Cesium carbonate is an inorganic compound with the chemical formula Cs2CO3. Cesium carbonate is a white powder that is easily soluble in water, slightly soluble in alcohol, and insoluble in ether. It is a strong base and weak acid salt, and hydrolysis is alkaline. Due to its hydrolysis characteristics, cesium carbonate is often used as a buffer to adjust the pH value of the solution. In addition, cesium carbonate also has a certain degree of hygroscopicity and needs to be stored in a sealed and dry environment. In practical applications, cesium carbonate can be used in chemical experiments, industrial production, analytical reagents, solvents, catalysts, etc.
Functionalized isonitriles have significant advantages in constructing diversified nitrogen-containing heterocycles. The application of representative isonitrile precursors such as isocyanates, biphenyl isonitriles, and tryptamine isonitriles in cyclization reactions has been widely reported. Despite this, the development of functionalized isonitrile chemistry still faces challenges such as a single reaction mode, low synthesis efficiency, and insufficient complexity/diversity. A research team designed and synthesized a novel functionalized isonitrile precursor for the first time. The precursor compound combines the reactivity of isocyano and propargyl alcohol ester groups, and uses cesium carbonate as a base for the synthesis reaction, showing unique advantages in the construction of polycyclic skeleton reactions.
The research team first studied the reaction of propargyl alcohol ester aromatic isonitrile and 2-amino aromatic imine ester. The optimized reaction conditions are: cesium carbonate as a base, chloroform as a solvent, and a reaction temperature of 80 °C. The universality study of the substrate found that the propargyl alcohol ester aromatic isonitrile substrate has good substrate applicability, and the reaction can proceed smoothly when the alkynyl group is connected with aromatic and aliphatic substituents, and has good tolerance to electron-rich and electron-deficient substituents.
Then the research team studied the reaction of propargyl alcohol ester aromatic isonitrile and 2-hydroxy aromatic imine ester. In addition to the quinoline ring product, this reaction also isolated a class of novel benzo-heterocyclic compounds. During the research process, the research team also found that using Cs2CO3 as a base and chloroform as a solvent (condition A) is conducive to the formation of quinoline ring products; using NaOH as a base and toluene as a solvent (condition B) is conducive to the formation of benzoheterocyclyl ring products. During the research process, it was also found that specific substituted propargyl alcohol ester aromatic isonitrile substrates can selectively generate benzoheterocyclyl ring compounds as the only product.
In order to further understand the mechanism, the research team performed DFT calculation analysis using the reaction as a model, showing that there are three possible pathways for the reaction. Among them, path A undergoes [3,3] migration of the acyloxy group to form the allene intermediate INT1. The corresponding transition state TS1 requires a high energy barrier, which is kinetically unfavorable for the formation of the allene intermediate INT1. In pathway B, the propargyl alcohol ester aromatic isonitrile can first form the cyclopropene imine intermediate INT2, which then reacts with the deprotonated raw material to undergo a stepwise [3+2] cycloaddition through TS3 and TS4. This step has a low energy barrier (< 6 kcal/mol), and a proton transfer process occurs simultaneously to generate the cyclopropane imine intermediate INT5. In pathway C, the isonitrile can directly undergo a [3+2] cycloaddition with the deprotonated 4a-Cs through TS5 to form the corresponding dihydropyrrole intermediate INT6. The isocyanate on INT6 can react with its own alkyne moiety through TS2 to generate the cyclopropene imine INT5. Given the proximity of the phenol anion to the cyclopropene imine fragment in INT5, the ring is opened by nucleophilic attack through two different pathways (path a vs. path b). In pathway a, the phenol anion attacks the cyclopropyl group at the benzylic position, and the ring is expanded through TS7 (energy barrier 10.3 kcal/mol) to generate the stable intermediate INT7. The next steps involve acetoxy leaving and aromatization to give the final quinoline annulation product. In pathway b, the intramolecular nucleophilic addition reaction of the imine moiety with the phenol anion proceeds first (energy barrier is only 4.6 kcal/mol), giving the polycyclic intermediate INT8. Finally, the benzohexadiazole polycyclic product is obtained by simultaneous ring expansion through the release of the acetoxy group (13.0 kcal/mol).
To further elucidate the reaction mechanism, the research team conducted corresponding mechanistic experiments based on DFT calculations. Initially, the reaction of cyclopropene acetate with 4a was tested, but no reaction occurred under standard conditions. Subsequently, the authors synthesized a more strained cyclopropene ketone acetate. The reaction of cyclopropene ketone acetate with 2-aminoaromatic aldimine and 2-hydroxyaromatic aldimine gave the products, respectively. The experimental results show that the highly strained cyclopropene ketone is a possible reaction intermediate. Next, the research team carried out the reaction of propargyl acetate with the substrate, but no [3+2] cycloaddition product was observed, which indicates that pathway C is unfavorable. The research team also carried out the reaction of 2-isocyanophenyl propargyl ester with 3-acyl-2-hydroxy-2-methylchromene and isolated a polycyclic compound. This result indicated that the reaction process involved a [4+2] cycloaddition similar to [3+2], providing new evidence for the formation of cyclopropylene imine intermediates.
