Mechanism of Rhodium-Catalyzed Carbon–Silicon Bond Cleavage for the Synthesis of Benzosilole Derivatives: A Computational Study

Rhodium-catalyzed carbon–silicon bond cleavage reaction is an efficient approach for the synthesis of silole derivates. The newly reported density functional theory method M11 is employed in order to elucidate how to cleave the inactive C­(methyl)–Si bond. The computational results indicate that oxidative addition/reductive elimination pathway is favored over direct transmetallation in the C­(methyl)–Si bond cleavage step. Alternatively, 1,4-rhodium–silicon exchange could take place before oxidative addition/reductive elimination. The rate-determining step for both pathways has been targeted on the initial transmetallation of 2-trimethylsilylphenyl boronic acid. The active catalytic species is a monomeric hydroxyrhodium complex, which could be regenerated from the hydrolysis of methylrhodium complex. In addition, theoretical calculations show that the hydrolyses of both aryl and vinyl intermediates are inhibited by intramolecular π-coordinated groups

Rhodium-Catalyzed Hetero-(5 + 2) Cycloaddition of Vinylaziridines and Alkynes: A Theoretical View of the Mechanism and Chirality Transfer

A newly reported density functional theory method, M11-L, was performed to study the mechanism and chirality transfer for the intramolecular formal hetero-(5 + 2) cycloaddition of vinylaziridines with alkynes. Both (<i>E</i>)- and (<i>Z</i>)-olefinic substrates were considered in the density functional theory calculations. The computational results suggested a metallahydropyridine pathway for the generation of azepines, which involves aziridine cleavage, 2π insertion of the alkyne group into the Rh–C bond, and reductive elimination from a rhodium­(III) cation. The chirality transfer process for the (<i>E</i>)-alkene substrate is shown to occur on the <i>re</i> face of the alkene, whereas the (<i>Z</i>)-alkene cycloaddition chirality transfer occurs on the <i>si</i> face. The high enantioselectivity in this type of reaction is attributed to the greater ring strain in the <i>trans</i> allylic rhodium complex

Computational Studies on an Aminomethylation Precursor: (Xantphos)Pd(CH₂NBn₂)⁺

(Xantphos)­Pd­(CH₂NBn₂)⁺ is an important precursor for aminomethylation reactions. In this study, density functional theory is used to clarify the structure of the complex and the mechanism of these types of reactions. The complex can be described as a mixture of square-planar nitrogen-coordinated aminomethyl–Pd­(II) and triangular iminium-coordinated Pd(0). Frontier molecular orbital analysis favors the latter. The mechanisms of selected aminomethylation reactions are investigated by density functional theory calculations. The computational results reveal that the Xantphos ligand aids in forming iminium-coordinated palladium complexes, promotes the reductive elimination step of aminomethylation, and can stabilize Pd(0) species

Reactivity for the Diels–Alder Reaction of Cumulenes: A Distortion-Interaction Analysis along the Reaction Pathway

Cumulenes, including allene, ketenimine, and ketene, can be employed as dienophiles in Diels–Alder type reactions. The activation energies of a Diels–Alder reaction between cyclopentadiene and either the CC bond or the other CX (X = C, N, or O) bond in cumulenes have been calculated by G3B3, CBS-QB3, M06-2X, and B3LYP methods. The reactivity trend for the CC bond in cumulenes is allene > ketenimine > ketene and that of the CX bond in cumulenes is ketene > allene > ketenimine. Application of distortion-interaction analysis only at transition states does not give a satisfactory explanation for these reactivities. By employing distortion-interaction analysis along reaction pathways, we found that the reactivity of the CC and CX bond in cumulenes is controlled by both of its distortion and interaction energies. The lowest distortion energy of allene leads to its highest reactivity; the higher interaction energy results in higher activation energy of ketene than that of ketenimine. Compared with the reactivity of the CX bond in cumulenes, the CO bond in ketene has the lowest activation energy to react with cyclopentadiene, due to its lowest interaction energy, whereas the lower distortion energy of ketenimine than that of allene leads to a higher reactivity. The distortion energy of the reactants can be attributed to folding ability and molecule strain. The corresponding interaction energy of the reactants is controlled by orbital interaction, closed-shell repulsion, and static repulsion

Why Nature Eschews the Concerted [2 + 2 + 2] Cycloaddition of a Nonconjugated Cyanodiyne. Computational Study of a Pyridine Synthesis Involving an Ene–Diels–Alder–Bimolecular Hydrogen-Transfer Mechanism

An intramolecular formal metal-free intramolecular [2 + 2 + 2] cycloaddition for the formation of pyridines has been investigated with M06-2X and B3LYP density functional methods, and compared to the experimentally established three-step mechanism that involves ene reaction–Diels–Alder reaction–hydrogen transfer. The ene reaction of two alkynes is the rate-determining step. This is considerably easier than other possible mechanisms, such as those involving an ene reaction of an alkyne with a nitrile, a one-step [2 + 2 + 2] cycloaddition, or a 1,4-diradical mechanism. The relative facilities of these processes are analyzed with the distortion-interaction model. A bimolecular hydrogen-transfer mechanism involving a radical-pair intermediate is proposed rather than a concerted intramolecular 1,5-hydrogen shift for the last step in the mechanism

Rhodium-Catalyzed Cyclocarbonylation of Ketimines via C–H Bond Activation

A novel rhodium-catalyzed oxidative cyclocarbonylation of ketimines via cleavage of two C–H bonds was established, which provided a direct and reliable method for the synthesis of a wide range of 3-methyleneisoindolin-1-ones with mostly moderate yields. Preliminary experimental mechanistic studies and DFT calculations revealed that this reaction proceeds via imine–enamine tautomerization, N–H cleavage, C–H bond activation, CO insertion, and reductive elimination. The mechanism studies further ruled out an isolated cyclometalated rhodium complex being involved in the present reaction, which was different from many other documented rhodium-catalyzed C–H cyclization reactions

Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis

<div><p>Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the <i>OSR1</i> gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney. Whereas mice heterozygous for either an <i>Osr1</i> or <i>Wt1</i> null allele have normal kidneys at birth, most mice heterozygous for both <i>Osr1</i> and <i>Wt1</i> exhibit defects in metanephric kidney development, including unilateral or bilateral kidney agenesis or hypoplasia. The developmental defects in the <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> mouse embryos were detected as early as E10.5, during specification of the metanephric mesenchyme, with the <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> mouse embryos exhibiting significantly reduced Pax2-positive and Six2-positive nephron progenitor cells. Moreover, expression of <i>Gdnf</i>, the major nephrogenic signal for inducing ureteric bud outgrowth, was significantly reduced in the metanephric mesenchyme in <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> embryos in comparison with the <i>Osr1</i>^<i>+/-</i> or <i>Wt1</i>^<i>+/-</i> littermates. By E11.5, as the ureteric buds invade the metanephric mesenchyme and initiate branching morphogenesis, kidney morphogenesis was significantly impaired in the <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> embryos in comparison with the <i>Osr1</i>^<i>+/-</i> or <i>Wt1</i>^<i>+/-</i> embryos. These results indicate that Osr1 and Wt1 act synergistically to regulate nephron endowment by controlling metanephric mesenchyme specification during early nephrogenesis.</p></div

Aryne Trifunctionalization Enabled by 3‑Silylaryne as a 1,2‑Benzdiyne Equivalent

An unprecedented aryne 1,2,3-trifunctionalization protocol from 2,6-bis­(silyl)­aryl triflates was developed under transition-metal-free conditions. The reaction of generated 3-silylaryne with both pyridine <i>N</i>-oxide and <i>N</i>-hydroxylamide afforded <i>o</i>-silyl triflate/tosylate in a one-pot transformation, allowing the formation of 2,3-aryne precursors with various vicinal pyridinyl/amido substituents. These pyridinyl-substituted 2,3-aryne intermediates exhibit a broad scope of reactivity with diverse arynophiles in good yields and high selectivity

Molecular marker expression in the metanephric mesenchyme in <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> embryos and littermates.

<p>Whole mount <i>in situ</i> hybridization detection of <i>Gdnf</i> (A-C), <i>Eya1</i> (D-F), and <i>Sall1</i> (G-I) mRNA expression in E10.5 embryos. Scale bar, 200 μm. (J) Real-time RT-PCR analysis of the levels of expression of <i>Gdnf</i>, <i>Eya1</i>, and <i>Sall1</i> mRNAs in Wt1-GFP+ cells from E9.5 <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> embryos and <i>Wt1</i>^<i>+/-</i> littermate. *, p < 0.05.</p

Analysis of cell apoptosis and proliferation during early kidney development in <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> embryos and littermates.

<p>(A-H) Cell apoptosis is analyzed by TUNEL (green) and counterstained with DAPI (blue). TUNEL assay detected no obvious change in cell apoptosis in <i>Osr1</i>^<i>+/-</i><i>Wt1</i>^<i>+/-</i> metanephric mesenchyme (C, D, G, H) compared with <i>Osr1</i>^<i>+/-</i> (A, E) and <i>Wt1</i>^<i>+/-</i> (B, F) metanephric mesenchyme at E10.5 (A-D) and E11.5 (E-H). (I-P) Analysis of cell proliferation by BrdU incorporation at E10.5 (I-L) (n = 18) and E11.5 (n = 7) (M-P) embryos. BrdU index is calculated by the ratio of BrdU-positive cells (green) versus Six2-positive cells (red). Scale bar, 100 μm.</p