Journal of Organic Chemistry最新文献

A one-pot synthesis of a tricyclic guanidine scaffold is developed. The azido-bearing [3 + 2] adducts are used for cascade azide-isocyanide cross-coupling/nucleophilic cyclization/lactamization to afford highly condensed polyheterocycles. A wide range of azido-containing [3 + 2] adducts and isocyanides are tolerated in the sequential reactions.

We intended to realize aryl vinyl oxetane as a 4π-electrocyclization precursor to access indene ethanol. Interestingly, we found that the readily accessible aryl vinyl 1,3-diol, an intermediate en route to the synthesis of oxetane, is an equally potential precursor for the anticipated cyclization. Moreover, aryl vinyl 1,3-diol/oxetane and indene ethanol readily reacted with the subsequently added (het)aromatic aldehydes, providing various indene oxepines/acetaldehydes. Additionally, indenyl aldehyde served as a synthetic handle for FGI, further expanding this protocol’s scope.

Diarylethene photoswitches featuring azole-based diaryl units combined with benzoheteroarene π-linkers have gained significant research interest in recent years due to their potential to achieve higher photocyclization efficiencies compared to conventional dithienylethene switches. In this work, we investigate the suitability of these photoswitches for molecular solar thermal energy storage (MOST) applications through computational modeling of their electrocyclization and cycloreversion reactions. Our calculations demonstrate that it is possible to achieve simultaneously both large energy-storage densities (0.29–0.35 MJ kg^–1) and prolonged energy-storage times (half-lives of up to 124 days) under ambient conditions in dithiazolyl and dioxazolyl switches containing six distinct benzoheteroarene π-linkers. Furthermore, isomerization stabilization energy calculations and noncovalent interaction analysis reveal that the variations in energy-storage densities and times between the azole-based and dithienylethene switches stem from differences in aromaticities of the diaryl core and π-linker, as well as changes in noncovalent interactions. Notably, we demonstrate that the relative populations of photoreactive anti-parallel and non-photoreactive parallel conformers of the ring-open form of these switches are governed by weak intramolecular C···C interactions between the two aryl rings. These findings highlight the importance of optimizing such interactions to enhance energy-storage efficiencies in MOST systems.

We report a general C–H aminoalkylation of 5-membered heterocycles through a combined machine learning/experimental workflow. Our work describes previously unknown C–H functionalization reactivity and creates a predictive machine learning (ML) model through iterative refinement over 6 rounds of active learning. The initial model established with 1,3-azoles predicts the reactivities of N-aryl indazoles, 1,2,4-triazolopyrazines, 1,2,3-thiadiazoles, and 1,3,4-oxadiazoles, while other substrate classes (e.g., pyrazoles and 1,2,4-triazoles) are not predicted well. The final model includes the reactivities of additional heterocyclic scaffolds in the training data, which results in high predictive accuracy across all of the tested cores. The high prediction performance is shown both within the training set via cross-validation (CV R² = 0.81) and when predicting unseen substrates of diverse molecular weight and structure (Test R² = 0.95). The concept of feature engineering is discussed, and we benchmark mechanistically related DFT-based features that are more time-intensive and laborious in comparison with molecular descriptors and fingerprints. Importantly, this work establishes novel reactivity for heterocycles for which C–H functionalization methods are underdeveloped. Since such heterocycles are key motifs in drug discovery and development, we expect this work to be of significant use to the synthetic and synthesis-oriented ML communities.

Guanidines make up a class of compounds with important applications in catalysis and medicinal chemistry. In this systematic study, we report on the guanylation of aliphatic amines, anilines, (sulfon)amides, ureas, and carbamates by repurposing HATU, a common amide coupling reagent. The products are 2-substituted 1,1,3,3-tetramethylguanidines (TMGs), a group of sterically hindered superbases. The reaction of a guanidinium salt with aliphatic amines has been regarded as an unwanted side-reaction in amide coupling, yet the exact mechanistic details have been unclear. Our mechanistic investigation shows that the guanylation is highly dependent on the nature of the nitrogen nucleophile. Our findings were applied on two fronts: minimizing guanylation in competing amide coupling reactions as well as maximizing guanylation in a simple one-step synthesis of a broad variety of 2-substituted TMGs, including the late-stage functionalization of pharmaceuticals.