The Journal of Organic Chemistry最新文献

An efficient method for the construction of benzo[4,5]imidazo[1,2-a]pyrimidines using N,N-dimethylformamide as a one-carbon source and 2-aminobenzimidazoles and acetophenone as substrates through a one-pot, three-component cascade reaction is described. Spectra investigations indicated the fluorescent properties of selected products, exhibiting quantum yields 0.07-0.16 with maxima absorption at 266-294 nm and emission at 472-546 nm.

ortho-Phthalaldehyde (OPA) with high reactivity to the amine group has been widely used to modify proteins. We discovered new modifications of OPA and 2-acylbenzaldehyde and proposed the reaction mechanism. Using isotope labeling mass spectrometry-based experiment, we identified new cross-linking properties of OPA and 2-acylbenzaldehyde. This reactivity revealed that OPA has the potential to probe proximal amino acids in biological systems.

The use of photoredox catalysis for the synthesis of small organic molecules relies on harnessing and converting the energy in visible light to drive reactions. Specifically, photon energy is used to generate radical ion species that can be harnessed through subsequent reaction steps to form a desired product. Cyanoarenes are widely used as arylating agents in photoredox catalysis because of their stability as persistent radical anions. However, there are marked, unexplained variations in product yields when using different cyanoarenes. In this study, the quantum yield and product yield of an α-aminoarylation photoredox reaction between five cyanoarene coupling partners and N-phenylpyrrolidine were characterized. Significant discrepancies in cyanoarene consumption and product yield suggested a chemically irreversible, unproductive pathway in the reaction. Analysis of the side products in the reaction demonstrated the formation of species consistent with radical anion fragmentation. Electrochemical and computational methods were used to study the fragmentation of the different cyanoarenes and revealed a correlation between product yield and cyanoarene radical anion stability. Kinetic modeling of the reaction demonstrates that cross-coupling selectivity between N-phenylpyrrolidine and the cyanoarene is controlled by the same phenomenon present in the persistent radical effect.

A novel method for the synthesis of quinazolin-4(3H)-imines (QIs) by trimethylsilyl polyphosphate (PPSE) promoted reaction of 2-aminobenzonitrile with secondary amides is reported. The reaction is general and allows for the synthesis of N³-aryl and N³-alkyl QIs with variable 2-substituents affording high yields. The procedure was extended to derivatives bearing additional functional groups. The method is operationally simple, involves easily available starting materials and a mild dehydrating agent, with wide functional group tolerance. The reaction procedure proved to be suitable for scaling-up. A possible reaction path via an intermediate nitrilium ion is proposed on the basis of literature data and experimental observations.

Various structural elements of the Cinchona alkaloid dimers are interrogated to establish a structure-enantioselectivity relationship (SER) in three different halocyclization reactions. SER for chlorocyclizations of a 1,1-disubstituted alkenoic acid, a 1,1-disubstituted alkeneamide, and a trans-1,2-disubstituted alkeneamide showed variable sensitivities to linker rigidity and polarity, aspects of the alkaloid structure, and the presence of two or only one alkaloid side group defining the catalyst pocket. The conformational rigidity of the linker-ether connections was probed via DFT calculations on the methoxylated models, uncovering especially high barriers to ether rotation out of plane in the arene systems that include the pyridazine ring. These linkers are also found in the catalysts with the highest enantioinduction. The diversity of the SER results suggested that the three apparently analogous test reactions may proceed by significantly different mechanisms. Based on these findings, a stripped-down analogue of (DHQD)₂PYDZ, termed "(trunc)₂PYDZ", was designed, synthesized, and evaluated, showing modest but considerable asymmetric induction in the three test reactions, with the best performance on the 1,1-disubstituted alkeneamide cyclization. This first effort to map out the factors essential to effective stereocontrol and reaction promotion offers guidance for the simplified design and systematic refinement of new, selective organocatalysts.

The utilization of earth-abundant, cheap, and nontoxic transition metals in important catalytic transformations is essential for sustainable development, and iron has gained significant attention as the most abundant transition metal. A mixture of FeCl₂ (3 mol %), phenanthroline (6 mol %), and KOtBu (0.4 eqivalent) was used as an effective catalyst for the sp³ C–H alkylation of fluorene using alcohol as a nonhazardous alkylating partner, and eco-friendly water was formed as the only byproduct. The substrate scope includes a wide range of substituted fluorenes and substituted benzyl alcohols. The reaction is equally effective with challenging secondary alcohols and unactivated aliphatic alcohols. Selective mono-C9-alkylation of fluorenes with alcohols yielded the corresponding products in good isolated yields. Various postfunctionalizations of C-9 alkylated fluorene products were performed to establish the practical utility of this catalytic alkylation. Control experiments suggested a homogeneous reaction path involving borrowing hydrogen mechanism with the formation and subsequent reduction of 9-alkylidene fluorene intermediate.

Herein, we report radical chlorination of cubane-1,4-dicarboxylic acid leading preferentially to one monochlorinated cubane dicarboxylate (ca. 70%) that is accompanied by four dichlorinated derivatives (ca. 20% in total). The exact positions of the chlorine atoms have been confirmed by X-ray diffraction of the corresponding single crystals. The acidity constants of all dicarboxylic acids in water were determined by capillary electrophoresis (3.17 ± 0.04 and 4.09 ± 0.05 for monochlorinated and ca. 2.71 ± 0.05 and 3.75 ± 0.05 for dichlorinated cubanes). All chlorinated derivatives as well as the parent diacid showed high thermal stability (decomposition above 250 °C) as documented by differential scanning calorimetry. The probable reaction pathways leading to individual isomers were proposed, and the energies of individual transition states and intermediates were obtained using density functional theory calculations (B3LYP-D3BJ/6-311+G(d,p)). The relative strain energies for all newly prepared derivatives as well as for hypothetical hexahalogenated (fluorinated, chlorinated, brominated, and iodinated) derivatives of cubane-1,4-dicarboxylic acids were predicted using wavefunction theory methods. The hexafluorinated derivative was identified as the most strained compound (57.5 kcal/mol), and the relative strain decreased as the size of halogen atoms increased (23.7 for hexachloro, 16.7 for hexabromo, and 4.0 kcal/mol for the hexaiodo derivative).

N,N'-diacylhydrazines (R₁CO-NR₃-NR₄-COR₂) are a class of small molecules with a wide range of applications in chemistry and biology. They are structurally unique in the sense that their two amide groups are connected via a N-N single bond, and as a result, these molecules can exist in eight different isomeric forms. Four of these are amide isomers [trans-trans (t-t), trans-cis (t-c), cis-trans (c-t), and cis-cis (c-c)] arising from C-N bond restricted rotation. In addition, each of these amide isomers can exist in two different isomeric forms due to N-N bond restricted rotation, especially when R₃ and R₄ groups are relatively bigger. Herein, we have systematically investigated the conformations of 55 N,N'-diacylhydrazines using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations. Our data suggest that when the substituents R₃ and R₄ on the nitrogen atoms are both hydrogens. These molecules prefer twisted trans-trans (t-t) (>90%) geometries (H-N-C═O ∼ 180°), whereas the N-alkylated and N,N'-dialkylated molecules prefer twisted trans-cis (t-c) geometries. Herein, we have analyzed the stabilization of the various isomers of these molecules in light of steric and stereoelectronic effects. We provide a guideline to a priori predict the most stable conformers of the N,N'-diacylhydrazines just by examining their substituents (R₁-R₄).

In the past eight years, the selective cross-coupling of amides by N–C(O) bond activation has emerged as a highly attractive manifold for the manipulation of traditionally unreactive amide bonds. In this Special Issue on Next-Generation Cross-Coupling Chemistry, we report the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling of amides by selective N–C(O) cleavage catalyzed by bench-stable, well-defined carboxylate Pd(II)–NHC (NHC = N-heterocyclic carbene) catalysts {[(NHC)Pd(O₂CR)₂]}. This class of Pd(II)–NHCs promotes cross-coupling under exceedingly mild room-temperature conditions owing to the facile dissociation of the carboxylate ligands to form the active complex. These readily accessible Pd(II)–NHC precatalysts show excellent functional group tolerance and are compatible with a broad range of amide activating groups. Considering the mild conditions for the cross-coupling and the facile access to carboxylate Pd(II)–NHC complexes, we anticipate that this class of bench-stable complexes will find wide application in the activation of amide N–C(O) and related acyl X–C(O) bonds.

This Synopsis covers recent reports of metal-catalyzed alkene functionalizations that likely involve iterative outer-sphere reactions in which the substrate reacts directly with a metal ligand instead of with the metal center itself. Traditional metal hydride-catalyzed alkene functionalizations involve this latter pathway whereby the alkene forms part of the metal ligand sphere (i.e. an inner-sphere reaction). In contrast, alkenes do not ligate the metal in so-called outer-sphere reactions and instead react with a metal ligand. These transformations have proved crucial for the synthesis of high fraction sp³ (F_sp3) targets, especially in hindered fragment couplings of relevance to natural product space.