RESUMO
18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.
Assuntos
Clorofluorcarbonetos de Metano/química , Radioisótopos de Flúor/química , Peptídeos/química , Compostos de Enxofre/química , Metilação , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/químicaRESUMO
A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.
Assuntos
Antineoplásicos/síntese química , Cloretos/química , Clorofluorcarbonetos de Metano/química , Propanóis/síntese química , Tiazóis/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Propanóis/química , Espectroscopia de Prótons por Ressonância Magnética , EstereoisomerismoRESUMO
A theoretical analysis of the reaction of oxidative sulfamidation of several alkenes was performed in order to explain the various experimental observations and different reactivity of triflamide and non-fluorinated sulfonamides. Transformations occurring in the system alkene-sulfonamide in the presence of oxidative system (ButOCl + NaI) were analyzed at the MP2/DGDZVP//B3LYP/DGDZVP level of theory using the IEF-PCM method for taking into account the solvent acetonitrile (MeCN) effect. As the model substrates, styrene, trimethyl(vinyl)silane, dimethyl(divinyl)silane and diphenyl(divinyl)silane were chosen and mesylamide, triflamide, tosylamide and p-nosylamide were taken as the reagents. ButOI generated from ButOCl and NaI reacts with sulfonamides to give N-iodinated sulfonamides RSO2NHI and RSO2NI2 as active intermediates, the iodinating activity of the latter being notably higher. The analysis allowed to answer such challenging questions as different reactivity of nonfluorinated sulfonamides leading to aziridination and of triflamide resulting in the formation the main products of bis-triflamidation, or different regioselectivity of halogenation of styrene and trimethyl(vinyl)silane caused by a linear intermediate iodonium cation in the former case and a cyclic one in the latter.
Assuntos
Clorofluorcarbonetos de Metano/química , Sulfonamidas/química , Alcenos/química , Amidas/química , Cátions , Simulação por Computador , Halogenação , Iodo/química , Conformação Molecular , Oxirredução , Estresse Oxidativo , Silanos/química , Estireno/químicaRESUMO
Insights into the structure and dynamics of large biological systems has been greatly improved by two concurrent NMR approaches: the application of transverse relaxation-optimized spectroscopy (TROSY) techniques in multi-dimensional NMR, especially the methyl-TROSY, and the resurgence of 19F NMR using trifluoromethyl (CF3) probes. Herein we investigate the feasibility of combining these approaches into a trifluoromethyl-TROSY experiment. Using a CF3-labelled parvalbumin, we have evaluated the natural abundance 13C-19F correlation spectra and find no indication of a CF3 TROSY at high magnetic fields.
Assuntos
Isótopos de Carbono/análise , Clorofluorcarbonetos de Metano/química , Flúor/análise , Campos Magnéticos , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Estudos de Viabilidade , Humanos , Espectroscopia de Ressonância Magnética/instrumentação , Parvalbuminas/químicaRESUMO
Nitrogen-doped activated carbon (N-AC) obtained through the thermal treatment of a mixture of HNO3-pretreated activated carbon (AC) and urea under N2 atmosphere at 600 °C was used as the carrier of Pd catalyst for both liquid-phase hydrodechlorination of 2,4-dichlorophenol (2,4-DCP) and gas-phase hydrodechlorination of chloropentafluoroethane (R-115). The effects of nitrogen doping on the dispersion and stability of Pd, atomic ratio of Pd/Pd2+ on the surface of the catalyzer, the catalyst's hydrodechlorination activity, as well as the stability of N species in two different reaction systems were investigated. Our results suggest that, despite no improvement in the dispersion of Pd, nitrogen doping may significantly raise the atomic ratio of Pd/Pd2+ on the catalyst surface, with a value of 1.2 on Pd/AC but 2.2 on Pd/N-AC. Three types of N species, namely graphitic, pyridinic, and pyrrolic nitrogen, were observed on the surface of Pd/N-AC, and graphitic nitrogen was stable in both liquid-phase hydrodechlorination of 2,4-DCP and gas-phase hydrodechlorination of R-115, with pyridinic and pyrrolic nitrogen being unstable during gas-phase hydrodechlorination of R-115. As a result, the average size of Pd nanocrystals on Pd/N-AC was almost kept unchanged after liquid-phase hydrodechlorination of 2,4-DCP, whereas crystal growth of Pd was clearly observed on Pd/N-AC after gas-phase hydrodechlorination of R-115. The activity test revealed that Pd/N-AC exhibited a much better performance than Pd/AC in liquid-phase hydrodechlorination of 2,4-DCP, probably due to the enhanced stability of Pd exposed to the environment resulting from nitrogen doping as suggested by the higher atomic ratio of Pd/Pd2+ on the catalyst surface. In the gas-phase hydrodechlorination of R-115, however, a more rapid deactivation phenomenon occurred on Pd/N-AC than on Pd/AC despite a higher activity initially observed on Pd/N-AC, hinting that the stability of pyridinic and pyrrolic nitrogen plays an important role in the determination of catalytic performance of Pd/N-AC.
Assuntos
Carbono/química , Clorofluorcarbonetos de Metano/química , Clorofenóis/química , Nitrogênio/química , Catálise , Carvão Vegetal/química , Paládio/química , Ureia/químicaRESUMO
The trifluoromethoxy (OCF3 ) radical is of great importance in organic chemistry. Yet, the catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, the design and development of a redox-active cationic reagent (1) that enables the formation of the OCF3 radical in a controllable, selective, and catalytic fashion under visible-light photocatalytic conditions is reported. More importantly, the reagent allows catalytic, intermolecular C-H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1 resulting in exclusive liberation of the OCF3 radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.
Assuntos
Clorofluorcarbonetos de Metano/química , Indicadores e Reagentes/química , Processos Fotoquímicos , Catálise , Oxirredução , Prótons , Relação Estrutura-AtividadeRESUMO
Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.
Assuntos
Compostos de Benzil/química , Clorofluorcarbonetos de Metano/química , Luz , Níquel/química , Brometos/química , Catálise , Desenho de Fármacos , OxirreduçãoRESUMO
We describe a simple, metal- and oxidant-free photochemical strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes under either ultraviolet or visible light irradiation. We demonstrated that photoexcited aliphatic ketones, such as acetone and diacetyl, can be used as promising low-cost radical initiators to generate CF3 radicals from sodium triflinate efficiently. The broad utility of this strategy and its benefit to medicinal chemistry are demonstrated by the direct trifluoromethylation of unprotected bidentate chelating ligand, xanthine alkaloids, nucleosides, and related antiviral drug molecules.
Assuntos
Clorofluorcarbonetos de Metano/síntese química , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/efeitos da radiação , Acetona/química , Alcaloides/química , Antivirais/síntese química , Antivirais/química , Quelantes/química , Clorofluorcarbonetos de Metano/química , Diacetil/química , Química Verde/métodos , Indicadores e Reagentes , Cetonas/química , Ligantes , Luz , Processos Fotoquímicos , Raios UltravioletaRESUMO
Thorough mechanistic studies and DFT calculations revealed a background radical pathway latent in metal-catalyzed oxidation reactions of methane at low temperatures. Use of hydrogen peroxide with TFAA generated a trifluoromethyl radical (â¢CF3), which in turn reacted with methane gas to selectively yield acetic acid. It was found that the methyl carbon of the product was derived from methane, while the carbonyl carbon was derived from TFAA. Computational studies also support these findings, revealing the reaction cycle to be energetically favorable.
Assuntos
Clorofluorcarbonetos de Metano/química , Metano/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-l-rhamnosidase inhibition. Difluoro or trifluoro units influenced the inhibitory activities of iminosugars in a more complex manner than single fluoro substitution. This may be correlated with their highly hydrophobic character and strong electron-withdrawing effect.
Assuntos
Clorofluorcarbonetos de Metano/química , Glicosídeo Hidrolases/antagonistas & inibidores , Hidrocarbonetos Fluorados/química , Imino Furanoses/química , Óxidos de Nitrogênio/química , Clorofluorcarbonetos de Metano/síntese química , Ciclização , Hidrocarbonetos Fluorados/síntese química , Imino Furanoses/síntese química , Estrutura MolecularRESUMO
By involving the reversal of conventional reactivity expectations without external oxidants, we describe a novel and convenient protocol of remote cross-coupling of carbonyl compounds with a series of common and simple nucleophiles. This cross-coupling is triggered by radical trifluoromethylation of alkenes, thereby achieving highly selective remote difunctionalization of alkenes and α-position of the carbonyl group for facile access to trifluoromethyl α-halo- and α-cyanocarbonyl compounds. The reaction exhibits a broad substrate scope with excellent functionality tolerance and many different types of nucleophiles; further synthetic applicability of the obtained compounds proved to be suitable, thus showing great potential for synthetic utility.
Assuntos
Carbono/química , Clorofluorcarbonetos de Metano/química , Reagentes de Ligações Cruzadas/química , Compostos Heterocíclicos/química , Metilação , Estrutura MolecularRESUMO
An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which ß-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product.
Assuntos
Alcenos/química , Clorofluorcarbonetos de Metano/química , Cobre/química , Éteres Cíclicos/síntese química , Compostos Heterocíclicos/síntese química , Propanóis/química , Catálise , Éteres Cíclicos/química , Compostos Heterocíclicos/química , Metilação , Estrutura Molecular , EstereoisomerismoRESUMO
A tunable chemoselective trifluoromethanesulfonylation and trifluoromethylation of arenediazonium tetrafluoroborates with Langlois' reagent (NaSO2CF3) was developed. The Cu2O-catalyzed reaction in DMSO gave aryl trifluoromethanesulfones as the major products. On the other hand, the trifluoromethylated arenes were produced in the presence of oxidant tert-butyl hydroperoxide, CuBF4(MeCN)4, and 2,2';6',2â³-terpyridine (tpy). Both of these transformations proceed under mild conditions and tolerate functional groups.
Assuntos
Boratos/química , Clorofluorcarbonetos de Metano/química , Cobre/química , Compostos de Diazônio/química , Sulfatos/química , Catálise , Metilação , Estrutura MolecularRESUMO
Synthetic modification of trichlorofluoromethane (CFCl3) to non-volatile and useful fluorinated precursors is a cost-effective and an environmentally benign strategy for the safe consumption/destruction of the ozone depleting potential of the reagent. In this report, we present a novel method for in situ Grignard reaction using magnesium powder and CFCl3 for synthesis of dichlorofluoromethyl aromatic alcohols.
Assuntos
Aldeídos/síntese química , Química Orgânica/métodos , Clorofluorcarbonetos de Metano/química , Hidrocarbonetos Aromáticos/síntese química , Aldeídos/química , Hidrocarbonetos Aromáticos/química , Magnésio/química , PósRESUMO
A novel method for convenient access to CF3-containing azirines has been developed, and involves a copper-catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both terminal and internal alkynes are compatible with the mild reaction conditions, thus delivering the CF3-containing azirines in moderate to good yields. The azirines can be converted into various CF3-substituted aziridines.
Assuntos
Alcinos/química , Aziridinas/química , Azirinas/química , Cobre/química , Catálise , Clorofluorcarbonetos de Metano/química , LuzRESUMO
A novel copper-catalyzed intermolecular trifluoromethylarylation of alkenes is developed using less active ether-type Togni's reagent under mild reaction conditions. Various alkenes and diverse arylboronic acids are compatible with these conditions. Preliminary mechanistic studies reveal that a mutual activation process between arylboronic acid and CF3(+) reagent is essential. In addition, the reaction might involve a rate-determining transmetalation, and the final aryl C-C bond is derived from reductive elimination of the aryl(alkyl)Cu(III) intermediate.
Assuntos
Alcenos/química , Ácidos Borônicos/química , Clorofluorcarbonetos de Metano/química , Cobre/química , Hidrocarbonetos Cíclicos , Catálise , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
NMR spectroscopic studies of the catalytic addition reaction of ZnEt2 to PhC(O)CF3 in the presence of three very efficient catalysts [TMEDA, tBuBOX, and L; where L is a chiral diamine synthesized from optically pure (R,R)-1,2-diphenylethylenediamine and (S)-2,2'-bis-(bromomethyl)-1,1'-binaphthalene] reveal large differences in their behavior. For the ligands TMEDA and tBuBOX, the catalysis shows no unusual features and proceeds via [(NN)Zn(Et){OC(CF3 )(Et)Ph}]. For NNL, the observation of autocatalytic asymmetric enhancement during the catalysis, and unusual inverse concentration dependence on the reaction rate, indicate the participation of an additional novel catalytic cycle that goes through a dinuclear intermediate containing one ZnEt2 and one ZnEt fragment connected by NN and OR bridges. Interestingly, the (19) F NMR signals of the main product of the reaction ([Zn(Et){OC*(CF3 )(Et)Ph}]2 ) allowed us to assess the enantioselectivity of the processes in situ without the assistance of chiral chromatography.
Assuntos
Acetofenonas/química , Clorofluorcarbonetos de Metano/química , Diaminas/química , Compostos Organometálicos/química , Catálise , Espectroscopia de Ressonância Magnética , EstereoisomerismoRESUMO
Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [(18) F]trifluoromethylcopper, as well as its use for the radiosynthesis of [(18) F]trifluoromethylarenes and heteroarenes. Mild conditions of [(18) F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [(18) F]trifluoromethylarenes and heteroarenes.
Assuntos
Ácidos Borônicos/síntese química , Cobre/química , Radioisótopos de Flúor/química , Hidrocarbonetos Iodados/síntese química , Compostos Organometálicos/síntese química , Compostos Radiofarmacêuticos/síntese química , Alquilantes/química , Clorofluorcarbonetos de Metano/química , Cristalografia por Raios X , Hidrocarbonetos Iodados/química , Marcação por Isótopo/métodos , Metilação , Modelos Moleculares , Estrutura Molecular , Tomografia por Emissão de Pósitrons/métodosRESUMO
The application of ab initio and DFT computational methods at six different levels of theory (MP2/cc-pVDZ, MP2/aug-cc-pVTZ, B3LYP/cc-pVDZ, B3LYP/aug-cc-pVTZ, M06/cc-pVDZ, and M06/aug-cc-pVTZ) to meta- and para-substituted fluoro- and trifluoromethylbenzene derivatives and to 1-fluoro- and 1-trifluoromethyl-2-substituted trans-ethenes allowed the study of changes in the electronic and geometric properties of F- and CF3-substituted systems under the impact of other substituents (BeH, BF2, BH2, Br, CFO, CHO, Cl, CN, F, Li, NH2, NMe2, NO, NO2, OH, H, CF3, and CH3). Various parameters of these systems have been investigated, including homodesmotic reactions in terms of the substituent effect stabilization energy (SESE), the π and σ electron donor-acceptor indexes (pEDA and sEDA, respectively), the charge on the substituent active region (cSAR, known earlier as qSAR), and bond lengths, which have been regressed against Hammett constants, resulting mostly in an accurate correspondence except in the case of p-fluorobenzene derivatives. Moreover, changes in the characteristics of the ability of the substituent to attract or donate electrons under the impact of the kind of moiety to which the substituent is attached have been considered as the indirect substituent effect and investigated by means of the cSAR model. Regressions of cSAR(X) versus cSAR(Y) for any systems X and Y allow final results to be obtained on the same scale of magnitude.
Assuntos
Clorofluorcarbonetos de Metano/química , Flúor/química , Hidrocarbonetos Fluorados/química , Ligação de Hidrogênio , Modelos Moleculares , Teoria Quântica , TermodinâmicaRESUMO
Trifluoromethylated selenoethers are quite rare despite their potential and the interest that they generate. A series of trifluoromethylseleno derivatives, either primary and secondary aliphatic or aromatic and heterocyclic, is described herein by the reaction of easily prepared organic selenocyanates and CuCF3. Another beneficial feature of this reaction is the use of fluoroform as a source for the CF3 group, a compound whose chemistry is currently being intensively researched because it is a potent greenhouse gas that should not be released into the atmosphere.