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Commercially and readily available MSTFA [2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide] was identified as a highly effective TMS (trimethylsilyl) source for the convenient preparation of cyclic acetals under modified Noyori's conditions. The reactions proceeded smoothly under mild conditions, affording a wide range of the corresponding cyclic acetals with excellent yields in the presence of catalytic TMSOTf (trimethylsilyl trifluoromethanesulfonate). The present method does not require a large excess of diols that can be valuable and does not require presynthesized silylated diols. In contrast to other silylating reagents such as BSA [N,O-bis(trimethylsilyl)acetamide] and BSTFA [N,O-bis(trimethylsilyl)trifluoroacetamide], the application of MSTFA avoided the inhibition of catalytic acetalization by the side product 2,2,2-trifluoro-N-methylacetamide.
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This Article describes the development of a stable NiIV complex that mediates C(sp2)-H trifluoromethylation reactions. This reactivity is first demonstrated stoichiometrically and then successfully translated to a NiIV-catalyzed C-H trifluoromethylation of electron-rich arene and heteroarene substrates. Both experimental and computational mechanistic studies support a radical chain pathway involving NiIV, NiIII, and NiII intermediates.
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This Article demonstrates a mild oxidatively induced C(sp3)-H activation at a high-valent Ni center. In contrast with most C(sp3)-H activation reactions at NiII, the transformation proceeds at room temperature and generates an isolable NiIV σ-alkyl complex. Density functional theory studies show two plausible mechanisms for this C-H activation process involving triflate-assisted C-H cleavage at either a NiIV or a NiIII intermediate. The former pathway is modestly favored over the latter (by â¼3 kcal/mol). The NiIV σ-alkyl product of C-H cleavage reacts with a variety of nucleophiles to form C(sp3)-X bonds (X = halide, oxygen, nitrogen, sulfur, or carbon). These stoichiometric transformations can be coupled using N-fluoro-2,4,6-trimethylpyridinium triflate as a terminal oxidant in conjunction with chloride as a nucleophile to achieve a proof-of-principle NiII/IV-catalyzed C(sp3)-H functionalization reaction.
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This communication describes a series of oxidatively induced intramolecular arene C-H activation reactions of NiII model complexes to yield NiIV σ-aryl products. These reactions proceed within 10 min at room temperature, which represents among the mildest conditions reported for C-H cleavage at a Ni center. A combination of density functional theory and preliminary experimental mechanistic studies implicate a pathway involving initial 2e- oxidation of the NiII starting materials by the F+ transfer reagent N-fluoro-2,4,6-trimethylpyridinium triflate followed by triflate-assisted C-H cleavage at NiIV to yield the products.
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This communication demonstrates the first catalytic aminoboration of C-C π bonds by B-N σ bonds and its application to the synthesis of 3-borylated indoles. The regiochemistry and broad functional group compatibility of this addition reaction enable substitution patterns that are incompatible with major competing technologies. This aminoboration reaction effects the formation of C-B and C-N bonds in a single step from aminoboronic esters, which are simple starting materials available on the gram scale. This reaction generates synthetically valuable N-heterocyclic organoboron compounds as potential building blocks for drug discovery. The working mechanistic hypothesis involves a bifunctional Lewis acid/base catalysis strategy involving the combination of a carbophilic gold cation and a trifluoroacetate anion that activate the C-C π bond and the B-N σ bond simultaneously.
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Compostos de Boro/química , Indóis/química , Aminas/química , Compostos de Boro/síntese química , Técnicas de Química Sintética , Compostos Heterocíclicos/química , Indóis/síntese química , Pirróis/químicaRESUMO
The design and synthesis of a mixed 2-pyridonate-Ta(NMe2)3Cl complex for the direct C-H alkylation adjacent to nitrogen in unprotected secondary amines are reported. The hydroaminoalkylation of sterically demanding internal alkenes gives the direct, catalytic formation of C(sp(3))-C(sp(3)) bonds. Substrate scope investigations reveal key strategies for further catalyst development efforts in this 100% atom-economic synthesis of α-alkylated amines.
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Nickel K- and L2,3-edge X-ray absorption spectra (XAS) are discussed for 16 complexes and complex ions with nickel centers spanning a range of formal oxidation states from II to IV. K-edge XAS alone is shown to be an ambiguous metric of physical oxidation state for these Ni complexes. Meanwhile, L2,3-edge XAS reveals that the physical d-counts of the formally NiIV compounds measured lie well above the d6 count implied by the oxidation state formalism. The generality of this phenomenon is explored computationally by scrutinizing 8 additional complexes. The extreme case of NiF62- is considered using high-level molecular orbital approaches as well as advanced valence bond methods. The emergent electronic structure picture reveals that even highly electronegative F-donors are incapable of supporting a physical d6 NiIV center. The reactivity of NiIV complexes is then discussed, highlighting the dominant role of the ligands in this chemistry over that of the metal centers.
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A rapid, four-step approach to alkyl- and aryl-substituted benzomorpholines is accomplished by a Pd-catalyzed domino C-C/C-N bond coupling using a norbornene template. Extension to phenoxazines and dihydrodibenzoxazepines is presented.
Assuntos
Benzoxazinas/síntese química , Morfolinas/síntese química , Norbornanos/química , Oxazinas/síntese química , Paládio/química , Benzoxazinas/química , Catálise , Estrutura Molecular , Morfolinas/química , Oxazinas/química , EstereoisomerismoRESUMO
We report the synthesis of enantiomerically enriched 1,4-benzodioxanes containing alkyl, aryl, heteroaryl, and/or carbonyl substituents at the 2-position. The starting 1,4-benzodioxines were readily synthesized via ring closing metathesis using an efficient nitro-Grela catalyst at ppm levels. Excellent enantioselectivities of up to 99:1 er were obtained by using the versatile catalyst system [Ir(cod)Cl]2/BIDIME-dimer in the asymmetric hydrogenation of 2-substituted 1,4-benzodioxines. Furthermore, DFT calculations reveal that the selectivity of the process is controlled by the protonation step; and coordinating groups on the substrate may alter the interaction with the catalyst, resulting in a change in the facial selectivity.
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The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19â¯T790Mâ¯C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacocinética , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclização , Entropia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Feminino , Hepatócitos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report the development of an iron-catalyzed method for the selective oxyfunctionalization of benzylic C(sp(3))-H bonds in aliphatic amine substrates. This transformation is selective for benzylic C-H bonds that are remote (i.e., at least three carbons) from the amine functional group. High site selectivity is achieved by in situ protonation of the amine with trifluoroacetic acid, which deactivates more traditionally reactive C-H sites that are α to nitrogen. The scope and synthetic utility of this method are demonstrated via the synthesis and derivatization of a variety of amine-containing, biologically active molecules.
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Aminas/química , Aminas/síntese química , Compostos de Benzil/química , Ferro/química , Catálise , Estrutura MolecularRESUMO
In the present study, the oxyboration reaction catalyzed by IPrAuTFA in the presence and absence of NaTFA has been examined with kinetic studies, mass spectrometry, and 1H NMR and 11B NMR spectroscopy. Data from monitoring the reactions over the temperature range from 30 to 70 °C, the catalyst range from 1.3 to 7.5 mol %, and the NaTFA additive range from 2.5 to 30 mol % suggests a mechanism that involves rate-determining catalyst generation. Data from additive studies that replaced NaTFA with NaBARF (BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) or Bu4NTFA as an alternative additive suggest that catalyst quenching from residual NaCl remaining from a one-pot substrate synthesis/reaction method is the cause of this effect, despite the low solubility of this NaCl byproduct in toluene. Material produced through an alternative, sodium chloride free substrate synthesis exhibited faster reaction rates, consistent with a change in rate-determining step that depended on the substrate synthesis route.
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Fabrication of ZnO nanostructure via direct patterning based on sol-gel process has advantages of low-cost, vacuum-free, and rapid process and producibility on flexible or non-uniform substrates. Recently, it has been applied in light-emitting devices and advanced nanopatterning. However, application as an electrically conducting layer processed at low temperature has been limited by its high resistivity due to interior structure. In this paper, we report interior-architecturing of sol-gel-based ZnO nanostructure for the enhanced electrical conductivity. Stepwise fabrication process combining the nanoimprint lithography (NIL) process with an additional growth process was newly applied. Changes in morphology, interior structure, and electrical characteristics of the fabricated ZnO nanolines were analyzed. It was shown that filling structural voids in ZnO nanolines with nanocrystalline ZnO contributed to reducing electrical resistivity. Both rigid and flexible substrates were adopted for the device implementation, and the robustness of ZnO nanostructure on flexible substrate was verified. Interior-architecturing of ZnO nanostructure lends itself well to the tunability of morphological, electrical, and optical characteristics of nanopatterned inorganic materials with the large-area, low-cost, and low-temperature producibility.
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Chemoselectivity of intramolecular hydroaminoalkylation over hydroamination has been achieved with a bis(3-phenyl-2-pyridonate) titanium complex. Primary aminoalkenes are selectively α-alkylated by C-H functionalization adjacent to nitrogen to access five- and six-membered cycloalkylamines with a good substrate-dependent diastereoselectivity of up to 19:1.