Abstract:
Recently, the research group led by Professor Shu-Li You from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, has developed a phosphine-catalyzed asymmetric dearomative [3+2] annulation reaction of benzimidazoles with cyclopropenones. This method features a wide substrate scope, mild reaction conditions, and simple operation, providing a concise and efficient strategy for the synthesis of various chiral nitrogen-containing heterocycles. Scale-up reactions and product transformation experiments have demonstrated the potential practical application of this method.
Background:
Aromatic compounds, as simple and readily available starting materials, have been widely used in organic synthesis, medicinal chemistry, and other fields. Heteroaromatic compounds, especially those containing one or more nitrogen atoms, occupy a special position among aromatic compounds, and their derivatives are often found in many natural products and bioactive molecules. In recent years, the functionalization of these compounds has become a research hotspot and has received widespread attention from scientists. Catalytic asymmetric dearomatization (CADA) reactions, as an important transformation of aromatic compounds, provide an effective pathway for the direct conversion of simple two-dimensional planar aromatic compounds into three-dimensional chiral molecules. While significant progress has been made in dearomatization reactions involving electron-rich heteroaromatic compounds, reports on CADA reactions of electron-deficient heteroaromatic compounds, especially benzimidazoles, benzoxazoles, and benzothiazoles, are limited. Besides a few examples of metal-catalyzed CADA reactions (Figure 1), reactions catalyzed by chiral organic small molecules are rarely reported. Therefore, it is urgently needed to further develop different catalytic systems to achieve dearomatization reactions involving electron-deficient heteroaromatic compounds. On the other hand, cyclopropenones, as an important class of unsaturated tricyclic compounds, can undergo [3+2] annulation reactions with unsaturated double bonds, imines, and carbonyl groups, providing an efficient synthetic method for constructing structurally diverse organic molecules.
Highlights:
Based on the above research, the authors utilized commercially available chiral phosphine catalysts to achieve the intermolecular asymmetric dearomative [3+2] annulation reaction of benzimidazoles with cyclopropenones, synthesizing a series of dearomatized pyrrolo[1,2-a]imidazole nitrogen heterocycles with yields as high as 98% and enantiomeric excesses exceeding 99%.
Under optimal conditions, the asymmetric dearomative reaction exhibited excellent substrate generality and functional group compatibility. For cyclopropenone substrates (Figure 2), whether the benzene ring of the cyclopropenone is substituted with an electron-donating group or an electron-withdrawing group, the reaction can yield the desired product with excellent yields and excellent enantioselectivity (3ba-3bi, 82-98% yields, 90->99% ee). It is worth noting that when the benzene ring of the cyclopropenone is substituted with a substituent at the ortho position, under standard conditions, the reaction cannot smoothly yield the desired product (3bj-3bk), possibly due to steric hindrance. When the benzene ring of the cyclopropenone is replaced with a bulky naphthyl ring, the reaction can also proceed smoothly, but the yield and enantioselectivity are slightly reduced (3bl, 30% yield, 89% ee). For cyclopropenone substrates substituted with heteroaromatic rings 2m, the reaction can also smoothly yield the desired product 3bm with 98% yield and 73% enantioselectivity. Next, the effect of asymmetric cyclopropenone substrates on the reaction was investigated. For substrate 2n, under standard conditions, the reaction can only yield the desired product 3bn with 28% yield and 75% ee at room temperature for 24 hours, and the structure of the product was determined by two-dimensional spectra. It is worth noting that alkyl-substituted cyclopropenones are not compatible with this reaction system, possibly because alkyl-substituted cyclopropenones have low reaction activity.
Next, differentially substituted benzimidazole substrates were investigated, and the results are shown in Figure 3. Different types of substituents on the N atom of the benzimidazole have important effects on the yield and enantioselectivity of the product. Except for -iPr, when the N atom of the benzimidazole is substituted with benzyl, methyl, ethyl, tert-butyl, naphthylmethyl, cyclohexyl, and propargyl, these substrates all exhibit good compatibility, yielding the desired products with moderate to excellent yields and good to excellent enantioselectivity (3aa-3ia, 37-98% yield, 79-96% ee). For the substrate 1j substituted with propargyl, the reaction can only yield the corresponding product 3ja with 52% yield and 33% ee. While the benzimidazole substrate 1k unsubstituted at the N-H, although the reaction can proceed smoothly, the product 3ka can only achieve 53% yield and 78% ee under standard conditions. For benzimidazole substrates substituted with N-Ts and N-Ac electron-withdrawing groups (1l, 1m), the reaction can achieve 94% and 44% yields under standard conditions, respectively, but the enantiomeric selectivity of the products is poor (3la-3ma, 15% ee and 19% ee). In addition, the effect of different substituents on the benzene ring of benzimidazole on the reaction was also investigated. When the 5- and 6-positions of the benzene ring of the benzimidazole are substituted with -Me or halogen (-Cl, Br) substituents, under standard conditions, the reaction can yield the dearomatized products with excellent yields and enantioselectivity (3na-3pa, 72-91% yields, 96-97% ee). The 7-azaindole 1q also showed good compatibility with the system and yielded product 3qa with 92% yield and 96% ee. Finally, the effects of benzothiazole and benzoxazole substrates on the reaction were also investigated. Although the reactions can proceed smoothly and yield the desired products with good yields, the enantioselectivity of the products is not ideal (3ra, 73% yield, 51% ee; 3sa, 64% yield, 10% ee), possibly due to steric hindrance.
After completing the substrate expansion, to verify the practicality of this method, the authors conducted scale-up reactions and product transformation experiments (Figure 4). Under standard conditions, the reaction scale-up of template substrates 1b and 2a to 3 millimoles can achieve results comparable to small-scale reactions, that is, the target product 3ba with 91% yield and 96% ee. Next, the chiral product 3ba was subjected to product transformation, and the chiral product 3ba (96% ee) reacted with LDA in DCM at room temperature for 2 hours to smoothly transform into product 4 with a yield of 95%, while maintaining the enantioselectivity. In addition, the product 3ha substituted with propargyl underwent a copper-catalyzed click reaction with BnN3 to synthesize the triazole product 5 with a yield of 78% and an ee of 86%.
Based on the above experimental results and previous work, the authors also proposed a possible catalytic cycle and stereocontrol model for the reaction (Scheme 5). Firstly, cyclopropenone 2a is activated by the chiral phosphine catalyst PR3 to form a zwitterionic intermediate I; then the C-C bond of intermediate I is cleaved to generate an allene intermediate II; intermediate II is attacked by the nucleophilic benzimidazole substrate 1b to form intermediate III; subsequently, intermediate III undergoes intramolecular nucleophilic addition at the C2 position of the benzimidazole's Re-face to form intermediate IV, finally eliminating one molecule of the catalyst PR3 to generate the product 3ba, completing the catalytic cycle.
Summary and Outlook:
In summary, based on the chiral small molecule catalytic system, the authors used commercially available chiral phosphine catalysts as Lewis bases to achieve the intermolecular asymmetric dearomative [3+2] annulation reaction of benzimidazole compounds with cyclopropenones under mild conditions, synthesizing a series of nitrogen heterocycles with excellent yields (up to 98% yield) and excellent enantioselectivity (> 99% ee). The authors also proposed a possible catalytic cycle and stereocontrol model, and scale-up reactions and product transformation experiments confirmed the practicality of this method.
This work was published in the form of a Research Article in CCS Chemistry. Professor Shu-Li You from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, is the corresponding author, and Shan-Shan Zhang, a jointly trained Ph.D. student from East China Normal University and the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, is the first author. Special thanks to the support of the National Key R&D Program, the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission, and the New Cornerstone Investigator Program.
Article Details:
Phosphine-Catalyzed Asymmetric Dearomative [3+2] Annulation Reaction of Benzimidazoles with Cyclopropenones
Shan-Shan Zhang, Rui-Xiang Wang, Qing Gu and Shu-Li You*
Cite this by DOI: 10.31635/ccschem.024.202403981
Link: https://doi.org/10.31635/ccschem.024.202403981