Angelw, hanc research group, Lanzhou University: Deconstruction and oxidation of tension-free naphthenic amines

Fat ring is a kind of very important organic structure skeleton in drugs, natural products and functional materials It is an attractive synthetic strategy to construct new organic compounds by opening cycloalkane structure However, breaking the C-C bond requires a lot of energy, so it is very challenging to open the C-C bond of the tension-free fatty ring Because the ring opening rate of alkoxy group is several orders higher than that of anti cyclization, their ring opening process is advantageous in thermodynamics and kinetics Therefore, a promising strategy to solve this problem is to use the high reactive activity of oxygen radicals to promote ring opening through the cleavage of C-C bonds In addition to cycloalkoxy group, it is also feasible to use other types of free radicals to break the non tension fat ring, but so far, there are few effective methods reported In recent years, the ring opening reactions of cycloimines and cycloalkanes have attracted much attention (source: angelw Chem Int ed.) recently, the hanc group of Lanzhou University reported for the first time the ring opening reaction with amino radicals as intermediates, which was driven by the kinetics and thermodynamics of aromatization to open the ring of primary cycloalkylamine The relevant research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201914623) Firstly, the reaction of cyclohexylamine a 1, n-phenylbenzohydrazide chloride B 1 was studied After two steps of reaction, the self coupling product C1 was obtained with 20% yield The author conjectures that the formation of C1 is caused by the capture of open-loop carbon radicals by the open-loop amino radicals, which is attributed to the high stability of the formed amino radicals In addition, HRMS also confirmed the formation of stable amino radical RN It is also verified by DFT calculation that the high stability is due to the nonlocalization of single electron spin density on three nitrogen atoms (source: angelw Chem Int ed.) next, in order to prevent the formation of self coupling product C1, the author added the carbon free radical trapping agent tempo into the reaction system It is gratifying to note that the self coupling reaction was completely inhibited by adding 3.5 equivalent of tempo, and the ring opening product D1 captured by tempo was obtained in 74% yield Furthermore, D1 can be easily treated with m-chloroperoxybenzoic acid (m-CPBA) to obtain the target oxidation product, namely, non Cyclocarboxylic acid with 1,2,4-triazole structure (Table 1) (source: angelw Chem Int ed.) after determining the best reaction conditions, the author evaluated the scope of application of the reaction to the first-order naphthenic amine (scheme 2) A large number of naphthenic amines, including monocyclic (a1-a19), bicyclic (a20-a31), bridged (a32-a36) and complex natural product derivatives (a37-a42), have been effectively ring opened, deconstructed and oxidized The C-C bond can also be used for acyclic substrates containing ethylamine, such as pregnenolone derivative A43 (source: angel Chem Int ed.) on the other hand, 1,2,4-triazole skeletons have good biocompatibility and bioactivity They are found in antimicrobial drugs, such as taconazole, fluconazole and itraconazole, and aromatase inhibitors anastrozole and letrozole A series of aryl and alkyl substituted hydrazone chlorides are suitable for this transformation The yield of 1,3,5-trisubstituted-1,2,4-triazole is above medium (scheme 3) (source: angelw Chem Int ed.) based on previous reports and observations, the author proposed a possible reaction mechanism (scheme 4) Firstly, hydrazinamide I was prepared by affinity substitution reaction between naphthylamine and hydrazone chloride, then hydrazinyl radical II was formed by self oxidation of I in air, which experienced 1,5-hydrogen atom transfer and further oxidation / cyclization in series to form prearomatic compound III The third is to oxidize in air to form amino radical Ⅳ The latter was driven by aromatization to cleave C-C bond to form distal alkyl radical v V was immediately intercepted by tempo to obtain ring opening product VI The intermediate ⅶ of N-oxide was produced by the treatment of Ⅵ with m-CPBA ⅶ was immediately eliminated by cope, and the acyclic carbonyl compound E containing 1,2,4-triazole was obtained Under the existing conditions, acyclic aldehydes can be further converted into acyclic carboxylic acids by Baeyer Villiger oxidation (source: angelw Chem Int ed.) Summary: it is the first time for the author to discover the cleavage and ring opening of C (SP 3) - C (SP 3) single bond driven by aromatization, thus realizing the dissociation and oxidation of tension-free first-order naphthylamine The strategy not only uses in-situ pre aromatics as the source of aromatization driving force, but also realizes the automatic oxidation and ring opening of tension-free aliphatic rings under mild conditions This strategy can selectively deconstruct and oxidize a variety of substrates, including monocyclic, bicyclic, bridged primary cycloalkanes, alkaloids, osamines, peptides and steroids At the same time, the strategy can also effectively synthesize a series of acyclic carbonyl compounds with the characteristics of 1,2,4-triazole This new strategy will provide an efficient and convenient method for the later stage modification of drugs containing naphthylamine structure.