Synthesis of bridged tetrahydrobenzo [b] azatrel skeleton by aza piancatelli cyclization / Michael series reaction

Tetrahydrobenzo [b] azazoles are important N-containing heterocyclic compounds, which are widely found in the active molecules (tovaptan, benazepril, etc.) Therefore, chemists have developed many new and efficient strategies to synthesize these molecules, which further increases the complexity and diversity of the molecules In this respect, the synthesis of bridged tetrahydrobenzo [b] azazoles is still a difficulty Recently, Porco group synthesized aza rocaglate derivatives by using these structures as intermediates However, it is difficult to prepare these skeletons, which hinders the further study of their potential biological activities Therefore, the development of a general method to synthesize these compounds will not only have a huge impact on the pharmaceutical industry, but also fill the gap of such molecular synthesis In order to solve this challenging problem, Vincent Gandon and David LEB œ UF of the Southern University of Paris in France recently realized the synthesis of bridged tetrahydrobenzo [b] aza derivatives by aza piancatelli cyclization / Michael series reaction The reaction is carried out in a "one pot" way, and the synthesis method is simple Ketones and amines are used as "flexible" synthesis precursors, which can be used for diversity oriented molecular synthesis The related research results were published in angelw Chem Int ed (DOI: 1002 / anie 201911761) It is worth mentioning that the substituents produced by the cyclization of AZA piancatelli and Michael addition precursor are in the trans form, which is more conducive to the subsequent Michael tandem addition (source: angel Chem Int ed.) the author first used 2-furfuryl alcohol derivatives 1a and 4-Iodoaniline 2A substituted by sulfonamide as template substrate to optimize the reaction conditions (Table 1) By optimizing the reaction conditions such as solvent, alkali, catalyst dosage, temperature and reaction time, the author determined that the optimal reaction conditions were: Ca (NTF 2) 2 and NBU 4 NPF 6 As catalyst, et 3N as base, toluene and hexafluoroisopropanol (3:1) as mixed solvent, the substrate reacted at 20 ℃ for 9 h, and the final yield was 91% In addition, the reaction is easy to enlarge When the reaction is enlarged to 5 mmol, 86% yield can be obtained (source: angelw Chem Int ed.) after determining the optimal reaction conditions, the author extended the range of substrates in the reaction (scheme 2) The aryl iodide with rich and lack of electricity can participate in the reaction and get the target product with good yield In addition, in addition to primary aniline, n-alkyl substituted aniline and hydroxylamine can also participate in the reaction Subsequently, the author investigated the substrate range of benzenesulfonamide Similarly, the substituents for electron supply and electron absorption had no effect In addition, the third-order 2-furfuryl alcohol structure can also obtain the target product It is worth noting that the phenol structure can also be used as Michael addition precursor to get cyclized products When the structure of benzosulfonamide is replaced by that of n-alkylsulfonamide, the target product can be obtained in medium yield (30% - 60%) (source: angel Chem Int ed.) later, in order to illustrate the practicability of the reaction, the author carried out subsequent derivatization of the reaction substrate, including: 1) reduction of ketone group, allylation; 2) Sonogashira coupling with aryl iodine in the product; 3) Baeyer Villiger oxidation mediated by M CPBA; 4) removal of protective group on N; 5 ）Cu catalyzed intermolecular hydrogen amination produces corresponding indoles (source: angel Chem Int ed.) Summary: Vincent Gandon and David LEB œ UF started from simple raw materials, combined with aza piancatelli cyclization and Michael addition reaction, realized the first synthesis of bridged tetrahydrobenzo [b] azatrel skeleton The functional group of the reaction is well tolerated, and it is expected to have a positive impact on pharmaceutical chemistry research.