Xinhong Yu

Derivatives of 2‐aminopyridines are recognized for their significant biological activity and hold considerable pharmaceutical value. However, the synthetic methodologies available, particularly multi‐component reactions (MCRs), for preparing substituted 2‐aminopyridine derivatives remain relatively scarce, limiting structural diversity. Addressing this challenge, our study introduces an innovative one‐pot, three‐component cascade strategy. This approach capitalizes on the synergistic interplay between Knoevenagel condensation and nucleophilic aromatic substitution (S _N Ar) reactions. Utilizing readily accessible starting materials—specifically 2‐bromopyridine carboxaldehyde, ethyl cyanoacetate or cyanoacetamide, and diverse cyclic secondary amines—we efficiently assemble complex 2‐aminopyridine scaffolds. The reaction proceeds smoothly in ethanol under reflux conditions at ambient pressure for a concise period of only 3 hours. This mild, eco‐friendly, and highly efficient protocol achieves excellent yields of up to 94%. Its operational simplicity overcomes traditional synthesis limitations and significantly broadens the accessible substrate scope for these valuable compounds.

A novel organocatalytic one‐pot cascade alcohol oxidation iminium activation strategy for the 3‐alkenylation of oxindoles, benzofuranones, and indoles from substituted propanols with excellent stereo‐selectivity(E/Z up to >99:1) has been developed. This one‐pot seven‐step process involves the α ‐spirocyclopropanation of benzofuran‐2‐ones, indolin‐2‐ones, and indoles, and by adjusting the reaction temperature and base feeding, the stable α ‐spirocyclopropyl propionaldehyde intermediate was isolated.

The furan and thiophene skeleton structures are widely present in natural products and synthetic drugs, and display multiple bioactivities. An effective one-pot three-component reaction to access furan and thiophene derivatives from 2-bromo-5-(dichloromethyl)furan or -thiophene; cyanoacetate esters, cyanoacetamides, or malononitrile; and aliphatic secondary amines has been developed. The multicomponent reaction for the construction of new C–N and C–C bonds in one pot is simple, mild, and efficient, and the yield of the target product is as high as 96%.

A novel one-pot cascade process of oxidation-initiated, N-heterocyclic carbene catalyzed, reintegration of dibenzyl ethers has been developed for the first time. This protocol allows straightforward access to α-hydroxy ketones from dibenzyl ethers. It is noteworthy that the present method is the first attempt to synthesize benzoin from dibenzyl ether.

Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept of "escape from flatland". However, adopting this concept into the exploration of bioisosteres of pyridines remains elusive due to the challenge of incorporating a N atom into such bridged bicyclic structures. Herein, we report practical routes for the divergent synthesis of 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential bioisosteres of pyridines from the readily accessible vinyl azides and bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity of vinyl azides tailored with BCBs is the key to achieving divergent transformations. Ti^III-catalyzed single-electron reductive generation of C-radicals from BCBs allows a concise (3 + 3) annulation with vinyl azides, affording novel 2-aza-BCHepe scaffolds. In contrast, scandium catalysis enables an efficient dipolar (3 + 2) annulation with vinyl azides to generate 2-azidobicyclo[2.1.1]hexanes, which subsequently undergo a chemoselective rearrangement to construct 3-aza-BCHepes. Both approaches efficiently deliver unique azabicyclo[3.1.1]heptene scaffolds with a high functional group tolerance. The synthetic utility has been further demonstrated by scale-up reactions and diverse postcatalytic transformations, providing valuable azabicyclics including 2- and 3-azabicyclo[3.1.1]heptanes and rigid bicyclic amino esters. In addition, the related sp²-hybridized nitrogen atom and the similar geometric property between pyridines and corresponding aza-BCHepes indicate that they are promising bioisosteres of pyridines.

The NBS-mediated organocatalytic cascade synthesis of 4,5-dihydronaphtho[2,1-b]furan-1-carbaldehydes from α,β-unsaturated aldehydes and 2-tetralones have been developed. In this synthesis strategy, the C1 of in situ generated brominated 2-tetralone was used as identical twin electron donor–acceptor, and the Cβ and Cα of enals were used as the heterogeneous twin electron acceptor–donors. The process has been realized by a synergistic amine/p-TSA catalyzed one-pot cascade Michael addition–cyclopropanation–ring opening–oxa-Michael addition under mild conditions and without the use of transition metals.

This work reports a one-pot asymmetric synthesis of spirocyclopropyl propionaldehydes/propanols via β,γ-bifunctionalization of propanols through the synergistic effect of a secondary amine catalyst and an oxidant.

Saturated bicyclic amines are increasingly targeted to the pharmaceutical industry as sp³-rich bioisosteres of anilines. Numerous strategies have been established for the preparation of bridgehead aminobicyclics. However, methods to assemble the bridge-amino hydrocarbon skeleton, which serves as a meta-substituted arene bioisostere, are limited. Herein, a general approach to access 2-aminobicyclo[2.1.1]hexanes (aminoBCHs) by titanium-catalyzed formal [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes and 2-azadienes was developed. Simple derivatization of aminoBCHs leads to various medicinally and agrochemically important analogues.

This work reported a method for conversion of aryl allyl ethers into furancarbaldehydes via an ether oxidation iminium-ion activation cascade strategy. The method features simple operation, mild conditions, and especially high atomic utilization.