Colorectal cancer is among the most common and lethal malignancies globally, with K‐Ras mutations found in about 45% of colorectal cancer patients. Early‐stage BRAF‐specific inhibitors have been developed to prevent aberrant activation of RAS/RAF/MEK/ERK signaling caused by K‐Ras mutation, however, these BRAF‐specific inhibitors lead to RAF dimer formation and paradoxical CRAF activation. Consequently, there is a need to develop pan‐RAF inhibitors. In addition, it was reported that the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) is crucial for the treatment of colorectal cancer. In this study, we designed and synthesized 94 N‐(phenyl)‐3‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives, and discovered that N‐(5‐(3‐(9H‐purin‐6‐yl)pyridin‐2‐ylamino)‐2‐fluorophenyl)‐3‐(trifluoromethyl)benzamide (15h), 3‐(2‐cyanopropan‐2‐yl)benzamide derivative 16h, and 3,5‐bis(trifluoromethyl) benzamide derivative 17ab are the most potent dual inhibitors against LS513 (GI50 = 0.08, 0.2, and 0.3 μM, respectively) and VEGFR2 (IC50 = 0.01, 0.004, and 0.01 μM, respectively). These compounds are excellent preclinical candidates for the treatment of K‐Ras mutated colorectal cancer.

In this work, an efficient synthesis of 2-imino-1,3,4-oxadiazolines from acylhydrazides and isothiocyanates is described. In the presence of 4-dimethylaminopyridine (DMAP) and molecular oxygen, various 2-imino-1,3,4-oxadiazolines were produced in good to high yields. The developed method showed a broad substrate scope and was effective on the gram scale. On the basis of the mechanistic studies and previous literature, it was proposed that the mechanism consists of an aerobic oxidation of acylhydrazides facilitated by DMAP and isothiocyanates, followed by a DMAP-mediated annulation of the in situ generated acyldiazenes with isothiocyanates.

The framework of 1,3,4-oxadiazine is crucial for numerous bioactive molecules, but only a limited number of synthetic methods have been reported for its production. In 2015, Wang’s group developed a 4-(dimethylamino)pyridine (DMAP)-catalyzed [2 + 4] cycloaddition of allenoates with N-acyldiazenes, which provided an atom-efficient route for 1,3,4-oxadiazines. However, the practicality of this method was limited by the instability of N-acyldiazenes as starting materials. Building upon our ongoing research about the aerobic oxidation of hydrazides and their synthetic applications, we hypothesized that aerobic oxidative cycloadditions using acylhydrazides instead of N-acyldiazenes may provide a more practical synthetic route for 1,3,4-oxadiazines. In this manuscript, we describe a one-pot synthetic protocol for 1,3,4-oxadiazines from acylhydrazides and allenoates. The developed one-pot protocol consists of aerobic oxidations of acylhydrazides into N-acyldiazenes using NaNO2 and HNO3, followed by the DMAP-catalyzed cycloaddition of allenoate with the generated N-acyldiazenes. A variety of 1,3,4-oxadiazines were produced in good to high yields. In addition, the practicality of the developed method was demonstrated by a gram-scale synthesis of 1,3,4-oxadiazine.

A theoretical protocol based on long-range corrected density functional theory is suggested for a highly accurate estimation of the two-electron two-proton (2e2p) reduction potential of ethyl 2-phenylazocarboxylate derivatives. Geometry optimization and single-point energy refinement with ωB97X-D are recommended. The impact of polarization and diffusion functions in the basis sets on the 2e2p reduction potential is discussed. Further improvements can be achieved by tuning the range-split parameter based on the linear relationship between the Hammett constant of phenyl substituents and the optimal ω value that most accurately reproduces the experiments. The suggested protocol can accurately predict the 2e2p reduction potential of five ethyl 2-phenylazocarboxylate derivatives. Based on these findings, 22 additional candidates are suggested to enlarge the electrochemical window and to increase the selectivity of 2e2p reactions. This study contributes to the development of a theoretical approach to accurately estimate the 2e2p reduction potential of azo groups.

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