The Journal of Organic Chemistry最新文献

The synthesis of O-substituted 2-hydroxypyridines and N-substituted 2-pyridones, crucial for many bioactive compounds and drugs, faces challenges due to the tautomeric nature of 2-pyridones, which complicates selective alkylation. Here we developed an efficient method for regioselective O- and N-alkylation of 2-pyridones using Bro̷nsted acid-catalyzed ring opening of 2H-azirines. The process involves triflic acid for O-alkylation and p-toluenesulfonic acid for N-alkylation, achieving high yields under optimized conditions. For O-alkylation, a variety of 2-pyridones and 2H-azirines were used, resulting in significant yields of the desired products. Similarly, for N-alkylation, the optimized conditions produced excellent yields, highlighting the method's versatility. This methodology was further demonstrated through scaled-up syntheses and subsequent transformations, showcasing its practicality for complex molecular architectures. The proposed mechanism involves the protonation of 2H-azirine, followed by a regioselective S_N2-type attack and acid-catalyzed hydrolysis, leading to the desired alkylated products. This innovative approach, emphasizing Bro̷nsted acid catalysis and careful control of reaction conditions, represents a significant advancement in the selective alkylation of 2-pyridones, with broad implications for medicinal chemistry.

Herein, we report an expedient synthesis of aryl sulfonyl ureas 4 and 5 from N-amino pyridinium ylides and aryl isocyanates. N-Aminopyridinium ylides 3 are synthesized via blue light-emitting diode irradiation of pyridine/isoquinoline and appropriate iminoiodinanes. The strategy involved a hitherto unknown carboamination of imine moieties (of aryl isocyanates) via a three-component reaction of pyridine derivatives/isoquinoline 1, N-aryl sulfonyl iminoiodinanes 2, and numerous aryl isocyanates at room temperature in 2-methyl tetrahydrofuran to afford the target compounds in moderate to excellent yields. N-Arylpyridinium ylides 3 (as intermediates) undergo a [3+2] cycloaddition with the aryl isocyanates followed by the aromatization of the pyridine/isoquinoline moiety to afford compounds 4. On the basis of the substitution pattern among the reactants, in some cases pyridine extrusion occurs during the reaction to afford depyridinylated aryl sulfonyl ureas 5. In general, isocyanates are used as dipolarophiles in [3+2] cycloaddition reactions. However, regioselective amino pyridylation of these species is a first. Control experiments and density functional theory calculations elucidate the reaction mechanism. The batch process of the protocol could be seamlessly transferred to the photoflow synthesis.

Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.

Dicobalt hexacarbonyl complexes are well-known for their applications in the Nicholas reaction or simply as a protecting group for alkynes. To recover the alkyne, demetalation is necessary, which usually involves a stoichiometric amount of an oxidizing agent or a strong ligand. This article reports a demetalation methodology based on a photocatalytic process. This approach employs a photocatalyst under aerobic conditions, and the optimal results were achieved using mild near-infrared irradiation. A mechanistic investigation is also presented to elucidate how the photocatalytic system promotes this deprotection. This tool is compatible with the one-pot reaction and orthogonal deprotection of alkynes, offering new perspectives for further applications.

Photoactivatable (PA) rhodamine dyes are widely used in single-molecule tracking (SMT) and a variety of other fluorescence-based imaging modalities. One of the most commonly employed scaffolds uses a diazoketone to lock the rhodamine in the nonfluorescent closed form, which can be activated with 405 nm light. However, poor properties of previously reported dyes require significant washing, which can be resource- and cost-intensive, especially when performing microscopy in a large scale and high-throughput fashion. Here, we report improved diazoketorhodamines that perform exceptionally well in single-molecule tracking microscopy. We also report on the optimization of an improved synthetic method for further iteration and tailoring of diazoketorhodamines to the requirements of a specific user.

A sustainable protocol for Ru(II)-catalyzed regioselective C(sp²)-H methylation of indolines in the presence of ethanol has been explored. A wide array of substituted indolines were successfully methylated via the developed protocol with good to excellent yields. Deuterium labeling experiments suggested the reversible nature of the C-H activation step. Kinetic isotope effect studies revealed that C-H activation might be the rate-determining step. Gram scale reaction and post-transformation reactions of the methylated product demonstrated the potential of the developed protocol.

Herein, we describe a two-step, cis-diastereoselective synthesis of indoline-2,3-fused chromans from 3-substituted indoles. The method proceeds without intermediacy of ortho-quinone methides and leverages the dual function of TBS-protected 2-hydroxybenzyl iodides both as highly reactive alkylating agents in a t-BuONa/Et₃B-promoted dearomative alkylation step and as a source of masked phenoxide nucleophiles in a subsequent TBAF-induced one-pot deprotection-cyclization step of the resulting indolenines. Importantly, this two-step protocol can also be extended to access indoline-2,3-fused tetrahydropyrans. These syntheses of indoline-2,3-fused chromans and tetrahydropyrans proceed with operational convenience, use easily accessible substrates and reagents, and feature broad substrate scope, high yields and complete diastereoselectivity. Furthermore, the synthesized products have the potential to undergo late-stage functionalization.

The nucleofugality of dimethyl sulfide was measured in solvent mixtures containing ionic liquids. The first-order rate constants of the solvolysis of sulfonium salts were determined in mixtures containing different proportions of 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide in ethanol, representing the first report on the solvolysis of a charged species in an ionic liquid. Temperature-dependent kinetic studies allowed determination of activation parameters and rationalization of observed solvent effects in different ionic liquid mixtures. From the solvolysis data, the nucleofugality of dimethyl sulfide in different proportions of this ionic liquid in ethanol was determined. Further, the nucleofugality of dimethyl sulfide was determined in mixtures containing high proportions of each of seven other ionic liquids in ethanol. These data allowed quantification of the effects of varying both the amount of ionic liquid present and on changing the components of the ionic liquid on the nucleofugality of dimethyl sulfide. The ionic liquid mixtures were shown to affect the nucleofugality of this nucleofuge in a different manner to the previously studied monatomic charged nucleofuges, owing to different microscopic interactions in solution. This work highlighted the necessity of considering electrofuges with an appropriate range of electrofugality values along with the importance of the nucleofuge-specific sensitivity parameter.

We recently described the development and application of a new bioorthogonal conjugation, the triazinium ligation. To explore the wider application of this reaction, in this work, we introduce a general method for synthesizing C₃-substituted triazinium salts based on the Liebeskind-Srogl cross-coupling reaction and catalytic thioether reduction. These methods enabled the synthesis of triazinium derivatives for investigating the effect of different substituents on the ligation kinetics and stability of the compounds under biologically relevant conditions. Finally, we demonstrate that the combination of a coumarin fluorophore attached to position C₃ with a C₅-(4-methoxyphenyl) substituent yields a fluorogenic triazinium probe suitable for no-wash, live-cell labeling. The developed methodology represents a promising synthetic approach to the late-stage modification of triazinium salts, potentially widening their applications in bioorthogonal reactions.