Journal of Organic Chemistry

Atom transfer radical addition (ATRA) reactions are crucial for the dual functionalization of unsaturated hydrocarbons. Radical generation, pivotal in ATRA, has seen advancements from thermal to photochemical methods. Recent focus on halogen-bonding-based radical generation, including our group's innovative photochemical approach, offers cost-effective alternatives to transition-metal-dependent photocatalysts. This eliminates the need for high-energy UV light, enhancing the efficiency with noncovalent interactions...

Canthin-4-one is synthesized via a six-step procedure starting from commercially available 3-amino-4-bromopyridine in 26% overall yield. 3-Amino-4-bromopyridine is initially converted to 8-bromo-1,5-naphthyridin-4(1 H )-one. O-Methylation, intermolecular Pd-catalyzed C-C coupling, and demethylation afford the key intermediate, 8-(2-chlorophenyl)-1,5-naphthyridin-4(1 H )-one, for which intramolecular C-N coupling completes the synthesis of the canthin-4-one skeleton. Ten canthin-4-one analogues were prepared in addition to the parent compound...

Nitroarenes are known for their stability, low toxicity, easy availability, and cost-effectiveness, making them one of the most fundamental chemical feedstocks. The direct utilization of nitroarenes as nitrogen sources in amidation reactions offers significant advantages over using arylamines. Herein, we disclose a streamlined method for constructing α-ketoamides through the direct coupling of nitroarenes with α-oxocarboxylic acids. This transformation obviates the need for preparing, isolating, and purifying arylamines, leading to improved efficiency, cost-effectiveness, and time savings...

A novel synthesis of sitagliptin based on a redox-active ester derived from the chiral pool is reported. The key step is an electrochemical nickel-catalyzed sp2 -sp3 cross-coupling reaction using inexpensive nickel foam in an undivided cell. It was successfully applied to 21 examples in up to 88% yield. These sitagliptin-analogue precursors could potentially interact with the DPP4 enzyme. A full synthesis based on our new reaction pathway provided sitagliptin in an overall yield of 33%.

The nucleofugality of bromide was measured in solvent mixtures containing ionic liquids. The solvolysis rate constants of the bromides of well-defined electrofuges were determined in mixtures containing different proportions of 1-butyl-3-methylimidazolium bis (trifluoromethanesulfonyl)imide in ethanol. Temperature-dependent kinetic studies allowed an explanation of the observed solvent effects in different mixtures in terms of interactions in solution. Using the solvolysis data, the nucleofugality of bromide in these systems was determined...

The first paired electrolysis-enabled arylation of quinoxalin-2(1 H )-ones was achieved using cyanoarenes as the arylation reagents. A variety of 3-arylquinoxalin-2(1 H )-ones with various important functional groups were obtained in moderate to good yields under metal- and chemical oxidant-free conditions. With a pair of reductive and oxidative processes occurring among the substrates and reaction intermediates, the power consumption can be dramatically reduced.

An efficient 2,2,6,6-tetramethylpiperidinooxy (TEMPO)-mediated hydroxyfluoroalkylation of arylamines with polyfluorinated alcohols via a radical-triggered C(sp2 )-H/C(sp3 )-H dehydrogenative cross-coupling process was developed. This transformation features simple operation, high atom economy, broad substrate compatibility, and excellent regioselectivity, leading to a series of hydroxyfluoroalkylated arylamine derivatives. Importantly, these synthetic products were further used to evaluate the antitumor activity in cancer cell lines by Cell Counting Kit-8 assay and the outcomes indicated that some compounds show a potent antiproliferative effect...

Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield. This method presents a promising avenue for synthesizing aziridines from a wide range of alkenes, featuring the benefits of straightforward operation, mild reaction conditions, extensive substrate compatibility, and scalability...

A palladium-catalyzed carbohalogenation of olefins with alkynyl oxime ethers has been described, which provides efficient and practical access to various chlorine-containing isoxazoles. This method exhibits excellent regioselectivity, good functional group compatibility, and mild reaction conditions. The mechanistic studies suggest that the reaction proceeds via a stabilized π-benzyl palladium intermediate, which is essential for the formation of C(sp3 )-Cl bonds.

α-Ketoamides are highly valued in synthetic chemistry due to their incorporation into diverse natural products and drug molecules. Here, we present an innovative electrochemical approach for constructing α-ketoamides, utilizing a mild and environmentally friendly strategy in a user-friendly undivided cell setup under constant current. The excellent functional-group tolerance, convenient accessibility of reaction instruments and starting materials, and easy scalability collectively enhance the importance of this protocol compared to previous challenging methods...

This article demonstrates a late-stage modification of the cage propellanes that are transformed into intricate oxa-cycles via ring-rearrangement metathesis (RRM) and regioselective ring-closing metathesis (RCM) as crucial steps. In addition, we also report the extended pentacycloundecane (PCUD)-based oxa-cages involving the domino cycloetherification followed by olefin metathesis. These oxa-cages involve a domino sequence in which the PCUD core unit remains intact. [Ru]-based Grubbs catalysts are used to execute the metathesis step to assemble these higher-order oxa-cage systems...

The direct oxidations of meso -tetrakis(pentafluorophenyl)porphyrin using cetyltrimethylammonium permanganate (CTAP), RuCl3 /Oxone/base or Ag+ /oxalic acid each generate distinctive product mixtures that may contain, inter alia, porpho-mono-, di-, and trilactones. The CTAP and RuCl3 /Oxone/base oxidations also generate a unique open chain tripyrrin derived from the degradation of a porpholactone oxazolone moiety. Thus, its formation and structure are distinctly different from all biological or nearly all other nonbiological biliverdin-like linear porphyrinoid degradation products that are derived from ring cleavages between the pyrrolic building blocks...

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception...

Polycyclic energetic materials make up a distinctive class of conjugated structures that consist of two or more rings. In this work, 1,3-bis(3,5-dinitro-1 H -pyrazol-4-yl)-4,6-dinitrobenzene ( BDPD ) was synthesized and investigated in detail as a polycyclic heat-resistant energetic molecule that can be deprotonated by bases to obtain its anionic ( 3 - 5 ) salts. All compounds were thoroughly characterized by 1 H and 13 C NMR, infrared spectroscopy, high-resolution mass spectrometry, and elemental analysis...

We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides...

Introducing glycans represents an efficient chemical approach to improve the pharmacological properties of therapeutic biomolecules. Herein, we report an efficient synthesis of glycoconjugates through chlorooxime-thiol conjugation. The reactive glycosyl chlorooximes, derived from pyranoses or furanoses, readily couple to a wide range of thiol-containing substrates, including peptides, sugars, and thiophenols. This method features mild reaction conditions and fast kinetics. Capability for aqueous media and gram-scale synthesis demonstrates the potential of this method in the bioconjugation of saccharides with biologically active molecules...

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps...

The N , N '-bis(thiophen-2-ylmethyl)oxalamide (BTMO) was found to be an effective ligand for Cu-catalyzed ipso -nitration of (hetero)aryl halides (Br, I), making the coupling reaction with sodium nitrite proceed smoothly at 100-120 °C with 1-5 mol % CuI and BTMO. Electron-rich substrates were the best coupling partners to give the desired coupling products in good to excellent yields at 100 °C. Electron-neutral substrates required heating at 120 °C to get complete conversion, while rather low conversions were observed in the case of electron-poor (hetero)aryl bromides...

Despite growing interest in 2,1,3-benzothiadiazole (BTD) as an integral component of many functional molecules, methods for the functionalization of its benzenoid ring have remained limited, and many even simply decorated BTDs have required de novo synthesis. We show that regioselective Ir-catalyzed C-H borylation allows access to versatile 5-boryl or 4,6-diboryl BTD building blocks, which undergo functionalization at the C4, C5, C6, and C7 positions. The optimization and regioselectivity of C-H borylation are discussed...

An electrochemical protocol for benzylic C(sp3 )-H aminopyridylation via direct C-H/N-H cross-coupling of alkylarenes with N -aminopyridinium triflate has been developed. This method features excellent site-selectivity, broad substrate scope, redox reagent-free and facile scalability. The generated benzylaminopyridiniums can be readily converted to benzylamines via electroreductive N-N bond cleavage.