Dixon research group of Oxford University developed "one pot method" for catalytic asymmetric synthesis of 2-pyrazoline

Heterocycles containing N-N bonds are widely found in natural products, drug molecules and agricultural chemicals Pyrazoline and its derivatives (such as 2-pyrazoline) with optical activity have been widely used in small molecule drugs and agricultural chemicals (scheme 1) Therefore, the synthesis method of pyrazoline has attracted the attention of organic synthesis chemists At present, the literatures mainly focus on the synthesis of racemic 2-pyrazoline compounds, but the method of synthesis of 2-pyrazoline with optical activity is very limited Kanai group first reported the asymmetric synthesis of 2-pyrazoline by Lewis acid catalyzed 1,3-dipolar cycloaddition; then, list group reported the acid catalyzed electrocyclization method; Cordova and carill et al Synthesized 2-pyrazoline by pyrazoline In addition, briere group also reported the addition of hydrazinecarboxylate and chalcone catalyzed by phase transfer, and Dunli group used benzyl protected hydrazinecarboxylate to enantioselective synthesis of 2-pyrazoline (scheme 1b) So far, the high reactivity of hydrazine nucleophiles has limited the development of corresponding enantioselective methods Recently, Darren J Dixon group of Oxford University envisaged to inhibit the reactivity of hydrazine by using suitable hydrazone derivatives, and to selectively obtain enantiomeric enriched 2-pyrazoline (scheme 1c) immediately after hydrazone in-situ cracking and subsequent intramolecular condensation The results were recently published in angew Chem Int ed (DOI: 10.1002 / anie 201811471) (image source: angelw Chem Int ed.) firstly, the model reaction of hydrazone 1A derived from methylhydrazine and chalcone 2a was carried out, and it was assumed that bifunctional br / nsted alkali / hydrogen bond donor catalyst could affect enantioselective aza Michael addition The author found that quinidine (a) has potential selectivity through the screening of catalyst (Figure 1) Subsequently, the author studied other compounds derived from cinchona base (table 1a, e ntries 1-6), and finally determined that the catalyst f containing 3,5-dichlorobenzamide was the best catalyst (image source: angelw Chem Int ed.) next, the author turned his attention to the structure of hydrazine and its effect on stereochemistry (table1a, entries 7-6) The results show that the enantioselectivity can be improved by introducing methyl at the 2, 3 or 4 positions of the aromatic ring, the enantioselectivity of the substrate containing 4-tert-butyl can reach 90:10 Er, and the selectivity (95:5 ER) and conversion (93%) can be further improved by reducing the reaction temperature and prolonging the reaction time In addition, we found that hydroxylamine can be used to realize the quantitative in-situ cleavage of chiral hydrazone intermediates (thus releasing oxime 6b), without affecting the enantioselectivity (table 1b) (image source: angelw Chem Int ed.) then, the author combines the above optimized transformation methods, develops a simplified "one pot method" route, and evaluates its scope of application (scheme 2a) When the two aromatic rings of chalcone are replaced by electron rich or electron deficient groups, the enantioselectivity of the reaction is not affected; the functional groups such as cyano, vinyl and ester groups have good tolerance It should be noted that in addition to benzene ring, the reaction can also be compatible with pyrazine, pyridine, thiophene and other heterocycles In addition, N-ethyl, N-cyanoethyl and n-benzyl-2-pyrazoline were obtained by changing the hydrazine part, and the reaction rate was similar to that of methylhydrazine, which proved that the method had wide applicability In order to prove the expansibility of this method, the author has carried out a hundred gram scale reaction (scheme 2b) with ketene 2B The pyrazoline 5B (> 99.9:0.1er) was synthesized in 77% yield In addition, 89% of catalyst f was recovered, and the recovered catalyst can be reused (0.5 mmol scale), without loss of reactivity or selectivity (image source: angelw Chem Int ed.) in order to prove the practicability of the above method, the author carried out a later functionalization study (scheme 3) with pyrazoline 5b as the skeleton Under the catalysis of ruthenium, the author treated 5B with ethyl acrylate to obtain o-alkenylation product 8; treated 5B with acetic acid / zinc to obtain diamine 9 mixture (3:2dr) enriched with enantiomers; finally, the enantiomeric pure alkyne 10 was obtained by Sonogashira coupling 5B with mestranol Conclusion: Darren J Dixon group has designed and developed a method for asymmetric synthesis of optically active 2-pyrazoline skeleton from β - substituted alkenone and hydrazone derived from monoalkyl substituted hydrazine This method has good reactivity, enantioselectivity, functional group tolerance and scalability In addition, the late derivatization studies highlighted the synthesis of 2-pyrazoline reaction products with multiple functions, which have potential applications in biomedical and agricultural chemistry fields.