is found to be in the C(sp3)—H activation step. In comparison with Rh species, the lower activity of Co complex toward the C(sp3)—H activation could be ascribed to smaller atomic size of Co and thus larger steric repulsion between ancillary ligand and substrate along with the CMD pathway. In view of the EBAD pathway, however, the lower activity of Co species could be imputed to the triplet nature of Co center, which is against the electron transfer from the electron‐rich carbon atom of the deprotonating C(sp3)—H bond to the Co center. As to the subsequent decarboxylation and nitrene insertion steps, compared with the Co system, the relatively lower reactivity of Rh species is partially due to the stronger Rh—N bond, and the higher π(Rh—N) and π*(Rh—N) orbital energies of the corresponding transition state structure.

Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

Directed ortho‐Metalation of Aryl Amides, O‐Carbamates, and Methoxymethoxy Systems: Directed Metalation Group Competition and Cooperation

A systematic study on the competitive metalation of derivatives containing four directed metalation groups (DMGs), namely, Cl, OMe, methoxymethoxy (OMOM), and CONEt2, in comparison with the OCONEt2 DMG is described. In addition, the anionic ortho‐Fries (AoF) rearrangement, the double metalation–electrophile quench of 1,2‐ and 1,4‐O‐carbamates, and iterative metalation procedures are presented. The results provide new methodologies for the synthesis of contiguously functionalized 1,2,3‐ and 1,2,3,4‐substituted aromatic derivatives of difficult accessibility and potential broad utility. A comparison of the present methodology with previously developed routes is provided for selected examples with emphasis on such substituted compounds.

Putting the pieces into place: Properties of intact zinc metallothionein 1A determined from interaction of its isolated domains with carbonic anhydrase.

Mammalian metallothioneins (MTs) bind up to seven Zn(2+) using a large number of cysteine residues relative to their small size and can act as zinc-chaperones. In metal-saturated Zn7-MTs, the seven zinc ions are co-ordinated tetrahedrally into two distinct clusters separated by a linker; the N-terminal β-domain [(Zn3Cys9)(3-)] and C-terminal α-domain [(Zn4Cys11)(3-)]. We report on the competitive zinc metalation of apo-carbonic anhydrase [CA; metal-free CA (apo-CA)] in the presence of apo-metallothionein 1A domain fragments to identify domain specific determinants of zinc binding and zinc donation in the intact two-domain Znn-βαMT1A (human metallothionein 1A isoform; n=0-7). The apo-CA is shown to compete effectively only with Zn2-3-βMT and Zn4-αMT. Detailed modelling of the ESI mass spectral data have revealed the zinc-binding affinities of each of the zinc-binding sites in the two isolated fragments. The three calculated equilibrium zinc affinities [log(KF)] of the isolated β-domain were: 12.2, 11.7 and 11.4 and the four isolated α-domain affinities were: 13.5, 13.2, 12.7 and 12.6. These data provide guidance in identification of the location of the strongest-bound and weakest-bound zinc in the intact two-domain Zn7βαMT. The β-domain has the weakest zinc-binding site and this is where zinc ions are donated from in the Zn7-βαMT. The α-domain with the highest affinity binds the first zinc, which we propose leads to an unscrambling of the cysteine ligands from the apo-peptide bundle. We propose that stabilization of the intact Zn6-MT and Zn7-MT, relative to that of the sum of the separated fragments, is due to the availability of additional cysteine ligand orientations (through interdomain interactions) to support the clustered structures.

The Zinc Balance: Competitive Zinc Metalation of Carbonic Anhydrase and Metallothionein 1A

The small, cysteine-rich metallothionein family of proteins is currently considered to play a critical role in the provision of metals to metalloenzymes. However, there is limited information available on the mechanisms of these fundamentally important interactions. We report on the competitive zinc metalation of apocarbonic anhydrase in the presence of apometallothionein 1A using electrospray-ionization mass spectrometry. These experiments revealed the relative affinities of zinc to all species in solution. The carbonic anhydrase is shown to compete efficiently only against Zn5-7MT. The calculated equilibrium zinc binding constants of each of the 7 zinc metallothionein 1A species ranged from a high of (log(KF)) 12.5 to a low of 11.8. The 8 equilibrium constants connecting the 10 active species in competition for the zinc were modeled by fitting the KF values of the 8 competitive bimolecular reactions to the ESI-mass spectral data. These modeled K values are shown to be experimentally connected to the metalation efficiency of the carbonic anhydrase. The series of 7 metallothionein binding affinities for zinc highlight the buffering role of zinc metallothioneins that permit simultaneously zinc storage and zinc sensing. Finally, the significance of the multiple zinc binding affinities of zinc metallothionein is discussed in relation to zinc homeostasis.

Regioselective Cyclometalation of Planar Chiral Pyridine and Oxazoline Derivatives: peri- versus ortho-C–H Functionalization

The cyclopalladation of highly enantioenriched cyclopentadienyl(indenyl)ruthenium complexes featuring pyridine or oxazoline functionalities as directing groups is detailed. Two competitive metalation sites inherent to the fused ring system were selectively activated after appropriate tuning of the reaction conditions, enabling the access to both six (peri)- and five-membered (ortho) membered chelates. A peri → ortho isomerization was identified in the pyridine-based system, unveiling a kinetic preference for the peri-position and thermodynamic control for the ortho-cyclopalladation. In marked contrast, oxazoline derivatives incorporating a stereogenic center at C4 proved reluctant to form ortho-isomers and were exclusively converted into the corresponding peri-palladacyles at low temperatures.

Exploiting the Lithiation‐Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2‐Aryloxetane Scaffolds under Mild Conditions

Oxetane nudges in the DoM direction! Regioselective ortho-lithiation induced by an oxetane ring has been achieved. The reaction provides easy access to ortho-functionalized 2-aryloxetanes also through a lithiation/borylation Suzuki–Miyaura cross-coupling. The lithiation-directing ability of oxetane and the proton transfer mechanism have been investigated by competitive metalation and kinetic isotope effect studies.

Competitive ortho metalation effects: The kinetic and thermodynamic lithiation of 3-( tert-butoxycarbonyl)amino-4-carbomethoxythiophene

Deprotonation of the thiophene 1 under kinetically controlled conditions with LDA takes place next to the NHBoc group and under thermodynamic conditions next to the methyl ester. N-Methylation leads to exclusive lithiation next to the ester. The methyl ester was found to be superior to the diethylamide in facilitating lithiation.

Competitive metalation reactions between aliphatic and aromatic carbon atoms in N-benzylideneamines. X-ray molecular structure of [Pd[1-CH2-2-(HC:NPh)-3,5-(CH3)2C6H2]BrPPh3

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCompetitive metalation reactions between aliphatic and aromatic carbon atoms in N-benzylideneamines. X-ray molecular structure of [Pd[1-CH2-2-(HC:NPh)-3,5-(CH3)2C6H2]BrPPh3]Joan Albert, Jaume Granell, Joaquim Sales, Xavier Solans, and Manuel Font-AltabaCite this: Organometallics 1986, 5, 12, 2567–2568Publication Date (Print):December 1, 1986Publication History Published online1 May 2002Published inissue 1 December 1986https://doi.org/10.1021/om00143a034RIGHTS & PERMISSIONSArticle Views227Altmetric-Citations67LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (308 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Competitive metalation of η 5-indenyl- and η 5-cyclopentadienyltricarbonyl complexes of manganese and rhenium

Competitive metalation of the η 5-indenyl- and η 5-cyclopentadienyl-tricarbonyl complexes of manganese and rhenium by n-butyllithium in THF has been carried out and subsequent treatment of the lithium derivatives with trimethylchlorosilane has been performed. The following mixtures of compounds have been investigated: η 5-C 9H 7Mn(CO) 3 and η 5-C 5H 5Mn(CO) 3, η-C 9H 7Re(CO) 3 and η 5-C 5H 5Re(CO) 3, η 5-C 9H 7Mn(CO) 3 and η 5-C 9H 7Re(CO) 3, η 5-C 5H 5Mn(CO) 3 and η 5-C 5H 5Re(CO) 3. It was shown that η 5-C 9H 7Mn(CO) 3 and η 5-C 5H 5Mn(CO) 3 do not undergo metalation in the presence of the corresponding complexes of rhenium. On metalation η 5-indenyl and η 5-cyclopentadienyl ligands coordinated to the same metal differ slightly in reactivity. The trimethylsilyl derivatives of the η 5-indenyltricarbonyl complexes of manganese and rhenium were isolated as a mixture of two isomers in approximately equal amounts.

Synthesis and structural study of 2,5-dihydropyridines. Competitive metalation of 2-fluoropyridine

Synthesis and structural study of 2,5-dihydropyridines. Competitive metalation of 2-fluoropyridine

Substitution reactions in ruthenocene

1. Ruthenocene was sulfonated and its sulfo derivatives were obtained. 2. The mercuration of ruthenocene gave the complex of ruthenocene with mercuric chloride and diruthenocenylmercury. 3. Under competitive metalation conditions, ruthenocene is more active than ferrocene. 4. Ruthenocenylboric acid was synthesized and a number of new ruthenocene derivatives was obtained from it, and specifically the bromo- and chlororuthenocences, phenylruthenocene, ruthenocenyl acetate, the methyl ester of hydroxyruthenocene, and diruthenocenylmercury.

Competitive metalation of some nitrogen- and sulfur-containing heterocycles

It has been shown in three separate systems that metalation by n-butyllithium of sulfur-containing heterocycles occurs faster than similar heterocycles containing the N-methyl group. The systems selected for study were thiophene- N-methylpyrrole, thianaphthene- N-methylindole and N-methylphenothiazine. These data are in harmony with earlier studies of the dibenzothiophene- N-ethylcarbazole system and N-ethylphenothiazine, but not in line with predominant control of the metalation orientation by inductive effects predicted from relative electronegativities of sulfur and nitrogen. The results are rationalized in terms of equilibrium concentrations of the respective heterocycle- n-butyllithium complexes, rapid and reversible formation of which precedes rate-controlling removal of adjacent ring hydrogen.

Competitive Metalation of Diphenyl Sulfone and 4,4'-Dimethyldiphenyl Sulfone by n-Butyllithium

Competitive Metalation of Diphenyl Sulfone and 4,4'-Dimethyldiphenyl Sulfone by n-Butyllithium