Angelw: aza Wittig rearrangement of azaarenes catalyzed by chiral phosphite

Pyridine, quinoline and isoquinoline are widely used in drugs, natural products and chiral ligands (Figure 1a) Therefore, the asymmetric synthesis of chiral hexaazaarenes has attracted the attention of chemists, and has made good progress At present, the synthesis methods of chiral six component azaarenes are mainly asymmetric synthesis with acyclic precursors, pre functionalized azaarene halides and organometallic reagents as starting materials, as well as the recent direct C-H alkylation of azaarenes However, the asymmetric C-H allylation of azaarenes is still facing great challenges (Figure 1b) On the basis of the above research background, pradip maity team of National Chemical Laboratory of India reported the first case of [2,3] - aza Wittig rearrangement of azaarenes catalyzed by chiral phosphite, thus realizing asymmetric C-H allylation of azaarenes At the same time, the author speculates that the possible mechanism of this kind of reaction is (Figure 1c): in the alkaline condition, the product 3 combined with n-allylpyridinium salt and phosphite will undergo stereoselective aza Wittig rearrangement reaction, in which the stereoselectivity of this process is controlled by the chiral phosphite; subsequently, the rearrangement product 5 will remove the chiral phosphite and generate the product 6 through the aromatization process 。 Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201906681) (picture source: angel Chem Int ed.) the author selected n-allylisoquinoline 1A as template substrate, and determined the optimal conditions as (Table 1): 100 mol% 2K as catalyst, 100 mol% LiHMDS as alkali, THF as solvent, reaction at 0 ℃ for 48 hours; then added 2 equivalent LiHMDS, reaction at - 60 ℃ for 2 hours H The corresponding products can be obtained in 81% yield and 92% enantioselectivity (photo source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the substrate range of AZA aromatics (Table 2) The n-allylisoquinoline with R4 as a variety of substituents, R3 as a primary alkyl, cyclohexyl, six membered C1-C2 inner allyl and disubstituted geranyl can adapt to the reaction conditions well, and can obtain the corresponding products with good yield and excellent enantioselectivity At the same time, all kinds of substituted n-allylquinolines also have good tolerance, and the corresponding products can be obtained with good yield and enantioselectivity However, n-allylpyridine with no substitution and 4-chlorophenyl and 4-phenyl at C4 position can not obtain the corresponding chiral products, while 2-phenyl-n-allylpyridine can obtain the corresponding products with medium yield and good enantioselectivity (image source: angelw Chem Int ed.) considering the low enantioselectivity of n-allylquinoline and n-allylpyridine, the author decided to investigate the influence of the geometric configuration of allyl on the reaction (scheme 1) The results show that the enantioselectivity of CIS isoquinoline salt is slightly lower than that of trans quinoline salt and trans pyridine salt In order to further prove the reaction mechanism, the author carried out a series of control experiments (scheme 2) First of all, 1D and 1n were reacted under standard conditions at the same time, and no cross product was found (scheme 2a) Under the standard conditions, the intermediate 3 with different Dr value reacts with 2B respectively, and the product with the same EE value (scheme 2b) can be obtained In addition, two hydroisoquinolines can not be rearranged to produce corresponding products, but the formation of lactam compounds can be observed, which indicates that there is the formation of Wittig intermediate 9 (Scheme 2C) in the reaction These results further prove the mechanism of the reaction (photo source: angelw Chem Int ed.) Summary: pradip maity team of National Chemical Laboratory of India reported the first case of chiral phosphite catalyzed azaarene [2, 3] A series of asymmetric C-H allylation products of n-allylisoquinoline, n-allylquinoline and n-allylpyridine were obtained with good yield and enantioselectivity.